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CONTENTS FRONTISPIECE—Leonard A. Herzenberg and Leonore A. Herzenberg GENETICS, FACS, IMMUNOLOGY, AND REDOX: A TALE OF TWO LIVES INTERTWINED, Leonard A. Herzenberg and Leonore A. Herzenberg SELF- AND NONSELF-RECOGNITION BY C-TYPE LECTINS ON DENDRITIC CELLS, Teunis B.H. Geijtenbeek, Sandra J. van Vliet, Anneke Engering, Bert A. ’t Hart, and Yvette van Kooyk

x 1

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TRANSCRIPTIONAL CONTROL OF EARLY B CELL DEVELOPMENT, Meinrad Busslinger

UBIQUITIN LIGASES AND THE IMMUNE RESPONSE, Yun-Cai Liu LIGANDS FOR L-SELECTIN: HOMING, INFLAMMATION, AND BEYOND, Steven D. Rosen

55 81 129

INTEGRINS AND T CELL–MEDIATED IMMUNITY, Jonathan T. Pribila, Angie C. Quale, Kristen L. Mueller, and Yoji Shimizu

157

MULTIPLE ROLES OF ANTIMICROBIAL DEFENSINS, CATHELICIDINS, AND EOSINOPHIL-DERIVED NEUROTOXIN IN HOST DEFENSE, De Yang, Arya Biragyn, David M. Hoover, Jacek Lubkowski, and Joost J. Oppenheim

STARTING AT THE BEGINNING: NEW PERSPECTIVES ON THE BIOLOGY OF MUCOSAL T CELLS, Hilde Cheroutre THE BCR-ABL STORY: BENCH TO BEDSIDE AND BACK, Stephane Wong and Owen N. Witte

181 217 247

CD40/CD154 INTERACTIONS AT THE INTERFACE OF TOLERANCE AND IMMUNITY, Sergio A. Quezada, Lamis Z. Jarvinen, Evan F. Lind, and Randolph J. Noelle

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THE THREE ES OF CANCER IMMUNOEDITING, Gavin P. Dunn, Lloyd J. Old, and Robert D. Schreiber

AUTOIMMUNE AND INFLAMMATORY MECHANISMS IN ATHEROSCLEROSIS, Georg Wick, Michael Knoflach, and Qingbo Xu THE DYNAMIC LIFE OF NATURAL KILLER CELLS, Wayne M. Yokoyama, Sungjin Kim, and Anthony R. French

329 361 405

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THE ROLE OF COMPLEMENT IN THE DEVELOPMENT OF SYSTEMIC LUPUS ERYTHEMATOSUS, Anthony P. Manderson, Marina Botto, and Mark J. Walport

DROSOPHILA: THE GENETICS OF INNATE IMMUNE RECOGNITION AND RESPONSE, Catherine A. Brennan and Kathryn V. Anderson RAGS AND REGULATION OF AUTOANTIBODIES, Mila Jankovic,

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Rafael Casellas, Nikos Yannoutsos, Hedda Wardemann, and Michel C. Nussenzweig

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THE ROLE OF SUPPRESSORS OF CYTOKINE SIGNALING (SOCS) PROTEINS IN REGULATION OF THE IMMUNE RESPONSE, Warren S. Alexander and Douglas J. Hilton

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NATURALLY ARISING CD4+

REGULATORY T CELLS FOR IMMUNOLOGIC SELF-TOLERANCE AND NEGATIVE CONTROL OF IMMUNE RESPONSES, Shimon Sakaguchi PHOSPHOINOSITIDE 3-KINASE: DIVERSE ROLES IN IMMUNE CELL ACTIVATION, Jonathan A. Deane and David A. Fruman IMMUNITY TO TUBERCULOSIS, Robert J. North and Yu-Jin Jung MOLECULAR DEFECTS IN HUMAN SEVERE COMBINED IMMUNODEFICIENCY AND APPROACHES TO IMMUNE RECONSTITUTION, Rebecca H. Buckley PHYSIOLOGICAL CONTROL OF IMMUNE RESPONSE AND INFLAMMATORY TISSUE DAMAGE BY HYPOXIA-INDUCIBLE FACTORS AND ADENOSINE A2A RECEPTORS, Michail V. Sitkovsky, Dmitriy Lukashev, Sergey Apasov, Hidefumi Kojima, Masahiro Koshiba, Charles Caldwell, Akio Ohta, and Manfred Thiel

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T LYMPHOCYTE–ENDOTHELIAL CELL INTERACTIONS, Jaehyuk Choi, David R. Enis, Kian Peng Koh, Stephen L. Shiao, and Jordan S. Pober

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IMMUNOLOGICAL MEMORY TO VIRAL INFECTIONS, Raymond M. Welsh, Liisa K. Selin, and Eva Szomolanyi-Tsuda

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CENTRAL MEMORY AND EFFECTOR MEMORY T CELL SUBSETS: FUNCTION, GENERATION, AND MAINTENANCE, Federica Sallusto, Jens Geginat, and Antonio Lanzavecchia CONTROL OF T CELL VIABILITY, Philippa Marrack and John Kappler

745 765

ASTHMA: MECHANISMS OF DISEASE PERSISTENCE AND PROGRESSION, Lauren Cohn, Jack A. Elias, and Geoffrey L. Chupp

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CD1: ANTIGEN PRESENTATION AND T CELL FUNCTION, Manfred Brigl and Michael B. Brenner

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CHEMOKINES IN INNATE AND ADAPTIVE HOST DEFENSE: BASIC CHEMOKINESE GRAMMAR FOR IMMUNE CELLS, Antal Rot and Ulrich H. von Andrian

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INTERLEUKIN-10 AND RELATED CYTOKINES AND RECEPTORS, Sidney Pestka, Christopher D. Krause, Devanand Sarkar, Mark R. Walter, Yufang Shi, and Paul B. Fisher

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INDEXES Subject Index Cumulative Index of Contributing Authors, Volumes 12–22 Cumulative Index of Chapter Titles, Volumes 12–22

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ERRATA An online log of corrections to Annual Review of Immunology chapters may be found at http://immunol.annualreviews.org/errata.shtml

981 1011 1018

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Annu. Rev. Immunol. 2004. 22:1–31 doi: 10.1146/annurev.immunol.22.012703.104727 c 2004 by Annual Reviews. All rights reserved Copyright ° First published online as a Review in Advance on December 16, 2003

GENETICS, FACS, IMMUNOLOGY, AND REDOX: A Tale of Two Lives Intertwined

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Leonard A. Herzenberg and Leonore A. Herzenberg Genetics Department, Stanford University Medical School, Beckman Center, Stanford, California 94305–5318; email: [email protected], [email protected]

Key Words glutathione, B cells, flow cytometry, allotype, HIV

INTRODUCTION We (Len and Lee Herzenberg) have worked separately and together for more than 50 years. This blending of independence and mutual reliance is reflected here as we shift back and forth in telling the story of the laboratory we have led and the life we have lived. The space provided for this chapter is very generous. Yet, calculated out, it amounts to roughly 100 words per year for each of us. To make the most of this, we have written an autobiography rather than a history. In many instances, we have referred only briefly, or not at all, to work that had major influences on our thinking. In addition, we have adopted a policy of naming the many students, fellows, and collaborators with whom we have worked only by referring to our joint work with them. We hope the reader realizes there would be no biography worth writing were it not for the contributions made by these and all of our other colleagues.

THE CALTECH YEARS There were nine professors in genetics in the California Institute of Technology (Caltech) Biology Division when I arrived in 1952 as an entering graduate student. They worked with different organisms and taught different areas of biology, but they were united by a common theme—how genes are expressed and how they influence the appearance, physiology, function, and behavior of the organism. The Biology Division at that time was small—one three-story building housed the entire faculty, about a dozen postdocs, an equal number of graduate students, and a couple of undergraduate biology majors. Among the roughly 20 faculty members (visiting or permanent), there were seven Nobelists in the making: George Beadle, Max Delbruck, Ed Lewis, Renato Dulbecco, Roger Sperry, James Watson, and Barbara McClintock. Linus Pauling, Caltech Chemistry chair and winner of

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two Nobel prizes, was in the next building, connected to ours by a much-used corridor. Creative thinking and challenging discussion were the rule; research productivity was the outcome. The development of tools and techniques that removed barriers to experimentation also played a central role in the Caltech Biology Division culture. We routinely used the pH meter and DU spectrophotometer recently invented by former Caltech chemistry professor Arnold Beckman. My thesis advisor, H. K. Mitchell, was an extraordinary glass blower and tinkerer who worked with me on an electrophoresis device. Most things couldn’t be bought, so we had to build them. As I think about it now, the automated fly counter that Ed Lewis built probably sowed the seeds for the Fluorescence-Activated Cell Sorter (FACS) that I developed some years later. In the same way, looking back at the cross-discipline culture in the Caltech Biology Division, I see the origins of the eclectic research goals that Lee and I have pursued. Over the years, we have ranged broadly and drawn our students and fellows into immunology studies as diverse as showing that H-2 antigens are surface proteins, using immunoglobulin (Ig) allotypes and classical genetics to define the Ig heavy chain (IgH) chromosome region, demonstrating IgH allelic and haplotype exclusion in B cells, defining functional subsets of T and B human and murine lymphocytes, cloning and sequencing lymphocyte surface markers, identifying fetal cells in maternal circulation, understanding redox influences on transcription factor activation, and doing clinical studies to characterize and treat the glutathione deficiency in HIV infection. However, the twin themes of genetics and somatic cell function that guided (and still guide) this work, and the love of reading and talking about these diverse areas with people of different scientific interests, are well rooted in Caltech tradition. Political activism was also important at Caltech. Joseph McCarthy, the Senator from Wisconsin who made a career of finding communists under every bed, was threatening to disrupt academic and personal freedom. In response, we joined Linus Pauling, Matt Messelson, George Streisinger, and Arthur Galston, as well as other faculty, students, and fellows in establishing a Federation of American Scientists chapter and in protesting this “witch hunt.” A portion of Lee’s and my life ever since has been devoted to helping the United States be the kind of country we want our children and children’s children to grow up in. LEE: When Len left Brooklyn for Caltech, he was 21 and I was 17. Logically, because he had three years of graduate work ahead of him and I had three years to finish my undergraduate degree, we decided that we would marry when we both finished school. However, logic couldn’t overrule the three-thousand-mile distance, the loneliness, or the $3/minute (1953 dollars) the telephone company charged young lovers just to say hello. By the end of the fall of 1952, Len urged me to apply to schools near Caltech, and when I was admitted to Pomona College in Claremont we set a wedding date for the coming summer. Needless to say, our parents thought we were too young, too innocent, too poor, and too crazy. They were probably right. But we got married anyway, with their

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blessings, and set off on an adventure that is as exciting today as it was the day we piled our stuff into the car Len’s parents gave us and started the long drive across the country to Pasadena. At Caltech, I was as enchanted as Len was by how immersed people were in their work. I had already selected biology as my major, but I had no idea how interesting it could be. For the rest of the summer, until the fall term started at Pomona, I went to the lab every day with Len. I attended seminars; I read in the library; I learned how to help Len with experiments; sometimes I even had the courage to ask questions of someone other than Len. It was just plain fun, and I couldn’t get enough of it. Pomona College, on the other hand, turned out to be a disappointment. It was an excellent school. There is no question about that. The liberal arts courses were wonderful. But the Biology Department was still teaching gram stains (to identify bacteria) and grilling us on the anatomy of flowers and reptiles. Meanwhile, Jim Watson had just brought the double helix back to Caltech and was teaching about it while I was sitting in a classroom learning things useful only to a stodgy highschool biology teacher. I would have enrolled as a Caltech undergraduate, but women weren’t even admitted to Caltech graduate programs (there were only a few women postdocs and research associates). Nevertheless, the biology faculty believed that women were educable and worth educating. By the beginning of the second semester of the academic year, they worked out an auditing program for me in which I would be treated, and graded, like a Caltech biology major. They allowed me to take whatever courses I wanted to, and even found a part-time job for me so that Len and I could afford to eat. For each course I completed, the professor gave me a letter certifying that I had met the course requirements and received a grade (always As, as it turned out). So, although I didn’t get formal credit, I managed to take classes such as virology from Max Delbruck, bacteriology from Renato Dulbecco, and immunology from Ray Owen. I learned how to think about science from these teachers. Perhaps the most formative event for me during our time at Caltech, though, was a dinner with Barbara McClintock, who had recently come to the Biology Department as a revered visiting professor. Len and I had decided to drive into Los Angeles for a Chinese meal and were about to leave when we noticed that the only light left on in the building was coming from Dr. McClintock’s door. We peeked in and saw that she was working alone. Then we drew back into the shadows, debating whether we should tiptoe away and not interrupt her, or whether she might actually like to take a break and join us. Finally, we screwed up our courage and asked her if she would like to go. “I’d be delighted,” she replied, and off we went. At dinner, I naively asked Dr. McClintock how she made such wonderful discoveries. Her answer, simple and straightforward, became my long-standing rudder. She said that in the course of her work, she occasionally got a surprising result that could not be reconciled with existing theory. First, she would decide whether she believed the “exception”—in other words, she could not see any technical or

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interpretive flaws that undermined it. Next, if she believed it, she would commit it to memory and compare it with any other exceptions she had come across. Ultimately, a constellation of exceptions would coalesce to yield a testable hypothesis that, if validated by additional experimentation, would provide the basis for extending or altering the current paradigm. Len and I have never forgotten that dinner with Dr. McClintock. Somehow, it must have been meaningful for her as well. When I next met her, some ten years later, I introduced myself by name and started to say, “Dr. McClintock, you may not remember me. . .” when she cut me off with, “Oh, you’re the people who took me to that Chinese restaurant in L.A.,” and she greeted me thus ever after.

THE PARIS YEARS Len defended his thesis in August 1955. We left immediately for Paris, where Len had organized a postdoctoral fellowship with Jacques Monod at the Pasteur Institute. My childhood friend who had recently returned to her native France met us at the boat, found us a room in a student hotel in the Parisian Latin Quarter, and introduced us to the life poor students lived in Paris. It was great! And so was the laboratory at Pasteur. Jacques Monod’s laboratory at Pasteur was physically separate but intellectually allied with Andre Lwoff’s laboratory two floors above. Francois Jacob, the third member of the trio later awarded the Nobel Prize for their seminal molecular biology studies, worked in the Lwoff laboratory. The two laboratories lunched together virtually every day at a single long table in a small atrium on an inner Institute courtyard, where huge glass vessels rumored to have been used by Louis Pasteur were stored. Lunch was marvelous. It wasn’t a formal seminar, but conversation revolved around science in the lab and the world at large. Findings were analyzed, theories debated, visitors questioned. Every day was an intellectual feast. There were also many first-person history lessons about the days before World War II and what the war was like in France. Monod was a major figure in the resistance against the Nazis. Francois Jacob had been to Algeria and North Africa and participated with the Free French in the liberation of France. Georges Cohen, one of the Monod senior scientists and still a close friend today, survived the war as a Jew in France and talked about things he did in the Resistance. We heard stories about how the laboratory hid Jewish scientists when the SS came knocking. It all sounded very romantic in 1955, ten years after the war ended. But as Georges and Jacques Monod often reminded us, it wasn’t much fun when it was happening. I should mention that, like the Caltech Biology Division, the group at Pasteur accepted Lee as an unofficial student. At the beginning, she was pregnant with our first child and spent most of her time working with me. Later, she brought the baby to the lab most afternoons and continued working.

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The Cradle of Molecular Biology This was a very exciting time at Pasteur. The characteristics of the β-galactosidase (LacZ) operon were unfolding before our eyes as each new piece of work was completed. Under Monod’s leadership, I contributed two pieces to the puzzle: I showed that the galactoside-concentrating mechanism encoded by the permease gene in the LacZ operon increases the internal concentration of inducers that upregulate expression of the LacZ operon genes and thus is responsible for the autocatalytic increase in LacZ induction. In addition, I showed that the inducers are acetylated, rather than phosphorylated (as people had thought), during LacZ induction, thus opening the way to adding (after I left Pasteur) the β-galactoside acetylase gene to the LacZ operon. These and other findings led Monod, Jacob, and Lwoff to the discovery of the LacZ operon, which laid the groundwork for much of modern molecular biology. For this, they received the Nobel Prize. While at Pasteur, I met Melvin Cohen, who later became a Salk Institute immunologist. Mel had worked with Monod and returned to visit several times. Conversations with him then, as always, were highly stimulating. His presence in the Stanford Biochemistry Department was a key motivation in my decision to move to Stanford when the opportunity arose several years after I left Pasteur. LEE: Aside from birthing a baby and learning to balance being a mom with being a scientist (albeit only a budding one), I don’t have too much to show for my time at Pasteur. I did do one independent piece of work, but it wasn’t well received. Monod had several times said that the thiogalactosides that we used to induce expression of LacZ operon genes were unnatural compounds that could not be digested by bacteria. This didn’t seem right to “wise guy” me. So I went out and scooped up some fresh Parisian soil, put it into a flask with minimal medium containing thiogalactosides as the only carbon source, and put the flask into the cabinet under the bench. About a week later, the medium in the flask was cloudy, and a clear sulfur smell wafted out when I opened the top. Something was clearly growing and “knew how” to break down thiogalactosides. Excitedly waving the flask, I went to Jacques’ office to show him my prize. He was quite surprised and, in a manner I hope I have learned, graciously said he was pleased to be wrong in this case. Some time later, however, everyone in the laboratory was ready to kill me. While we never had to sterilize thiogalactoside stock solutions before my little experiment, after I opened Pandora’s flask, all of the thiogalactoside stocks got contaminated. From then on, they all had to be sterilized immediately after they were made! This incident aside, I mainly spent my time at Pasteur helping Len. Because I was rather sedentary during the first year, and because Len loved hands-on experimentation, I took over much of the data recording, computation, and display (plotting) that was needed. The work was tedious (slide rules were the closest thing to computers at the time). However, it gave me the opportunity to do a preliminary analysis of the data and try novel approaches to analyzing LacZ induction kinetics. Len left this to me. He was more interested in developing methods and

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experiment designs that would enable clear conclusions without a lot of mathematical interference. This division of labor, which reflects Len’s innate preference for concreteness and my innate love for theory, remains with us even today.

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THE NIH YEARS Just about the time that Len and I were considering what to do after Pasteur, an ominous postcard caught up with us. It had spent rather a long time traveling to France by surface mail, and it announced that Len should have reported for active duty in the U.S. Army several days before the postcard was loaded onto the slowest boat on the Atlantic. Late or not, the postcard made it quite clear that Len had been drafted! We immediately went to Jacques Monod for advice. He was as adamant as we were that it would be a pity to interrupt Len’s scientific career to serve in a peacetime army. “Why don’t you consider going to the National Institutes of Health, my boy? I have just had an inquiry from Harry Eagle looking for a fellow for his laboratory. He should be able to arrange for you to serve in the Public Health Service instead.” This was a shock, but I was not displeased with the idea of going to Harry Eagle’s laboratory. I had already been thinking about doing genetic studies with mammalian somatic cells. What better place to learn how to grow cells than the laboratory that had just developed Eagle’s medium? Leaving Pasteur and the Escherichia coli world would not be easy. But the challenges presented by mammalian studies would also be exciting. So, without further ado, I decided that I was lucky to have the opportunity to carry a pipette rather than a gun for my country and asked Jacques to write to Harry Eagle on my behalf. It took several months to untangle the draft board and Public Health Service mess and to wrap up my work in Paris. But by the summer of 1957, Lee, Berri (our toddler), and I were settled in the Bethesda area, and I began work at the NIH. Eagle’s laboratory operated with more of a top-down structure than Pasteur and lacked some of the intellectual and scientific excitement I was used to. However, my colleagues in the laboratory, notably Robert DeMars (now at the University of Wisconsin) and James Darnell (now at Rockefeller University), were great. “Captain Harry,” as we sometimes called Harry Eagle (to his face as well as behind his back), was focused on determining the nutritional conditions necessary to establish and maintain long-term cell lines. I was, too, because to do mutation and selection studies I needed to establish conditions that would allow individual clones to grow. My finding that adding pyruvate to Eagle’s medium was sufficient to support clonal growth let me begin exploring drug resistance markers for genetic studies. In addition, it led to the addition of pyruvate as a normal constituent of the medium. The Federation of American Scientists came back into our lives shortly after we arrived in Washington, because the national office was only a short distance

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from the NIH. Picking up where we left off at Caltech, we volunteered to work on the newsletter and do some administrative work for the organization. Ultimately, we helped to reorganize the office and put the administrative oversight into the hands of a liberal Washington, DC, law firm.

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Lee and the Salmonella Histidine Operon LEE: A few weeks after we arrived at the NIH, Len ran into Bruce Ames, a Caltech buddy who had just been appointed to a permanent staff position at the NIH. As luck would have it, Bruce was looking for his first technician and I was looking for my first job. Len made the match. Poor Bruce. No one should have had to put up with me as a technician. I was always asking “why” and looking for better ways to do things. As a graduate student, I would probably have been fine. But as a technician responsible for doing work that someone else gave me to do, and generating data that someone else was supposed to interpret, I was clearly a pain in the neck. Nevertheless, Bruce put up with me, and I learned to get the work done. I owe him a great deal. Bruce was working on the characterization of the enzymes in the histidine synthesis pathway in Salmonella. We had completed the work on three of the enzymes when Bruce left for a month to work in Arthur Kornberg’s department in St. Louis. As he went out the door, he handed me a tube containing the substrate for the last enzyme in the pathway and asked me to characterize that enzyme as we had the others. The only problem was that when I took the spectrum of the substrate, I found that its synthesis had gone wrong. I had no substrate to work with. Long-distance telephone calls, at that time, were very expensive. It was unthinkable to try to call Bruce and ask for instructions. So I took the question to one of the senior investigators in our department. “Find something useful to do. Bruce will be home soon,” he responded. I cogitated over this for a bit and then decided to apply some of the operon thinking I learned in Paris to the histidine pathway. I tried out some conditions I thought would reveal coordinated regulation of the expression of the enzymes that were already characterized and, to my surprise, readily found such conditions. Bruce was pleased with this finding when he returned, but he put it aside until the entire pathway was properly characterized. After a couple of months, I left Bruce’s lab because I was getting along in my second pregnancy. Bruce later completed the operon study with Barbara Garry. He included me as an author on the paper, which became my first peer-reviewed publication (1).

THE STANFORD YEARS The opportunity to move to Stanford came as a complete surprise. Joshua Lederberg visited Harry Eagle’s laboratory toward the end of my required Public Health Service “hitch.” We had a long discussion about the future of mammalian somatic cell genetics and the progress I had made thus far in developing useful

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markers for the cell lines I had chosen. I was a bit preoccupied at the time because I was in the midst of negotiating a permanent position at the NIH. However, the talk with Josh was really a delight. Later in the week, Harry Eagle called me into his office and suggested that I delay a bit before making any commitments at the NIH. I didn’t make the connection with Josh’s visit and was somewhat mystified. However, a few days later, a letter arrived inviting me to consider a faculty position in the Genetics Department that Josh was in the midst of establishing at Stanford! Our parents considered the offer a disaster. California was still a long, long way away from Brooklyn, and they now had two grandchildren they wanted to help raise. Lee and I were also somewhat negative about returning to the West Coast. However, just after the offer came, we made a trip to New York that reset our direction. We came to New York so I could attend the annual Federation of American Scientists meeting. Martin Kamen also attended the meeting and wound up walking with me at its close from upper Manhattan to the Times Square subway station. I had met Martin when I was at Caltech, at a benefit party Linus Pauling gave to help him raise funds for his legal fees. He was fighting the INS decision to revoke his passport (another McCarthy victim). We talked a bit about this, and then I told him about the possibility of going to Stanford in Josh’s new department. By the end of the walk, I realized that going to Stanford was a chance of a lifetime and that there was no way I could turn down a position there, if I got it. Why was Stanford so exciting? Well, with urging from Henry Kaplan, head of Radiology at the Stanford Medical School and the pioneering developer of treatment protocols for Hodgkins disease, Stanford President Wallace Sterling had mustered the resources to upgrade the Medical School to a first-rate institution with the twin goals of forefront research and excellent clinical practice. Arthur Kornberg, who would win the Nobel Prize in 1959, was recruited as chairman of Biochemistry, and he in turn recruited the cream of the department he chaired in St. Louis. Joshua Lederberg, who couldn’t interview me until February (1959) because he had a date with the Nobel Prize in December 1958, was brought in as chairman of Genetics. I was the first faculty member Josh recruited. Josh’s (first) wife Esther was also in the department. One reason she and Josh had chosen Stanford was that, unlike Berkeley and many other schools at the time, there were no nepotism rules at Stanford that prevented her from working with Josh. I noted this, although Lee planned to look for a job in another department or possibly go back to school to get the degree(s) she wanted. In September 1959, the Medical School began moving into its new building, which housed both the basic sciences and the hospital. Lee and I (and our two children) arrived just as this was happening. The Biochemistry Department was already in its quarters. Space had been opened for Josh’s lab and the Genetics office, but little else was ready. The landscaping had not even been started, so the building stood in the middle of a hot, dusty field.

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I was given temporary laboratory space in the nearby Applied Physics building and set up my lab so that I could get the cultures that I had shipped from the NIH growing. But California weather was not kind. September that year turned out to be mercilessly hot, and the building I was in didn’t have air conditioning. As it turned out, it would have been better if my incubator had had a water cooled, rather than a water heated, jacket! Fortunately, I was able to recover from frozen stocks much of what I had lost. Lee began working with me around this time. I had already applied for and gotten a grant to support my somatic cell genetics work. The funding was available, but the delays in completion of the Genetics space put everything else into chaos. I had made a list of equipment I wanted purchased before I arrived, but none of it had been ordered. The Genetics office was overworked and understaffed, and my cultures were cooking in the incubator. Lee decided to pitch in for a while to help me get started. Best decision we ever made! Stanford was great for another reason. During McCarthy times, the University of California and many other schools required faculty to sign a loyalty oath swearing that they were not now, and had never been, a member of the Communist Party or any other organization that advocated the overthrow of the federal government. Because the list of proscribed organizations was created at the whim of people who rose to power ferreting out supposed communists, its sweep was extremely broad. Many faculty members found the requirement of a loyalty oath repugnant and refused to sign. Stanford supported this view by refusing to institute a loyalty oath and by hiring people who left other institutions rather than sign such an oath. A number of eminent Berkeley physicists moved en masse from the Berkeley to the Stanford Physics Department. We were pleased to have the opportunity to meet and work with these physicists in the years that followed.

We Become Immunologists Shortly before coming to Stanford, Josh Lederberg had spent some time in Australia with Sir MacFarlane Burnet, who was head of the Hall Institute in Melbourne. Josh and Sir Mac applied genetic thinking to the immune response and came up with the idea that antibody responses reflect the clonal selection of cells that are individually committed to producing antibodies that recognize, and are triggered by, the immunizing antigen. This so-called clonal selection theory predicted that individual cells would make antibodies specific for a single antigen and stood in opposition to instructive theories that predicted much more plasticity for individual cells. The clonal selection hypothesis ultimately won out. However, at the time Lee and I arrived at Stanford, the jury was still out. To do the studies that would test this hypothesis, Josh appointed two young visiting faculty members: Gustav Nossal, who later followed Burnet as head of the Hall Institute, and Olli Makela, who later returned to Finland to do immunology

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research and eventually became Dean of the Medical School in Helsinki. Gus and Olli, and the mouse facility they would need, were to be housed in the same corridor as the lab being completed for my use. So the move to the new building, which occurred about December 1959, put my somatic cell genetics group right next to one of the most exciting immunology projects of the time.

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The First Immunology Studies LEE: By the time we came to Stanford, Len had already developed an interest in the practical side of immunology. Just before leaving the NIH, he arranged to visit George Snell at Bar Harbor to discuss the idea of using mouse histocompatibility antigens, rather than drug sensitivity, as somatic cell markers in cultured cell lines. Len thought it would be neat to use cytotoxic antibodies to the H-2 antigen (thought to be a single entity at the time, now recognized as the MHC) to select cell surface antigen variants in lymphocyte and other cell lines. However, he wondered whether this would be practical. So he went to talk to George, who was very encouraging and offered some antibodies for this purpose in case Len needed them. This idea lay fallow until we sorted out all the problems involved in getting the lab set up. However, once this was accomplished, Len suggested to me that I take on the job of anti-H-2 antisera so that we would have our own reagents with which to select variants. Of course, I had never touched a mouse and knew nothing about how to proceed other than what I could read. Nevertheless, I took on the job. Len and I both liked it as a project for me because I could work independently at my own speed without creating for him a bottleneck on a critical path. To figure out how to start, I went knocking on Gus and Olli’s door. They did indeed know how to proceed, and they showed me how to take out spleens, use spleen cells to immunize the mice, and do tail bleeds to collect the sera. They weren’t much help in setting up the erythrocyte agglutination assays that were used at the time to titer the sera. However, with their and Len’s advice and several quite good papers on the subject, I managed to get a test going and learn to reliably read it. There was already a great deal of serologic evidence characterizing the genetically distinct H-2 antigens expressed by various mouse strains. Because C57BL mice were known to make strong antibodies to the DBA/2 H-2, and because both kinds of mice were available from a local commercial breeder, I chose this combination. In addition, because female C57BL mice that had been retired from the breeding colony were large and could be obtained quite cheaply, I chose these mice to immunize. I got very good responses and was able to collect lots of good antisera that Len could use for selection. Surprisingly, however, some of the control sera that I took from the breeders before immunization turned out to have low but clearly positive levels of antibodies that agglutinated DBA/2 rbc but were clearly negative against the serum producer strain (C57BL). A bit of detective work soon showed that many of the retired breeders that we had purchased had been out crossed to DBA/2 to make F1 animals

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that were in high demand. Thus, by following my nose, I had discovered a potential model for human Rh immunization during pregnancy (2). Some time later, I showed these data to Ray Owen, the Caltech professor who taught the immunogenetics course I had taken. Ray shocked me by asking when I was going to publish it. I stammered and stuttered a bit until Ray finally said, “Well, if you are serious about being a scientist, then I guess you have to publish this.” So I did. For this and many other reasons, I often refer to Ray as the closest I ever had to a graduate professor.

Focus on H-2 Antigens With a plentiful supply of anti-H-2 antisera, I decided to phase out my drugresistance work and focus on using these sera for genetic studies with mouse cell lines. First, however, I needed to do some characterization of the H-2 antigen, at least to the point where I knew what it was. There was general confusion on this at the time. Immunologic evidence had located H-2 on the cell surface of many cell types. However, while some people thought the antigen was composed of carbohydrate or protein, no lesser a light than Peter Medawar, who would later be awarded the Nobel Prize for discovering adaptive immune tolerance, thought that H-2 was made of DNA. We soon laid this issue to rest by isolating plasma membranes and characterizing the H-2 antigen(s) associated with the membranes as a protein or glycoprotein (3). Working on H-2 drew me ever closer to the immunology community at Stanford. Gus and Olli became close friends as well as wonderful colleagues who loved discussing science as much as I did. Avrion Mitchison, who later headed a productive Immunology Department at University College, London, was also appointed as a visiting professor by Josh and began occupying the lab next door within the year. Together, we established an immunology journal club, which met one evening a week at my house as a no-holds-barred discussion in which we examined methodology, evaluated experiment design, questioned conclusions, and argued theory. The descendant of this journal club still functions in our laboratory today, with much the same rules. Gus and Olli were highly focused on testing the clonal selection theory (4) during this time. Their approach was to isolate individual antibody-producing cells and determine whether a single cell made antibodies to one or both of a pair of immunizing antigens. Their data, although limited by the number of cells they could isolate and test, clearly favored clonal selection. Mel Cohn, in the Biochemistry Department three floors up, with colleagues Lennox and Attardi at other institutions, were holding down the instructive corner of the argument. At the time all this was happening, I didn’t have a notion that I would one day develop an instrument (the FACS) that would make it possible to resolve this question. However, once we got the FACS running, we returned to these issues in studies that became a major focus of our laboratory for several years.

LEN:

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Enter Immunoglobulin Allotypes In the spirit of the times, the clonal selection debate did not sour my relationship with Mel Cohn, with whom it has always been fun to argue about anything. In any event, when Mel decided to leave Stanford in 1962, he “willed” the medical student working in his laboratory to me. John Wunderlich thus joined our group, bringing with him a project focused on producing antisera that would distinguish between antibody molecules produced in different mouse strains and putatively encoded by different alleles in those strains (5). Ultimately, this project blossomed into a full-scale study of the genetics of the Ig heavy-chain (IgH) chromosome region (6). Long before the structure of the IgH region was defined by molecular methods, studies with anti-isotype and antiallotype antisera showed that IgH isotypes are encoded by a series of closely linked loci and that various mouse strains have distinctive alleles at these loci. The IgH isotypes were defined by other laboratories; we produced many of the antiallotype sera and used these sera in genetic studies (gel immunoprecipitation and radioimmune assay) to demonstrate the close linkage of several of the IgH (isotype) loci. In addition, we defined a series of IgH haplotypes based on the combinations of alleles represented at the IgH constant region loci on the IgH chromosome in each of the standard mouse strains and showed that these were codominantly inherited. Interestingly, the IgH haplotypes defined in this way provided the basis for the Jan Klein and Don Shreffler model for organization of the MHC chromosome region. We reported our IgH genetic studies at a Cold Spring Harbor Symposium (7) at which Henry Kunkel presented evidence for similar close linkage of the human IgH loci. Together, these studies solidified a paradigm that was extended by the recognition of additional loci and haplotypes and laid the groundwork for the modern understanding of Ig rearrangement, isotype switching, and haplotype (allelic) exclusion during B-cell development.

Regulation of Memory-B-Cell Expression LEE: Although I was working actively on allotype genetics, I maintained an independent interest in maternal immunization to fetal antigens (H-2 in particular) and in the effects of such immunization on the developing fetus. Therefore, when maternal antiallotype antibodies were shown to pass to the fetus and to delay the initial appearance of the paternal allotype in allotype heterozygotes, Len suggested that I get this to work with some of our mouse strains. I did, further extending my independent work in the lab. Ultimately, Len’s suggestion led us to the discovery of “chronic” allotype suppression. This occurs when SJL males are mated to immunized BALB/C females producing high-titer antiallotype antibodies reactive with the paternal Igh-1b (IgG2a) allotype. This finding then led to the discovery and characterization of CD8 suppressor T cells that control the expression of IgG2a (Igh-1b) memory B cells without impacting survival of the memory population (8).

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While exploring the mechanism(s) underlying allotype suppression, we recognized (as others had before us) that priming with typical protein antigens enabled a strong secondary response to the determinants present on the priming antigen. Such priming also resulted in suppressed responses to new epitopes such as haptens introduced on the priming antigen at the time of the secondary challenge. Because this suppression persists when carrier/hapten-carrier-immunized animals are challenged with the new epitope (hapten) on a different carrier protein, we refer to it as epitope-specific suppression (9). Although these studies were highly rigorous, they were not met with universal acclaim, perhaps because of the confusion they introduced and perhaps because they occurred just at the dawn of the molecular era in immunology. Nevertheless, the findings are “alive and well” in the vaccine world, where they have been confirmed with a variety of antigens and provide an important caveat when generating vaccine strategies. Similarly, the immunoregulatory-circuits model we had constructed just prior to beginning the epitope-specific work (10), which predicted much of what we found, was not roundly embraced by immunologists, but it too is alive and well, I am told, among today’s immune-system model builders.

THE FACS As I became more deeply involved in immunology, I became increasingly aware of the need to characterize and isolate the different kinds of lymphocytes that were beginning to be visualized with fluorescent-labeled antibodies under the microscope and studied functionally by sensitivity to complement-mediated depletion after treatment with antibodies (in conventional antisera). The need for better cell-isolation methods here dovetailed completely with the need for developing a method for positive selection of variants in the somatic-cell genetics projects that I was also engaged in. So I started asking around to see whether anyone had solved this problem. I soon found out that a group at Los Alamos (led by Mack Fulwyler and Marvin Van Dilla) had developed a machine that could examine and sort large numbers of cell-sized particles on the basis of particle volume. I immediately planned a trip to see whether I could convince them to add a fluorescence-detection system so I could use their machine to measure the amount of fluorescence associated with individual cells and to sort cells according to this measure in addition to volume. They demurred, saying that this “was not part of their mission.” [They were funded to build a machine to count and size particles, not cells, obtained from the lungs of mice and rats sent up in balloons to inhale debris generated by atomic-bomb testing (11).] I persisted, and they finally agreed to give me a set of engineering drawings and the permission to use them as the basis of a machine designed to distinguish cells labeled with fluorescent antibodies. Little did I know when I brought these plans back to Stanford that I was starting on a lifework that continues today as a major activity in our laboratory.

LEN:

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Back at Stanford, I took advantage of my close proximity to the instrumentation research laboratory set up by Joshua Lederberg to look for life in outer space (on Mars or on the Moon). I asked the engineer I knew best to look at the plans and estimate the cost to replicate the Los Alamos machine. He came to me a few days later and said, “Okay, I’ve got good news and I’ve got bad news. Which do you want to hear first?” I opted for the good news, and he said, “Well, I think the machine can be built here and I’ve completed a list of parts to be ordered.” I asked what it would cost, and he answered, “Something like $14,000.” That was a lot for those days, but it could probably be managed. So I asked him, “What’s the bad news?” He answered, “The bad news is that I’m leaving Stanford. I’ve got another position.” I next talked to Josh and the head of the Instrumentation Laboratory. They agreed that despite the loss of this key engineer, they could provide the engineering help I needed for the project. I went to Henry Kaplan, who was head of the Radiology Department and was working on thymic function and development (Irving Weissman worked with him). I told him how I thought a fluorescencebased cell-analysis and -sorting machine could be used to study the thymus and asked him to join me in funding the development of this machine. He agreed. I put up $7,000 from my somatic-cell genetics grant, he put up the remaining $7,000 needed to meet the estimate, and the project got under way. I didn’t do any of the engineering on this project. However, I was deeply involved in the daily development. I was essentially the head of the design team and took responsibility for assuring that the machine would be usable by scientists doing immunological or genetic studies. For example, at one meeting, the engineers told me that the best they could do was to take data from about one million cells in an hour. This was too few to be useful, so I insisted that they either increase the speed by an order of magnitude or close the project down. At first there was some discussion about “repealing the laws of physics,” but eventually an engineer came up with a solution and we were off and running again. I was also responsible for getting new capabilities designed and tested. I loved this role because it encouraged me to think broadly about potential applications for the nascent FACS and to develop collaborations within and outside our laboratory to generate and test these kinds of ideas. In fact, although FACS development has long since ceased to be an activity occurring solely within my purview, I still enjoy the development of new FACS applications and the scientific breakthroughs such development engenders. Our first cell-sorting paper was published in Science in 1969 and was entitled “Cell sorting: automated separation of mammalian [plasma] cells as a function of intracellular fluorescence” (12). The instrument we used for this study had a xenon light source, which we replaced with a laser shortly thereafter. By 1972, we had developed a much improved instrument and decided to call it the Fluorescence-Activated Cell Sorter (FACS). The engineering team was also much improved because I was able to recruit Richard Sweet, inventor of the ink-jet printer, to head the team. In essence, I pointed out to Dick that the sorting module

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in the FACS was based on his invention and asked him to join our group. He responded, “There’s nothing I’d like to do more. I’d like to see biological applications of my inventions.” And see he did, as he applied himself to the development of several of the core features still with us in the modern FACS instrument. Dick’s initial work generated a paper, published in the Review of Scientific Instruments, that was really the first one describing the modern FACS (13). He also joined us as an author of a 1976 Scientific American article in which we introduced the FACS and the idea of using this novel instrument to track the expression of genes encoding surface molecules that distinguish various kinds of lymphocytes and other cells (14).

FACS Goes Commercial The next major milestone in the development of the FACS was a meeting I had with a vice president of Becton-Dickinson (BD), parent company of the current BD Biosystems (BDB), and with Bernie Shoor, then a local BD representative who ran an engineering group in the Stanford area. Bernie and the vice president came to me because they wanted help with making (conventional) antibodies. I changed the subject and said, “Well if you’re interested in making antibodies, then you’re interested in immunology. The most exciting thing in immunology right now is our fluorescence-activated cell analysis and sorting [FACS] instrument, which we have been developing for some time and is now working!” Bernie was interested in the machine but didn’t think it was commercially viable. “I think maybe we could sell 10 of these instruments worldwide,” he said. I thought 30, or possibly as high as 100 sales were more likely, but neither number seemed high enough to BD to support turning FACS into a commercial machine. BD, in the person of Bernie Shoor, would have walked away from the venture if I hadn’t gotten an NIH contract that would let me subcontract the building of two such instruments to Bernie’s group and let me collaborate in the effort. It’s also true, though, that I might not have gotten the contract if I did not have BD on board to build it. We eventually built two FACS instruments, one for Stanford and one for the National Cancer Institute (NCI), which put up the money as part of the “war on cancer” (15). Within a short time (as such projects go), we had a commercial instrument to replace “Whizzer,” the breadboard model we had been running until then. FACS-1 was later upgraded to FACS-2, which ran for many years both in our laboratory and at the NCI. Ultimately, the NCI instrument wound up in an NIH museum. Our instrument went to the Smithsonian Institute in Washington, DC, and is presently on display at the Walter Reed Army Institute of Pathology. The Walter Reed exhibit includes a tape recording of me describing some of the early work our group did and some of the work done by Bernie Shoor and his group. After the NIH contract work was completed, BD successfully marketed FACS-2 and we continued our independent development effort. Within the next few years,

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we had made some key improvements, including the addition of fluorescencecompensation circuitry to correct for spectral overlap between dyes and fourdecade logarithmic amplifiers to allow the full range of FACS data to be displayed on a single data plot. In addition, we introduced the use of computers for data collection and built the first software for FACS data computation and display.

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Monoclonal Antibodies as FACS Reagents LEE: In 1975, just about the time that Cesar Milstein and George Kohler succeeded in immortalizing spleen cells that produce antibodies by fusing them with a longestablished myeloma cell line, Len arranged a sabbatical in Cesar’s laboratory at the Medical Research Council (MRC) in Cambridge, England. He chose the MRC to learn the new molecular biology methods (which he did). However, by the time we reached Cambridge in the fall of 1976, the fusion work was in full swing, and Len was quick to realize that the ability to produce monoclonal antibodies to cell-surface determinants would remove what had come to be the most irritating restriction to FACS work at the time. The conventional antibody reagents that we were using for FACS studies were made primarily in mice or rats and were always in short supply. Furthermore, the specificity was always questionable because the animals were immunized with cell preparations that contained many different potential antigens. Finally, the ability to produce directly conjugated reagents was very limited, making background staining by the second-step reagents a major problem. No wonder then that Len was anxious to tap this new monoclonal reagent resource. Cesar, on the other hand, had not attended the many meetings we had at which discussions of potential problems with conventional antibody reagents had been narrowed down to the need for groups to exchange staining reagents before the findings could be evaluated. Therefore, Cesar was not highly motivated to have Len delve into the monoclonal technology and urged him instead to pursue the molecular biology studies he had come to do. The solution to this came when Vernon Oi, then a graduate student in our laboratory at Stanford, came to Cambridge for a prolonged stay. I was working, in principle, at the Babraham laboratories with Arnold Feinstein. However, I had not made much use of the space Arnold gave me because I had to write several chapters for the Weir Handbook of Experimental Immunology as well as several papers that had piled up before I left Stanford. Arnold was pleased to let Vernon take my place, and with agreement from Cesar, he outfitted a laboratory in which Vernon (with help from Len and me) could make a set of monoclonal antibody reagents that would detect allotypic determinants on IgG molecules (16). We brought this technology home at the end of the sabbatical year and, with a FACS available for screening for antibodies to cell surface determinants, began making a series of monoclonal reagents (17) to mouse MHC and other cell-surface molecules (16, 18). Shortly thereafter, we made a unilateral decision to make our monoclonal reagents, and the cell lines that produced them, freely available to the

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scientific community. I had the pleasure of announcing this at a large MHC workshop meeting and was pleased when Baruch Benacerraf approached me after the session to compliment our laboratory specifically on this decision. Breaking into the circle surrounding me, he said, “I would like to shake your hand.” And he did! Len also recognized at this time that distributing cell lines that produce important monoclonal reagents would not be sufficient to ensure the availability of these reagents to the overall immunology community. While still in Cambridge, he had phoned Bernie Shoor to suggest that he get BD to set up a commercial mechanism for producing and distributing monoclonal FACS reagents. It took some time for this to occur, but BD ultimately set up a business whose growth and importance to research and medical practice has well validated the original idea. Interestingly, neither BD nor we thought it necessary or appropriate to patent the monoclonal reagents that the BD monoclonal center was producing, or even to restrict the dissemination of the cell lines that produce these antibodies. Bernie felt, and was proven correct, that people would prefer to buy well-characterized fluorochrome-conjugated reagents rather than produce these reagents themselves. This view is probably more correct now than it was at the time. However, it became untenable as patents for biological material became commonplace and suits for patent infringement began invading the biomedical arena. Some time later (1982), Vernon Oi and I teamed up with Sherie Morrison (on sabbatical leave with Paul Berg at Stanford at the time and now at UCLA) to make human/mouse chimeric antibodies in which the antibody specificity was encoded by variable-region genes derived from mouse and the heavy-chain constant region was encoded by human IgH genes (19). Because we believed that chimeric antibodies of this type were likely to be useful as functional antibodies and therapeutic reagents, we applied for a patent for this molecular method (issued in 1998). We have been pleased to see the method applied by others, e.g., in the production of chimeric anti-TNF-α used in the treatment of human autoimmune diseases.

FACS: The First Biotech Instrument? If the biotechnology (biotech) industry can appropriately be characterized as an industry built around defining, measuring, and making use of gene expression in biology and medicine, then the FACS as we built, described, and used it in the early 1970s readily qualifies as a biotech instrument. In fact, to our knowledge, it is the first such instrument. In addition, Garry Nolan (Medical Microbiology and Immunology, Stanford) points out that FACS should be recognized as a key proteomics instrument, since it has been used in numerous studies to define the functions and demonstrate the interactions of surface and intracellular proteins. Although titles shouldn’t really matter in science, it is appropriate to grant the FACS these distinctions. Similarly, it is appropriate to congratulate Bernie Shoor and BD for having had the foresight to build the first biotech company and to lay the foundations for it to grow to its current status as Becton-Dickinson Biosciences (BDB).

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Len, of course, has been honored many times for his innovative role in developing the FACS and demonstrating its applications in biology and medicine. Notably, he was cited for this work when elected to the National Academy of Sciences in 1982.

Breaking the FACS Color Barrier At the beginning of the 1980s, we realized that the immunology and other studies that we wanted to do were limited by the number of individual fluorescence measurements (sometimes called parameters) that a single-laser instrument could make on individual cells. There were enough markers known on T cells, for example, to suggest that multiple subsets existed. However, we recognized that using these markers effectively requires their simultaneous measurement on individual cells. Measuring their expression two by two, or even three by three, is not adequate. Information is lost when the measurements are separated and cannot be regained by trying to merge them during analysis. David Parks, then a member and later the leader of our FACS Development Group, solved this problem by extending the FACS-2 to create a dual-laser FACS instrument that would, at a minimum, double the number of markers we could measure on a given cell. In addition, he independently developed single-cell cloning and added this capability to the dual laser instrument (20–22). This was not the first dual-laser FACS (one had already been created by an instrumentation research group in Germany). However, it was the first dual-laser instrument put into routine use for immunologic studies and hence was the first instrument to demonstrate the effectiveness of using multiparameter FACS methods for distinguishing lymphocyte subsets and for sorting these subsets for functional studies. Many of the key findings made over the years by our group and by other research groups at Stanford were enabled by the development of this dual-laser instrument and its installation in the Stanford Shared FACS Facility, which Len helped to organize some years ago and which David Parks now directs. We put the dual-laser instrument into routine service in 1983. Roughly 15 years later (1998), we put into operation a hybrid instrument (BD bench, Cytomation electronics) that provides three independent laser illuminations and can simultaneously measure up to 11 distinct fluorescence emissions from individual cells. The number of markers measured with this high-definition (Hi-D) FACS (23–25) instrument, and with our recently purchased BDB Hi-D instruments (FACS DIVA and ARIA), has grown from an initial 8 to the current 11, now the standard for most work in our laboratory. Mario Roederer and his group at the NIH have extended FACS DIVA and located additional fluorescent dyes that can be measured simultaneously to further increase the number of measurements that can be made per cell.

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LEN:

The Soft Side of FACS LEE: The original FACS data were collected by photographing histograms traced on an oscilloscope screen. Although these were the early days for using computers

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to collect data from laboratory instruments, we once again were able to capitalize on our connection with Josh Lederberg’s exobiology engineering group and, with their help, began using the Digital PDP-8 computer to collect FACS data. Wayne Moore, who joined the FACS development group shortly thereafter and has since built or supervised the building of all of our FACS software, moved the FACS data collection and analysis to the PDP-11 platform. On this platform, he developed models for much of the data analysis and display methods that are still in use, including the equal-density (probability) contouring method that is today’s standard. FACS/Desk, which Moore introduced at about the same time that our duallaser FACS was put into operation (26), was built on a VAX-11/780 platform and offered a nonprocedural (keystroke rather than command line) user interface. This interface, which had windows that opened and asked for user input, foreshadowed what I was later to see in the Apple Macintosh windowing environment. Sometime around 1980, Len had to raise nearly half a million dollars to buy the VAX computer and build the specialized computer facility necessary to house it, but we have always considered this well worth the trouble. The capabilities that Moore’s full FACS/Desk system provided, and still provides, have enabled countless large multiparameter experiments and have provided a permanent, searchable record of all FACS experiments done in the Stanford Shared FACS Facility. For the past several years, we have been working on a replacement for FACS/ Desk. Some time ago, we did the initial designs for a new FACS analysis package. These provided the basis for Mario Roederer’s extensions and ultimately for the commercially developed FlowJo package (TreeStar.com), which is widely used today. At present, we are migrating data stored in FACS/Desk to our new FACS DataStore, whose capabilities are much improved over the older system, and have completed an initial version of a searchable Directory Server that can be closely integrated with the new DataStore. We, in collaboration with Mark Musen, Medical Information Sciences, Stanford, and Stephen Meehan, Meehan Metaspace, are also about to complete the first version of a FACS protocol editor (FacsXpert) that provides an advanced user interface coupled to knowledge-based technology to facilitate design of 12-color FACS staining protocols. FacsXpert is also designed to “painlessly” capture the information (metadata) necessary to annotate data for analysis output (e.g., for axes and table heads) and to facilitate searches with the Directory Server. Ultimately, we hope to make all these capabilities available to the scientific community and to extend the system to take and store data from multiple instruments. This goal, however, may have to wait until we can find a willing and appropriate commercial partner. Len has been both contributive and supportive in this software development effort. However, in some ways it has been very much “my baby.” Although I have written only a small part of the overall system (specifically, the FACS Facility instrument scheduler), I have frequently participated in the design process and have opened relevant collaborations with colleagues in the Stanford Computer Science

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and Statistics Departments. In addition, I pioneered the connection of FACS/Desk and FACS analysis output to the SAS Institute JMP statistics package to enable analysis of data from our HIV clinical trials. For this effort, and for the development of the overall FACS/Desk system, we were awarded the Computer World Smithsonian Award in recognition of our visionary use of information technology in the field of medicine.

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A Note about Innovation Although all the key flow cytometry technologies that we developed were eventually adopted as standards by the commercial and academic flow-cytometry community, we have routinely encountered substantial resistance to the initial spread of these technologies. Biological innovations such as the use of monoclonal antibodies as FACS reagents were readily and rapidly accepted (27). However, technological innovations not part of the biological idiom fared less well, particularly when statistical or mathematical treatments were involved. Hopefully, this will change as these modes of data analysis become more common within the biomedical research community.

THE FACS IN THE SERVICE OF IMMUNOLOGY (AND VICE VERSA) This and the following sections summarize the work we have done over the past 50 years, organized longitudinally by subject area. Presenting the work this way provides a clear view of how our interests in various areas have played out, but it tends to obscure the ways in which the work in each area influenced the development of work in the others. This interplay, generated by the simultaneous pursuit of diverse studies within Lee’s and my jointly run group, is one of the key elements in what might be termed the Herzenberg laboratory experience. Interactions with our contemporaries at other institutions also played a key role in shaping our work. It’s hard to convey the fun we all had working individually, but nonetheless as a group, to unfold the immune system and pry its secrets loose. Immunology, particularly the study of cells and cell functions in the immune system, was a small discipline at the time. By and large, those of us working in this area communicated with each other frequently. We made a point of sharing reagents, knowledge, students, and fellows in a way that has become more difficult as we have gotten older and the field has gotten larger. But although our specific interests have diverged and the work of our close circle of collaborators has overlapped less, we remain friends and still love an evening of “talking science” over a good bottle of wine. Av Mitchison, Gus Nossal, and Olli Makela, as we have indicated, were part of this early immunology group, as were Tomio Tada, Klaus Rajewsky, Richard Gershon, Bill Paul, Max Cooper, Charlie Janeway, Eli Sercarz, Ray Owen, Hugh

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McDevitt, Ben Pernis, and Spedding Micklem. Elizabeth Simpson, Irving Weissman, Robert Mishell, Patricia Jones, Harvey Cantor, Ko Okumura, Lee Hood, and Fred Alt formed a younger contingent with whom we also interacted frequently. Of course there were many others, including the students and fellows in our laboratory (whom we have named by reference). But when we think of “the old days,” the people we have named here immediately come to mind as the friends and colleagues who contributed most to our development as immunologists and scientists.

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IgH Allelic and Haplotype Exclusion Our first serious application of FACS in immunology was done using the breadboard machine to characterize, sort, and transfer rabbit B cells according to Ig allotype expression. These early studies confirmed that the Ig-bearing cells in spleen and lymph nodes are precursors of antibody-producing cells, a conclusion that had been based, until this point, on sensible logic and correlations between enrichment of Ig-bearing cells and increases in functional activity in adoptive transfer studies (28). In addition, these studies provided the first indication that the allelic exclusion visible in IgG- and IgA-producing plasma cells in allotype heterozygotes has already occurred in the B cells that give rise to these plasma cells (29, 30). In subsequent studies conducted with FACS-1 and FACS-2, we used murine IgH allotype markers on IgM, IgD, IgG, and IgA to further characterize the Ig isotype and allotype commitment of naive B cells and their memory (IgG+)-B-cell progeny. These studies, which showed that a B cell and its progeny are committed to producing Ig heavy chains encoded by only one of the two parental IgH chromosomes (haplotypes), led us to propose that allotype exclusion should more appropriately be called haplotype exclusion (6, 7). Thus, this work laid the groundwork for current understanding of IgH rearrangement and isotype-switching mechanisms. In additional B cell studies, we showed that the IgG isotype expressed on memory cells indicates the commitment of its Ig-producing cell progeny (31) and that specificity of the surface Ig on memory cells indicates the specificity of the adoptive response they will produce (32, 33). This latter work, done by sorting cells that bound keyhole limpet hemocyanin (KLH), also provided direct evidence for the one-cell/one-antibody concept, which was still an issue at the time.

B Cells Subdivided LEE: Randy Hardy and Kyoko Hayakawa arrived in our laboratory just about the time that David Parks brought the dual-laser (multiparameter) FACS to a location where it could be used regularly for immunology studies. Several T-cell subsets were already known at this point, and others seemed imminent. B cells, in contrast, were thought to be largely homogenous except for the kinds and amounts of Ig molecules they expressed. Although we were principally interested in doing functional studies with T cells, we decided to exercise the new instrument on something

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relatively simple by focusing it on an investigation of B-cell heterogeneity in the spleen. We figured that three months should wrap up this B-cell work, and then we could get on to T cells. Wrong guess! We immediately uncovered several B-cell subsets (34–36) and found a third (B-1) shortly thereafter (37). In fact, two decades later, we and a host of other laboratories are still working on a definition of the B-cell subsets within the mature B-cell population and of the developmental subdivisions that occur as unrearranged progenitors differentiate to mature B cells in bone marrow. In our most recent work, we have used Hi-D FACS methods to examine these developmental subsets, as have Hardy and Hayakawa, whose pioneering work in their own laboratories some time ago defined the basic stages (so-called Fractions A-F) of B-cell development and identified many of the key genes expressed at these stages (38). Our studies of B-1 cells, which express low levels of CD5 and have quite different immune response properties, have spawned a great deal of controversy over whether B-1 and B-2 cells derive from the same or different progenitors (39, 40). However, the key evidence still supports placing these cells in separate developmental lineages. In essence, we and others have repeatedly confirmed the results of our original cotransfer studies, which show that progenitors from adult bone marrow give rise to few, if any, B-1 cells in adoptive recipients in which cotransferred progenitors from fetal liver fully repopulate the B-1 compartment (41–45). We agree that CD5 expression can be induced on bone marrow–derived (B-2) cells under some conditions and that selection impacts B-1 and B-2 development differently. However, these findings are consistent with either a one-lineage or a two-lineage model. In fact, all the data advanced so far in favor of the onelineage model are also explainable within a two-lineage model. Therefore, until a compelling reason emerges to ignore the cotransfer results, which clearly favor separate lineages for B-1 and B-2, we will stay in the two-lineage camp.

T Cells Subdivided and a Bit More on B Cells The idea that Ig-bearing (B) cells produce antibodies and T cells help them to do so emerged as a paradigm just about the time that FACS-1 was delivered to our laboratory. FACS sorting, transfer, and cell-culture studies with the new machine completed the proof needed for this basic concept and, by introducing adoptive cotransfer methods into the lab, set the stage for much of our memory-Bcell and allotype suppression studies over the next decade. Shortly before we left for sabbatical at Cesar Milstein’s laboratory, we completed a collaborative study with Harvey Cantor and Ted Boyse that provided the first evidence distinguishing the helper and suppressor/cytotoxic T-cell subsets from each other on the basis of reactivity with conventional antibodies to Lyt-1 and Lyt-2 (46). When we returned from sabbatical, the first monoclonal antibodies that we produced to mouse cell-surface antigens contained several that stained T cells (18,

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47–50). Studies with these antibodies brought our focus back to the T-cell subsets (51, 52), but (amusingly, from a current perspective) in a way that also wound up creating a mini tempest in a pint-sized teapot. One of the antibodies we produced reacted with a T-cell surface molecule whose physical properties and distribution on T cells corresponded to Lyt-2 (now known as CD8) and a second antibody reacted with a molecule (now known as CD5) whose physical properties were identical to those reported for Lyt-1. However, the expression of this molecule on T cells, as detected by FACS, did not match the expected pattern. Rather than being restricted to a helper-T-cell subset, it was detectable on all T cells (18, 47). [In fact, as later studies showed, it is also expressed on developing thymocytes and is even present on a subset of B cells (37, 50).] The demonstration that the Lyt-1 (CD5) molecule is expressed at roughly the same level on all T cells caused some consternation. It clearly did not erode the functional distinction between the helper and suppressor/cytotoxic subsets; but, for the moment, it scuttled the idea that helper and suppressor/cytotoxic T cells each express a unique surface antigen. This was resolved (and the mini tempest dissipated) some time later by the isolation of a monoclonal antibody to human cell surface (CD4) and the isolation, by Frank Fitch, of a monoclonal antibody (L3T4) that reacts with the corresponding murine molecule (53). LEE: From T-cell subsets in mice, we extended our studies to human T cells. Bernie Shoor (still at BD) put us in contact with Robbie Evans at Rockefeller Institute, who was looking for someone to characterize the monoclonal antibodies he had made to human lymphocyte surface antigens. The work with these antibodies revealed the amazing homology, both at the molecular and the distributional level, of the markers defining human and mouse T-cell subsets (54). It also led Len to comment one day that, “really, the best study of man is man,” and it refocused much of our laboratory’s energy onto human lymphocyte studies.

T-Cell Subsets in Disease The loss of CD4 T cells in HIV disease is well known. However, the selectivity of this loss is overrated. Multiparameter FACS analyses of naive T cells in PBMC samples from HIV-infected people at various stages of disease shows that CD8 naive T cells are lost at the same rate as CD4 naive T cells (55). CD4 memory T cells are also lost, although not as quickly as CD4 and CD8 naive T cells. CD8 memory T cells, in contrast, increase in frequency as HIV disease progresses and are only lost at the end stages of the disease (55). Consistent with the idea that the coordinate loss of naive T cells in both subsets reflects the loss of thymic function during HIV progression, we have shown that both subsets of naive T cells are greatly decreased or missing entirely in recovered Hodgkin’s patients treated with radiation to the thymic region (56). In more recent studies on T-cell subsets, we have used 8 to 11 fluorescence colors in Hi-D FACS studies characterizing cytokine production, TCR antigen

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(“tetramer”) binding, glutathione levels, metabolic markers, and other properties of the naive- and memory-T-cell subsets as well as subsets within these subsets (57–59). The introduction of BD’s DIVA and ARIA instruments, both capable of 12-color FACS studies, has now enabled these kinds of studies in other laboratories. Mario Roederer, who pioneered much of the Hi-D FACS subset analysis while in our lab, is now doing forefront work in this area in his own laboratory at the NIH (60).

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Somatic Cell Genetics, Modern Style I have often pointed out that monoclonal antibodies and the FACS are complementary tools that synergize to enable studies for which neither alone is sufficient (27, 61). For somatic-cell genetics, the joint use of these tools allowed us (and others) to use the cell lines that produce monoclonal antibodies to investigate isotype expression (isotype switch variants) (62) and antigen-combining site variants (affinity variants) (20). In addition, of key importance for gene cloning and expression studies, these complementary tools provide the ability to select cells expressing particular molecules or variants thereof. Thus, among other things, they allowed us to clone the murine CD8 and CD5 genes (63–65) and to explore the gene amplification (double-minute/minichromosome) mechanism (66) that controlled the level of expression of the CD8 gene cloned into a nonlymphoid cell line.

LEN:

Fetal Cells in Maternal Circulation Many years ago, when the FACS was still a “baby,” we decided to use it to see if we could detect fetal cells in human maternal circulation as the first step toward developing a noninvasive method for prenatal diagnosis. We were indeed able to detect the fetal cells (67). However, we didn’t follow the project much farther, in part because there was reason to suspect that the cells we detected might not have derived from the current fetus. Indeed, current studies show that fetal cells persist for long times in the mother. In addition, these studies surprisingly now indicate that the presence of these cells is closely associated with the development of maternal autoimmune disease and that maternal cells are found in small numbers in multiple tissues of the newborn (68, 69).

HIV, NF–κb, and Redox LEE: Living in the San Francisco area in the early days of the AIDS epidemic was like living in a war zone, where the dead were counted weekly, and the casualty lists frequently included friends or friends of friends. In this climate, it was impossible to go to work in the laboratory without wondering whether something you were doing could be of help. Therefore, we took an interest in a letter sent by Wolf Droge (Heidelberg, Germany) reporting that glutathione (GSH), a multifunctional cysteine-containing tripeptide, is depleted in HIV disease and suggesting, on the basis of his in vitro work charting nutritional requirements for T-cell function, that

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the GSH depletion results in oxidative stress that may decrease the function of the dwindling number of T cells in HIV patients (70). He also showed that GSH levels were low at the later stages of HIV disease (71). Droge recommended treating HIV-infected people with N-acetylcysteine (NAC), a well-known nontoxic cysteine prodrug used clinically to prevent hepatotoxicity by providing the cysteine necessary to replenish GSH depleted by acetaminophen overdose. In addition, he reported that his neighbor’s HIV-infected son was greatly helped by oral NAC administration. This anecdotal finding was not highly convincing. However, we respected Droge’s logic and began seriously exploring the idea of NAC treatment for HIV disease. In the laboratory, we began what appeared to be an independent HIV project in which we made a construct that put the β-galactosidase (LacZ) gene under the control of the HIV-LTR and developed FACS methods for measuring the activity of this reporter gene. However, two projects merged when, after hearing Tony Fauci speak about TNF-α triggering of HIV replication, we arranged to test whether NAC would inhibit triggering of the HIV-LTR by TNF (72). The results of these studies provided the first evidence demonstrating that intracellular GSH levels regulate NF-κb induction and HIV-LTR activity in cell lines (73, 74). Importantly for T-cell function, we also showed that intracellular GSH regulates TCR-stimulated calcium flux in cell lines and in primary human T cells in vitro. The Heidelberg group extended this finding by showing, in their placebocontrolled studies with HIV patients, that NAC treatment improves the in vitro function of T cells taken from these patients (75). In the placebo-controlled trial that we conducted sometime before, we demonstrated that NAC treatment replenishes GSH in HIV-infected people (76). We did not detect any impact of the NAC treatment on HIV viral load. However, we found a marked correlation between NAC treatment and improved survival in the open-label portion of this trial, which was conducted prior to introduction of the more effective, current antiviral therapies (76, 77). Collectively, these findings are consistent with NAC being a useful adjunct therapy in HIV disease, and they support Droge’s initial suggestion that GSH replenishment may be most important for maintaining the overall health and defense against opportunistic infection in the HIV patient. As befits a primarily basic science laboratory, the redox studies we were doing were initially relevant to HIV disease but soon engendered a broader interest in the mechanisms through which intracellular GSH levels influence signal transduction and other physiologic properties of cells. To approach these questions more effectively, we established FACS assays for intracellular GSH levels and, more recently, for surface thiols (57), intracellular thioredoxin, and intracellular protein glutathionylation in primary lymphocytes (78). In addition, we began examining other consequences of GSH depletion (79, 80). This burgeoning project continues unabated in our laboratory and now involves studies with samples from metabolic disease, cystic fibrosis, CLL, HIV, and other types of patients. At the time we were working with HIV-infected subjects, we found that thioredoxin (Trx), a key intracellular redox molecule, is released into circulation and

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blocks neutrophil chemotaxis when present at high levels in blood. Consistent with this finding, we found that among HIV-infected subjects with T cell counts below 200/µl blood, those with elevated Trx levels died within 15 months, even though they had no signs of ill health at the time of assay. This led us to propose that Trx interference with innate responses may render immune-compromised HIV-infected patients more susceptible to progress to the kinds of opportunistic infections that led to death (81). Interestingly, in vitro studies indicate that NAC treatment decreases thioredoxin release (79).

Glutathione/Cysteine-Deficiency Disease Together with a broad series of collaborators with expertise in various aspects of GSH deficiency, we recently completed a literature survey of more than 50 placebocontrolled trials in which beneficial effects were demonstrated for NAC treatment in diseases ranging from chronic bronchitis to diabetes. Collectively, these studies indicate that GSH/cysteine deficiency commonly accompanies a wide variety of clinically important diseases and conditions and that treatment of this deficiency may significantly improve health. Thus, we hope this work will call physicians’ attention to this problem and the ways that it can be minimized.

FAMILY, FRIENDS, AND POLITICS LEN AND LEE: We have not spoken very much here about our family, although all who know us know that the dividing line between work and family is virtually indistinguishable in our lives. Our students, fellows, and laboratory personnel have in many different ways contributed to the upbringing of our children. Berri, our eldest, now runs the Bicycle Trip (http://www.bicycletrip.com), a bicycle shop in Santa Cruz, California. Janet, or Jana as she is now called, is a singer/songwriter who has just released a CD through Motema Music (http://www.motema.com), a small but up-and-coming record label for which she is the CEO. Rick has become a serious salesman and and a fine potter; and Michael, our Down’s Syndrome son, is living nearby and working one afternoon at the lab and the rest of the time at a local workshop. We are pleased that many of our friends and previous coworkers have established independent relationships with our children. We are also pleased that the entire family still puts in political time trying to make the world a better place to live in.

ACKNOWLEDGMENTS We owe much to Jeannette Colyvas, whose oral-history interviews of each of us independently and of both of us together helped us focus on and organize the material presented here. We also thank John Mantovani, our administrator, editorial assistant, friend, and friendly goad, without whom it is doubtful that we

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could have completed this project. This work was supported in part by grants from the National Institutes of Health: grant numbers EB000231 and HL68522. The Annual Review of Immunology is online at http://immunol.annualreviews.org

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LITERATURE CITED 1. Ames BN, Garry B, Herzenberg LA. 1960. The genetic control of the enzymes of histidine biosynthesis in Salmonella typhimurium. J. Gen. Microbiol. 22:369–77 2. Herzenberg LA, Gonzales B. 1962. Appearance of H-2 agglutinins in outcrossed female mice. Proc. Natl. Acad. Sci. USA 48:570–73 3. Herzenberg LA, Herzenberg LA. 1961. Association of H-2 antigens with the cell membrane fraction of mouse liver. Proc. Natl. Acad. Sci. USA 47:762–67 4. Burnet FM. 1959. The Clonal Selection Theory of Acquired Immunity. Cambridge, UK: Cambridge Univ. Press 5. Wunderlich J, Herzenberg LA. 1963. Genetics of a gamma globulin isoantigen (allotype) in the mouse. Proc. Natl. Acad. Sci. USA. 49:592–98 6. Herzenberg LA, Minna JD, Herzenberg LA. 1967. A chromosome region for immunoglobulin heavy chains in the mouse: allelic electrophoretic mobility differences and allotype suppression. Cold Spring Harb. Symp. Quant. Biol. 32:181–86 7. Herzenberg LA. 1964. A chromosome region for gamma2a and beta2A globulin H chain isoantigens in the mouse. Cold Spring Harb. Symp. Quant. Biol. 29:455462 8. Herzenberg LA, Okumura K, Metzler CM. 1975. Regulation of immunoglobulin and antibody production by allotype suppressor T cells in mice. Transplant. Rev. 27:57–83 9. Herzenberg LA, Tokuhisa T, Hayakawa K. 1983. Epitope-specific regulation. Annu. Rev. Immunol. 1:609–32 10. Herzenberg LA, Black SJ. 1980. Regulatory circuits and antibody responses. Eur. J. Immunol. 10:1–11

11. Van Dilla MA, Fulwyler MJ, Boone IU. 1967. Volume distribution and separation of normal human leucocytes. Proc. Soc. Exp. Biol. Med. 125:367–70 12. Hulett HR, Bonner WA, Barrett J, Herzenberg LA. 1969. Cell sorting: automated separation of mammalian cells as a function of intracellular fluorescence. Science 166:747–49 13. Bonner WA, Hulett HR, Sweet RG, Herzenberg LA. 1972. Fluorescence activated cell sorting. Rev. Sci. Instrum. 43: 404–9 14. Herzenberg LA, Sweet RG. 1976. Fluorescence-activated cell sorting. Sci. Am. 234: 108–17 15. Herzenberg LA. 1973. Curing cancer by federal fiat. Hosp. Pract. 8:16 16. Oi VT, Jones PP, Goding JW, Herzenberg LA. 1978. Properties of monoclonal antibodies to mouse Ig allotypes, H-2, and Ia antigens. Curr. Top. Microbiol. Immunol. 81:115–20 17. Milstein C, Herzenberg LA. 1977. T and B Cell Hybrids. Presented at Regul. Gen. Immune Syst.: ICN-UCLA Symp. Mol. Cell. Biol., Los Angeles 18. Ledbetter JA, Herzenberg LA. 1979. Xenogeneic monoclonal antibodies to mouse lymphoid differentiation antigens. Immunol. Rev. 47:63–90 19. Morrison SL, Johnson MJ, Herzenberg LA, Oi VT. 1984. Chimeric human antibody molecules: mouse antigen-binding domains with human constant region domains. Proc. Natl. Acad. Sci. USA 81: 6851–55 20. Parks DR, Bryan VM, Oi VT, Herzenberg LA. 1979. Antigen-specific identification and cloning of hybridomas with

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a fluorescence-activated cell sorter. Proc. Natl. Acad. Sci. USA 76:1962–66 Parks DR, Hardy Richard A, Herzenberg LA. 1983. Dual immunofluorescence— new frontiers in cell analysis and sorting. Immunol. Today 4:145–50 Parks DR, Hardy RR, Herzenberg LA. 1984. Three-color immunofluorescence analysis of mouse B-lymphocyte subpopulations. Cytometry 5:159–68 De Rosa SC, Herzenberg LA, Herzenberg LA, Roederer M. 2001. 11 color, 13 parameter flow cytometry: identification of naive T cells by phenotype, function and T cell receptor. Nat. Med. 7:245–48 Baumgarth N, Roederer M. 2000. A practical approach to multicolor flow cytometry for immunophenotyping. J. Immunol. Methods 243:77–97 Roederer M, Herzenberg LA. 1999. Flow cytometry. In Encyclopedia of Molecular Biology, ed. TE Creighton. pp. 1–4. New York: Wiley Moore W, Kautz R. 1986. Data analysis for flow cytometry. In The Handbook of Experimental Immunology, ed. LA Herzenberg, DM Weir, CC Blackwell, LA Herzenberg. Edinburgh: Blackwell Scientific, pp. 30–36 Herzenberg LA, Ledbetter JA. 1979. Monoclonal antibodies and the fluorescenceactivated cell sorter: complementary tools in lymphoid cell biology. In Molecular Basis of Immune Cell Function, pp. 315– 30. Amsterdam: Elsevier/North-Holland Biomedical Jones PP, Cebra JJ, Herzenberg LA. 1973. Immunoglobulin (Ig) allotype markers on rabbit lymphocytes: separation of cells bearing different allotypes and demonstration of the binding of Ig to lymphoid cell membranes. J. Immunol. 111:1334–48 Jones PP, Tacier-Eugster H, Herzenberg LA. 1974. Lymphocyte commitment to Ig allotype and class. Ann. Immunol. (Paris) 125C:271–76 Jones PP, Craig SW, Cebra JJ, Herzenberg LA. 1974. Restriction of gene expression in B lymphocytes and their progeny. II. Com-

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mitment to immunoglobulin heavy chain isotype. J. Exp. Med. 140:452–69 Okumura K, Julius MH, Tsu T, Herzenberg LA. 1976. Demonstration that IgG memory is carried by IgG-bearing cells. Eur. J. Immunol. 6:467–72 Julius MH, Masuda T, Herzenberg LA. 1972. Demonstration that antigen-binding cells are precursors of antibody-producing cells after purification with a fluorescenceactivated cell sorter. Proc. Natl. Acad. Sci. USA 69:1934–38 Julius MH, Janeway CA Jr., Herzenberg LA. 1976. Isolation of antigen-binding cells from unprimed mice. II. Evidence for monospecificity of antigen-binding cells. Eur. J. Immunol. 6:288–92 Hardy RR, Hayakawa K, Haaijman J, Herzenberg LA. 1982. B-cell subpopulations identified by two-colour fluorescence analysis. Nature 297:589–91 Hardy RR, Hayakawa K, Parks DR, Herzenberg LA. 1983. Demonstration of B-cell maturation in X-linked immunodeficient mice by simultaneous three-colour immunofluorescence. Nature 306:270–72 Hardy RR, Hayakawa K, Parks DR, Herzenberg LA. 1984. Murine B cell differentiation lineages. J. Exp. Med. 159:1169– 88 Hayakawa K, Hardy RR, Parks DR, Herzenberg LA. 1983. The “Ly-1 B” cell subpopulation in normal immunodefective, and autoimmune mice. J. Exp. Med. 157:202–18 Li YS, Hayakawa K, Hardy RR. 1993. The regulated expression of B lineage associated genes during B cell differentiation in bone marrow and fetal liver. J. Exp. Med. 178:951–60 Herzenberg LA, Kantor AB. 1993. B-cell lineages exist in the mouse. Immunol. Today 14:79–83; discussion 8–90 Wortis HH, Berland R. 2001. Cutting edge commentary: origins of B-1 cells. J. Immunol. 166:2163–66 Stall AM, Adams S, Herzenberg LA, Kantor AB. 1992. Characteristics and

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of glutathione to protein thiol groups in lymphocytes under oxidative stress and HIV infection. Mol. Immunol. 38:773– 80 79. Nakamura H, De Rosa S, Roederer M, Anderson MT, Dubs JG, et al. 1996. Elevation of plasma thioredoxin levels in HIV-infected individuals. Int. Immunol. 8:603–11 80. Nakamura H, Herzenberg LA, Bai J, Araya

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S, Kondo N, et al. 2001. Circulating thioredoxin suppresses lipopolysaccharideinduced neutrophil chemotaxis. Proc. Natl. Acad. Sci. USA 98:15143–48 81. Nakamura H, De Rosa SC, Roederer M, Yodoi J, Holmgren A, et al. 2001. Chronic elevation of plasma thioredoxin: inhibition of chemotaxis and curtailment of life expectancy in AIDS. Proc. Natl. Acad. Sci. USA 98(5):2688–93

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Annu. Rev. Immunol. 2004. 22:33–54 doi: 10.1146/annurev.immunol.22.012703.104558 c 2004 by Annual Reviews. All rights reserved Copyright ° First published online as a Review in Advance on September 15, 2003

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SELF- AND NONSELF-RECOGNITION BY C-TYPE LECTINS ON DENDRITIC CELLS Teunis B.H. Geijtenbeek,1 Sandra J. van Vliet,1 Anneke Engering,1 Bert A. ’t Hart,2,3 and Yvette van Kooyk1 1

Department of Molecular Cell Biology and Immunology, Vrije Universiteit Medical Center Amsterdam, 1081 BT Amsterdam, Netherlands; email: Y.vankooyk @vumc.nl 2 Department of Immunobiology, Biomedical Primate Research Center, 2280 GH Rijswijk, Netherlands 3 Department of Immunology, Erasmus Medical Centre, 3015 GE Rotterdam, Netherlands

Key Words DC-SIGN, carbohydrates, antigen recognition, pathogen, dendritic cells ■ Abstract Dendritic cells (DCs) are highly efficient antigen-presenting cells (APCs) that collect antigen in body tissues and transport them to draining lymph nodes. Antigenic peptides are loaded onto major histocompatibility complex (MHC) molecules for presentation to na¨ıve T cells, resulting in the induction of cellular and humoral immune responses. DCs take up antigen through phagocytosis, pinocytosis, and endocytosis via different groups of receptor families, such as Fc receptors for antigen-antibody complexes, C-type lectin receptors (CLRs) for glycoproteins, and pattern recognition receptors, such as Toll-like receptors (TLRs), for microbial antigens. Uptake of antigen by CLRs leads to presentation of antigens on MHC class I and II molecules. DCs are well equipped to distinguish between self- and nonselfantigens by the variable expression of cell-surface receptors such as CLRs and TLRs. In the steady state, DCs are not immunologically quiescent but use their antigenhandling capacities to maintain peripheral tolerance. DCs are continuously sampling and presenting self- and harmless environmental proteins to silence immune activation. Uptake of self-components in the intestine and airways are good examples of sites where continuous presentation of self- and foreign antigens occurs without immune activation. In contrast, efficient antigen-specific immune activation occurs upon encounter of DCs with nonself-pathogens. Recognition of pathogens by DCs triggers specific receptors such as TLRs that result in DC maturation and subsequently immune activation. Here we discuss the concept that cross talk between TLRs and CLRs, differentially expressed by subsets of DCs, accounts for the different pathways to peripheral tolerance, such as deletion and suppression, and immune activation.

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DENDRITIC CELLS Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that are seeded throughout peripheral tissues to act as sentinels that process and present antigen to mount adequate immune responses. Depending on the type of antigen, and the tissue localization, the immune response is suppressed or activated (1, 2). DCs differentiate from bone marrow stem cells and migrate as precursor DCs into the blood. Immature DCs populate all body tissues where they sample either self- or nonself-antigens. Self-antigens can be derived from their innocuous environment, such as necrotic and apoptotic cells that need to be scavenged before they disintegrate. Alternatively, nonself-antigens are foreign products from invading pathogens that need to be eliminated. The main function of DCs is to capture antigen for processing and presentation as antigenic fragments on major histocompatibility complex (MHC) class I or II molecules to na¨ıve T cells (1). In a steady-state situation, prior to acute infection and inflammation, DCs are in an immature state and are not fully differentiated to carry out their known roles as inducers of immunity. They are not unresponsive as they actively circulate through tissues and into lymphoid organs, capturing self-antigens as well as innocuous environmental proteins. In a state of alarm such as a microbial invasion, or massive cell death, immature DCs receive simultaneous activation signals through the binding of conserved molecular motifs by pattern recognition receptors, such as Toll-like receptors (TLRs) or specific TNF family members (1, 3). This results in DC maturation and migration to secondary lymphoid organs, where DCs present the processed antigens to na¨ıve T cells and induce antigen-specific immune responses. The maturation and migration of DCs is carefully orchestrated by certain chemokines, adhesion molecules, and co-stimulatory molecules. These factors control the differentiation stages of the DC and direct the migration of the various DC subtypes (4). Chemokines generated within the lymph nodes attract na¨ıve T cells toward the DC, enabling maximal exposure of MHC-peptide complexes to na¨ıve T cells. Adhesion molecules are crucial for the cellular interactions that DCs undergo during their journey from bone marrow through blood into peripheral organs and subsequently lymphoid tissues, where they enable DC–T cell interactions necessary for T cell activation. Recently, many novel cell-surface molecules have been identified that are involved in antigen capture by DCs. In particular, a large diversity of C-type lectin receptors (CLRs) has been identified on DCs that are involved in the recognition of a wide range of carbohydrate structures on antigens (5, 6). Especially the resident immature tissue DCs express a wide variety of C-type lectins that seem to be involved in the specific recognition of both self-antigens and pathogens. Although little is known about their specific carbohydrate recognition profile and antigen specificity, it is becoming evident that some of the CLRs, such as Dectin1, DC-SIGN, and the mannose receptors (MRs), are more than just scavenger receptors and they may regulate signaling events or function as cell adhesion receptors.

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One of the major enigmas in immunology concerns those regulatory mechanisms that maintain the unresponsiveness of self-reactive T cells in the normal repertoire to self-antigens while at the same time allowing effective immune reactions to foreign antigens to be mounted. We propose here that both of these functions are coordinated by DCs, using distinct characteristics of the various receptor classes, such as CLRs and TLRs, present on their surface.

ANTIGEN RECOGNITION RECEPTORS ON DCs: TLRs AND CLRs Next to MHC, CD1, and FcR, the main DC receptors engaged in the direct recognition of characteristic molecular patterns on antigens are the TLRs and CLRs (7–9). TLRs are pathogen recognition receptors (10) that recognize characteristic molecular patterns present in microbial lipids, lipoprotein, lipopolysaccharides (LPS), nucleic acids, or bacterial DNA, as well as factors secreted upon tissue damage such as heat shock proteins (Hsp 70) (11, 12). The recognition by TLRs triggers intracellular signaling cascades that result in DC maturation and the induction of inflammatory cytokines, ultimately leading to T cell activation (7, 10). In contrast, CLRs recognize specific carbohydrate structures on self-antigens or cell wall components of pathogens. Their main function is to internalize antigens for degradation in lysosomal compartments to enhance antigen processing and presentation by DCs (5, 13). To date, several CLRs have been found to function as pathogen recognition receptors, whereas only a few have been shown to recognize self-antigens. Specific pathogens target CLRs to circumvent processing and presentation and to prevent immune activation. By targeting certain CLRs, such as DEC-205, tolerance can be induced in vivo, indicating that the sampling of self-antigens by specific CLRs may set the stage for tolerance induction and immune suppression (2). These findings illustrate a possible function for CLRs in the recognition of a wide variety of carbohydrate structures on self-glycoproteins to allow specific homeostatic control to self-antigens and to mediate cellular processes such as cell signaling, cell adhesion, and migration (5). In contrast, specific pathogens benefit from their capacity to target host C-type lectins, using the function of the C-type lectins to induce nonresponsiveness against their processed antigens with the aim to promote their survival by escaping immune activation. There are new indications that TLRs and CLRs communicate with each other, and it is proposed that the cross talk between TLRs and CLRs may fine-tune the balance between immune activation and tolerance (14–17). Recognition of self-antigen by CLRs alone will favor immune suppression, whereas pathogen recognition or self-recognition in a situation of danger where both TLRs and CLRs are triggered induces immune activation. Thus, in a steady-state situation, antigens are captured by CLRs to maintain tolerance, whereas in a dangerous situation, CLR binding to the same antigen occurs in the presence of TLR triggering, and the immunostimulatory function of TLRs overrules the tolerizing function of CLRs, resulting in immune activation (18).

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Depending on their tissue localization and differentiation state, DCs express unique sets of TLRs and CLRs. Many different CLRs are expressed by immature monocyte-derived DCs (5), such as the MR (CD206) (19), DEC-205 (CD205) (20), DC-SIGN (CD209) (21), BCDA-2 (22), Dectin-1 (23), DCIR (24), DCAL-1 (25), C-LEC (26), and DC-ASGPR (27)/MGL-1 (28). In contrast, only a few Ctype lectins have been identified on blood DCs and Langerhans cells. Langerhans cells express specifically Langerin (CD207) (29) and DEC-205, whereas plasmacytoid DCs express BDCA-2, Dectin-1, and DEC-205. Many C-type lectins are not exclusively expressed by DCs but are also expressed by other APCs such as macrophages. However, other CLRs are DC-specific, such as DEC-205 on murine DCs (30), Langerin on human Langerhans cells (29), and DC-SIGN expression that is confined to human DCs both in vitro and in vivo (31). DC-SIGN is abundantly expressed on both monocyte- and CD34+-derived DCs, as well as dermal DCs, but not by Langerhans cells in the epidermis (21). In vivo, DC-SIGN is expressed by immature DCs in peripheral tissues like skin, gut mucosa, cervix, rectum, placenta, and lung, as well as on DCs present in lymphoid tissues, lymph nodes, tonsils, and spleen (21, 32). Two DC-SIGN-positive DC precursor populations that differ in CD14 expression were found to be present in peripheral blood (33). Importantly, the expression of DC-SIGN is strongly dependent on Th2 cytokines such as IL-4, linking high expression of DC-SIGN on DCs to Th2 polarization (34). CLRs are highly expressed on immature DCs that are efficient in antigen capture and processing, whereas upon maturation CLR expression is readily decreased. Reflecting the large variety of CLRs on DC subsets, a large diversity of TLRs are also expressed by these DC subsets (35). Myeloid DCs express TLR2, 4, and 6, whereas plasmacytoid DCs express TLR7 and 9 (36, 37). That distinct DC subsets carry different sets of TLRs and CLRs raises the possibility that subsets of DCs recognize distinct classes of self- and nonself-antigens to induce tolerance or activate immunity. The expression pattern of CLRs and TLRs in vivo is as yet an unexplored field, but it needs to be developed as knowledge about expression of certain sets of antigen recognition receptors is essential for our understanding of how these DC subsets handle antigens and induce or suppress immunity.

FUNCTIONAL CHARACTERISTICS OF C-TYPE LECTINS Most CLRs on DCs are type II transmembrane proteins, with the exception of the MR and DEC-205, which are both type I transmembrane proteins (5). All C-type lectins contain carbohydrate-binding activity based on the presence of at least one carbohydrate recognition domain (CRD) (9). The CRD of the C-type lectin DC-SIGN is a globular protein that contains two Ca2+-binding sites, of which one directly coordinates the binding specificity of the carbohydrate structures (38). Calcium binding is essential for the function of CLRs because mutation of either Ca2+-binding site in DC-SIGN leads to the loss of ligand binding

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(39). Depending on the amino acid sequence, the CRD bears specificity for either mannose, galactose, or fucose structures. However, binding of these carbohydrate structures to the different CLRs is also dependent on carbohydrate branching, spacing, and multivalency. The involvement of specific C-type lectins in ligand binding is often demonstrated by the ability of specific carbohydrate components, such as mannan, or a calcium chelator to block the interaction. However, coexpression of several CLRs—with the same carbohydrate specificity and calcium-dependency—on one DC subset makes it essential to use CLRspecific blocking antibodies to demonstrate specific CLR functions.

RECOGNITION OF CARBOHYDRATES BY C-TYPE LECTINS Several C-type lectins expressed by DCs have specificity for mannose-containing carbohydrates. However, each C-type lectin may recognize a unique branching and positioning of mannose residues on a given pathogen or self-antigen structure (19, 21, 27, 40–44). Also, multimerization of the receptor influences carbohydrate specificity (42). For example, the neck domain of DC-SIGN consists of 7 repetitive sequences that are thought to effect oligomer formation. The oligomerization of lectin domains alters the affinity and specificity of carbohydrate recognition (45). Strikingly, MR and MGL-1 form trimers, whereas DC-SIGN has been shown to form tetramers (42), which may partly explain the differences in carbohydrate specificity (38). To date, little is known about the carbohydrate and antigen specificity of CLRs expressed by DCs. The MR, DC-SIGN, and Langerin have been demonstrated to recognize mannose-containing carbohydrates but with a different specificity that is dictated by the branching of the mannose structures. Whereas the MR recognizes end-standing single mannose structures or di-mannose clusters, DC-SIGN recognizes, besides end-standing di-mannoses, also internal mannosebranched structures (high mannose) (21, 38, 41). The MR has also been shown to recognize fucose-, glucose- and GlcNAc—but not galactose-containing structures (46). Screening panels of synthetic glycoconjugates, containing mannose, galactose, and fucose residues, including their multimeric derivatives, can be used to delineate the specificity of C-type lectins (47–49). These experiments revealed that DC-SIGN recognizes a profile of carbohydrates distinct from what was initially thought. Next to recognizing mannose-containing structures, DC-SIGN has a higher specificity for fucose-containing carbohydrates, which is present in Lewis blood group antigens (Lex, Ley, Lea, Leb) that contain fucose residues in different anomeric linkages (49, 50). In contrast, the MR does not recognize Lex structures even though it has specificities for fucose (41). Sialylation of Lex (yielding sialyl-Lex), a L-, E-, and P-selectin ligand, completely abrogates recognition by DC-SIGN, indicating that DC-SIGN has a distinct carbohydrate specificity from the selectins that mediate leukocyte rolling (49). The CLR ASGPR/MGL-1 is rather unique in its carbohydrate-recognition profile, as it primarily recognizes

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galactose but not mannose or fucose residues (27, 51). Some CLRs have overlapping carbohydrate specificity and recognize a wide variety of carbohydrate structures, yet others have a rather unique recognition profile. Many of the recognized carbohydrate structures, such as Lex and mannose-containing carbohydrates, can be present on both self-glycoproteins and pathogens, supporting a role for C-type lectins in both self- and pathogen-recognition.

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CLRs IN THE REGULATION OF ANTISELF IMMUNE REACTIONS Many C-type lectins serve as antigen receptors (5). The main function of C-type lectins on DCs is to interact with a large variety of conserved molecular patterns present on self- and nonself-antigens (52, 53). Most C-type lectins contain putative internalization motifs, such as the di-leucine motif and the tri-acidic clusters (54), and their function as endocytic receptors has been demonstrated by their capacity to internalize specific antibodies (5). For some C-type lectins, internalization of CLR-specific murine IgG antibodies was shown to lead to antigen presentation to murine IgG-specific CD4+ T cells. Most C-type lectins containing a tri-acidic cluster (DEC-205, DC-SIGN, BDCA-2, Dectin-1, and CLEC-1) target internalized antigens to lysosomes and MHC class II+ late endosomes (Figure 1) (20, 55). In contrast, other C-type lectins, such as the MR, quickly recycle via early endosomes to ensure uptake of large amounts of antigen (Figure 1) (19). This process is mediated by a tyrosine-based motif in the cytoplasmic tail of the MR (56). Similar to DEC-205, DC-SIGN contains a tri-acidic cluster in its cytoplasmic tail, and accordingly DC-SIGN-ligand complexes are targeted to lysosomal compartments where ligands are processed for MHC class II presentation to T cells, indicating an important function for DC-SIGN as an antigen receptor (13). However, DC-SIGN also contains a di-leucine motif that appears to be essential for rapid internalization of soluble ligands by DC-SIGN (Figure 1) (13). Although most C-type lectins are endocytic receptors, it is unknown whether they can direct antigens to different intracellular compartments. To date, the exact mechanism of antigen presentation by C-type lectins in vivo is poorly understood. Antigens targeted to the CLRs DEC-205 and the MR are processed by DCs for presentation on both MHC class I and II, leading to a more specific and efficient antigen presentation (57–59). Other studies show that MR is engaged in the presentation of glycolipids via CD1. Uptake of M. tuberculosis lipoarabinomannan (LAM) by DCs through MR resulted in presentation by CD1b to specific T cells (60). C-type lectin receptors are not only involved in the recognition of pathogens but they might also contribute to the capture and presentation of glycosylated selfantigens. For example, the MR recognizes lysosomal hydrolases, certain collagenlike peptides in serum (61), and thyroglobulin, a well known self-antigen (43), and may have a role in autoimmunity (62).

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The natural ligands of DEC-205 and its carbohydrate specificity are currently unknown. However, using DEC-205-specific antibodies as surrogate ligands, it has been demonstrated that this CLR mediates routing to MHC class II compartments and facilitates a 30–100 times more efficient presentation of captured antigens as compared to the MR (20). Similarly, targeting of DEC-205 using anti-DEC205 antibodies facilitates efficient antigen presentation by MHC class I molecules (63). In vivo targeting of ovalbumin conjugated with DEC-205-specific antibodies to DCs induces tolerance, whereas coinjection of agonistic anti-CD40 antibody reverses the outcome from tolerance to prolonged T cell activation and immunity (Figure 2A) (55, 63). These experiments elegantly demonstrate that under steady-state conditions in vivo, DCs have the capacity to induce peripheral T cell unresponsiveness, but a robust immune response is induced to the same antigen in the presence of danger signals (Figure 2A). In summary, in vivo antigen targeting to DCs under steady-state conditions seems to induce deletional tolerance when immunity is induced in conditions where DC maturation is triggered. Tolerance can be achieved with small amounts of protein and is manifested as profound unresponsiveness, indicating that the mechanisms dictating tolerance and immune activation are strictly regulated. More than 50% of the proteins in the human body are glycosylated, and it can be envisaged that in the steady state, DCs define immunological self on the basis of sugar structures, thereby suppressing the self-reactivity of the T cell repertoire. When in a danger state, DC maturation is induced by a microbial infection: the repertoire and the immune attack are selectively focused on elimination of the pathogen. CLRs in particular play an important role in the capture and uptake of self-antigens by binding to specific carbohydrate structures present on cells or secreted proteins that need to be scavenged. Also, the in vivo localization of CLR expression hints to the important function of CLRs in self-antigen clearance and their potential role in tolerance induction. For example, DC-SIGN is highly expressed by DCs in placenta at the interface of mother/child antigen transmission, a site of immune tolerance (32, 64). DC-SIGN is also highly expressed on ellipsoids in spleen at those sites where a direct contact between blood and tissue exists to enable antigen clearance from blood, without induction of an immune response. DC-SIGN is highly expressed in lymph nodes on DCs located in the T cell area as well as on immature DCs located at the site close to the efferent sinus (21, 32). Moreover, the structural related CLR of DCSIGN, L-SIGN/DC-SIGNR, is highly expressed on liver sinusoidal endothelial cells (LSECs), a resident APC population of monocyte origin (65, 66). LSECs are known to mediate the clearance of many potentially antigenic proteins from the circulation in a similar manner as DCs in lymphoid organs/peripheral tissues (67). The tissue localization and ligand-binding properties of L-SIGN support a physiological role for this CLR in antigen clearance. LSECs can induce tolerance in the liver (68), and L-SIGN may be involved in the antigen capture. In particular, apoptotic cells alter their glycosylation pattern (69) and are therefore candidates to be cleared by L-SIGN in the liver. Another CLR, Endo-180, which is expressed on endothelium, appears to be involved in the clearance of collagen, which under

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steady-state conditions is continuously synthesized and degraded during the normal turnover of connective tissue (70). This process involves specific binding of collagen fibrils to the CLR, followed by the cellular uptake and degradation of the internalized collagen in the lysosomal compartment (71).

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CLR AND THE RECOGNITION OF SELF-GLYCOPROTEINS TO MEDIATE CELL ADHESION DC-SIGN functions as a cell-adhesion receptor that regulates DC migration (72) and DC-T cell interaction (21) through its interaction with the self-glycoproteins ICAM-2 and ICAM-3, respectively. The natural ligand of DC-SIGN on lymphocytes, ICAM-3, contains N-linked glycosylations consisting of high-mannose-type oligosaccharides (73), and enzymatic removal of the N-linked carbohydrates from ICAM-3Fc completely abrogates its binding to DC-SIGN (39). These data indicate that DC-SIGN recognizes high-mannose-type carbohydrates on ICAM-3, but the specific carbohydrate structure on ICAM-3 has not yet been identified. Results suggest that DC-SIGN does not preferentially bind to all ICAM-3-expressing cells, but only interacts with specific leukocyte subsets. These findings hint to cell-specific glycosylation of ICAM-3 enabling only binding of subsets of cells (K. van Gisbergen, unpublished results). The other self-glycoprotein, ICAM-2, plays a central role in DC migration and homing to secondary lymphoid tissues. Although DC-SIGN binds to both ICAM2 and ICAM-3 under static conditions, only the DC-SIGN-ICAM-2 interaction resists the shear stresses encountered under physiological flow conditions (33). Remarkably, DC-SIGN behaves as a DC-specific rolling receptor for ICAM-2 and is thus functionally similar to the selectins, which are well known for their regulation of leukocyte rolling upon carbohydrate-structure recognition (74). Despite the fact that both DC-SIGN and selectins mediate leukocyte rolling, they have a distinct carbohydrate-recognition repertoire, i.e., Lex versus sialyl-Lex, illustrating that they may be involved in transendothelial migration at distinct sites. Recently, it has been reported that the MR also recognizes sialyl-Lex structures expressed by endothelial cells; thus this CLR may also contribute to the rolling interactions of DCs (75). The MR is also expressed by lymphatic endothelial cells, where it can interact with L-selectin to mediate lymphocyte binding (76). This illustrates that several CLRs, including DC-SIGN, selectins, and the MR, can regulate leukocyte rolling and migration, processes regulated by the expression of the appropriate carbohydrate structures on target cells. Whereas DC-SIGN recognizes high-mannose and Lex structures, both the MR and the selectins mediate rolling upon recognition of endothelial ligands that present sialyl- Lex structures. We predict that tissue-restricted glycosylation of ICAM-2 and expression of sialyl Lex and Lex structures may direct the migration of DC to particular sites. Cell- and tissue-specific glycosylation of a protein (post-translational modification) is driven by the tissue-specific expression of certain glycosyltransferases and glycosidases,

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which add or remove specific carbohydrate residues, respectively. The expression of a large variety of these enzymes is tightly regulated during the differentiation and activation of leukocytes and by specific cytokines. Because specific carbohydrate structures dictate the specificity of the interaction with certain CLRs, the impact of altered glycosylation of a given glycoprotein can change the recognition by CLRs and subsequently alter cell-cell interactions (77). Indeed, tissue- and cellspecific homing and migration by selectins are regulated by the expression of a selected set of fucosyltransferases resulting in expression of specific carbohydrate structures (78). Understanding the carbohydrate specificity of DC-SIGN and other DC-expressed CLRs is a recent topic of interest in the field of glycobiology and immunology (49) (http://web.mit.edu/glycomics/consortium).

CLRs: A TARGET FOR PATHOGENS Some CLRs have been implicated in the recognition of pathogens, yet specific pathogens target CLRs to escape immune activation. This paradox raises the question of whether the main function of CLRs is to capture pathogens or to recognize self-antigen and suppress immunity. Both the MR and DC-SIGN have been demonstrated to capture pathogens, and in particular DC-SIGN is targeted by pathogens that seek immune escape. The identification of DC-SIGN as a DC-specific adhesion receptor (21) revealed its 100% identity to the previously cloned (HIV)-1 envelope-binding C-type lectin, and as such the first pathogen that interacts with DC-SIGN was discovered (79, 80). DC-SIGN does not only interact with M- and T-tropic HIV-1, HIV-2, and simian immunodeficiency virus (SIV) (61, 80–82), but also with other viruses such as Ebola virus, Cytomegalovirus, Hepatitis C virus, and Dengue virus (83–90). DC-SIGN recognizes the viral envelope glycoproteins that contain a relatively large number of N-linked carbohydrates. In particular, for HIV-1, Ebola, and Dengue virus it has been demonstrated that differential glycosylation of the envelope glycoproteins affects DC-SIGN binding and subsequently infection and viral transmission (91, 92). Other viruses that do express heavily glycosylated glycoproteins on their surface (e.g., VSV) fail to interact with DCSIGN (93), suggesting a certain degree of specificity in DC-SIGN recognition. Even though it is likely that high-mannose structures on gp120 are recognized by DC-SIGN (91, 92, 94), it is not ruled out that protein-protein interactions may also be involved in binding (39). Additionally, nonviral pathogens can interact with DC-SIGN. Helicobacter pylori and certain Klebsiella pneumonia strains interact with DC-SIGN through LPS that contain Lex and mannose structures, respectively (49). Mycobacterium tuberculosis interacts with DC-SIGN on DCs via the mannose cap of the cellwall component ManLAM (49, 95). Parasites such as Leishmania amastigotes and Schistosoma mansoni are recognized by DC-SIGN through the mannosecapped surface lipophosphoglycan (49, 96) and the Lex-positive soluble egg antigen (50), respectively, whereas the specific structure for fungus Candida albicans

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is not yet identified (97). In conclusion, a large panel of pathogens are primarily captured by DCs through binding to the DC-specific C-type lectin DC-SIGN.

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DC-SIGN: A RECEPTOR TO ALLOW VIRAL DISSEMINATION In contrast to CD4, DC-SIGN does not function as a classical HIV-1 entry receptor (80) but acts as an HIV-1 transreceptor that binds HIV-1 and transmits the virus very efficiently to neighboring permissive target cells (80). The presence of DC-SIGN+ DCs in mucosal tissues and DC-SIGN+ DC precursors in blood that efficiently transmit HIV-1 to T cells (98) makes DC-SIGN a candidate to be a key molecule in HIV-1 dissemination both after sexual transmission and through blood contamination (99, 100). DC-SIGN not only captures and transmits HIV-1, but it also enhances T cell infection because at low virus titers, CD4/CCR5-expressing cells are not detectable as being infected by HIV-1 without the assistance of DCSIGN in trans (80). Conditions in which the number of HIV-1 particles is limiting likely occur shortly after infection in vivo. This suggests that DC-SIGN may not only be required for HIV-1 transmission from mucosa to lymphoid tissues, but also for efficient infection of T cells. Neutralization of the pH within the HIV-1-containing compartments or prevention of internalization by deletion of the DC-SIGN cytoplasmic region abrogates DC-SIGN-mediated enhanced transinfection of T cells (93). This indicates that the internalization of the infectious HIV-1 particle is essential for transinfection of T cells. The clathrin-dependent sorting pathway likely mediates DC-SIGN endocytosis and recycling through recognition of the di-leucin motif. Clathrinindependent pathways may additionally be used during virus-induced DC-SIGN internalization. It is presently unclear whether intact HIV-1 virions escape targeting to lysosomes, as was described for other internalized DC-SIGN-ligands (13), and how these virions are protected against full processing. Whereas DC-SIGN-bound ligands are internalized for processing in lysosomal compartments, HIV-1 bound to DC-SIGN is remarkably stable and remains infective for prolonged periods (Figure 1) (80). Enzymatic digestion of cell surface–bound HIV-1 demonstrated that HIV-1 is protected and probably hides within cellular compartments close to the cell membrane without being degraded. An immunofluorescence study by Kwon et al. has demonstrated that HIV-1 is indeed internalized upon binding to DC-SIGN into nonlysosomal acidic organelles (93). In mature DCs, DC-SIGN is targeted to early endosomal compartments, in which HIV-1 would be protected against degradation (13), suggesting that maturation of DCs by HIV-1 may lead to its altered internalization. Finding a way to override this mechanism and to target internalized DC-SIGN-HIV complexes to lysosomes would facilitate HIV-1 processing in DCs, and it would enhance specific anti-HIV-1 immune responses while reducing infection of T cells (Figure 1) (13, 93).

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At high concentrations, HIV-1 can infect DCs in cultures that coexpress CD4 and chemokine receptors (57, 101, 102). HIV-1 can replicate in immature as well as in mature DCs that interact with T cells (82, 103). In particular, the initial quantity of virus that enters the mucosal tissues may be decisive in whether DCs become infected by HIV-1 or whether the virus is captured for efficient transinfection of T cells (80). The Nef protein of HIV-1 appears to be crucial for DC–T cell binding (104). In addition, Nef can interact with the cell-sorting machinery to downregulate expression levels of CD4 and MHC class I and thus facilitate immune evasion (101). Expression of Nef in immature DCs results in a redistribution of DC-SIGN to the cell surface, thus reducing DC-SIGN internalization in favor of cell-surface expression and facilitating increased cell adhesion and virus transmission to T cells (82). Redistribution of DC-SIGN requires the di-leucine motif in the cytoplasmic tail of DC-SIGN, as well as a di-leucine motif in Nef, indicating that Nef interferes with the recognition of DC-SIGN by the sorting machinery (82). Recently, other CLRs, such as Langerin and MR, were shown to bind HIV gp120 through recognition of mannose-containing carbohydrates present on HIV gp120 (105–108). However, only the MR has been shown to capture and transmit HIV-1 to permissive T cells similar to DC-SIGN (109). Interestingly, HIV bound to the MR on macrophages has a lower half-life than free HIV-1, and no transmission occurred beyond 24 h after initial capture of the virus (109). The finding that the longevity of HIV-1 when captured by DC-SIGN exceeds five days indicates that the HIV-1 internalization routes are different for the MR and DC-SIGN. On monocyte-derived immature DCs, DC-SIGN is the major HIV-1 receptor despite coexpression of the MR (80). It will be interesting to find out whether different subsets of DCs expressing different arrays of CLRs handle HIV-1 differently, leading either to immune escape and HIV dissemination or to immune activation through processing and presentation of the virus.

CLR AND TLR CROSS TALK Nonviral pathogens also target CLRs to infect DCs (89–90, 96). Most striking is that several pathogens subvert DC-SIGN function to escape immune surveillance by a mechanism other than HIV-1 (110). Mycobacterium tuberculosis is a potent inducer of T helper 1 (Th1)-polarized immune response, and mycobacterial components have often been shown to stimulate expression of costimulatory molecules and IL-12 production in DCs through TLR2 and TLR4 triggering. An immunocompetent host controls infection with M. tuberculosis, yet complete eradication of the pathogen does not occur. When the immune response is impaired, active disease can develop, normally through reactivation of quiescent organisms or in some cases through reinfection. Although alveolar macrophages are the primary targets for infection by mycobacteria, DCs are important for activation of the cellular immune response (111, 112). M. tuberculosis and M. bovis bacillus Calmette-Gu´erin (BCG) strongly bind to DC-SIGN

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through their mannose-capped cell-wall component lipoarabinomannan (ManLAM) (15, 95). ManLAM is abundant in slow-growing mycobacteria comprising virulent species such as M. tuberculosis and M. leprea. AraLAM, which is abundant in fast-growing atypical avirulent mycobacteria such as M. smegmatis, M. fortuitum, and M. chelonae, does not interact with DC-SIGN, indicating that particular virulent strains have adapted to target DC-SIGN (15, 113). DC-SIGN is a major receptor of DC for mycobacteria (15). Although immature DCs also express high levels of the receptors MR, CD11b, and CD11c, which can mediate binding of mycobacteria by macrophages (114, 115), DC-SIGNspecific antibodies, in contrast to MR-specific antibodies, inhibit the interaction of DCs with both M. bovis BCG and ManLAM by more than 80% (15). Captured mycobacteria are targeted to the lysosomal compartment (15, 113), although it is not yet clear whether some mycobacteria can escape degradation in DCs. However, DCs do not support mycobacterial growth due to IL-10-induced reversion of DC maturation (116, 117). The cell-wall component ManLAM, which is considered to be a virulence factor, is also secreted in vivo by macrophages infected with M. tuberculosis (118, 119). This suggests that mycobacteria may specifically secrete ManLAM to interfere with the immune function of bystander DCs. Strikingly, secreted ManLAM from mycobacteria-infected macrophages targets CLRs to alter the immune response through cross talk between CLRs and TLRs (Figure 2B) (13, 15, 120). In particular, binding of the mycobacterial component ManLAM to immature DCs inhibited LPS-mediated IL-12 induction (120). This study suggested that ManLAM binding to the MR on immature DCs interferes with TLR4 signaling. Nigou et al. implicated MR as the main ManLAM-binding C-type lectin on DCs (120). However, recent work shows that ManLAM inhibits LPS-induced DC maturation by interacting with DC-SIGN because LPS-induced DC maturation in the presence of ManLAM is fully restored by inhibiting DC-SIGN-ManLAM interaction with specific antibodies (15). Also, viable M. bovis BCG induced DC maturation (15), probably through TLR2 and TLR4 signaling (121), and as observed with LPS, ManLAM specifically blocked the M. bovis BCG-induced DC maturation (15). The inhibition of DC maturation caused by ManLAM binding to DC-SIGN could be fully restored by antibodies against DC-SIGN (15). This illustrates that DC-SIGN, upon binding ManLAM, delivers a negative signal for M. bovis BCGinduced DC maturation, presumably induced via TLR4 (Figure 2B). Furthermore, ManLAM binding to DC-SIGN induced the production of the anti-inflammatory cytokine IL-10 by LPS-activated DCs (15). The inhibition of DC maturation and the induction of IL-10 may contribute to the virulence of mycobacteria; immature DCs and IL-10-treated DCs are not only less efficient in the stimulation of T cell responses but also induce a state of antigen-specific tolerance (Figure 2B) (122). Thus, pathogen recognition by DC-SIGN may modulate DC-induced immune responses, shifting the balance from immune activation toward impairment of immune responses, which would be beneficial to pathogen survival. How DCSIGN signals are propagated within DCs is not yet clear, but the presence of

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immunoreceptor tyrosine-based activation motifs (ITAMs) in its cytoplasmic tail suggests that DC-SIGN is capable of direct signaling (54). Both DC-SIGN and Dectin-1 contain ITAMs. DCIR contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) (54, 123, 124). The function of these so-called activating or inhibitory signaling motifs is not yet clear, but recent data demonstrate that upon pathogen recognition by CLRs, such as DC-SIGN and Dectin-1, intracellular signaling processes initiated by TLR activation are inhibited (15–17). The C-type lectin Dectin-1, recognized as a receptor for the yeast component zymosan, acts in concert with TLR2/4 to enhance the production of IL-12 and TNFα in DCs, facilitating a Th1 response (16, 17). These studies demonstrated that the cytoplasmic tail of Dectin-1, and in particular the ITAM motif, is involved in enhancing stimulatory capacity. Remarkably, DC-SIGN also contains an ITAM motif, yet when targeted by M. tuberculosis, the immune response is driven toward immunosuppression by the induction of IL-10 and the inhibition of DC maturation. These studies demonstrate that the collaborative recognition of distinct microbial components by different classes of innate immune receptors (CLRs and TLRs) is crucial for orchestrating inflammatory or inhibitory responses. The balance between TLR stimulation and C-type lectin occupation may fine-tune regulatory mechanisms to allow appropriate immune responses. The inflammatory and pathogenic consequence of this recognition is dependent on both the receptor repertoire and the functional cooperation between the signals generated downstream of receptor-ligand interaction. Yet we should not forget that in some pathological situations, the pathogens have evolved to direct the balance toward immune suppression, for instance by the secretion and production of a large quantity of soluble factors that target CLRs such as DC-SIGN (15).

CONCLUDING REMARKS AND FUTURE DIRECTIONS Within the past few years, various CLRs have been identified on DCs. The pattern of CLR expression depends on the DC subset. Whereas CLRs are abundantly expressed by immature DCs in peripheral tissues, the expression of most CLRs is rapidly downregulated upon DC maturation. Although CLRs initially were regarded as scavenger receptors, it is now clear that they bind a variety of antigens via specific recognition of particular carbohydrate profiles with interesting and important consequences. CLR-bound antigens are processed and presented to T cells, thus enhancing antigen presentation and immune activation. Strikingly, in vivo targeting of CLRs induces immune suppression, hinting to an important function of CLRs in the tolerance toward self-antigen. It has been well established that T cells reactive to self-antigen are part of the normal immune repertoire of mice, nonhuman primates, and humans at frequencies comparable to patients with autoimmune diseases. The fact that most of us do not develop autoimmune diseases shows that the autoreactive cells are kept under tight control. As the majority of self-antigens are glycosylated, we postulate that tolerance is maintained by the

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interaction with CLRs on DCs. However, when DCs obtain stimuli that result in maturation, such as upon pathogen recognition by TLR or CD40 triggering, this signaling overrules the tolerizing effects of CLRs. Certain pathogens that can stimulate DCs via TLRs, likely in the presence of CD40 engagement, can break the tolerant state. In an experimental setting, this is modeled when self-antigen is injected in an emulsion with strong bacterial antigens. Under these conditions the mechanisms that keep autoreactive T cells quiescent are broken, and autoimmune diseases develop. The human body uses regulatory T cells (Tregs) to control unwanted immune reactivity (125). Natural Tregs are localized in the thymus and inhibit T cell activation primarily via cell-cell contact, whereas inducible Tregs are distributed over the lymphoid organs and exert their suppressive activity via secretion of cytokines. It has yet to be proven whether DCs that have taken up autoantigen via their CLRs present processed antigen to inducible Tregs and in this way maintain systemic tolerance. It will be very important to understand if all CLRs process antigen in a similar fashion and whether they all contribute to self-tolerance or whether some CLRs may also process antigen to induce antigen-specific immune activation, especially since some CLRs contain ITIM or ITAM motifs. Intriguingly, specific pathogens target CLRs to escape immunosurveillance and to promote their survival by sequestration in DCs and by reducing their powerful antigen-presenting capacities. After HIV-1 was shown to bind DC-SIGN to hide within DCs, the same sophisticated escape mechanism was shown to be exploited by a steadily expanding repertoire of viruses that cause serious diseases in the human population, including CMV, Ebola virus, and Dengue virus. Also, nonviral pathogens may target DC-SIGN to escape immune surveillance. M. tuberculosis targets DC-SIGN to inhibit DC maturation and induce IL-10 production by a mechanism that interferes with TLR signaling. Our present knowledge of the variety of CLRs expressed on DCs, the exact mechanisms via which they exert their functions, and the positive or negative interaction with other receptor families (TLRs) is still very limited. It will be challenging to understand the function of C-type lectins in signaling and communication to other receptors on DCs, such as TLRs. A common feature of pathogens that interact with DC-SIGN is that they cause chronic infections that may persist lifelong, and secondly, that a disturbed Th1/Th2 balance by the pathogens is central to their persistence. Therefore, pathogens that target DC-SIGN may not only infect DCs but also shift the Th1/Th2 balance toward a response in favor of their persistence. The intriguing question arises of whether oligosaccharides on cellular counterstructures allow DC migration to specific sites as well as DC interactions with specific T cell subsets. Future research addressing carbohydrate-recognition profiles by C-type lectins and the regulation of glycosylation on its cellular counterstructures by post-translational modification will provide insight as to how these cell-surface receptors mediate cellular interactions and regulate DC function. Also, understanding the carbohydrate-recognition element present on self-antigens or

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pathogens that regulate the interaction with a specific CLR may have consequences for how the pathogen or antigen is processed by DC.

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ACKNOWLEDGMENTS We thank all former and present members of our group, including our collaborators whose work has helped shape the ideas expressed here. We are grateful to the Netherlands Organisation for Scientific Research (NWO) Pioneer grant 016.036.607 and VENI grant 916.36.009, the AIDS Foundation, the Dutch Digestive Diseases Foundation (MLDS), and the Dutch Cancer Foundation (NKB) for their financial support. The Annual Review of Immunology is online at http://immunol.annualreviews.org

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92. Lin G, Simmons G, Pohlmann S, Baribaud F, Ni HP, et al. 2003. Differential N-linked glycosylation of human immunodeficiency virus and Ebola virus envelope glycoproteins modulates interactions with DC-SIGN and DC-SIGNR. J. Virol. 77:1337–46 93. Kwon DS, Gregorio G, Bitton N, Hendrickson WA, Littman DR. 2002. DCSIGN-mediated internalization of HIV is required for trans-enhancement of T cell infection. Immunity 16:135–44 94. Hong PW, Flummerfelt KB, de Parseval A, Gurney K, Elder JH, Lee B. 2002. Human immunodeficiency virus envelope (gp120) binding to DC-SIGN and primary dendritic cells is carbohydrate dependent but does not involve 2G12 or cyanovirin binding sites: implications for structural analyses of gp120DC-SIGN binding. J. Virol. 76:12855– 65 95. Maeda N, Nigou J, Herrmann JL, Jackson M, Amara A, et al. 2003. The cell surface receptor DC-SIGN discriminates between Mycobacterium species through selective recognition of the mannose caps on lipoarabinomannan. J. Biol. Chem. 278:5513–16 96. Colmenares M, Puig-Kroger A, Pello OM, Corbi AL, Rivas L. 2002. Dendritic cell (DC)-specific intercellular adhesion molecule 3 (ICAM-3)-grabbing nonintegrin (DC-SIGN, CD209), a C-type surface lectin in human DCs, is a receptor for Leishmania amastigotes. J. Biol. Chem. 277:36766–69 97. Cambi A, Gijzen K, de Vries JM, Torensma R, Joosten B, et al. 2003. The C-type lectin DC-SIGN (CD209) is an antigen-uptake receptor for Candida albicans on dendritic cells. Eur. J. Immunol. 33:532–38 98. Engering A, Van Vliet SJ, Geijtenbeek TBH, van Kooyk Y. 2002. Subset of DCSIGN(+) dendritic cells in human blood transmits HIV-1 to T lymphocytes. Blood 100:1780–86

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C-1

Figure 1 Internalization of antigens by different C-type lectins leads to antigen routing to distinct intracellular compartments. The MR rapidly internalizes antigens and detaches from the antigen in early endosomes to cycle back to the cell surface. The antigen is subsequently targeted to the lysosomes. DC-SIGN internalizes antigens to lysosomes to allow loading on MHC class II molecules. HIV-1 interferes with the DC-SIGN internalization pathway to hide within early endosomes in an infectious form. Internalization pathways of CLRs are dependent on their cytoplasmic regions. Many CLRs contain different internalization signals.

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Figure 2 Balanced activation of C-type lectins (CLRs) and Toll-like receptors (TLRs) determines DC differentiation and the resulting immune responses. (A) Recognition of self-antigens by CLRs can lead to a differential outcome of immune response. Targeting of CLRs with self-antigens, in the absence of TLR triggering, leads to processing of antigen, without any DC maturation leading to tolerance induction. During inflammatory responses, TLRs are triggered, and subsequently DCs maturate. When simultaneously self-antigens are captured by CLRs, T cell reactivity against self-antigens is initiated leading to autoimmunity. (B) Cross talk between CLRs and TLRs is essential in finetuning immune responses. Recognition of pathogens such as mycobacteria by the CLR DC-SIGN and TLRs can lead to immune activation when the TLR-signal overrules that of the CLR, and this includes DC differentiation. This can occur when low amounts of pathogens target the CLR. When high concentrations of pathogens target the CLR DCSIGN, the immune tolerizing signals can overrule the TLR-induced signals and inhibit DC differentiation, leading to immune suppression and pathogen survival.

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CONTENTS FRONTISPIECE—Leonard A. Herzenberg and Leonore A. Herzenberg GENETICS, FACS, IMMUNOLOGY, AND REDOX: A TALE OF TWO LIVES INTERTWINED, Leonard A. Herzenberg and Leonore A. Herzenberg SELF- AND NONSELF-RECOGNITION BY C-TYPE LECTINS ON DENDRITIC CELLS, Teunis B.H. Geijtenbeek, Sandra J. van Vliet, Anneke Engering, Bert A. ’t Hart, and Yvette van Kooyk

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TRANSCRIPTIONAL CONTROL OF EARLY B CELL DEVELOPMENT, Meinrad Busslinger

UBIQUITIN LIGASES AND THE IMMUNE RESPONSE, Yun-Cai Liu LIGANDS FOR L-SELECTIN: HOMING, INFLAMMATION, AND BEYOND, Steven D. Rosen

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INTEGRINS AND T CELL–MEDIATED IMMUNITY, Jonathan T. Pribila, Angie C. Quale, Kristen L. Mueller, and Yoji Shimizu

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MULTIPLE ROLES OF ANTIMICROBIAL DEFENSINS, CATHELICIDINS, AND EOSINOPHIL-DERIVED NEUROTOXIN IN HOST DEFENSE, De Yang, Arya Biragyn, David M. Hoover, Jacek Lubkowski, and Joost J. Oppenheim

STARTING AT THE BEGINNING: NEW PERSPECTIVES ON THE BIOLOGY OF MUCOSAL T CELLS, Hilde Cheroutre THE BCR-ABL STORY: BENCH TO BEDSIDE AND BACK, Stephane Wong and Owen N. Witte

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CD40/CD154 INTERACTIONS AT THE INTERFACE OF TOLERANCE AND IMMUNITY, Sergio A. Quezada, Lamis Z. Jarvinen, Evan F. Lind, and Randolph J. Noelle

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THE THREE ES OF CANCER IMMUNOEDITING, Gavin P. Dunn, Lloyd J. Old, and Robert D. Schreiber

AUTOIMMUNE AND INFLAMMATORY MECHANISMS IN ATHEROSCLEROSIS, Georg Wick, Michael Knoflach, and Qingbo Xu THE DYNAMIC LIFE OF NATURAL KILLER CELLS, Wayne M. Yokoyama, Sungjin Kim, and Anthony R. French

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CONTENTS

THE ROLE OF COMPLEMENT IN THE DEVELOPMENT OF SYSTEMIC LUPUS ERYTHEMATOSUS, Anthony P. Manderson, Marina Botto, and Mark J. Walport

DROSOPHILA: THE GENETICS OF INNATE IMMUNE RECOGNITION AND RESPONSE, Catherine A. Brennan and Kathryn V. Anderson RAGS AND REGULATION OF AUTOANTIBODIES, Mila Jankovic,

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Rafael Casellas, Nikos Yannoutsos, Hedda Wardemann, and Michel C. Nussenzweig

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THE ROLE OF SUPPRESSORS OF CYTOKINE SIGNALING (SOCS) PROTEINS IN REGULATION OF THE IMMUNE RESPONSE, Warren S. Alexander and Douglas J. Hilton

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NATURALLY ARISING CD4+

REGULATORY T CELLS FOR IMMUNOLOGIC SELF-TOLERANCE AND NEGATIVE CONTROL OF IMMUNE RESPONSES, Shimon Sakaguchi PHOSPHOINOSITIDE 3-KINASE: DIVERSE ROLES IN IMMUNE CELL ACTIVATION, Jonathan A. Deane and David A. Fruman IMMUNITY TO TUBERCULOSIS, Robert J. North and Yu-Jin Jung MOLECULAR DEFECTS IN HUMAN SEVERE COMBINED IMMUNODEFICIENCY AND APPROACHES TO IMMUNE RECONSTITUTION, Rebecca H. Buckley PHYSIOLOGICAL CONTROL OF IMMUNE RESPONSE AND INFLAMMATORY TISSUE DAMAGE BY HYPOXIA-INDUCIBLE FACTORS AND ADENOSINE A2A RECEPTORS, Michail V. Sitkovsky, Dmitriy Lukashev, Sergey Apasov, Hidefumi Kojima, Masahiro Koshiba, Charles Caldwell, Akio Ohta, and Manfred Thiel

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T LYMPHOCYTE–ENDOTHELIAL CELL INTERACTIONS, Jaehyuk Choi, David R. Enis, Kian Peng Koh, Stephen L. Shiao, and Jordan S. Pober

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IMMUNOLOGICAL MEMORY TO VIRAL INFECTIONS, Raymond M. Welsh, Liisa K. Selin, and Eva Szomolanyi-Tsuda

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CENTRAL MEMORY AND EFFECTOR MEMORY T CELL SUBSETS: FUNCTION, GENERATION, AND MAINTENANCE, Federica Sallusto, Jens Geginat, and Antonio Lanzavecchia CONTROL OF T CELL VIABILITY, Philippa Marrack and John Kappler

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ASTHMA: MECHANISMS OF DISEASE PERSISTENCE AND PROGRESSION, Lauren Cohn, Jack A. Elias, and Geoffrey L. Chupp

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CD1: ANTIGEN PRESENTATION AND T CELL FUNCTION, Manfred Brigl and Michael B. Brenner

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CHEMOKINES IN INNATE AND ADAPTIVE HOST DEFENSE: BASIC CHEMOKINESE GRAMMAR FOR IMMUNE CELLS, Antal Rot and Ulrich H. von Andrian

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INTERLEUKIN-10 AND RELATED CYTOKINES AND RECEPTORS, Sidney Pestka, Christopher D. Krause, Devanand Sarkar, Mark R. Walter, Yufang Shi, and Paul B. Fisher

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INDEXES Subject Index Cumulative Index of Contributing Authors, Volumes 12–22 Cumulative Index of Chapter Titles, Volumes 12–22 Annu. Rev. Immunol. 2004.22:33-54. Downloaded from arjournals.annualreviews.org by HINARI on 09/01/07. For personal use only.

ERRATA An online log of corrections to Annual Review of Immunology chapters may be found at http://immunol.annualreviews.org/errata.shtml

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Annu. Rev. Immunol. 2004. 22:55–79 doi: 10.1146/annurev.immunol.22.012703.104807 c 2004 by Annual Reviews. All rights reserved Copyright ° First published online as a Review in Advance on September 15, 2003

TRANSCRIPTIONAL CONTROL OF EARLY B CELL DEVELOPMENT1

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Meinrad Busslinger Research Institute of Molecular Pathology, Vienna Biocenter, A-1030 Vienna, Austria; email: [email protected]

Key Words Ikaros, PU.1, E2A, EBF, Pax5 ■ Abstract The generation of B-lymphocytes from hematopoietic stem cells is controlled by multiple transcription factors regulating distinct developmental aspects. Ikaros and PU.1 act in parallel pathways to control the development of lymphoid progenitors in part by regulating the expression of essential signaling receptors (Flt3, c-Kit, and IL-7Rα). The generation of the earliest B cell progenitors depends on E2A and EBF, which coordinately activate the B cell gene expression program and immunoglobulin heavy-chain gene rearrangements at the onset of B-lymphopoiesis. Pax5 restricts the developmental options of lymphoid progenitors to the B cell lineage by repressing the transcription of lineage-inappropriate genes and simultaneously activating the expression of B-lymphoid signaling molecules. LEF1 and Sox4 contribute to the survival and proliferation of pro-B cells in response to extracellular signals. Finally, IRF4 and IRF8 together control the termination of pre-B cell receptor signaling and thus promote differentiation to small pre-B cells undergoing light-chain gene rearrangements.

INTRODUCTION The pluripotent hematopoietic stem cell (HSC) with its extensive self-renewal potential regenerates all blood cell types throughout life by differentiating to progenitor cells with gradually restricted developmental potential. An early step in 1

Abbreviations used: bHLH, basic helix-loop-helix; BSAP, B-cell-specific activator protein; CLP, common lymphoid progenitor; CMP, common myeloid progenitor; DN, dominantnegative; EBF, early B cell factor; ELP, earliest lymphocyte progenitor; ETP, early T-lineage progenitor; FL, Flt3 ligand; HAT, histone acetyltransferase; HDAC, histone deacetylase; HMG, high mobility group; HMTase, histone methyltransferase; HSC, hematopoietic stem cell; IgH, immunoglobulin heavy-chain; IgL, immunoglobulin light-chain; MPP, multipotent progenitor; PDZ, postsynaptic density protein, disks large, zonula occludens (this abbreviation is based on the first proteins where this protein-protein interaction domain was identified); RSS, recombination signal sequences; SCF, stem cell factor; SET, Su(var)3-9, Enhancer of zeste, Trithorax (this abbreviation is based on the first proteins where this enzymatic domain was identified); TAD, transactivation domain; TCR, T cell receptor.

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Figure 1 B cell development in the bone marrow. The expression of signaling receptors, the rearrangement status of immunoglobulin genes and the initiation of expression of characteristic cell surface proteins are indicated for successive progenitor cell stages of mouse B-lymphopoiesis. For further details, see references describing the characterization of the different cell types: HSC (hematopoietic stem cell) (1), MPP (multipotent progenitor) (3, 4), ELP (earliest lymphocyte progenitor) (5), ETP (early T-lineage progenitor) (6), CLP (common lymphoid progenitor) (1, 7), CLP-2 (8, 9), B-lymphocytes of fractions A–E (10–12), and CMP (common myeloid progenitor) (2). LIN−, negative for the expression of lineage-specific markers.

hematopoiesis is the commitment of multipotent progenitors (MPP) to either the lymphoid or erythro-myeloid lineages, resulting in the formation of the common lymphoid (CLP) or common myeloid (CMP) progenitors (1, 2) (Figure 1). The loss of long-term self-renewal capacity is accompanied by expression of the tyrosine kinase receptor Flt3 (also known as Flk2) in MPP cells (3, 4). The Flt3+ MPPs subsequently differentiate to the earliest lymphocyte progenitors (ELP), which initiate RAG1 and RAG2 expression and start to undergo DH-JH rearrangements at the immunoglobulin heavy-chain (IgH) locus (5) (Figure 1). The ELP cell is likely to give rise to the recently identified early T-lineage progenitor (ETP) in the thymus (6) and to the CLP in the bone marrow, which is able to develop into four distinct cell types: B, T, NK, and DC cells (1, 7) (Figure 1). Subsequent expression of the B cell marker B220 coincides with differentiation to CLP-2 cells (8, 9), constituting a subset of fraction A cells (10, 11) that enter the B cell pathway upon induction of CD19 expression and complete DH-JH rearrangements at the early pro-B cell stage (fraction B; Figure 1) (10, 12, 13). Productive VH-DJH recombination in late pro-B cells (fraction C) results in cell surface expression of the Igµ proteins as part of the pre-B cell receptor (pre-BCR), which acts as an important checkpoint to control the transition from the pro-B to the pre-B cell stage. Signaling from the pre-BCR promotes allelic exclusion at the IgH locus, stimulates proliferative cell expansion, and induces differentiation to small pre-B cells, which start to recombine immunoglobulin light-chain genes (14). Successful light-chain gene

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rearrangement leads to the emergence of immature IgM+ B cells that emigrate from the bone marrow to peripheral lymphoid organs (14). Signaling via different transmembrane receptors is essential for guiding the differentiation of HSCs along the B cell pathway. Activation of the tyrosine kinase receptor c-Kit by its ligand SCF (stem cell factor) promotes the survival of long-term reconstituting HSCs in vitro (3, 15), although the absence of c-Kit does not affect the survival and engraftment of HSCs in vivo in a viable c-kitW/W (Vickid) mouse strain (16). The CLP and all later stages of B cell development are, however, severely depleted in the bone marrow of adult c-kitW/W mice (16). Similarly, signaling through the Flt3 receptor is required for efficient formation of the CLP and subsequent development of pro-B and pre-B cells, as these cell types are strongly reduced in the absence of the Flt3 ligand (FL) in the bone marrow of FL−/− mouse (17, 18). In contrast, normal numbers of the CLP are generated in γ c−/− mice lacking a functional IL-7 receptor, which is composed of the IL-7Rα protein and the signaling γ c chain (19). The CLP is, however, severely compromised in its ability to differentiate even to the earliest pro-B cell stage in the adult bone marrow of γ c−/−, IL-7Rα −/−, or IL-7−/− mice (19, 20). Consistent with this early developmental block, the lymphoid cytokine IL-7 not only signals pro-B cell survival, but also functions as a differentiation factor to induce B cell development of the CLP (19). Double-mutant flt3−/−IL-7Rα −/− mice entirely lack B-lymphocytes in the bone marrow (21). Likewise, early B cell development is more severely affected in flt3−/−c-kitW/Wv mice compared with single-mutant mice (22). Hence, the c-Kit, Flt3, and IL-7R signaling systems together account for the generation of all B-lymphocytes in the bone marrow of adult mice. In addition to cytokine signaling, a multitude of lineage-restricted transcription factors control B cell development from the HSC to immunoglobulin-secreting plasma cells (23). This review focuses on the transcription factors that regulate early B-lymphopoiesis in the bone marrow.

GENERATION OF LYMPHOID PROGENITORS FROM THE HSC Ikaros Controls the Development of Lymphoid Progenitors Ikaros together with Helios and Aiolos constitute a family of zinc finger transcription factors involved in hematopoietic cell fate decisions (24). These transcription factors form homo- or heterodimers via two C-terminal zinc fingers, while their DNA-binding specificity is determined by the N-terminal zinc fingers (Figure 2a). The Ikaros gene is expressed in all hematopoietic lineages including stem cells and multipotent progenitors (25–27) and gives rise, by alternative splicing, to eight different Ikaros isoforms, some of which lack the DNA-binding domain and thus function as dominant-negative proteins by sequestering members of the Ikaros

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Figure 2 Ikaros and PU.1 control the development of multiple hematopoietic lineages. The functional domains of the longest Ikaros isoform 1 (a) and of PU.1 (b) are shown together with the corresponding consensus DNA-binding sequence, the null phenotype, and known target genes. Genes that have been identified as direct targets of these transcription factors are shown in bold face. The six zinc fingers (F1–F6) and three targeted mutations of the Ikaros gene are indicated. For further explanations, see text with its cited literature.

protein family into inactive heterodimers (28). Targeted deletion of the N-terminal zinc finger exons therefore results in a dominant-negative (DN) Ikaros (Ik) allele, which also interferes with Helios and Aiolos function (29), whereas inactivation of the C-terminal zinc fingers eliminates the dimerization function and thus creates an Ikaros null (−) allele (30) (Figure 2a). IkDN/DN mice fail to generate any B, T, NK, and DC cells, indicating that Ikaros together with its family members are required for the development of all lymphocytes (29, 31). The Ikaros null mutation causes a 30- to 40-fold reduction of the long-term reconstitution activity of HSCs (32), prevents B and NK cell development, and leads to a strong reduction of DC differentiation and to abnormal T-lymphopoiesis in postnatal mice (30, 31) (Figure 2a). These lymphoid-specific defects can be explained by the recent finding that the generation of the CLP is entirely lost, whereas development of the early T-lineage progenitor (ETP) is fairly normal in Ik−/− mice (6). Ikaros also plays an essential

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role within the B-lymphoid lineage, as the development of B cells is arrested at the pro-B to pre-B cell transition in mice homozygous for a hypomorphic IklacZ allele (33) (Figure 2a). At later stages, Ikaros acts in concert with Aiolos (25) to control B cell maturation, proliferation, and germinal center formation (33, 34). The differentiation of erythroid and myeloid cell types is only mildly affected in Ikaros mutant mice (30, 31, 35, 36). The Ikaros null mutation even leads to a relative increase of erythroid and myeloid progenitors in the bone marrow and spleen, in contrast to its pronounced effects on the generation of lymphoid precursor cells (32). Ikaros therefore influences the outcome of early lineage decisions by promoting lymphocyte differentiation at the expense of myeloid development and thus contributes to the commitment of HSCs to the lymphoid lineages (24). At the molecular level, Ikaros acts as an unconventional transcription factor to repress or activate genes by recruiting potent corepressor complexes (containing Sin3 or CtBP) or chromatin remodeling machines (NuRD or SWI/SNF) to its target genes (37–39). Instead of regulating the transcription initiation process itself, Ikaros is thought to function as an epigenetic regulator by either modulating the local chromatin structure (38, 40) or targeting genes to the pericentromeric heterochromatin (41, 42). The GM-CSFRα gene is derepressed in Lin−c-Kitlow progenitors of the Ik−/− bone marrow, suggesting that Ikaros promotes lymphoid cell fates by repressing key myeloid genes (32). On the other hand, Ikaros is essential for activating the c-kit and flt3 genes in HSCs and multipotent progenitors (32). The loss of flt3 transcription and the reduction of c-kit expression are likely to account for the lack of the CLP and its lymphoid progeny in the bone marrow of Ik−/− mice, as the generation of the CLP depends on signaling of both tyrosine kinase receptors (16, 18).

PU.1 is Involved in the Myeloid Versus Lymphoid Lineage Decision PU.1 (Spi-1) is a member of the Ets transcription factor family, which is required for the generation of both the innate and adaptive immune systems (43, 44) (Figure 2b). PU.1 is expressed in hematopoietic stem cells, multipotent progenitors, and all differentiating cells except erythroblasts, megakaryocytes, and T cells (2, 45, 46). PU.1-deficient embryos die around birth and fail to generate myeloid as well as lymphoid cells, whereas erythrocytes and megakaryocytes develop normally in the fetal liver (43, 44, 47). PU.1 is stringently required for the development of macrophages, osteoclast, mast cells, and B-lymphocytes (43, 47–49), while the differentiation of granulocytes, NK, and T cells is delayed and severely affected in the absence of PU.1 (44, 50–52) (Figure 2b). PU.1 appears to act at the level of multipotent myeloid-lymphoid progenitors, which are reduced in the fetal liver of PU.1-deficient embryos (47). The PU.1−/− progenitors can be propagated in vitro in the presence of the multilineage cytokines IL-3, IL-6 and SCF, but fail to respond to the myeloid cytokines M-CSF, G-CSF, GM-CSF, and lymphoid cytokine IL-7 owing to the absence or reduced expression of the corresponding receptors (50, 53)

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(Figure 2b). Hence, PU.1 controls the cytokine-dependent proliferation, survival, and differentiation of multipotent progenitor cells (50). Retroviral reconstitution experiments have implicated PU.1 in the myeloid versus lymphoid lineage decision, as low PU.1 expression induces B cell development in PU.1−/− progenitors, whereas high PU.1 levels suppress the B cell fate and promote instead macrophage differentiation under in vitro culture conditions (54). Hence, graded expression of PU.1 specifies either the myeloid or lymphoid fate of early hematopoietic progenitors. Interestingly, Ikaros is normally expressed in PU.1−/− progenitors (47, 53), suggesting that PU.1 and Ikaros act in parallel pathways to regulate lymphoid development in agreement with the distinct phenotypes of Ik−/− and PU.1−/− mice (Figure 2). The IL-7Rα gene was recently identified as a direct target of PU.1, as it contains a functional PU.1 binding site in its 50 region and fails to be transcribed in PU.1−/− progenitors (53). Moreover, retroviral expression of the IL-7Rα gene alone is sufficient to instruct PU.1−/− progenitors to differentiate into pro-B cells at low efficiency (53). Hence, PU.1 regulates early B cell development, at least in part, by activating the IL-7Rα gene and thus rendering lymphoid progenitors responsive to the pro-B cell differentiation and survival factor IL-7.

TRANSCRIPTIONAL CONTROL OF PRO-B CELL DEVELOPMENT Coordinate Regulation of Pro-B Cell Development and Survival by E2A and EBF Differentiation of the CLP to committed pro-B cells depends critically on the three transcription factors E2A, EBF, and Pax5 (23). The E2A gene codes for the alternative splice products E12 and E47 (55), which together with HEB and E2-2 constitute a family of related basic helix-loop-helix (bHLH) proteins (known as E proteins; Figure 3a). Although the widely expressed E2A proteins normally form heterodimers with tissue-restricted bHLH proteins, they specifically function as homodimers in the B-lymphoid lineage (56). The B-cell-specific homodimerization may be caused by hypophosphorylation (57) or, more likely, by increased expression (58) of the E2A protein at the onset of B-lymphopoiesis and is a possible reason why the B-lymphoid lineage is most severely affected by mutation of the E2A gene. B cell development in E2A−/− mice is arrested at its earliest stage in the absence of DH-JH rearrangements at the IgH locus (59, 60). The few B220+CD43+ cells (fraction A) in the E2A−/− bone marrow may even be precursors of other lineages, as they only express IL-7Rα, Igβ (B29), and immunoglobulin µo transcripts, whereas RAG1, Igα (mb-1), Iµ, λ5, CD19, and Pax5 expression could not be detected in these cells (59, 61). Importantly, B-lymphopoiesis is dependent on the combined dosage of all expressed E proteins, as pro-B cell development is severely affected in the absence of either E12 or E47 (58, 61), whereas it is reduced twofold in mice lacking HEB or E2-2 (62).

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Figure 3 Cooperative activation of B-cell-specific genes by E2A and EBF. (a) The functional domains of E2A (55) and EBF (63) are shown together with the consensus recognition sequences. The E2A isoforms E12 and E47 differ only in the basic helixloop-helix (bHLH) region (55). TAD, transactivation domain. (b) A schematic diagram of the λ5 and mb-1 promoters indicates the arrangements of functional binding sites for the different transcription factors (70, 73).

The early B cell factor (EBF) also forms homodimers and recognizes DNA via an N-terminal domain containing an essential zinc coordination motif (63, 64) (Figure 3a). In contrast to E2A, EBF is specifically expressed in pro-B, pre-B, and B cells within the hematopoietic system (63). Interestingly, the loss of EBF results in a similar arrest of early B cell development, as observed in E2A mutant mice (65). The few B220+CD43+ cells (fraction A) present in the bone marrow of EBF−/− mice contain the IgH gene in germline configuration and express IL7Rα as well as immunoglobulin µo and Iµ transcripts, but fail to transcribe the RAG1, RAG2, Igα (mb-1), Igβ (B29), λ5, VpreB, CD19, and Pax5 genes (65). The similarity of the B cell developmental arrest in E2A and EBF mutant mice strongly suggests that the two transcription factors act in concert to control the earliest phase of B-lymphopoiesis. This concept is supported by the results of three different experiments. First, compound heterozygous E2A+/−EBF+/− mice provide genetic evidence for cooperation between E2A and EBF, as B cell development is arrested at the pro-B cell stage in these mice because of reduced expression of multiple B-lymphoid genes including RAG1 and RAG2 (66). Second, forced expression of E2A or EBF in non-B-lymphoid cell lines activates the expression of similar B-cell-specific genes (67–69). More importantly, E2A and EBF act in

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strong synergy to induce the transcription of the endogenous λ5 and VpreB genes upon ectopic expression in a hematopoietic progenitor cell line (70). Third, detailed molecular analyses demonstrate that E2A and EBF bind to and cooperatively activate the promoters of the λ5 (70, 71), VpreB (72), and Igα (mb-1) (73) genes, whereas so far only EBF was shown to regulate the Igβ (B29) promoter (74) (Figure 3b). Moreover, chromatin immunoprecipitation experiments confirmed a direct interaction of E2A with all four target genes (75). This molecular and genetic evidence indicates that E2A and EBF cooperatively regulate the expression of the surrogate light chain (λ5, VpreB) and signaling (Igα, Igβ) components of the pre-BCR, as well as transcription of the RAG1 and RAG2 subunits of the V(D)J recombinase. None of the identified target genes can account for the early developmental block in E2A−/− and EBF−/− mice. Moreover, the inability to grow E2A- or EBFdeficient progenitors in vitro precludes a systematic search for E2A and EBF target genes. However, the HLH inhibitors of the Id family provide an alternative approach for studying E2A function, as these proteins lack the basic region required for DNA binding and thus act as negative regulators by sequestering the E2A protein into inactive heterodimers (76). Constitutive expression of a B-cell-specific Id1 transgene results in an early developmental block resembling that of E2Adeficient mice (77). Under physiological conditions, the endogenous Id3 gene is rapidly activated in B cell progenitors by TGF-β1, which is a potent inhibitor of lymphocyte growth and survival (78). Retroviral expression of Id3 in pro-B cells also results in the loss of cell viability, suggesting that the control of progenitor cell growth and survival is an essential function of E2A in early B cell development (78). Transgenic expression of the anti-apoptotic Bcl-2 protein is, however, unable to rescue the developmental block in E2A−/− mice, pointing to an additional role for E2A in controlling early differentiation (79). Pro-B cell development is characterized by successive rearrangements of the IgH locus first at the DH-JH segments, followed by VH-DJH recombination. E2A and EBF control the first rearrangement step in part by regulating the expression of RAG1 and RAG2 (59, 65, 66, 69). A more direct role of E2A and EBF in V(D)J recombination was indicated by reconstitution experiments in a human embryonic kidney cell line (80, 81). Upon ectopic expression, the E2A or EBF protein functions in concert with RAG1 and RAG2 to activate DH-JH rearrangements of the endogenous IgH locus in these non-B-lymphoid cells (80). The transactivation function of E2A is essential for inducing these rearrangements and the corresponding germline transcription (80), in agreement with the fact that the immunoglobulin Eµ enhancer with its E2A-binding sites is essential for proper regulation of V(D)J recombination (82, 83). However, not all DH and JH segments are equally accessible for V(D)J recombination, suggesting that the presence of E2A- or EBF-binding sites in the vicinity of each segment determines the local accessibility and thus the rearrangement frequency (81). E2A most likely opens up the local chromatin by using the N-terminal transactivation domain to recruit the SAGA histone acetyltransferase complex to its target sequences (84).

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Circumstantial evidence indicates that E2A may act upstream of EBF in the genetic hierarchy of B cell development. First, fraction A cells of EBF−/− mice express almost normal levels of E2A mRNA (65), whereas EBF transcripts appear to be reduced in E2A−/− bone marrow cells (61). Second, ectopic expression of E2A activates the endogenous EBF gene in a 70Z/3 macrophage cell line in contrast to EBF, which is unable to induce E2A transcription in the same cells (69). Finally, the activity of the EBF promoter seems to depend on a functional E2A-binding site (85).

B-Lineage Commitment by Pax5 (BSAP) The mere activation of B-cell-specific genes and V(D)J recombination by E2A and EBF is not sufficient to commit B cell progenitors to the lymphoid lineage in the absence of Pax5 [also known as B-cell-specific activator protein (BSAP)] (86) (Figure 4a). B cell development is arrested at an early pro-B cell stage in the bone marrow of Pax5−/− mice (87). Pax5−/− pro-B cells, which can be cultured ex vivo in the presence of IL-7 and stromal cells (88), still retain a broad lymphomyeloid potential characteristic of uncommitted progenitors (89, 90). Upon IL-7 withdrawal and appropriate cytokine stimulation, the Pax5−/− pro-B cells are able to differentiate in vitro into functional NK cells, dendritic cells, macrophages,

Figure 4 Dual role of Pax5 in early B cell development. (a) The functional domains and consensus recognition sequence of Pax5 are shown. BSAP, B-cell-specific activator protein; HD, partial homeodomain; ID, inhibitory domain; OP, conserved octapeptide. (b) Pax5 represses lineage-inappropriate genes (such as MPO, Notch1, M-CSFR) and simultaneously activates B-cell-specific genes (such as BLNK, Igα, CD19) at B-lineage commitment (89). MPO, myeloperoxidase.

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osteoclasts, and granulocytes (89). This multilineage potential of Pax5−/− pro-B cells is, however, suppressed by retroviral restoration of Pax5 expression, which rescues development to the mature B cell stage (89). Hence, Pax5 is the critical B-lineage commitment factor that restricts the developmental options of early progenitors to the B cell pathway. After injection into sublethally irradiated mice, the Pax5−/− pro-B cells home to the bone marrow, where they undergo self-renewal and develop into functional cells of all major hematopoietic lineages except for B-lymphocytes (89–91). Although the Pax5−/− pro-B cells share the characteristic features of long-term reconstitution, self-renewal, and multipotency with the HSC (91, 92), they differ from pluripotent stem cells in that they fail to radioprotect lethally irradiated mice. This inability is caused by the different efficiency of Pax5−/− pro-B cells in giving rise to the distinct blood cell types in vivo. Pax5−/− pro-B cells rapidly develop into T-lymphocytes within one week after cell transfer (90), whereas macrophages and granulocytes require 2 to 3 months and erythrocytes 4 to 6 months for their generation (91). However, ectopic expression of myeloid C/EBPα or GATA transcription factors strongly promotes myeloid differentiation of Pax5−/− pro-B cells in vitro as well as in vivo, which indicates that Pax5−/− pro-B cells are lymphoid progenitors with a latent erythro-myeloid developmental potential (93). Pax5 is exclusively expressed within the hematopoietic system from the pro-B to the mature B cell stage (86), raising the question of whether Pax5 is required to maintain B cell identity throughout B-lymphopoiesis. Indeed, conditional Pax5 inactivation leads to loss of the identity and function of mature B cells (94). Cre-mediated gene deletion in committed pro-B cells demonstrated that Pax5 is essential not only to initiate its B-lymphoid transcription program, but also to maintain it in early B cell development (95). As a consequence of Pax5 inactivation, previously committed pro-B cells regain the capacity to differentiate into macrophages in vitro and to reconstitute T cell development in vivo (95). The loss of Pax5 alone is therefore sufficient to reverse B-lineage commitment by converting pro-B cells with a restricted B-lymphoid potential into early progenitors with a broad developmental potential. Committed B-lymphocytes thus retain a surprising degree of epigenetic plasticity. As expected for uncommitted hematopoietic progenitors (96), the Pax5−/− proB cells not only transcribe genes characteristic of the pro-B cell stage (97), but also express genes of other lineage-specific programs (89). At lineage commitment, Pax5 fulfills a dual role by repressing lineage-inappropriate genes and simultaneously activating B-cell-specific genes, which leads to the consolidation of the B-lymphoid gene expression program (89) (Figure 4b). The Pax5-dependent repression of the M-CSFR and Notch1 genes illustrates at the molecular level how developmental options are suppressed in committed B-lymphocytes, as these cells are no longer responsive to the myeloid cytokine M-CSF or to T-cell-inducing Notch1 ligands (89, 98). On the other hand, activated Pax5 target genes code for essential components of the (pre)BCR signaling pathway, including the receptor signaling chain Igα (mb-1) (88, 99), the stimulatory coreceptor CD19 (97,

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100), and the central adaptor protein BLNK (101) (Figure 4b). CD19 and BLNK are critical Pax5 target genes, as B cell development is stringently arrested in CD19−/−BLNK−/− mice at a stage similar to that of Pax5−/− mice (102). Pax5 also facilitates expression of the Igµ chain by controlling the second VH-DJH recombination step of the IgH gene, as rearrangement of the numerous distal VHJ558 genes is reduced 50-fold in Pax5−/− pro-B cells (88), although the proximal VH genes recombine at almost normal frequency (103). Pax5 was recently shown to cooperate with chromatin regulators to induce large-scale contraction of the IgH locus, which promotes long-range VH-DJH recombination by juxtaposition of distal VH genes next to the proximal DHJH-rearranged gene segment (M. Fuxa, J. Skok, & M. Busslinger, unpublished data). In conclusion, Pax5 seems to control B-lineage commitment, at least in part, by shutting down inappropriate signaling systems and by simultaneously facilitating signal transduction from the pre-BCR and BCR, which both execute important checkpoint functions in B cell development. The transcriptional activity of Pax5 is determined by its interaction with distinct partner proteins. For instance, Pax5 is converted from a transcriptional activator to a repressor through interaction with corepressors of the Groucho protein family (104). However, Pax5 requires the cooperation of another Groucho-interacting transcription factor (such as PU.1) to stably recruit Groucho proteins in a contextdependent manner to repressed target genes (105). A second well-studied example is the cooperative binding of Pax5 and Ets proteins to the mb-1 promoter, which results in transcriptional activation (99) (Figure 3b). In this case, the paired domain of Pax5 recruits a subset of Ets proteins to a low-affinity Ets-binding site by directly interacting with the Ets domain (99) and thereby altering its DNA sequence recognition (106). E2A, EBF, and their target genes are normally expressed in Pax5−/− pro-B cells, which demonstrates that Pax5 functions downstream of E2A and EBF in the control of B cell development (88, 97). In contrast, Pax5 expression is reduced in pro-B cells of compound heterozygous E2A+/−EBF+/− mice (66) and can be induced by ectopic expression of E2A or EBF in a 70Z/3 macrophage cell line (69). E2A and EBF are therefore thought to directly regulate the Pax5 gene, although so far there is no conclusive evidence for such a regulation in B-lymphocytes.

Cross-Repression of Lymphoid Pathways The development of NK cells depends on the inhibitory HLH protein Id2, which is specifically expressed in NK cell progenitors where it plays an essential role in controlling commitment to the NK cell lineage (107, 108). Id2−/− mice additionally lack two subsets of DCs, the splenic CD8α + DCs and Langerhans cells, in agreement with the observation that Id2 expression is strongly induced in differentiating DC progenitors (109, 110). Conversely, forced expression of Id2 or Id3 is compatible with in vitro differentiation of human hematopoietic progenitors into DC and NK cells, whereas it efficiently prevents the generation of B-lymphocytes (111, 112). Consequently, DC and NK cell development can take place only if

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Id2 actively suppresses the B cell option of lymphoid progenitors by antagonizing E2A, the first essential regulator of the B-lymphoid lineage (Figure 5). B cell development therefore appears to be the primary or default fate of the CLP in the bone marrow, whereas Id2 functions as a molecular switch to activate the secondary DC and NK cell fates. Early T cell development requires Notch1 signaling, which is activated by Delta and Jagged ligands expressed on stromal cells of the thymus (113). Upon ligand binding, the intracellular domain is cleaved from the Notch1 receptor and then functions as a transcription factor to initiate T-cell-specific gene expression in lymphoid progenitors (113). Notch1 has been implicated in T-lineage specification by gain- and loss-of-function experiments. Retroviral expression of the active intracellular Notch1 domain induces T cell development at the expense of B-lymphopoiesis in hematopoietic progenitors of the bone marrow (114). Likewise, HSCs fail to develop into B cells, but differentiate into CD4+CD8+ T cells upon co-culture with Delta-1-expressing stromal cells (115, 116). In complementary experiments, conditional inactivation of Notch1 in HSCs arrests T cell development at the earliest precursor stage, while simultaneously promoting B cell development in the thymus (117, 118). Hence, lymphoid progenitors in the thymus adopt the default B cell fate in the absence of Notch1 signaling. Notch1 is thought to suppress B-lymphopoiesis by interfering with the transcriptional activity of E2A, although the exact molecular mechanism of the Notch1-E2A antagonism remains to be elucidated (114, 119) (Figure 5). In conclusion, the commitment of lymphoid progenitors to the DC, NK, and T cell lineages relies on a similar strategy for suppressing the primary B cell fate by inactivating the first regulator E2A of the B cell pathway. Interestingly, Pax5 and Notch1 influence the

Figure 5 Transcriptional control and cross-repression of lymphoid pathways. See text for explanations and references.

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B- versus T-lineage choice precisely in the opposite manner, as pan-hematopoietic expression of Pax5 strongly promotes B cell development at the expense of Tlymphopoiesis (98, 120). At the molecular level, Pax5 represses transcription of the Notch1 gene, thereby suppressing the T cell option at B-lineage commitment (98).

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REGULATORS OF THE TRANSCRIPTIONAL RESPONSE TO EXTRACELLULAR SIGNALS LEF1 and Wnt Signaling The survival and proliferation of pro-B cells depends on IL-7 signaling (121, 122). A similar role has been described for Wnt signaling based on targeted inactivation of the HMG box-containing protein LEF1, which regulates the transcriptional response of the canonical Wnt/β-catenin pathway (123). The LEF1 gene is expressed under the control of Pax5 (97) in pro-B cells (123) and is then rapidly repressed in response to pre-BCR signaling (101). Although B cells still develop normally in the absence of LEF1, their number is considerably reduced because of impaired proliferation and increased apoptosis of LEF1−/− pro-B cells (123). Consistent with the notion that LEF1 mediates Wnt signaling, a complementary phenotype is seen in wild-type pro-B cells exposed to the Wnt3A ligand, which induces cell cycle entry and proliferation of these cells (123). Consequently, Wnt signaling has a mitogenic role in early B cell development similar to its self-renewal function in HSCs (124).

Signal-Dependent Activation of Sox4 at the Plasma Membrane Sox4 codes for another HMG box-containing transcription factor that is expressed in early B-lymphopoiesis similar to LEF1 (125). In contrast to the LEF1 mutation, B cell development is stringently arrested at the pro-B to pre-B cell transition in the absence of Sox4 (126). The pro-B cells in Sox4−/− mice are moderately reduced in number, but strongly impaired in their capacity to proliferate in response to IL-7 (126). Paradoxically, however, IL-5 signaling has been shown to stimulate the transactivation potential of Sox4 (127). The PDZ domain-containing adaptor protein syntenin thereby recruits the Sox4 protein directly to the α chain of the IL-5 receptor (127). Sox4 therefore resembles the SMAD and STAT transcription factors with regard to its receptor-proximal activation. IL-5 is unlikely to be the physiological signal for Sox4 activation, as conventional B-lymphocytes develop normally in IL-5Rα −/− mice, whereas the peritoneal B-1 cells are moderately reduced (128). In addition to its IL-5Rα interaction, the adaptor molecule syntenin associates with the cytoplasmic domains of other transmembrane receptors, including syndecans (129) and ephrins (130). Hence, the signaling system that is responsible for syntenin-mediated activation of Sox4 in early B cell development remains to be identified.

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Termination of Pre-BCR Signaling by IRF4 and IRF8 The early regulators E2A, EBF, and Pax5 set up the pre-BCR signaling system during pro-B cell development by controlling the synthesis of all pre-BCR components (λ5, VpreB, Igα, Igβ, and Igµ) and the expression of the central adaptor protein BLNK (see above). In contrast, pro-B cell development proceeds normally in the absence of both IRF4 (Pip) and IRF8 (ICSBP), which belong to the family of interferon regulatory factors (131). B-lymphopoiesis is, however, arrested at the pre-B cell transition in IRF4−/−IRF8−/− mice, as B cell precursors continue to cycle owing to persistent expression and unimpeded signaling of the pre-BCR (131). The double-mutant cells fail to rearrange immunoglobulin light-chain (IgL) genes, do not express the corresponding germline transcripts, and are unable to repress the surrogate light-chain genes λ5 and VpreB in response to pre-BCR signaling (131). Hence, IRF4 and IRF8 together appear to control the termination of preBCR signaling by downregulating λ5 and VpreB expression (131), which results in differentiation to small pre-B cells and initiation of IgL gene rearrangements (132).

EPIGENETIC CONTROL OF B CELL DEVELOPMENT Gene expression is determined not only by the available combination of transcription factors, but also by the structure of the local chromatin, which is the physiological substrate for all nuclear processes including transcription and recombination. The chromatin structure and its accessibility to regulatory factors thus contribute to cell-fate decisions by facilitating the establishment of tissuespecific gene expression patterns that are then epigenetically maintained during multiple rounds of DNA replication and cell division. Below, I discuss two aspects of the rapidly evolving field of epigenetic research: the developmental changes of the chromatin structure at the IgH locus and the role of Ikaros in the epigenetic control of lymphopoiesis.

Developmental Regulation of the Chromatin Structure at the IgH Locus The histone tails on the nucleosome surface are subject to enzyme-catalyzed, posttranslational modifications that, singly or in combination, form a “code” specifying chromatin accessibility and gene expression patterns. These modifications, which include lysine acetylation, lysine and arginine methylation, as well as serine phosphorylation, are not only a means of reorganizing nucleosome structure, but also provide a rich source of epigenetic information (“histone code”), which is read by nonhistone proteins that bind in a modification-sensitive manner to the N-terminal histone tails (133, 134). Histone acetylation is a characteristic feature of open, transcriptionally competent chromatin and is determined by the opposing activities of histone acetyltransferases (HATs) and deacetylases (HDACs). In contrast, the more permanent methylation of specific lysine residues (in particular lysine 9

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of histone H3) has been associated with repressive chromatin and is introduced by SET domain-containing histone methyltransferases (HMTases) (133). These histone-modifying enzymes are components of large coactivator (HATs) or corepressor (HDACs and HMTases) complexes that are recruited to target genes by specific transcription factors (133, 135, 136). V(D)J recombination of immunoglobulin and T cell receptor (TCR) genes is developmentally controlled by enhancers that regulate the differential accessibility and germline transcription of specific gene segments prior to rearrangement (137). As predicted by the accessibility hypothesis, V(D)J rearrangement must be preceded by the acquisition of an open chromatin structure, which allows RAG proteins to recognize and cleave DNA at the recombination signal sequences (RSS) (137). Analysis of the TCRα/δ locus has unequivocally demonstrated that enhancer activity imparts developmentally regulated, long-range changes in acetylation of histone H3 and that the H3 acetylation status is tightly linked to V(D)J recombination (138). During B cell development, the IgH locus is activated in discrete, independently regulated domains at the chromatin level. A 120-kb region encompassing the D, J, and Cµ gene segments is first hyperacetylated at histones H3 and H4 in early pro-B cells (139). Following DH-JH recombination, the chromatin of the JH-proximal VH genes also becomes acetylated, whereas IL-7 signaling is required for acetylation of the JH-distal VHJ558 genes (139). Interestingly, acetylation is narrowly confined to the VH gene segments, their promoters, and RSS elements, which indicates local recruitment of HAT complexes by DNA sequence-specific regulators controlling VH gene transcription (140). As IL-7Rα expression is downregulated in response to pre-BCR signaling (101), the unrearranged VHJ558 genes revert to a less accessible, hypoacetylated chromatin state in pre-B cells (141). Consequently, the loss of IL-7-mediated hyperacetylation seems to contribute to allelic exclusion of the IgH locus in small pre-B cells (141). Surprisingly, histone acetylation of VH genes is not sufficient to facilitate VHDJH recombination, as the acetylated distal VHJ558 genes are rearranged with only low efficiency in pro-B cells lacking the HMTase Ezh2 (142). The Ezh2 protein as part of a large Polycomb complex methylates lysine 27 of histone H3, although the specific regions characterized by an increase in this methylation mark have not yet been mapped within the VH gene cluster of pro-B cells (142). Hence, the rearrangement of distal VHJ558 genes critically depends on chromatin changes that are induced by both histone acetylation as well as methylation.

Epigenetic Control of Lymphopoiesis by Ikaros Proteins Although Ikaros is a key regulator of lymphoid cell fates (Figure 2a), it does not function as a conventional transcription factor, but instead is the prototype of a novel class of chromatin regulators (24, 143). The nuclear periphery and pericentromeric heterochromatin are the two major transcriptionally repressive compartments of the nucleus that are important for propagating the inactive state of genes in hematopoietic cells (41, 144). While the IgH loci are preferentially located at the nuclear periphery in nonexpressing cells (144), other transcriptionally

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silent genes of B- and T-lymphocytes are associated with pericentromeric heterochromatin (41, 145), which is enriched in modifiers of repressive higher-order chromatin (133, 134). In cycling cells, the Ikaros protein colocalizes with silent genes at pericentromeric regions and is therefore thought to play an essential role in heritable gene silencing by directly recruiting repressed target genes to pericentromeric foci (41, 143, 145). Consistent with this hypothesis, the Ikaros protein is present in multimeric complexes (146) that may bind simultaneously to target genes and pericentromeric repeat sequences (42). In quiescent cells, the Ikaros protein is diffusely distributed throughout the nucleus (145, 147), and silent genes are not associated with pericentromeric heterochromatin (145). Mitogenic stimulation of resting lymphocytes leads to a rapid increase and accumulation of Ikaros at pericentromeric clusters (145, 147) and concomitant repositioning of inactive genes to these foci (145). Consistent with a role for Ikaros in gene silencing is the fact that Ikaros sets the threshold for B and T cell activation and thus regulates the proliferative expansion of mature lymphocytes in response to antigen receptor engagement (33, 147). A decrease or loss of Ikaros expression leads to T cell hyperproliferation and lymphomagenesis, indicating that Ikaros functions as a tumor suppressor by controlling cell cycle entry, DNA replication, and stable chromosome propagation (30, 147). Ikaros also has the potential to activate genes, although it is unable to stimulate transcription by itself (148). Instead, Ikaros is an integral component of two higher-order chromatin remodeling complexes, which function to promote a dynamic equilibrium between open and closed chromatin states (38, 149). The more abundant Ikaros-NuRD complex contains 10 to 12 Ikaros molecules together with HDAC1, HDAC2, and the ATPase Mi-2β; is active in chromatin remodeling as well as histone deacetylation; and is recruited to pericentromeric heterochromatin in activated lymphocytes (38). In contrast, the less abundant Ikaros-SWI/SNF complex is excluded from heterochromatin (38) and may contain the Sin3 corepressor together with its associated HDAC activities (37, 150). A role for Ikaros in genespecific targeting of chromatin remodeling machines has recently been suggested for the regulation of CD8α. In immature T cells, Ikaros functions as an activator of the CD8α gene by binding to upstream regulatory sequences, where the Ikarosassociated remodeling activity is thought to open up the local chromatin, thus enabling transcriptional activators to access their sites (40). In conclusion, Ikaros is an essential component of functionally diverse chromatin-remodeling networks.

EPILOGUE To date, we may not yet know all regulators of the transcriptional network controlling early B cell development. For instance, a novel zinc-finger transcription factor, Bcl11a (Evi9), was recently shown to play an essential role in early B-lymphopoiesis (151). Most of the known transcription factors are also involved in the development of other organs, leading to embryonic or postnatal lethality of the corresponding mutant mice. Conditional gene inactivation will be required for

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a more detailed analysis of the B-lymphoid function of these regulators. Moreover, the critical target genes causing the early B cell developmental arrest in mutant mice still need to be identified for most transcription factors. In addition, the characterization of B-cell-specific enhancers and associated DNA-binding factors of individual transcription factor genes will identify important upstream regulators, which in turn will provide further insight into the regulatory network of early B cell development. Finally, there is an urgent need to learn more about the epigenetic control of B-lymphopoiesis. ACKNOWLEDGMENTS I thank C. Bonifer, A. Rolink, L. Klein, J. Skok, and T. Jenuwein for critical reading of the manuscript and members of the Busslinger laboratory for helpful discussions. This work was supported by Boehringer Ingelheim and in part by the Austrian Industrial Research Promotion Fund. The Annual Review of Immunology is online at http://immunol.annualreviews.org

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CONTENTS FRONTISPIECE—Leonard A. Herzenberg and Leonore A. Herzenberg GENETICS, FACS, IMMUNOLOGY, AND REDOX: A TALE OF TWO LIVES INTERTWINED, Leonard A. Herzenberg and Leonore A. Herzenberg SELF- AND NONSELF-RECOGNITION BY C-TYPE LECTINS ON DENDRITIC CELLS, Teunis B.H. Geijtenbeek, Sandra J. van Vliet, Anneke Engering, Bert A. ’t Hart, and Yvette van Kooyk

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TRANSCRIPTIONAL CONTROL OF EARLY B CELL DEVELOPMENT, Meinrad Busslinger

UBIQUITIN LIGASES AND THE IMMUNE RESPONSE, Yun-Cai Liu LIGANDS FOR L-SELECTIN: HOMING, INFLAMMATION, AND BEYOND, Steven D. Rosen

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INTEGRINS AND T CELL–MEDIATED IMMUNITY, Jonathan T. Pribila, Angie C. Quale, Kristen L. Mueller, and Yoji Shimizu

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MULTIPLE ROLES OF ANTIMICROBIAL DEFENSINS, CATHELICIDINS, AND EOSINOPHIL-DERIVED NEUROTOXIN IN HOST DEFENSE, De Yang, Arya Biragyn, David M. Hoover, Jacek Lubkowski, and Joost J. Oppenheim

STARTING AT THE BEGINNING: NEW PERSPECTIVES ON THE BIOLOGY OF MUCOSAL T CELLS, Hilde Cheroutre THE BCR-ABL STORY: BENCH TO BEDSIDE AND BACK, Stephane Wong and Owen N. Witte

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CD40/CD154 INTERACTIONS AT THE INTERFACE OF TOLERANCE AND IMMUNITY, Sergio A. Quezada, Lamis Z. Jarvinen, Evan F. Lind, and Randolph J. Noelle

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THE THREE ES OF CANCER IMMUNOEDITING, Gavin P. Dunn, Lloyd J. Old, and Robert D. Schreiber

AUTOIMMUNE AND INFLAMMATORY MECHANISMS IN ATHEROSCLEROSIS, Georg Wick, Michael Knoflach, and Qingbo Xu THE DYNAMIC LIFE OF NATURAL KILLER CELLS, Wayne M. Yokoyama, Sungjin Kim, and Anthony R. French

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THE ROLE OF COMPLEMENT IN THE DEVELOPMENT OF SYSTEMIC LUPUS ERYTHEMATOSUS, Anthony P. Manderson, Marina Botto, and Mark J. Walport

DROSOPHILA: THE GENETICS OF INNATE IMMUNE RECOGNITION AND RESPONSE, Catherine A. Brennan and Kathryn V. Anderson RAGS AND REGULATION OF AUTOANTIBODIES, Mila Jankovic,

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Rafael Casellas, Nikos Yannoutsos, Hedda Wardemann, and Michel C. Nussenzweig

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THE ROLE OF SUPPRESSORS OF CYTOKINE SIGNALING (SOCS) PROTEINS IN REGULATION OF THE IMMUNE RESPONSE, Warren S. Alexander and Douglas J. Hilton

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REGULATORY T CELLS FOR IMMUNOLOGIC SELF-TOLERANCE AND NEGATIVE CONTROL OF IMMUNE RESPONSES, Shimon Sakaguchi PHOSPHOINOSITIDE 3-KINASE: DIVERSE ROLES IN IMMUNE CELL ACTIVATION, Jonathan A. Deane and David A. Fruman IMMUNITY TO TUBERCULOSIS, Robert J. North and Yu-Jin Jung MOLECULAR DEFECTS IN HUMAN SEVERE COMBINED IMMUNODEFICIENCY AND APPROACHES TO IMMUNE RECONSTITUTION, Rebecca H. Buckley PHYSIOLOGICAL CONTROL OF IMMUNE RESPONSE AND INFLAMMATORY TISSUE DAMAGE BY HYPOXIA-INDUCIBLE FACTORS AND ADENOSINE A2A RECEPTORS, Michail V. Sitkovsky, Dmitriy Lukashev, Sergey Apasov, Hidefumi Kojima, Masahiro Koshiba, Charles Caldwell, Akio Ohta, and Manfred Thiel

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T LYMPHOCYTE–ENDOTHELIAL CELL INTERACTIONS, Jaehyuk Choi, David R. Enis, Kian Peng Koh, Stephen L. Shiao, and Jordan S. Pober

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IMMUNOLOGICAL MEMORY TO VIRAL INFECTIONS, Raymond M. Welsh, Liisa K. Selin, and Eva Szomolanyi-Tsuda

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CENTRAL MEMORY AND EFFECTOR MEMORY T CELL SUBSETS: FUNCTION, GENERATION, AND MAINTENANCE, Federica Sallusto, Jens Geginat, and Antonio Lanzavecchia CONTROL OF T CELL VIABILITY, Philippa Marrack and John Kappler

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ASTHMA: MECHANISMS OF DISEASE PERSISTENCE AND PROGRESSION, Lauren Cohn, Jack A. Elias, and Geoffrey L. Chupp

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CD1: ANTIGEN PRESENTATION AND T CELL FUNCTION, Manfred Brigl and Michael B. Brenner

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CHEMOKINES IN INNATE AND ADAPTIVE HOST DEFENSE: BASIC CHEMOKINESE GRAMMAR FOR IMMUNE CELLS, Antal Rot and Ulrich H. von Andrian

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INTERLEUKIN-10 AND RELATED CYTOKINES AND RECEPTORS, Sidney Pestka, Christopher D. Krause, Devanand Sarkar, Mark R. Walter, Yufang Shi, and Paul B. Fisher

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INDEXES Subject Index Cumulative Index of Contributing Authors, Volumes 12–22 Cumulative Index of Chapter Titles, Volumes 12–22 Annu. Rev. Immunol. 2004.22:55-79. Downloaded from arjournals.annualreviews.org by HINARI on 09/01/07. For personal use only.

ERRATA An online log of corrections to Annual Review of Immunology chapters may be found at http://immunol.annualreviews.org/errata.shtml

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Annu. Rev. Immunol. 2004. 22:81–127 doi: 10.1146/annurev.immunol.22.012703.104813 c 2004 by Annual Reviews. All rights reserved Copyright ° First published online as a Review in Advance on September 15, 2003

UBIQUITIN LIGASES AND THE IMMUNE RESPONSE Yun-Cai Liu Annu. Rev. Immunol. 2004.22:81-127. Downloaded from arjournals.annualreviews.org by HINARI on 09/01/07. For personal use only.

Division of Cell Biology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121; email: [email protected]

Key Words ubiquitination, HECT, RING, lymphocyte, immunity ■ Abstract Ubiquitin (Ub)-protein conjugation represents a novel means of posttranscriptional modification in a proteolysis-dependent or -independent manner. E3 Ub ligases play a key role in governing the cascade of Ub transfer reactions by recognizing and catalyzing Ub conjugation to specific protein substrates. The E3s, which can be generally classified into HECT-type and RING-type families, are involved in the regulation of many aspects of the immune system, including the development, activation, and differentiation of lymphocytes, T cell–tolerance induction, antigen presentation, immune evasion, and virus budding. E3-promoted ubiquitination affects a wide array of biological processes, such as receptor downmodulation, signal transduction, protein processing or translocation, protein-protein interaction, and gene transcription, in addition to proteasome-mediated degradation. Deficiency or mutation of some of the E3s like Cbl, Cbl-b, or Itch, causes abnormal immune responses such as autoimmunity, malignancy, and inflammation. This review discusses our current understanding of E3 Ub ligases in both innate and adaptive immunity. Such knowledge may facilitate the development of novel therapeutic approaches for immunological diseases.

INTRODUCTION Highly relevant to the immune system, ubiquitin (Ub) was first discovered as a lymphocyte differentiation-promoting factor close to three decades ago (1). The small peptide of 76 amino acids is highly conserved during evolution and forms a compact globular structure with C-terminal glycine residues protruding from the main body of the protein. Ub conjugation to the protein substrate, or ubiquitination, involves a cascade of enzymatic reactions (reviewed in Reference 2): Ub is first activated by a Ub-activating enzyme or E1 and forms a highly active thioester bond between the C-terminus glycine residue of Ub and an active cysteine group of E1; the activated Ub can then be transferred to one of a family of Ub conjugating enzymes (Ubc) or E2s via a similar thioester linkage; an E3 Ub protein ligase is required for the covalent isopeptide bond formation between Ub and the εamino group of lysine residues in the substrate protein; E3s recruit both Ub-loaded E2s and the target protein, and they facilitate the transfer of Ub from E2 to the substrate and also govern the formation of a poly-Ub chain on the substrate via 0732-0582/04/0423-0081$14.00

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an isopeptide bond between the ε-amino group of lysine residues on adjacent Ub molecules. Thus, the E3s are the critical components that provide specificity to the Ub conjugation system by direct and specific interaction with the substrate (3, 4). It is becoming increasingly clear that protein ubiquitination is involved in a wide array of cellular processes, including cell-cycle control, signal transduction, transcriptional regulation, DNA repair, receptor downregulation, antigen presentation, and apoptosis (2). Abnormalities in the Ub system have been shown to cause pathological responses, including malignant transformation, and several genetic diseases (5). Ub tagging to intracellular substrates serves as a marker that can be recognized by the 26S proteasome for degradation to remove excessive cellular responses (2), whereas Ub conjugation to cell surface receptors causes their downmodulation through the endosomal-lysosomal pathway (6). Recently, it has been appreciated that protein ubiquitination represents an important means of posttranscriptional modification in a proteolysis-independent manner, and like protein phosphorylation on tyrosine or serine/threonine residues of signaling molecules, Ub conjugation has been manifested in Ub-dependent protein processing, proteinprotein interaction, subcellular translocation, kinase activation, and transcriptional activation, as is discussed in this review. Most of the multicellular organisms are capable of defending themselves from infectious intruders by mounting the immune response through a mechanism of innate immunity (7). The innate immune response is induced by the binding of the pattern-recognition receptors in the host to the pathogen-derived substances. Triggering of these germline-encoded receptors allows the host to destroy the invading microbes as well as to initiate intracellular signaling events leading to the gene transcription of antimicrobial molecules or proinflammatory cytokines. In higher eukaryotes, microbial infection can also mount adaptive immune response through somatic DNA rearrangement to produce pathogen-specific receptors such as the B cell antigen receptor (BCR) on B cells and the T cell antigen receptor (TCR) on T cells or produce pathogenic antigen-specific antibodies. The innate immunity, as the initial defense against the pathogen, can modulate adaptive immune response by providing processed antigens or by inducing the expression of costimulatory molecules to the T cells (8). Evidence accumulated over the past decade clearly indicates that E3 Ub ligases and/or proteasomal-dependent degradation are involved in the regulation of both innate and adaptive immune responses. The intracellular signaling pathways that are activated by receptor triggering of both innate and adaptive immune systems share some similarities, such as the activation of nuclear factor-κB (NF-κB). For example, it is well known that the lipopolysaccharide of Gram-negative bacteria or the proinflammatory cytokine, interleukin-1 (IL-1), induces the activation of NFκB via a critical step of ubiquitination and subsequent degradation of the inhibitor of kB (IκB) (9). More recent data suggest that E3 ligases functioning in IL-1- or lipopolysaccharide-induced signaling events are also involved in the regulation of antigen receptor-mediated signaling pathways (10). Another well-known example of the Ub system in immune regulation is the proteasomal-dependent processing

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of antigenic peptides in antigen-presenting cells (11). Given that the list of newly identified E3 Ub ligases emerges so rapidly, it is almost impossible to discuss each and every E3 ligase and its potential roles in the immune regulation. In this review, I first give a description of the Ub conjugation system and then introduce several examples of E3s that have been directly or indirectly implicated in the immune response, in the hope of casting a brick to attract jade.

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THE UB CONJUGATION SYSTEM The E1 and E2s Ub conjugation is initiated by the activation of Ub at the C-terminal glycine residue in an ATP-dependent manner by the E1 Ub activating enzyme. A single E1 enzyme in humans and the yeast is required for the catalysis of the Ub conjugation cascade (2). E1 is essential for cell viability because deletion of E1 is lethal in yeast (12). A temperature-sensitive inactivation of E1 in mammalian cells causes reduced antigen presentation (13), an early demonstration that the Ub pathway is involved in the immune system. In contrast to E1, there are 13 isoforms of E2s in yeast and more than 20 E2s in humans. All E2s contain a core structure of ∼150 amino acids, called the Ubc domain. In the core structure, there are interfaces for the interaction with Ub. More importantly, the active cysteine in the core structure forms a thioester bond with the activated Ub glycine residue transferred from the E1 (3). Unlike other Ubc E2s, Ubc9 does not form a thioester bond with Ub, but with a Ub-like molecule, small Ub-like modifier (SUMO) (14, 15). SUMO-conjugated protein substrates are not degraded by the 26S proteasome. Protein sumoylation has been implicated in protein stability enhancement, protein-protein interaction, subcellular translocation, and transcriptional control (16). In addition to the classical Ubc E2s, there are noncanonical Ub E2 variants (UEVs). One such UEV is the yeast MMS2, which resembles conventional E2s but does not contain the catalytically active site to form a thioester bond with the activated Ub (17). MMS2 forms a complex with a conventional E2, Ubc13, which is implicated in postreplicative DNA repair. Interestingly, the MMS2-Ubc13 complex is involved in a novel assembly of poly-Ub chains via the lysine-63 in the Ub molecule, instead of the usual lysine-48-linked chain formation. Uev1, a mammalian MMS2 homologue, also forms a complex with Ubc13 and is involved in lysine-63-linked polyubiquitination in the NF-κB signaling pathway (18). Another well-studied UEV is the tumor susceptibility gene 101 (Tsg101), which was originally identified as a tumor suppressor whose aberrant expression is associated with many human malignancies (19). It has a structure very similar to conventional E2s, but it lacks the catalytic cysteine residue for Ub conjugation (20). Tsg101 is involved in the traffic of endocytosis by delivering ubiquitinated cargo proteins into multivesicular bodies (20) and in the budding of viral particles from virus-infected cells (21).

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The E3 Ub Ligases The E3 Ub ligases play a critical role in the Ub conjugation cascade by recruiting Ub-loaded E2, recognizing specific substrates, and facilitating the Ub transfer from the E2 to the lysine residues of the substrate. Compared with only dozens of E2s, a search of the gene database reveals that there are hundreds of E3s. The E3s are present in the form of either a single protein or multisubunit complexes. According to the homology of the amino acid sequences in the E2-binding domain, E3s can be generally divided into two large groups: the homology to the E6associated protein carboxyl terminus (HECT) domain-containing E3s, and the really interesting new gene (RING) domain-containing E3s. In the RING-type E3s, there are single subunit E3s and multisubunit E3s. More recently, RINGlike domain-containing E3 ligases have been identified, such as the PIAS family SUMO ligases, the plant homeodomain (PHD) domain-containing E3s, and the U-box E3s.

HECT-Type E3 Ligases Studies on human papillomaviruses led to the discovery of the viral E6-associated protein (E6-AP), which forms a complex with the oncogenic E6 to induce the degradation of the p53 tumor suppressor (22). Later on, the same group identified a family of proteins that have a highly conserved region of ∼350 amino acids similar to the C-terminus of E6-AP, named the HECT domain (23). In the Cterminus of the HECT domain, there exists a conserved active cysteine residue, which forms a high-energy thioester bond with Ub and constitutes a necessary step for the Ub transfer to the substrate. Interestingly, E6-AP seems not to be the physiological E3 ligase because it does not induce p53 degradation in HPVuninfected cells (24). Recent studies have demonstrated that Src family kinases are the potential targets for E6-AP (25, 26). Importantly, genetic analysis has linked the disruption of the maternal copy of E6-AP with Angelman syndrome, a genetic neurological disorder (27). E6-AP also acts as a coactivator for steroid hormones through ligase-dependent or -independent mechanisms (28). With the exception of E6-AP, other HECT domain–containing E3 ligases often contain an N-terminal Ca2+-binding, protein kinase C-related C2 domain, followed by multiple WW domains, in addition to the C-terminal HECT domain (29). WW domains derive their name from the presence of two highly conserved tryptophan (W) residues, which are spaced 20–22 amino acids apart. They normally contain 38–40 amino acids in a triple-stranded β sheet and are found in proteins that participate in cell signaling or regulation. These domains are implicated in mediating protein-protein interactions by binding to proline-rich motifs (30) or phosphoserine- and phosphothreonine-containing elements in their binding partners (31). One of the well-studied WW domain–containing HECT-type E3s in mammalian cells is Nedd4, which is implicated in the regulation of the epithelial Na+ channel in the kidney and other tissues, and whose deletion is

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related to the human Liddle’s syndrome, a hereditary form of hypertension (32). The WW domains of Nedd4 associate with a PPXY motif in the channel protein, and mutations of the PPXY motif were found in the patients with Liddle’s syndrome. More relevant to the immune system is the HECT-containing Itch E3 Ub ligase, whose deficiency results in abnormal immunological and inflammatory responses and which is discussed later in this review.

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RING-Type E3 Ligases Compared with the early discovery of HECT-type E3s, the identification of RINGtype E3 ligases is a relatively recent event. RING finger is characterized by the presence of the consensus sequence of C3HC4 (C, cysteine; H, histidine) or C3H2C3, which coordinates two cross-braced Zinc-binding sites (33). Database search revealed that there are hundreds of RING-containing proteins, in contrast to the limited number of HECT-type E3s. Unlike the HECT-type E3s, which have an active cysteine in the HECT domain for the Ub binding and transfer, RING-type E3s do not form a thioester bond with Ub, but rather bring the Ub-loaded E2s and the substrate into proximity, and promote the Ub transfer directly from the E2 to the substrates (34). Depending on whether the RING finger is present in the form of a functional domain in a single protein or in the form of a subunit in a protein complex, the RING-type E3s are subdivided into single protein E3s and multisubunit E3s (3). SINGLE PROTEIN RING-TYPE E3S In this subgroup, the RING finger constitutes a functional portion of a single protein, in which a protein-interaction domain or domains are also present for the substrate recruitment. One of the earliest identified E3s of this subgroup is Cbl. Cbl is a 120 kDa protooncogene product that is comprised of an N-terminal tyrosine kinase–binding (TKB) domain, a RING finger, and C-terminal proline-rich sequences and tyrosine phosphorylation sites (35). Cbl acts as an E3 Ub ligase, whose RING finger recruits Ub-loaded E2, and its TKB domain binds to tyrosine phosphorylated receptor tyrosine kinases (36–38). The crystal structure of Cbl RING-E2 complex further supports a role of Cbl in Ub conjugation, in which the Cbl RING finger forms a shallow grove on to which the two loops of UbcH7 bind (39). More interestingly, the E2-binding grove in the Cbl RING domain is quite similar to that in the HECT domain of E6-AP (40), and UbcH7 uses the same structural elements for interaction with both domains, even though there is no similarity in amino acid sequences between a RING finger and a HECT domain. Another example of the single peptide E3s is MDM2, which binds to the tumor suppressor p53 and promotes its ubiquitination (41). The number of this subgroup of E3s has increased considerably, and I discuss several of them later in this review. MULTISUBUNIT RING-TYPE E3s This subgroup consists of a superfamily of E3s including the SCF (Skp1-Cullin 1-F box protein), the APC (Anaphase-promoting complex), and the VCB (VHL-elongin C/elongin B) (3, 42). All three E3s contains

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an ∼100 amino acid RING finger, Roc1/Rbx1 or Apc11, which together with its binding component, Cullin in the SCF or VCB E3s, or Apc2 in the APC, forms a core enzymatic structure for Ub-charged E2 recruitment. The substrate recognition is mediated via another subunit, which contains binding domains for another E3 component, Skp1, as well as binding domains for the substrate protein. In the SCF complex E3s, the F box proteins are responsible for the substrate recruitment and gene database revealed that there are hundreds of them in the yeast and humans, suggesting the diversity and specificity of these subfamily E3s in substrate targeting. A recent crystal structure study of the SCF complex revealed how these components are coordinated to facilitate Ub transfer from the E2 to a substrate (43), in which Cullin acts as a scaffold to position Rbx1/E2 complex and the Skp1/F box complex in a rigid distance. Such rigidity of the SCF complex may be important for the specific targeting of the lysine residues on a particular substrate. One of the well-characterized F box proteins implicated in the immune regulation is β-tranducin repeat-containing protein (β-TrCP), which binds to several critical molecules in lymphocyte signaling and is described below. Like the SCF complex, the VCB E3 ligase complex is also comprised of multiple components that include Roc1/Rbx1, Cullin 2, the Skp1-like protein elongin C, the Ub-like elongin B, and the substrate recruiting subunit pVHL (44). The pVHL was originally discovered as a protein product of the von Hippel-Lindau tumor suppressor gene, whose inactivation is associated with hereditary blood-vessel tumors in the nervous system and clear-cell kidney cancers (45). pVHL contains two domains, the α domain and the β domain. The α domain binds to elongin C, which forms a complex with Cullin 2 and Roc1 (46, 47). The β domain recognizes a substrate protein, hypoxia-inducible factor-α (HIF-α), and induces its ubiquitination and degradation (48, 49). The interaction between pVHL and HIF-α is regulated by oxygen, which induces hydroxylation of a particular proline residue on HIF-α (50–52). Crystal structure analysis showed that the hydroxyproline in HIF-α inserts into a gap in the pVHL hydrophobic core to form direct contact with the β domain of pVHL (53, 54). HIF-α forms a heterodimer with a constitutively expressed HIF-β subunit to function as a transcription factor central to cellular responses to hypoxia (55). Under normal conditions, HIF-α is hypoxylated and rapidly degraded by pVHLinduced ubiquitination. Under low-oxygen concentrations, HIF-α hydroxylation is inhibited and stabilized. Accumulation of HIF-α causes the gene transcription of several critical cellular factors involved in angiogenesis and glycolysis. Consistent with this notion, HIF is constitutively activated in the kidneys of patients with VHL disease (56), although it remains questionable whether stabilization of HIF-α alone is sufficient for tumorigenesis (57, 58).

PIAS Family SUMO Ligases Recent studies have identified a new family of RING-type E3 ligases, the PIAS (protein inhibitor of activated STAT) family, in catalyzing SUMO conjugation

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(59, 60). The PIAS proteins contain a RING-like domain, in which (unlike the classical C3HC4 or C3H2C3 alignment) the two conserved cysteine residues for zinc binding are replaced with serine and aspartic acid, but it can associate with SUMO-conjugated Ubc9, and it promotes sumoylation to the PIAS-binding proteins such as septins in yeast (61, 62) and p53 in mammalian cells (63). PIASs have also been shown to act as SUMO E3 ligases for c-Jun and androgen receptors (64–66). Interestingly, sumoylation of these transcription factors leads to the repression of the transcriptional activity, although the molecular mechanism for the inhibition is not clear.

PHD Domain-Containing E3 Ligases The PHD or leukemia-associated protein domain consists of ∼60 amino acids, which are characterized by a consensus C4HC3 zinc-binding sequence, distinct from classical arrangement in a RING finger (67). The PHD domain has a structural feature that is very similar to the one in the RING domain, suggesting a role for this domain in the Ub conjugation pathway (68). As an example of mammalian PHDcontaining protein as an E3, MEKK1, a MAPK kinase kinase, exhibits E3 ligase activity and mediates ubiquitination and degradation of downstream targets, Erk1/2 (69). Interestingly, because MEKK1 is also an upstream activator of Erk, demonstration of MEKK1 as a negative regulator of Erk through its E3 ligase activity suggests a novel feedback mechanism for the regulation of this signaling network. In addition, a separate study showed that MEKK1 undergoes self-ubiquitination, which inhibits its kinase activity of its direct downstream substrates, MKK1 and MKK4 (70). The PHD domain is present in more than 400 eukaryotic proteins, many of which are involved in transcriptional regulation (67). The importance of this domain is further underscored by the findings that natural mutations of the PHD domain are implicated in the pathogenesis of human diseases including mental disorders, autoimmune diseases, and the formation of carcinomas (71). Further characterization of these PHD domain–containing proteins will reveal their physiological functions in normal cells.

U-Box E3 Ligases Originally identified as a novel ubiquitination factor, or E4 in yeast, UFD2 (Ub fusion degradation 2) works in conjunction with E1 and E2, and a HECT-type E3 to facilitate longer Ub chain assembly (72). A database search revealed homologues in other eukaryotes, including humans, that contain highly conserved C-terminal ∼100 residues similar to that in UFD2, designated as the U-box (UFD2-homology domain). A later study showed that the U-box of UFD2 and its homologues directly associates with E2s, including Ubc4 and UbcH5C, and the U-box-containing proteins themselves function as a new family of E3 ligases (73). In particular, the C-terminus of heat-shock protein (Hsc70)-interacting protein, CHIP, a mammalian U-box protein, is a cochaperone of heat-shock proteins, Hsc70 or Hsc90,

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and promotes Ub conjugation to the Hscs, or Hsc-capatured unfolded proteins (74, 75). Interestingly, structural modeling of the U-boxes predicts a feature similar to the RING finger (76). Although the U-box lacks the zinc-binding cysteine or histidine residues for the stabilization of the RING finger, it may use salt-bridges and hydrogen bonds to form a RING-like structural scaffold. The aromatic tryptophan resides conserved in the RING finger, which is required for E2 binding (36), is also present in the U-box and is exposed to contribute to E2 binding.

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ITCH E3 LIGASE IN LYMPHOCYTE REGULATION Itch was identified through the study of the agouti locus on mouse chromosome 2, and mutation at this locus results in a wide variety of coat color alterations (77). The agouti protein induces the production of yellow pigment by melanocytes and thus determines the amount of yellow present in the hair. One of these mutations, 18H, which displays a darker coat, causes immunological disorders. The most obvious disorder is ear and skin scarring due to constant itching (thus called itchy mice) starting from 16-week-old or older mice. The mutant mice have enlarged spleens and lymph nodes, possibly due to lymphocyte hyperproliferation. Genetic studies have shown that 18H mutation results from a chromosomal inversion that deletes 18 and 20 bp from the proximal and distal inversion breaks, respectively. This inversion disrupts the expression of agouti and another novel protein, named Itch (78). Subsequent cDNA cloning showed that the Itch gene encodes 854 amino acids with a molecular weight of ∼113 kDa. It consists of an N-terminal protein kinase C-related C2 domain, four WW protein-protein interaction domains, and a C-terminal HECT Ub ligase domain. Itch therefore is a member of the HECT domain-containing E3 Ub protein ligases. The data based on itchy mice clearly suggest a critical role of E3 ligase or ubiquitination in the regulation of the immune system.

Itch in T Cell Differentiation A recent study showed that the thymocyte development in Itch-/- was relatively normal compared to wild-type controls (79). Itch-/- T cells showed slightly enhanced T cell proliferation and IL-2 production upon anti-CD3 engagement. In aging mice, Itch-/- T cells displayed increased cell surface expression of CD69 activation marker, suggesting a chronic activation of T cells in the absence of Itch. Interestingly, increased serum levels of IgG1 and IgE in itchy mice as well as a T helper cell type 2 (Th2)-biased differentiation were observed in itchy mice. The molecular mechanism underlying Itch-mediated T cell differentiation was further explored by using biochemical approaches. Itch was found to associate with Jun-B, through a PPXY motif in Jun-B and the WW domains of Itch, and to promote Jun-B ubiquitination (Figure 1A). Interestingly, Jun-B has been implicated in the gene regulation of Th2 cytokines such as IL-4 (80). In Itch-/T cells, the rate of Jun-B degradation was reduced, in parallel with increased

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nuclear translocation and DNA binding activity of Jun-B. Na¨ıve CD4+ T cells differentiate into Th1 and Th2 effector cells based on their cytokine profiles and distinct functions (81, 82). Whereas Th1 cells produce IL-2 and IFN-γ , Th2 cells produce IL-4 and IL-5. In addition, the differential production of Th1 versus Th2 cytokines plays an important role in determining the immune response to intracellular and extracellular infections. Thus, the data point out a negative role for Itch in Th2 differentiation, which may be causal to the abnormal immunological responses in itchy mice. Annu. Rev. Immunol. 2004.22:81-127. Downloaded from arjournals.annualreviews.org by HINARI on 09/01/07. For personal use only.

c-Jun Ubiquitination and Activation Initiation of eukaryotic gene transcription requires the assembly of a multimolecular complex, including RNA polymerase II, transcription factors, and chromotinmodulating enzymes (83). Transcription factors are normally comprised of a transcription activation domain and a DNA-binding domain. The DNA-binding domain confers specificity by interacting with particular consensus nucleotide sequences, whereas the activation domain stimulates the activity of RNA polymerase II through direct protein-protein interaction (83). Given the critical role for transcription factors in gene expression, it can be assumed that they are tightly regulated by diverse mechanisms such as phosphorylation, translocation, or their own gene expression. One of the emerging mechanisms is Ub-dependent proteolysis, which has been implicated in the regulation of many critical transcription factors, including c-Jun, p53, c-Myc, NF-κB (84). However, our knowledge on the molecular details of how ubiquitination regulates transcription factors remains elusive. The Jun family of transcription factors consists of three members: c-Jun, Jun-B, and Jun-D (85, 86). They heterodimerize with Fos family transcription factors to form activation protein 1 (AP-1) transcription factor, which recognizes a consensus TPA responsive element and is implicated in the gene transcription of diverse cellular processes critical for cell proliferation, cell death, and tumorigenesis. It is particularly pertinent to immune regulation that many cytokine promoters contain AP-1 binding sites, and the AP-1 transcription factor is indeed involved in cytokine production and immune responses (87). c-Jun is one of the earliest identified transcription factors that is regulated by protein ubiquitination (88). Multiubiquitination of c-Jun was demonstrated both in vitro and in vivo, and a delta domain in the transcriptional activation domain was proposed to be responsible for Ub conjugation. Interestingly, this delta domain is missing in v-Jun, which is a transforming form of c-Jun. Thus, ubiquitination of c-Jun and its subsequent degradation by the 26S proteasome is implicated in the control of oncogenesis. Although c-Jun ubiquitination has previously been reported, the E3 Ub ligase that catalyzes Ub conjugation to c-Jun is still unclear. Because both Jun-B and c-Jun, but not Jun-D, contain a PPXY motif, it is possible that Itch is a promising E3 ligase for c-Jun as well. To support this, it was recently observed that Itch indeed induces Ub conjugation to c-Jun (D. Fang & Y.C. Liu, unpublished data). Recent studies have suggested a correlation between the transcription activation domain and proteolysis-dependent degradation (89). Many transcription

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factors such as c-Myc, p53, the viral protein VP16, or even c-Fos or c-Jun contain the signal for Ub-mediated proteolysis in their transcription activation domains (90). More intriguingly, using a fusion containing VP16 transcription activation domain and a bacterial DNA-binding domain of LexA, Salghetti et al. (91) further demonstrated that Ub conjugation to the VP16 transcription activation domain is required to activate transcription. Thus, ubiquitination serves a dual signal in regulating transcription factors, one for activation and another for destruction. The Jun family members are regulated by upstream kinases, and in the case of c-Jun, it is phosphorylated by Jun N-terminal kinase (JNK) at serines 63 and 73 of the transcriptional activation domain, which is required for its activation (86). A previous study demonstrated that phosphorylation of c-Jun by JNK in fact reduces its ubiquitination, thus suggesting an inverse relationship between c-Jun phosphorylation and its degradation (92). The data also call into question the “suicide” model for the regulation of transcriptional activators. Whether Itch-mediated ubiquitination of c-Jun is implicated in c-Jun degradation or its activation is not known at present. Obviously, further detailed function-structural analysis of Itch-mediated ubiquitination of c-Jun and its function is needed.

Itch Regulation of B Cell Development and Activation A potential role of Itch in the regulation of B cells emerges from the studies on Epstein-Barr virus latent membrane protein 2A (LMP2A) (93, 94). LMP2A is a membrane protein expressed on infected human B cells and implicated in lifelong infection with Epstein-Barr virus (95). It contains an N-terminal transmembrane domain, and intracellular consensus ITAM motif, and two highly conserved PPXY motifs. Using the PPXY motif as a probe, two groups isolated WW domaincontaining HECT E3 ligases including Nedd4 and the human Itch homologue, AIP4 (93, 94). It was shown that coexpression of LMP2A and AIP4 can induce Ub conjugation to Lyn and Syk, and the degradation of Lyn (93, 96). It has been known that LMP2A inhibits BCR signaling (95). The link of AIP4 (or other HECT E3s) to LMP2A suggests a novel Ub-dependent mechanism underlying LMP2Amediated regulation of B cell signaling. It should be mentioned that LMP2A can also block BCR signaling by prohibiting BCR from entering membrane rafts (97). In addition, whether AIP4 functions as an E3 ligase for Lyn or Syk only in the presence of LMP2A is not clear. To understand whether Itch deficiency affects B cells in itchy mice, we recently performed a systematic analysis of B cells in the mutant mice (D. Fang & Y.C. Liu, unpublished data). We found that B cell numbers are increased at different stages of B cell development, including those in the bone marrow and spleen of itchy mice. Itch-/- B cells from bone marrow display an enhanced response to interleukin-7 (IL-7) stimulation. Interestingly, the IL-7 receptor α and γ chains contain a consensus PPXY motif that binds directly to the WW domains of Itch, suggesting that Itch may target the IL-7 receptor for ubiquitination and induce its downmodulation. Both the IL-7 receptor α chain and the γ chain have been

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implicated in the differentiation from pro-B cells into pre-B cells (98–100). Thus, Itch may regulate B cell development through the downregulation of the IL-7 receptor.

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CBL PROTEINS AS RING-TYPE E3 LIGASES Numerous previous studies demonstrated that Cbl (Casitas B-cell lymphoma) protein functions as an adaptor protein by interacting with cell surface receptor and intracellular protein tyrosine kinases (PTKs), and other critical signaling molecules such as phosphatidylinositol (PI)-3 kinase, Crk-L, 14-3-3, and Grb2 (35, 101). In addition to Cbl, there are two close mammalian homologues, Cbl-b and Cbl3, which have similar N-terminal TKB domain, a RING finger, and C-terminal proline-rich sequences, except for Cbl-3, which contains a shorter C-terminal region (102, 103). The identification of Cbl as a RING-type E3 Ub ligase, as described earlier, suggests a distinct mechanism by which Cbl participates in the negative regulation of signal transduction. Recent studies have elegantly documented that Cbl is an E3 ligase for the activated protein tyrosine kinases of the Src and Syk/ZAP-70 families in lymphocytes, and Cbl-mediated ubiquitination of these kinases leads to their degradation, thus resulting in attenuation of antigenreceptor signaling (104–107), as recently reviewed (108, 109). Here I discuss some other Ub ligase-related aspects of Cbl and Cbl-b relevant to the lymphocyte regulation.

Cbl in T Cell Antigen Receptor Downmodulation Activation-induced internalization of cell surface receptor or receptor PTKs has long been known to be a very important means to terminate receptor signaling. One of the mechanisms to switch off such signaling is ubiquitination of the receptor that serves a signal for degradation (110). Cbl acts as an E3 Ub ligase to promote Ub conjugation to receptor PTKs such as EGFR and PDGFR (reviewed in Reference 109). It was proposed that Cbl is recruited to the activated receptor PTKs at the plasma membrane and induces their ubiquitination, which serves as a signal for the internalization and subsequent endocytotic sorting (111). Engagement of the TCR by the peptide major histocompatibility complex (MHC), or anti-TCR/CD3 antibodies also results in downregulation of the TCR/ CD3 complex (112–114). Downregulation of the TCR/CD3 complex is considered to be a self-limiting factor to terminate a sustained signaling in the MHC-TCR conjugated T cells, and it is also proposed to be responsible for unresponsiveness and/or tolerance induction of the self-reactive T cells (115, 116). Ub conjugation to the TCR/CD3 subunits, and particularly to the TCRζ chain, has been shown in activated T cells (117, 118). Multiple lysine residues in the intracellular domain of TCRζ chain are potential sites for Ub attachment (119). The enhanced cell surface expression of TCR/CD3 complex in Cbl-/- thymocytes clearly suggests a

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functional role of Cbl in their downmodulation. In support of this notion, it was demonstrated that Cbl acts as an E3 Ub ligase to promote Ub conjugation to TCRζ (120). More importantly, Zap-70 plays an adaptor’s role in facilitating Ub transfer to the TCRζ , instead of being a direct target for Cbl, as can be predicated from studies on receptor PTKs (Figure 1B). Therefore, the study provides a molecular link between the enhanced cell surface expression of TCR/CD3 in Cbl-/- thymocytes (121, 122) and its E3 Ub ligase activity. In addition, Cbl is implicated in the internalization of pre-TCR (123) as well as in the allelic exclusion of the T cell alpha chain in thymocyte development (124). A recent study on T cells deficient in both Cbl and Cbl-b showed a more profound effect on TCR/CD3 downregulation (125). Cbl may use alternative pathways to induce downregulation of activated receptor tyrosine kinases (126, 127). Cbl forms a complex with a Cbl-interacting protein of 85 kDa (CIN85) and endophilin. Endophilin has been implicated in receptor-mediated endocytosis through the invagination of the lipid bilayer (128). Although CIN85 constitutively binds to endophilin, the CIN85/endophilin complex is recruited to Cbl upon receptor activation. Therefore, Cbl can induce their downmodulation via the E3 ligase-independent endophilin-CIN85-Cbl complex formation. However, one of the two groups later showed that Cbl also induces monoubiquitination of CIN85 (129), and it seems that Cbl and CIN85 can form a complex with the activated receptor independent of endophilin. Thus, CIN85 plays a dual role in internalization and endocytic degradation. Whether similar mechanisms function in lymphocytes remains unclear. Another potential mechanism by which Cbl regulates TCR downmodulation is through the Src-like adaptor proteins (SLAPs). SLAP-deficient thymocytes display upregulation of TCR and CD5 at the CD4+CD8+ stage, a phenotype similar to the Cbl-/- thymocytes (130). In transiently tranfected cells, SLAP-2, a SLAP homologue, is shown to inhibit antigen receptor signaling (131) and reduces the surface expression of CD3 through a direct interaction with Cbl (132). Thus, Cbl may participate in the downmodulation of the TCR/CD3 complex via multiple pathways. It should be noted that not all Cbl-binding proteins are mediators for the regulation of receptor downregulation by Cbl. The Sprouty adaptor proteins associate with Cbl and are themselves the targets of Cbl-mediated polyubiquitination (133– 135). The interaction of Sprouty with Cbl can either reduce the E3 ligase activity of Cbl by blocking the E2-Ub loading to the RING finger (133) or sequester Cbl from its access to the activated receptor PTK, and its subsequent ubiquitination and degradation (134).

Proteolysis-Independent Regulation of PI3-kinase by Cbl-b The effective activation of naive T cells requires two signals: The first one is antigen-specific and is generated by the recognition of an antigenic peptide presented through MHC complex by the TCR; the second signal is antigen-nonspecific and is provided by interaction of the B7 ligand on the antigen-presenting cell with

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its receptor, CD28, a costimulatory cell surface molecule on the T cell (136). In the presence of both signals, the T cell will proliferate and secrete cytokines. Genetic studies showed that Cbl-b-deficient peripheral T cells uncouple CD28 costimulation: Cbl-b-/- T cells proliferate and secrete IL-2 in the absence of CD28 costimulation. Cbl-b-deficient mice develop autoimmune responses (137–139). The findings that c-Cbl RING finger can recruit Ubc E2 and that it facilitates Ub conjugation to protein tyrosine kinases to which Cbl binds suggest that Cbl or Cbl family proteins function as Ub protein ligases or E3s to downregulate intracellular signaling (36). Consistent with this, it was recently identified that p85, the regulatory subunit of PI3-kinase, is a substrate for Cbl-b (140). More interestingly, ubiquitination of p85 seems not to induce its degradation because p85 is a very stable protein and its stability is not affected by either Cbl-b overexpression or Cbl-b deficiency (141). It was found that the interaction of p85 with the cell surface CD28 or TCR/CD3 complex is increased in Cbl-b-/- T cells. Thus, Cbl-b regulates p85 in a proteolysis-independent manner through affecting protein-protein interactions. It can be theorized that Ub conjugation to p85 may cause structural hindrance to prevent its interaction with other binding proteins such as CD28, although future study is needed to test this hypothesis.

Crk-L as a Common Target for Cbl and Cbl-b Cbl forms a complex with another adaptor protein, Crk-L, through two C-terminal tyrosine residues (tyrosine-700 and tyrosine-774) of Cbl and the SH2 domain of Crk-L (reviewed in Reference 109). Crk-L also constitutively interacts with a guanine exchange factor, C3G, which preferentially catalyzes the conversion from a GDP-bond form of Rap1 to a GTP bond form (142). Consistent with this, it was shown that in T cells, activation of Fyn kinase induces phosphorylation of Cbl and subsequently triggers the Cbl-Crk-L-C3G signaling pathway, which eventually leads to Rap1 activation (143). In insulin-stimulated adipocytes, a similar Cbl-mediated pathway causes the activation of the small GTP-binding protein TC10 (144). In fibroblast cells, triggering cAMP/PKA activates Src kinase, which in turn induces Cbl-Crk-L-C3G complex formation as well as Rap1 activation (145). All these data collectively point out a positive role of Cbl in the activation of Rap1. However, the genetic evidence to implicate Cbl in Rap1 signaling is lacking. Surprisingly, Cbl deficiency causes an activation of Rap1, which is supported by an increase in Crk-L-C3G association, C3G membrane translocation, and the exchange activity of C3G (146). The current model is that Cbl, as an E3 ligase, promotes ubiquitination of Crk-L, which inhibits the interaction with C3G. It seems that, genetically, Cbl is a negative regulator of Crk-L-C3G signaling, which is in sharp contrast to its previous documentation as a positive regulator. As described earlier, genetic studies showed that Cbl and Cbl-b target different lymphoid tissues. We (147) proposed that the differential functions of Cbl and Cblb are mediated by targeting different substrates for ubiquitination, with Cbl being

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an E3 ligase for a TCR/CD3 complex and Cbl-b for a PI3-kinase. However, given the high homology between these two molecules, it was not surprising to learn that they have overlapping functions. Cbl-b also associates with Crk-L (148). It seems that like Cbl, Cbl-b also negatively regulates Crk-L-C3G complex formation in a proteolysis-independent manner and that the activation of Rap1 in Cbl-b-/peripheral T cells is augmented (149). Thus, Crk-L may act as a common target for Cbl and Cbl-b E3 ligases.

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E3 Ub Ligases in T Cell Tolerance The immune system has evolved mechanisms by which it mounts defensive responses to invading pathogens and at the same time, the self-tissues are protected from destruction. The capacity to distinguish self and nonself results from at least two stages of tolerance induction (150, 151). The first stage is in the thymus, where maturing T cells of self-reactivity are eliminated by negative selection. However, thymic deletion is a leaky process and the self-reactive T cells can escape such negative selection and enter the peripheral lymphoid tissues including the spleen and lymph nodes. Then comes the second stage of immune tolerance induction that is acquired by several mechanisms, including ignorance, activation-induced cell death, anergy, and the generation of regulatory T cells. Genetic and/or environmental changes may cause the breakdown of immune tolerance, which can result in the development of autoimmune diseases. T cell anergy represents a state of hypo- or nonresponsiveness in response to restimulation with antigen plus antigen-presenting cells (152). In recent years, numerous studies have focused on the elucidation of the intracellular signaling pathways responsible for the anergy induction. Earlier studies showed that anergized T cells display a block in Ras or Erk and Jnk activation (153, 154). In anergic T cells, Rap1 is preferentially activated through a Fyn-dependent Cbl-Crk-L-C3G signaling pathway (143). Rap1 has been proposed to be an antagonist of Ras by sequesting Raf kinase from Ras (142). This model is further supported by findings that costimulation with anti-CD28 causes the inhibition of Rap1 activation (155, 156), thus rescuing the anergic state. However, as described earlier, Cbl and/or Cbl-b seem to be negative regulators in Rap1 activation (146, 149). A recent study showed that T cells from Rap1 transgenic mice do not have defects in Ras signaling; rather, Rap1 activates the TCR-induced integrin signaling (157). In fact, Cbl-/- thymocytes or Cbl-b-/- peripheral mature T cells also show increased integrin activation, including enhanced binding to ICAM-1 or augmented LFA-1 clustering in response to TCR stimulation (146, 149). A recent study shed new light on the mechanisms of T cell anergy induction, in which an unbalanced and sustained Ca2+-dependent activation of NFAT leads to the transcriptional expression of anergy-associated genes (158). The products of these genes are distinct from those induced by normal productive T cell triggering and can together render T cells into the anergic state. This new model is supported by the observation that NFAT1-/- T cells are resistant to anergy induction (158). Some of these genes

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encode proteins involved in proteolytic pathways, such as caspases, or the RING finger-containing E3 ligases like SOCS-1 and TRAF6, suggesting that proteins functioning in the proteolytic pathways are involved in T cell anergy induction. In a subsequent study by the same group, it was shown that sustained Ca2+ signaling increases the expression of the E3 ligases Itch and Cbl-b, and the UEV Tsg101 (V. Heissmeyer & A. Rao, submitted manuscript), which results in selective downmodulation of critical signaling molecules PLC-γ 1 and PKCθ and the failure to form mature immunological synapse (Figure 2). The data thus clearly link the Ub conjugation pathway to the induction of lymphocyte tolerance. Another recent study identified a novel RING-containing protein, GRAIL (gene related to anergy in lymphocytes), in T cell unresponsiveness. GRAIL is a transmembrane protein residing in the endocytic compartment that exhibits in vitro E3 ligase activity (160). Expression of GRAIL in a T cell hybrid inhibits both IL-2 and IL-4 production, which depend on a functional endocytic pathway. It was suggested that GRAIL plays a role in T cell anergy induction by regulating endosome-dependent sorting of cell surface receptors and/or intracellular signaling molecules.

E3 LIGASES IN NF-κB SIGNALING TRAFs in the Formation of Variant Ub Chain and Kinase Activation Tumor necrosis factor (TNF) receptors are a superfamily of type II receptors involved in many aspects of the immune responses, including lymphoid organ formation, the development, activation, and death of lymphocytes, and inflammation (161). TNF receptors transduce signaling through adaptor molecules that bridge the receptor intracellular domains with downstream effectors. One group of the adaptor molecules is TNF receptor-associated factors (TRAFs), which have at least six members, TRAF1 to TRAF6. With the exception of TRAF1, all other TRAFs have an N-terminal RING domain, which suggests that this family of proteins plays a role in protein ubiquitination. The first evidence that TRAFs are involved in protein ubiquitination came, however, from studies on IL-1-induced NF-κB signaling (18). Like TNF receptors, the IL-1 receptor transduces signal leading to the activation of IkB kinase or IKK and NF-κB by the initial formation of multimolecular complex including Myd88, IRAK, and TRAF6 (162). Biochemical fractionation of this complex revealed the presence of two additional molecules, Ubc13 and Uea1A. The Ubc13/Uea1A complex is required for the activation of IKK by TRAF6. It turned out that TRAF6 facilitates the assembly of a lysine-63-mediated poly-Ub chain with the help of Ubc13/Uea1A. A subsequent study by the same group showed that lysine-63-linked polyubiquitination by TRAF6 and Ubc13/Uea1A is involved in TAK1 kinase complex activation and phosphorylation of IKK, and that TARF6 itself is the substrate for lysine-63-linked polyubiquitination (120). These studies also highlighted a proteolysis-independent role of protein ubiquitination.

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Another recent study on TNFα-induced activation of germinal center kinase also demonstrated that TRAF2 is involved in the activation of downstream signaling through a complex formation with Ubc13/Uea1A (163). Thus, TRAF proteins may have a general role in promoting self-ubiquitination, subsequent oligomerization, and activation of downstream kinases.

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E3 Ub Ligases for TRAFs If TRAFs promote lysine-63-linked polyubiquitination on their own and activate kinase complexes, one may wonder whether there is a mechanism by which TRAFs are degraded by the classical proteasomal dependent pathways. Indeed, stimulation of CD40, a member of TNF receptor family, on B cells caused 26S proteasomedependent degradation (164). Studies on inhibitors of apoptosis (IAPs) provide further clues to TRAF degradation. The IAPs are originally found in baculoviruses as inhibitors of cell death in infected cells and are a family of proteins containing one or more baculovirus IAP repeat (165). Some of the IAPs, like c-IAP1, c-IAP2, or X-linked IAP (XIAP) also contain a C-terminal RING finger. It is known that thymocytes become apoptotic upon stimulation with glucocorticoids, irradiation, and antigen receptor engagement. It was found that treatment of thymocytes with such stimuli selectively induces the loss of XIAP and c-IAP1, which can be prevented by proteasome inhibitors (166). In addition, both XIAP and c-IAP1 induces selfubiquitination that is dependent on a functional RING domain. Thus, the results provide an explanation for thymocyte apoptosis by inducing self-ubiquitination and their own degradation of IAP proteins. IAPs also directly interact with activated caspases through their baculovirus IAP repeat domains and inhibit the caspase activities (167). It was shown in an in vitro system that c-IAP1 catalyzes Ub conjugation to caspase-3 and caspase-7 (168), and XIAP promotes ubiquitination and proteasomal degradation of caspase-3, and thus exerts its antiapoptotic effect in Fas-induced cell death (169). Back to the degradation of TRAF proteins, it was found that stimulation of TNF receptor type II, but not type I, causes decreases in the TRAF2 protein level, which can be reversed by the addition of proteasomal inhibitors (170). In the study, c-IAP1 was identified as an E3 ligase for TRAF2 ubiquitination and degradation. It can be assumed that c-IAP-mediated TRAF2 ubiquitination is lysine-48-linked poly-Ub chain, which differs from TRAF and Ubc13/Uea1A-mediated lysine-63-linked Ub conjugation. A differential Ub chain formation thus results in totally opposite functional consequences. The molecular details when TRAF functions as an E3 ligase to activate downstream signaling, and when it functions as a substrate for IAPs to block apoptosis, have yet to be determined. It should be mentioned that in CD40-mediated signaling of B cells, TRAF2 is also shown to be self-ubiquitinated and induce its own degradation (164).

Ubiquitination of IκB Stimulation by proinflammatory cytokines such as TNFα, or IL-1, microbial products as well as stress exposure causes the activation of the IKK complex that

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consists of IKKα, IKKβ, and a regulatory subunit, NEMO (9). The activated IKK then phosphorylates IκB, which is then recognized by β-TrCP, a component of SCF Ub ligase. Under resting conditions, IκB forms a complex with NF-κB and retains NF-κB in the cytoplasm. Upon stimulation, IκB is ubiquitinated and degraded by the 26S proteasome, liberating NF-κB to allow it to translocate into the nucleus and exert its transcriptional activity. The NF-κB signaling pathway is essential in mediating both innate and adaptive immunity in both mammals and insects (171). Likewise, the fly IκB homologue, Cactus, is also ubiquitinated and degraded by Slimb, a Drosophila homologue of β-TrCP (159). In mammalian cells, IKKβ, and to a less extent, IKKα, induces phosphorylation of Ser-32 and Ser-36 of the N-terminal IκB protein, which creates the docking site for the WD40 repeat in β-TrCP. β-TrCP also forms a complex with Skp1, Cullin 1, and Roc1 through its F-Box domain. The RING domain in Roc1 then recruits Ub-loaded Ubc E2 to transfer Ub to IκB protein (10). It appears that the proteasomal-dependent degradation of IκB is a very rapid process, occurring only minutes after stimulation, which may ensure a timely release of NF-κB from the IκB-NF-κB complex.

Ub-Dependent Processing of NF-κB2 p100 The NF-κB transcription factor consists of a family of structurally related proteins, including c-Rel, RelA, RelB, NF-κB1 p50/p105, and NF-κB2 p52/p100 (172). Both the Rel and NF-κB proteins share a highly conserved N-terminal Rel homology domain that mediates DNA binding, dimerization, and association with IκB. The NF-κB p105 and p100 are the precursors for p50 and p52, respectively. Like IκB, p105 and p100 contain a C-terminal ankyrin repeat domain. Therefore, these two precursor proteins not only generate p50 and p52 NF-κB molecules, but also act like IκB as inhibitors for the NF-κB dimeric complex. In addition to the canonical Ub-mediated degradation of IκB, both p105 and p100 are processed proteolytically to generate p50 and p52, as well as to release the sequestered NF-κB complex through a Ub-proteasomal pathway. An early study showed that p52 is generated from a p100 precursor along with B cell development (173). Transient transfection studies in 293 T cells suggested that the NF-κB-inducing kinase (NIK) acts as an upstream kinase to induce the processing of p100 (174). NIK binds to and induces phosphorylation of p100, which is required for p100 ubiquitination and subsequent processing. A natural mutation in the NIK gene identified in aly mice markedly reduces its ability to induce p100 processing. Studies on IKKα-deficient mice further support a role of NIK in regulating NF-κB2 p100 processing (175). It seems that NIK phosphorylates specifically IKKα, which preferentially phosphorylates NF-αB2 p100. NIK-induced phosphorylation of p100 at its C-terminal region creates a binding site for β-TrCP (176). It turns out that p100 contains a very conserved serine-rich motif compared to other β-TrCP-binding proteins such as IκB. It is intriguing that the same E3 ligase component β-TrCP induces Ub conjugation to both IκB

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and to NF-κB2, but with totally different outcomes: Ubiquitination of IκB results in complete degradation, whereas NF-κB2 ubiquitination causes regulated proteolytic processing. A recent study may shed light on the molecular mechanism underlying the proteasomal-dependent cleavage of p100 (177). By using a yeast two-hybrid screen, a C-terminal dead domain in p100 is shown to interact with S9, a 19S proteasome subunit. The p100/S9 interaction is dependent on NIK-induced phosphorylation and ubiquitination of p100. In addition, S9 is required for NIKinduced p100 processing. The data provide a link between p100 ubiquitination and its processing via the binding of S9. Two recent studies demonstrated that triggering of two TNF receptor family members, CD40 and B cell activating factor (BAFF) receptor, induces the processing of p100 to p52 (178, 179). In 293 cells transfected with CD40 plasmid, antiCD40 cross-linking induces p52 production, which occurs 3 to 6 h after stimulation and requires de novo protein synthesis (178). The second study demonstrated a critical role of BAFF-induced p100 processing in B cell maturation (179). In NF-κB1/2 double-deficient mice, the development of B cells is blocked at the early transitional 1 (T1) stage. Using B cells deficient in BAFF receptor, NIK, or NF-κB, the authors (179) further demonstrated that BAFF regulates B cell maturation through a signaling pathway that requires BAFF receptor, NIK, and NF- κB2, and induces p100 processing. The data clearly indicate that BAFF activates NF-κB through the processing of p100 to generate p52, which correlates with a T1 stage of B cell maturation. In addition to CD40 and BAFF receptors, stimulation of the BCR also activates NF-κB signaling. In PKCβ-deficient B cells, the activation of IKKα, and to a less extent, IKKβ, are decreased upon anti-IgM stimulation (180). Although the protein expression of other Rel family members seems relatively normal, PKCβdeficient B cells display an increased amount of unprocessed p100. It appears that PKCβ functions like NIK to phosphorylate IKKα and the subsequent processing of p100, which links the BCR signaling to the noncanonical NF-κB pathway.

Processing of NF-κB1 p105 Although generation of p52 requires stimulation-dependent processing of p100, the NF-κB1 precursor p105 undergoes constitutive cleavage to produce p50, which is abundant in cells (9). At least two mechanisms have been proposed for the generation of p50, and both models require the involvement of proteasome. In the first model, p50 is generated during translation and forms a homodimer with its precursor, p105 (181, 182). This homodimer formation may stabilize the Rel homology domain and further proteolytic degradation of p105 C-terminus results in the formation of p50 homodimer. The second model proposes that p105, like p100, is processed through a β-TrCP Ub ligase-dependent processing, in which C-terminal phosphorylation of p105 by IKK is required for the p105 cleavage (183). Indeed, two C-terminal serine residues, serine-927 and serine-932, in the C-terminus of p105 are phosphorylated by IKKα and IKKβ in response to TNFα stimulation (184). However, the phosphorylated p105 has lower affinity for β-TrCP than the phosphorylated IκB, probably due to the presence of an additional

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amino acid residue in p105 compared with the consensus sequence for IKK phosphorylation in IκB. In addition to a potential role of ubiquitination of p105 in proteasomal-dependent processing, it was shown that IKK-induced phosphorylation of p105 and subsequent ubiquitination by β-TrCP causes rapid degradation without concomitant production of p50 (185). It remains to be resolved how the same E3 ligase component, β-TrCP, promotes Ub conjugation to three substrates IκB, p100, and p105, but causes different outcomes: degradation for IκB, regulated processing for p100, and processing or degradation for p105. It is possible that in addition to the kinase-mediated phosphorylation of these substrates and recognition by β-TrCP, other factors may also affect the outcomes. Recently, it was shown that β-TrCP-induced ubiquitination is regulated by NEDD8 modification (186), which may provide a clue to the differential role of the SCF-β-TrCP Ub complex in the regulation of NF-κB signaling. It should also be noted that the stimulation-induced degradation of IκB occurs rapidly, whereas Ub-dependent p100 processing is a slow process, usually hours after receptor engagement. IκB degradation can be triggered by various stimuli in many types of cells; p100 processing may be restricted to certain types of stimulation and/or cells, such as B cells by CD40- or BAFF receptor-mediated signaling. Therefore, β-TrCP-mediated ubiquitination of these substrates takes place in differentially temporal and spatial fashions, which may have different biological consequences.

TGF-β SIGNALING REGULATION BY SMURFS Transforming growth factor-β (TGF-β) is a multifunctional cytokine that controls a wide spectrum of biological processes including cell proliferation, differentiation, extracellular matrix formation, and apoptosis (187). It functions from the very early stage of embryogenesis to the tissue organization and to the cancer development. In addition, TGF-β has long been known to play an important role in immune regulation (188–190): First, TGF-β is produced by a wide range of lymphoid lineage cells, such as lymphocytes, macrophages, and dendritic cells; second, like in many other types of cells, TGF-β is a suppressive cytokine of T cell proliferation and inhibits the differentiation of naive T cells into effector cells; third, it is implicated in the induction of T cell anergy, and a membrane-bound form of TGF-β is important for the inhibitory function of CD4+CD25+ regulatory T cells; and fourth, TGF-β regulates the function of antigen-presenting cells by inhibiting MHC class II expression. The involvement of TGF-β in immune regulation is further underscored by the generation of TGF-β-deficient mice, which display profound autoimmune and inflammatory responses (191, 192). TGF-β signals through transmembrane serine/threonine kinase receptors (193): TGF-β binds to the type-II receptor of TGF-β (TGF-βRII), which recruits and phosphorylates TGF-βRI. The type-I and type-II receptors form heterotetrameric complexes and transduce signaling through a group of Smad proteins. The Smads

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are named from the original identification of Caenorhabditis elegans Sma and Drosophila Mad proteins and are grouped into receptor-restricted Smads (RSmads, Smad1, 2, 3, 5), common-partner Smad (co-Smad, Smad4), and inhibitory Smads (I-Smads, Smad6 and 7), based on their functions. Activation of a TGF-β receptor first induces the phosphorylation of Smad2 or 3, which then dissociates from the receptor and forms a complex with the co-Smad, Smad4. The Smads are then translocated into the nucleus, which then interacts with transcriptional coactivators, such as p300 and its homologue, CREB-binding protein (CBP), or corepressors like Ski or SnoN for the transcriptional regulation of TGF-β target genes. On the other hand, TGF-β signaling upregulates the expression of the inhibitory Smads like Smad7. Smad7 is then translocated into the cytoplasm to interfere with TGF-β signaling by directly associating with TGF-β receptor and blocking the phosphorylation of the R-Smads, thus providing a negative feedback mechanism for TGF-β signaling (194, 195). By using Xenopus Smad1 as bait, Zhu et al. (196) identified an interacting protein with high homology to the HECT subclass of E3 Ub ligases, which was named as Smad ubiquitination regulatory factor-1 or Smurf-1. Smurf-1 targets ubiquitination and degradation of Smad1, thus demonstrating the first E3 ligase in Smad signaling. A subsequent database search revealed a closely related homologue, Smurf-2 (197, 198). Smurf-2 was shown to reduce the steady-state levels of Smad1 and Smad2, but not Smad3 and Smad4, in transfected cells. Structurally, the Smurf-Smad interaction is mediated by the WW domains in the Smurfs and a conserved PPXY motif in the linker regions of Smads (197). A later study suggests that Smurf-2 associates with Smad2 but does not induce a direct degradation of Smad2; rather, TGF-β induces a complex formation of Smurf-2-Smad2 with another Smad2-binding protein, SnoN (199). Smad2 then acts as an adaptor protein to facilitate the ubiquitination and proteasome-dependent degradation of downstream molecules like SnoN. SnoN is a negative repressor of Smad function by directly associating with Smad, and upon TGF-β stimulation, SnoN becomes rapidly degraded, thus allowing the Smad to activate transcription of TGF-β-responsive genes (200). Thus, during the initiation of TGF-β signaling, Smurf-2-Smad2mediated degradation of SnoN helps the transduction of intracellular signaling. On the other hand, it was shown that Smurf-1 and Smurf-2 also play a role in opposing TGF-β signaling. TGF-β stimulation causes a complex formation between Smurf2 and Smad7, an I-Smad in the nucleus (201). The Smurf-2-Smad7 complex is then exported to the cytoplasm and binds to the activated TGF-β receptor through Smad7. When a multimolecular complex forms, Smurf-2 promotes Ub transfer to the activated TGF-β receptor and its subsequent downmodulation. It was later found that Smurf-1 has a similar role in the turnover of TGF-β receptors through Smad7 adaptor function (202). Thus, Smurf proteins have a dual function in regulating TGF-β-induced signaling transduction: first as a positive regulator in the initiation of signaling through the degradation of SnoN, and second as a negative regulator in terminating the signaling through the downmodulation of the activated TGF-β receptor.

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PROTEIN UBIQUITINATION IN NOTCH SIGNALING Notch signaling mediates evolutionarily conserved cellular processes important in cell-fate decisions in diverse organisms including worms, flies, and humans (203). Notch proteins are a family of cell surface receptors that consist of an extracellular ligand binding domain, transmembrane region, and intracellular signaling domains. The extracellular domain is comprised of epidermal growth factor (EGF)-repeats, and the intracellular domain contains multiple ankyrin repeats and a PEST (proline-glutamate-serine-threonine)-rich region. Upon binding to their ligands, Jagged or Delta, Notch proteins go through a series of proteolytic cleavage, which release the intracellular domain (Notch IC) from the membrane and allow it to translocate to the nucleus, where Notch IC binds to a complex of transcription corepressors of CSL/RBP-Jκ and converts them from repressors to activators. Given the important function of Notch in cell specification in many developmental systems, it is not surprising that Notch is also implicated in the regulation of the immune system. One of the earliest studies showed that transgenic overexpression of Notch IC in the developing T cells of the mouse leads to an increase in CD8 linage T cells, but a decrease in CD4 lineage T cells (204). A later study demonstrated that Notch, together with the newly formed antigen receptor, directs the αβ versus γ δ T cell lineage decision (205). Notch also confers resistance to glucocorticoid-induced cell death in transfected thymoma cells and in DP thymocytes harboring Notch IC transgene (206). Notch signaling in DP thymocytes promotes the maturation of both CD4 and CD8 SP thymocytes (207). A role of Notch in T lineage induction is further supported by the observation of deficiency in thymocyte development by induced inactivation of Notch gene (208). Retroviral transduction of Notch IC in the bone marrow promotes T lineage development, but inhibits B lineage commitment (209). A later study showed that Notch IC in fact abrogates differentiation of immature DP thymocytes into both CD4 and CD8 mature SP T cells (210). Such inhibitory function is accounted for by the interference with TCR signal strength. However, another study employing Notch antisense and anti-Notch antibody approaches showed that Notch signaling affects the duration of TCR signaling, and it is selectively required for CD8 T cell maturation (211). The discrepancies among the published data may be due to the different approaches used for the studies. Another explanation may be that the gain-of-function experiments mostly using constitutively active Notch IC do not represent the physiological function of the intact Notch protein. Indeed, a recent study using a conditional knockout technique showed that inactivation of Notch1 in immature thymocytes does not affect CD4+ or CD8+ T cell development (212), but αβ T cell lineage development (213). Because Notch has four isoforms (Notch 1 to 4) and at least three of them (Notch 1 to 3) are expressed in the thymus, it can be imagined that there might be overlapping redundancy among Notch proteins (214). To further complicate this issue, of the Notch ligands (Jagged 1 and 2, Delta-like-1 and 3), both Jagged 1 and 2 are known to be present in the thymus (215). It becomes obvious that an in vitro system is required to recapitulate the

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in vivo findings. An elegant study recently reported that ectopic expression of a Notch ligand, Delta-like-1, in a bone marrow stromal cell line, results in the loss of its ability to support B cell development, but it can help generate mature T cells (216). The data at least support a biological function of Notch-Delta interaction in T lineage cell commitment and differentiation. Given the conserved role of Notch in diverse organisms, it is no surprise that such important Notch signaling is regulated by protein ubiquitination. The first evidence that ubiquitination has a role in the downregulation of Notch signaling came from a genetic study in Drosophila (217). Mutations in Deltex, a Notch regulator, results in a phenotype resembling loss-of-function Notch mutation, which can be suppressed by mutation in another gene, suppressor of Deltex [Su(dx)], suggesting that Su(dx) is a genetically negative regulator of Notch signaling. Subsequent cloning of the Su(dx) revealed that it belongs to the HECT-type E3 ligases, with a typical Nterminal C2 domain, four WW domains, and a C-terminal HECT ligase domain. Inspired by this genetic observation, we examined whether Itch, a mammalian homologue of Su(dx), is involved in Notch signaling in cultured T cells (218). It was found that Itch induces Ub conjugation to Notch both in vitro and in vivo (218), suggesting that Itch is an E3 ligase for Notch in mammalian cells. Three later studies identified another E3 ligase component, Sel-10, as an inhibitor of Notch signaling that targets Notch for Ub-mediated degradation (219–221). Sel-10 protein contains an F-Box and seven WD-40 repeats, and belongs to the subgroup of SCF E3 ligase complexes. Sel-10 interacts with Notch through its WD-40 repeats and a region close to the PEST sequences in Notch, and the interaction is dependent on Notch phosphorylation. Interestingly, it seems that the Notch interaction with, and its ubiquitination by, Sel-10 takes place in the nucleus (219, 221). This suggests that Sel-10 is responsible for the proteasomal-dependent degradation after a nuclear phosphorylation event. More recently, Cbl was added to the list of E3 Ub ligases in Notch ubiquitination (222). Notch is tyrosine-phosphorylated after stimulation and becomes associated with Cbl. The data suggest another layer of Notch regulation by modulating its downmodulation at the cell surface. Because of its conserved role in regulating cell differentiation in diverse cell types and organisms, it can be postulated that Notch is tightly regulated by different mechanisms. In this context, it is not surprising that several different E3 ligases participate in the Ub conjugation to Notch, either at the cell surface, intracellular cytoplasm, or the nucleus, through lysosomal- or proteasomal-dependent degradation pathways. It is important to keep in mind, however, that almost all the published data are based on overexpression studies in cultured cells, even though the genetic observation in Drosophila may support such a conclusion. Obviously, genetic studies in mice are required to further confirm such biochemical observations. In addition to regulation of Notch by ubiquitination, studies from several groups have documented that the Notch ligand Delta is also targeted for protein ubiquitination (223–225). The protein product, Neur, contains a C-terminal RING finger that acts as an E3 ligase to promote Ub conjugation to the Notch ligand, Delta.

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Ubiquitination of Delta enhances its endocytosis and decreases the cell surface levels of Delta in Drosophila. Interestingly, endocytosis of Delta also triggers the transendocytosis and the ectodomain shedding of Notch, which is critical for the activation of Notch signaling. Thus, Neur plays a positive role in Notch pathway by promoting ubiquitination of Delta. Similar to the function of Neur, a recent study showed that another RING-type E3 ligase, Mind bomb, is also able to promote Delta ubiquitination and internalization (226). Mind bomb contains multiple ankyrin repeats and three C-terminal RING domains. It directly associates with the intracellular regions of Delta and induces Delta ubiquitination. Together with Neur, Mind bomb participates in modulating Notch signaling by inducing a Ubdependent endocytosis of Delta.

UBIQUITINATION IN WNT SIGNALING PATHWAY Similar to the Notch pathway, Wnt-induced signaling represents another wellconserved cascade that plays important roles in cell fate specification, proliferation, and cell death (227). Wnt proteins are a family of secreted glycoproteins that bind to two groups of cell surface receptors: the Frizzled and the low-density lipoprotein-related protein. In the absence of Wnt, the intracellular protein βcatenin forms a complex with a number of proteins including the scaffold protein Axin, the tumor suppressor adenomatous plyposis coli, and the kinase glycogen synthase kinase-3β (GSK-3β). β-catenin is phosphorylated by GSK-3β at the N-terminal serine/threonine residues in this complex. Phosphorylation at these sites recruits β-TrCP (228–230). Thus, the SCF β-TrCP complex induces the ubiquitination of β-catenin and its degradation. When Wnt binds to the receptors, it induces the inhibition of the kinase activity of GSK-3β through another protein, Disheveled. β-catenin is then stabilized, translocated to the nucleus, and binds to transcription factors of T cell factor (TCF) or lymphoid enhancer factor (LEF). Much of our understanding on Wnt signaling in lymphocyte regulation is based on the studies of the TCF/LEF transcription factors. In unstimulated cells, TCF/LEF factors interact with transcriptional co-repressors to repress target gene transcription. In the presence of Wnt, β-catenin binds to TCF/LEF and switches from repression to transactivation. TCF/LEF factors have DNA-binding activity to the enhancers of the TCR complex components CD3ε and TCRα (231). Gene targeting of TCF-1 results in an age-dependent block of early T cell development, but normal proliferation and function of peripheral T cells (232, 233). TCF mutant LEF-1 knockout mice display more severe defects, with a complete block at the immature single-positive stage (234). A more recent study directly linked β-catenin to thymocyte development (235). In this study, a region of β-catenin containing the phosphorylation sites was conditionally deleted, which resulted in accumulation of β-catenin mutant protein in thymocytes. Surprisingly, stabilization of β-catenin in thymocytes led to the generation of single positive T cells lacking the αβ TCR

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expression in a Rag-2-/- background. Another recent study provided further information on the transgenic expression of TCF isoforms and found that only the intact form containing β-catenin-binding domain can rescue the thymocyte development in TCF-deficient mice (236). These studies together suggest that Wnt signaling is an important regulator in early thymocyte development, and β-catenin, whose stability is tightly controlled by protein ubiquitination, is a critical mediator to transduce Wnt signaling. In addition to its role in cell fate determination, β-catenin is also a protooncogene whose mutations have been associated with human cancers (237). Independently, two groups have demonstrated that another E3 ligase component, Siah, mediates β-catenin degradation (238, 239). Siah contains an N-terminal RING finger that binds to E2 and targets several proteins for proteasomal-dependent degradation (240–243). Siah is present at a very low amount in normal cells. However, activation of p53 by genotoxic stress or irradiation upregulates Siah expression (244). Thus, Siah may act as a mediator for p53-induced cell cycle arrest and tumor suppression through targeting Ub-dependent proteolysis of β-catenin. However, the results derived from gene-targeted mice seem at odds with the biochemical observations. Cells deficient in Siah proteins are relatively normal in p53 function (245). The genetic evidence may suggest that Siah targets other protein substrates than β-catenin for protein ubiquitination. Indeed, the same group showed that male mice deficient in Siah display a block in spermatogenesis, although the exact physiological targets for Siah E3 ligase activity are not known at present (246).

MDM2 AS AN E3 LIGASE FOR p53 p53 is a key tumor suppressor whose mutation is linked to many human cancers (247). The importance of p53 is further underscored by the development of multiple malignancies including the dominant occurrence of lymphoma in p53 gene-targeted mice (248). p53 acts as a transcription factor to induce gene transcription of multiple proteins involved in cell cycle arrest and apoptosis (247). In addition to its role as a tumor suppressor, p53 has been implicated in physiological immune regulations such as thymocyte development (249), and peripheral mature T cell apoptosis triggered by TCR engagement (250), whereas the role of p53 in regulating the expansion of antigen-specific CD8+ T cells seems to be relatively minor (251). In normal cells, p53 is kept at a very low level through an autoregulatory feedback loop by inducing the expression of Mdm2. Mdm2 is RING fingercontaining E3 ligase that promotes Ub conjugation to p53 and subsequent degradation via proteasome-mediated proteolysis (41, 252). The Ub conjugation region was mapped to several lysine residues at the extreme C-terminus of p53 (253, 254), and ubiquitination of these lysine residues by Mdm2 could unmask the buried nuclear export signal in p53 through its conformational changes and initiate the export

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of p53 into the cytoplasm, where it is degraded by the 26S proteasome (255–257). To support a role of Mdm2 in regulating Mdm2 stability, conditional knockout of Mdm2 in mice leads to a greater accumulation of p53 and increased apoptosis in response to ionizing radiation (258). Interestingly, the mutant mice exhibit defects in multiple hematopoietic lineages, including the decreases in T and B lymphocyte numbers, and in the sizes of the thymus, lymph nodes, and the spleen. The genetic study clearly indicates an important role of Mdm2 in hematopoietic tissues, particularly during lymphopoiesis. Exposure of the cells to DNA damage such as ionizing irradiation or stress stimulation causes the activation of p53, primarily through the regulation of p53 stability (259). One current model is that DNA damage can activate a checkpoint kinase Chk2, which in turn induces the phosphorylation of p53 at serine-20. Phosphorylation of this serine residue disrupts the interaction of 53 with Mdm2 and thus increases the p53 stability (260, 261). Supporting this model, Chk2-deficient thymocytes were resistant to DNA damage–induced apoptosis and were defective for p53 stabilization following irradiation (262). In addition to serine-20, there are other potential serine phosphorylation sites in p53 that may also contribute to the regulation of p53 stability. Indeed, thymocytes harboring serine-20 mutation showed normal p53 stability and p53-dependent apoptosis (263). Another mechanism by which p53 is stabilized in response to DNA damage is acetylation of p53 by CBP/p300 (259). Interestingly, p53 is acetylated at the C-terminal lysine residues that overlap with Mdm2-mediated ubiquitination sites. Thus, acetylation of p53 potentially attenuates its Ub conjugation by Mdm2 and increases its stability (264). Once p53 has exerted its transcriptional activity, it needs to be deacetylated. Recent studies suggest that Mdm2 inhibits CBP/p300mediated acetylation (265). Furthermore, Mdm2 recruits the deacetylase HDAC1, which removes the acetyl groups from the p53 lysine residues and allows Mdm2 to promote p53 degradation (266). Thus, Mdm2 plays a dual role in safeguarding the p53 protein level by promoting direct Ub conjugation to p53 and by recruiting deacetylase to trigger p53 deacetylation. Contrary to a role of p300 in stabilizing p53 through acetylation, a recent study demonstrated that p300 acts as an E4 and together with Mdm2 to catalyze the polyubiquitination of p53, whereas Mdm2 only induces p53 monoubiquitination (267). In addition, a Parkin-like E3 ligase, Parc, and another RING-type E3, Pirh2, have been recently identified as the E3 ligases for p53 (268, 269). These new data suggest that the stability of p53 is regulated by multiple E3 ligases.

UBIQUITINATION IN THE PROCESSING OF ANTIGENIC PEPTIDE T cell activation is a central step in the development of the adaptive immune response, which is initiated by the binding of the TCR to the antigenic peptide presented by MHC on the antigen-presenting cells. There are two classes

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of MHCs: The MHC class I presents endogenous antigenic fragment to CD8+ T cells, and the MHC class II presents exogenous antigen peptide to the CD4+ T cells (270, 271). MHC class I is expressed in almost any cells in which antigens such as virus proteins or tumor antigens are processed in the cytosol and translocated into the endoplasmic reticulum to associate with the class I complex (270). MHC class II is only expressed in professional antigen-presenting cells, such as macrophages, dendritic cells, or B cells, where it picks up exogenous antigenic peptide derived from bacteria or dead cell debris processed in endolysomal compartments (271). The generation of antigenic peptide for MHC class I presentation is dependent on proteasome-dependent processing (11). By using cells with a temperaturesensitive defect in E1 Ub–activating enzyme, it was shown that the Ub-dependent proteolytic pathway is required for MHC class I–restricted presentation of ovalbumin introduced into the cytosol (13). In addition, during viral infection, IFNγ is produced and causes the production of two MHC-encoded enzymatic subunits— LMP2 and LMP7—and the non–MHC encoded MECL-1, which replace three proteasome subunits in the 20S catalytic proteasome to form the immunoproteasome (272, 273). The newly assembled immunoproteasome alters peptidase activity and produces antigenic peptides more suitable for binding to MHC class I (274). To further support a role of the proteasome in antigen presentation, a proteasomespecific inhibitor, lactacystin, blocks presentation of influenza-derived viral epitopes to cytotoxic T cells (275). More recently, it was shown that ubiquitinated proteins accumulate during dendritic cell maturation (276). Inflammation causes the transient formation of the Ub-containing aggresome-like structure, which requires continuous protein synthesis and stems from endogenous proteins because endocytosized exogenous protein is not incorporated into the structure. Such aggregate formation in dendritic cells may represent an antigen storage structure, which may have impact in determining MHC class I loading and peptide presentation. Although a relationship between the Ub-proteasome pathway and MHC class I antigen presentation is well established, it is not clear whether the generation of antigenic peptide is truly dependent on the classical Ub conjugation pathway. Indeed, it was also shown that presentation of both endogenous and exogenous antigens is not affected by the inactivation of the E1 Ub-activating enzyme (277). In addition, newly synthesized defective ribosomal products, or DRiPs, rather than stable intracellular proteins, are the major source of self- and viral peptides (278). Supporting this notion, nearly 30% of newly synthesized proteins are DRiPs, and some of these protein fragment products are tagged with Ub (279). During an acute influenza infection, the transporter associated with antigen processing (TAP) is rapidly loaded with newly synthesized proteins, which may ensure a timely presentation of viral antigen to the immune system (280). However, it remains unclear whether the E2 or E3 Ub conjugation components are involved in antigen processing and presentation by the MHC class I. In this regard, it has been shown that tumor cells of many types present antigenic peptides derived from both p53 and Mdm2 (281, 282). It might be possible that Mdm2 also helps process both p53

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and itself as tumor antigens in the cytosol, which allows the presentation by MHC class I to cytotoxic T cells under pathological conditions.

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VIRAL E3 LIGASES IN IMMUNE EVASION Although the immune system has evolved machinery to eradicate virally infected cells, many viruses can persist inside cells to cause latent or chronic infection of the host. DNA viruses like human cytomegalovirus (hCMV) or herpesvirus are examples of viruses causing immune evasion. One mechanism used by the virus to avoid immune surveillance is the downregulation of MHC class I to reduce antigen presentation (283). For example, the US11 and US2 proteins of hCMV cause reverse translocation of MHC class I from the endoplasmic reticulum (ER) into the cytosol, where MHC class I is polyubiquitinated and degraded by the proteasome-dependent pathway (284, 285). Another mechanism of viral subversion is the identification of virus-encoded PHD-containing E3 Ub ligases. Several viral proteins contain a PHD domain, which is involved in the downmodulation of antigen-presenting MHC class I molecules (286, 287). Two herpesvirus proteins, K3 and K5, have E3 Ub ligase activity and downregulate cell surface molecules such as MHC class I (288, 289). The human herpesvirus K3 and K5 proteins have E3 ligase activity to induce Ub conjugation to MHC class I in transfected cells, and a critical cysteine residue in the PHD domain of K5 is required for its self-ubiquitination in vitro (288). Similarly, the K3 of murine γ -herpesvirus also downmodulates the class I molecule in a PHD domain–dependent manner (289). The C-terminal domain of K3 and the cytoplasmic tail of class I were essential for the association of K3 with the newly synthesized class I molecule in the ER membrane and its subsequent degradation. The K3-mediated Ub conjugation of class I results in subsequent binding by Tsg101, an E2 variant protein implicated in trafficking of membrane-associated proteins into the endolysosomal pathway (290). The K3 of murine γ -herpesvirus requires some of the MHC class I assembly components to exert its function (291), as it failed to downmodulate class I in cells deficient in TAP or tapasin and it directly associates with TAP and tapasin in the absense of class I. It seems that the K3 or K5 uses TAP and/or tapsin to form an indirect complex with class I that helps transfer Ub to the class I molecule. The PHD-containing viral E3 ligases also induce downmodulation of other cell surface molecules in addition to MHC class I. The cell surface molecules such as B7 and ICAM-1, which are important for the co-stimulation of T cells, are downregulated by K5 of human herpesvirus (288). Another PHD domain protein, M153R of myxomavirus, which causes myxomatosis in rabbit, induces internalization and lysosomal degradation of CD4 in T cells (292) as well as MHC class I (293). Viral proteins can also use the cellular E3 ligases to induce CD4 downregulation. The Vpu membrane protein of human immunodeficiency virus type-1 (HIV-1) causes downmodulation of CD4, which is dependent on an intact Ub conjugation system

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and C-terminal lysine residues in CD4 (294). Vpu interacts with the E3 ligase component of β-TrCP through a C-terminal intracellular domain of Vpu and the WD repeat of β-TrCP. The Ub is then transferred through a β-TrCP SCF complex to CD4 through the adaptor function of Vpu, which leads to CD4 ubiquitination (295). Taken together, it can be concluded that Ub-dependent downmodulation of cell surface proteins induced by either viral or cellular E3 Ub ligases represents an important means for the virus to evade immune surveillance.

UB AND RETROVIRUS BUDDING Not only do viruses contain E3 Ub ligases to downmodulate MHC class I and other cell surface molecules, some enveloped RNA viruses also exploit the cellular ubiquitination machinery for their own benefit. The critical steps in the retrovirus life cycle are virion assembly and fusion with the plasma membrane of infected cells, and the final release or budding from the host cell (296). Studies from three independent groups showed that proteasomal inhibitors interfere with the budding process of HIV, Rous sarcoma virus, or Ebola virus (297–299). The retroviral Gag protein is essential for the budding process, and it contains conserved motifs (or late budding domains) like PPXY or PTAP sequences (299). Using the PPXY motif as bait, several groups subsequently identified WW domain–containing HECT E3 ligases such as Nedd4 or Nedd4-like proteins (300–302). A functional E3 ligase is required for viral budding because expression of the WW domains alone inhibits the release of mature viral particles from the host cell (301, 302). In the case of Ebola virus, the late domain–containing VP40 protein is a target for Ub conjugation by the Nedd4 yeast homologue Rsp5 (300). Thus, HECT-type E3 ligases are involved in viral budding through their recruitment to the PPXY motifs in the late budding domains. Another exciting discovery on the Ub system involves HIV budding. Unlike other retroviruses, HIV does not contain the PPXY motif in the Gag protein, but has a PTAP motif, which has been implicated in viral budding (303). By using the yeast two-hybrid screen with the HIV Gag as bait, two groups identified Tsg101 as a binding partner (21, 304). The PATP motif in the HIV Gag protein mediates direct binding with the UEV domain in the N-terminus of Tsg101. More importantly, depletion of Tsg101 by using small interfering RNAs significantly reduces budding of HIV from infected cells (21). Structure studies of the Tsg101 UEV domain in the complex with the HIV PTAP motif demonstrated that the UEV domain forms a binding groove that makes close contacts with the PTAP residues (305). The importance of Tsg101 in HIV budding is further supported by the finding that overexpression of the N-terminal UEV domain of Tsg101 inhibits HIV budding, suggesting that the full-length Tsg101 is required for facilitating virus release (306). As described earlier, Tsg101 belongs to the UEV family that contains E2 homologous sequences but not the active cysteine, and it functions in late endosomal trafficking for the activated EGF receptor in mammalian

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cells (20). In yeast, the Tsg101 homologue vacuolar-protein sorting 23 (Vps23) forms a multimolecular complex with other Vps proteins, called ESCRT-1, which recognizes monoubiquitinated cargo and helps sort it into multivesicular bodies (MVBs) (307). Interestingly, the MVB pathway is quite similar to the viral budding process, both of which involve invagination of lipid membrane. In addition, a recent study showed that Tsg101 is recruited together with other ESCRT-1 components to the late budding domain (308). One distinctive difference is that Tsg101 directly binds to the PTAP motif in HIV, instead of the ubiquitinated cargo protein, as in the MVB pathway in the yeast. Enveloped viruses therefore can utilize at least two cellular Ub machineries for release from the host cell: One is the recruiting of HECT-type E3 ligases by the PPXY motif, and another is the binding of Tsg101 and the ESCRT-1 complex. However, these two pathways may be not mutually exclusive because Tsg101 also contains a weak Ub binding site (309), and Ub conjugation to HIV Gag protein in fact enhances Tsg101 binding (21). Some viruses, like Ebola, contain both PPXY and PTAP motifs (299); the PTAP motif in Ebola indeed binds Tsg101, and this interaction is essential for virion release (310). Moreover, the late domain of Ebola virus recruits both Nedd4 and Tsg101 for effective budding (311, 312). However, the exact mechanism for the interplay between the late domains of budding viruses and cellular Ub factors such as Tsg101 or E3 ligases remains to be elucidated.

CONCLUDING REMARKS AND PERSPECTIVES Our understanding of Ub ligases in the regulation of cellular functions has tremendously improved with the identification of new E3 ligases and their specific substrates over the past few years. At the same time, it is clear that Ub conjugation to a substrate may not always leads to its degradation, but instead to proteolysisindependent functional modification. Ubiquitination of cell surface receptors may be a means of terminating signaling, whereas at other times receptor-induced ubiquitination of intracellular proteins is an essential step to initiate signaling transduction. Likewise, protein ubiquitination does not always play a negative role, but sometimes positively regulates kinase activation, protein-protein interaction, or gene transcription. Because the numbers of E3s are huge, it can be imagined that all these diverse biological functions primarily rely on the specificity of the E3s, in addition to the differential uses of Ub or Ub-like proteins, as well as the selection of Ubc E2s. However, the question of how a particular E3 mediates Ub transfer to a substrate and then induces totally different outcomes still awaits elucidation. In regard to the immune response, we now know that E3s are implicated in many aspects of both innate and adaptive immunity, such as the downregulation of antigen receptors, modulation of intracellular signaling molecules and transcription factors, and antigen processing or MHC expression (Table 1). Biochemical approaches will still be critical for the identification of the substrates for a particular E3 in lymphocytes. However, one has to be aware that a substrate identified in an

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Smurf 1, 2 Itch

RING-type Cbl

Cbl-b MDM2 TRAF IAP SCF/β-TrCP

Siah VBC/VHL Viral K3, K5 ?? GRAIL

Substrates

Function

Src kinase Steroid hormone receptor Na channel Gag protein Smads, SnoN, TGF-β receptor Notch Jun-B IL-7 receptor PLCγ 1, PKCθ

B cell signaling Transcription Hypertension Virus budding TGF-β signaling ?? T helper cell differentiation B cell development T cell anergy

TCR/CD3 Syk/Zap70 and Lck Crk-L p85 of PI3-K Crk-L p53 IKK complex TRAF, Self IkB NF-kB (p100 and p105) β-catenin β-catenin HIFα MHC class I Antigen (native or unfolded) ??

Receptor downregulation Tyrosine kinase degradation Rap1 activation T cell activation Rap1 activation Cell cycle control NF-κB activation Apoptosis Degradation Processing Cell cycle/T cell development Cell cycle/T cell development Angiogenesis/inflammation Immune evasion Antigen presentation T cell anergy

in vitro system may not represent a physiologic target in vivo. Genetic approaches using mice deficient in an E3 ligase will definitely be important to complement the biochemical analysis. On the other hand, because lymphocytes go through a series of developmental and selection steps, the phenotypes revealed in the gene-targeted mice may not be the direct result of E3 deficiency, but rather a secondary effect. Thus, a combination of biochemical and genetic analysis is required to fully appreciate the biological significance of an E3 in the immune regulation. At present, we know extremely little about the regulation of E3 ligases, although recent studies have pointed out that conjugation by the Ub-like molecule Nedd8 to, or its removal from, the SCF E3 complex modulates the ligase activity of the latter (313, 314). Similarly, reversal of Ub conjugation or deubiquitination is emerging as another important regulatory mechanism for Ub-dependent protein modification. Further understanding of these molecular insights may lead to new therapeutic approaches for the treatment of immunological abnormalities. Obviously, we are

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facing many challenges ahead, and at the same time we are also provided with many opportunities to undertake steps to gradually fill in the gaps in our knowledge on this complex Ub conjugation system. As the Chinese proverb goes, the journey of a thousand miles starts with a single step.

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ACKNOWLEDGMENTS I would like to thank former and present members of my laboratory for their contributions to the E3 Ub ligase projects, V. Heissmeyer, A. Rao, and D. Fang for the unpublished data, and my colleagues at the Division of Cell Biology for support. I apologize to those whose important literature is not in this review or is not properly cited in this review. The research in this laboratory is supported by the National Institutes of Health grants RO1DK56558, RO1AI50280, and R21AI48542, a research project grant from the American Cancer Society, and a biomedical science grant from the Arthritis Foundation. The Annual Review of Immunology is online at http://immunol.annualreviews.org

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binding to target proteins. Mol. Cell Biol. 19:724–32 Lorick KL, Jensen JP, Fang S, Ong AM, Hatakeyama S, Weissman AM. 1999. RING fingers mediate ubiquitinconjugating enzyme (E2)-dependent ubiquitination. Proc. Natl. Acad. Sci. USA 96:11364–69 Germani A, Bruzzoni-Giovanelli H, Fellous A, Gisselbrecht S, Varin-Blank N, Calvo F. 2000. SIAH-1 interacts with alpha-tubulin and degrades the kinesin Kid by the proteasome pathway during mitosis. Oncogene 19:5997–6006 Tiedt R, Bartholdy BA, Matthias G, Newell JW, Matthias P. 2001. The RING finger protein Siah-1 regulates the level of the transcriptional coactivator OBF-1. EMBO J. 20:4143–52 Amson RB, Nemani M, Roperch JP, Israeli D, Bougueleret L, et al. 1996. Isolation of 10 differentially expressed cDNAs in p53-induced apoptosis: activation of the vertebrate homologue of the drosophila seven in absentia gene. Proc. Natl. Acad. Sci. USA 93:3953–57 Frew IJ, Dickins RA, Cuddihy AR, Del Rosario M, Reinhard C, et al. 2002. Normal p53 function in primary cells deficient for Siah genes. Mol. Cell Biol. 22: 8155–64 Dickins RA, Frew IJ, House CM, O’Bryan MK, Holloway AJ, et al. 2002. The ubiquitin ligase component Siah1a is required for completion of meiosis I in male mice. Mol. Cell Biol. 22:2294–303 Ashcroft M, Vousden KH. 1999. Regulation of p53 stability. Oncogene 18:7637– 43 Donehower LA, Harvey M, Slagle BL, McArthur MJ, Montgomery CA Jr, et al. 1992. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356:215–21 Costello PS, Cleverley SC, Galandrini R, Henning SW, Cantrell DA. 2000. The GTPase rho controls a p53dependent survival checkpoint during

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LIU thymopoiesis. J. Exp. Med. 192:77– 85 Boehme SA, Lenardo MJ. 1996. TCRmediated death of mature T lymphocytes occurs in the absence of p53. J. Immunol. 156:4075–78 Grayson JM, Lanier JG, Altman JD, Ahmed R. 2001. The role of p53 in regulating antiviral T cell responses. J. Immunol. 167:1333–37 Honda R, Tanaka H, Yasuda H. 1997. Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett. 420:25–27 Nakamura S, Roth JA, Mukhopadhyay T. 2000. Multiple lysine mutations in the C-terminal domain of p53 interfere with MDM2-dependent protein degradation and ubiquitination. Mol. Cell Biol. 20:9391–98 Rodriguez MS, Desterro JM, Lain S, Lane DP, Hay RT. 2000. Multiple Cterminal lysine residues target p53 for ubiquitin-proteasome-mediated degradation. Mol. Cell Biol. 20:8458–67 Boyd SD, Tsai KY, Jacks T. 2000. An intact HDM2 RING-finger domain is required for nuclear exclusion of p53. Nat. Cell Biol. 2:563–68 Gu J, Nie L, Wiederschain D, Yuan ZM. 2001. Identification of p53 sequence elements that are required for MDM2mediated nuclear export. Mol. Cell Biol. 21:8533–46 Lohrum MA, Woods DB, Ludwig RL, Balint E, Vousden KH. 2001. C-terminal ubiquitination of p53 contributes to nuclear export. Mol. Cell Biol. 21:8521–32 Mendrysa SM, McElwee MK, Michalowski J, O’Leary KA, Young KM, Perry ME. 2003. mdm2 is critical for inhibition of p53 during lymphopoiesis and the response to ionizing irradiation. Mol. Cell Biol. 23:462–72 Prives C, Manley JL. 2001. Why is p53 acetylated? Cell 107:815–18 Chehab NH, Malikzay A, Stavridi ES, Halazonetis TD. 1999. Phosphorylation

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of Ser-20 mediates stabilization of human p53 in response to DNA damage. Proc. Natl. Acad. Sci. USA 96:13777–82 Unger T, Juven-Gershon T, Moallem E, Berger M, Vogt Sionov R, et al. 1999. Critical role for Ser20 of human p53 in the negative regulation of p53 by Mdm2. EMBO J. 18:1805–14 Hirao A, Kong YY, Matsuoka S, Wakeham A, Ruland J, et al. 2000. DNA damage-induced activation of p53 by the checkpoint kinase Chk2. Science 287: 1824–27 Wu Z, Earle J, Saito S, Anderson CW, Appella E, Xu Y. 2002. Mutation of mouse p53 Ser23 and the response to DNA damage. Mol. Cell Biol. 22:2441– 49 Li M, Luo J, Brooks CL, Gu W. 2002. Acetylation of p53 inhibits its ubiquitination by Mdm2. J. Biol. Chem. 277: 50607–11 Jin Y, Zeng SX, Dai MS, Yang XJ, Lu H. 2002. MDM2 inhibits PCAF (p300/CREB-binding protein-associated factor)-mediated p53 acetylation. J. Biol. Chem. 277:30838–43 Ito A, Kawaguchi Y, Lai CH, Kovacs JJ, Higashimoto Y, et al. 2002. MDM2HDAC1-mediated deacetylation of p53 is required for its degradation. EMBO J. 21:6236–45 Grossman SR, Deato ME, Brignone C, Chan HM, Kung AL, et al. 2003. Polyubiquitination of p53 by a ubiquitin ligase activity of p300. Science 300:342– 44 Nikolaev AY, Li M, Puskas N, Qin J, Gu W. 2003. Parc: a cytoplasmic anchor for p53. Cell 112:29–40 Leng RP, Lin Y, Ma W, Wu H, Lemmers B, et al. 2003. Pirh2, a p53-induced ubiquitin-protein ligase, promotes p53 degradation. Cell 112:779–91 Pamer E, Cresswell P. 1998. Mechanisms of MHC class I–restricted antigen processing. Annu. Rev. Immunol. 16: 323–58

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UBIQUITINATION AND IMMUNE REGULATION 271. Villadangos JA, Ploegh HL. 2000. Proteolysis in MHC class II antigen presentation: Who’s in charge? Immunity 12:233–39 272. Glynne R, Powis SH, Beck S, Kelly A, Kerr LA, Trowsdale J. 1991. A proteasome-related gene between the two ABC transporter loci in the class II region of the human MHC. Nature 353:357–60 273. Hisamatsu H, Shimbara N, Saito Y, Kristensen P, Hendil KB, et al. 1996. Newly identified pair of proteasomal subunits regulated reciprocally by interferon gamma. J. Exp. Med. 183:1807– 16 274. Gaczynska M, Rock KL, Goldberg AL. 1993. Gamma-interferon expression of MHC genes regulate peptide hydrolysis by proteasomes. Nature 365:264–67 275. Cerundolo V, Benham A, Braud V, Mukherjee S, Gould K, et al. 1997. The proteasome-specific inhibitor lactacystin blocks presentation of cytotoxic T lymphocyte epitopes in human murine cells. Eur. J. Immunol. 27:336–41 276. Lelouard H, Gatti E, Cappello F, Gresser O, Camosseto V, Pierre P. 2002. Transient aggregation of ubiquitinated proteins during dendritic cell maturation. Nature 417:177–82 277. Cox JH, Galardy P, Bennink JR, Yewdell JW. 1995. Presentation of endogenous and exogenous antigens is not affected by inactivation of E1 ubiquitin-activating enzyme in temperature-sensitive cell lines. J. Immunol. 154:511–19 278. Yewdell JW, Anton LC, Bennink JR. 1996. Defective ribosomal products (DRiPs): a major source of antigenic peptides for MHC class I molecules? J. Immunol. 157:1823–26 279. Schubert U, Anton LC, Gibbs J, Norbury CC, Yewdell JW, Bennink JR. 2000. Rapid degradation of a large fraction of newly synthesized proteins by proteasomes. Nature 404:770–74 280. Reits EA, Vos JC, Gromme M, Neefjes J. 2000. The major substrates for TAP

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in vivo are derived from newly synthesized proteins. Nature 404:774–78 DeLeo AB. 1998. p53-based immunotherapy of cancer. Crit. Rev. Immunol. 18:29–35 Dahl AM, Beverley PC, Stauss HJ. 1996. A synthetic peptide derived from the tumor-associated protein mdm2 can stimulate autoreactive, high avidity cytotoxic T lymphocytes that recognize naturally processed protein. J. Immunol. 157:239–46 Furman MH, Ploegh HL. 2002. Lessons from viral manipulation of protein disposal pathways. J. Clin. Invest. 110:875– 79 Shamu CE, Flierman D, Ploegh HL, Rapoport TA, Chau V. 2001. Polyubiquitination is required for US11-dependent movement of MHC class I heavy chain from endoplasmic reticulum into cytosol. Mol. Biol. Cell 12:2546–55 Kikkert M, Hassink G, Barel M, Hirsch C, van der Wal FJ, Wiertz E. 2001. Ubiquitination is essential for human cytomegalovirus US11-mediated dislocation of MHC class I molecules from the endoplasmic reticulum to the cytosol. Biochem. J. 358:369–77 Ishido S, Choi JK, Lee BS, Wang C, DeMaria M, et al. 2000. Inhibition of natural killer cell-mediated cytotoxicity by Kaposi’s sarcoma-associated herpesvirus K5 protein. Immunity 13: 365–74 Coscoy L, Ganem D. 2000. Kaposi’s sarcoma-associated herpesvirus encodes two proteins that block cell surface display of MHC class I chains by enhancing their endocytosis. Proc. Natl. Acad. Sci. USA 97:8051–56 Coscoy L, Sanchez DJ, Ganem D. 2001. A novel class of herpesvirus-encoded membrane-bound E3 ubiquitin ligases regulates endocytosis of proteins involved in immune recognition. J. Cell Biol. 155:1265–73 Boname JM, Stevenson PG. 2001.

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LIU MHC class I ubiquitination by a viral PHD/LAP finger protein. Immunity 15: 627–36 Hewitt EW, Duncan L, Mufti D, Baker J, Stevenson PG, Lehner PJ. 2002. Ubiquitylation of MHC class I by the K3 viral protein signals internalization and TSG101-dependent degradation. EMBO J. 21:2418–29 Lybarger L, Wang X, Harris MR, Virgin HWt, Hansen TH. 2003. Virus subversion of the MHC class I peptide-loading complex. Immunity 18:121–30 Mansouri M, Bartee E, Gouveia K, Hovey Nerenberg BT, Barrett J, et al. 2003. The PHD/LAP-domain protein M153R of myxomavirus is a ubiquitin ligase that induces the rapid internalization and lysosomal destruction of CD4. J. Virol. 77:1427–40 Guerin JL, Gelfi J, Boullier S, Delverdier M, Bellanger FA, et al. 2002. Myxoma virus leukemia-associated protein is responsible for major histocompatibility complex class I and Fas-CD95 downregulation and defines scrapins, a new group of surface cellular receptor abductor proteins. J. Virol. 76:2912–23 Schubert U, Anton LC, Bacik I, Cox JH, Bour S, et al. 1998. CD4 glycoprotein degradation induced by human immunodeficiency virus type 1 Vpu protein requires the function of proteasomes and the ubiquitin-conjugating pathway. J. Virol. 72:2280–88 Margottin F, Bour SP, Durand H, Selig L, Benichou S, et al. 1998. A novel human WD protein, h-beta TrCp, that interacts with HIV-1 Vpu connects CD4 to the ER degradation pathway through an F-box motif. Mol. Cell 1:565–74 Vogt VM. 2000. Ubiquitin in retrovirus assembly: actor or bystander? Proc. Natl. Acad. Sci. USA 97:12945–47 Schubert U, Ott DE, Chertova EN, Welker R, Tessmer U, et al. 2000. Proteasome inhibition interferes with gag polyprotein processing, release, and mat-

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uration of HIV-1 and HIV-2. Proc. Natl. Acad. Sci. USA 97:13057–62 Patnaik A, Chau V, Wills JW. 2000. Ubiquitin is part of the retrovirus budding machinery. Proc. Natl. Acad. Sci. USA 97:13069–74 Strack B, Calistri A, Accola MA, Palu G, Gottlinger HG. 2000. A role for ubiquitin ligase recruitment in retrovirus release. Proc. Natl. Acad. Sci. USA 97:13063– 68 Harty RN, Brown ME, Wang G, Huibregtse J, Hayes FP. 2000. A PPxY motif within the VP40 protein of Ebola virus interacts physically and functionally with a ubiquitin ligase: implications for filovirus budding. Proc. Natl. Acad. Sci. USA 97:13871–76 Kikonyogo A, Bouamr F, Vana ML, Xiang Y, Aiyar A, et al. 2001. Proteins related to the Nedd4 family of ubiquitin protein ligases interact with the L domain of Rous sarcoma virus and are required for gag budding from cells. Proc. Natl. Acad. Sci. USA 98:11199–204 Yasuda J, Hunter E, Nakao M, Shida H. 2002. Functional involvement of a novel Nedd4-like ubiquitin ligase on retrovirus budding. EMBO Rep. 3:636–40 Huang M, Orenstein JM, Martin MA, Freed EO. 1995. p6Gag is required for particle production from full-length human immunodeficiency virus type 1 molecular clones expressing protease. J. Virol. 69:6810–18 VerPlank L, Bouamr F, LaGrassa TJ, Agresta B, Kikonyogo A, et al. 2001. Tsg101, a homologue of ubiquitinconjugating (E2) enzymes, binds the L domain in HIV type 1 Pr55(Gag). Proc. Natl. Acad. Sci. USA 98:7724–29 Pornillos O, Alam SL, Davis DR, Sundquist WI. 2002. Structure of the Tsg101 UEV domain in complex with the PTAP motif of the HIV-1 p6 protein. Nat. Struct. Biol. 9:812–17 Demirov DG, Ono A, Orenstein JM, Freed EO. 2002. Overexpression of the

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N-terminal domain of TSG101 inhibits HIV-1 budding by blocking late domain function. Proc. Natl. Acad. Sci. USA 99: 955–60 Katzmann DJ, Babst M, Emr SD. 2001. Ubiquitin-dependent sorting into the multivesicular body pathway requires the function of a conserved endosomal protein sorting complex, ESCRT-I. Cell 106:145–55 Martin-Serrano J, Zang T, Bieniasz PD. 2003. Role of ESCRT-I in retroviral budding. J. Virol. 77:4794–804 Pornillos O, Alam SL, Rich RL, Myszka DG, Davis DR, Sundquist WI. 2002. Structure and functional interactions of the Tsg101 UEV domain. EMBO J. 21: 2397–406 Martin-Serrano J, Zang T, Bieniasz PD. 2001. HIV-1 and Ebola virus encode small peptide motifs that recruit Tsg101 to sites of particle assembly to facilitate egress. Nat. Med. 7:1313–19

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311. Timmins J, Schoehn G, Ricard-Blum S, Scianimanico S, Vernet T, et al. 2003. Ebola virus matrix protein VP40 interaction with human cellular factors Tsg101 and Nedd4. J. Mol. Biol. 326:493–502 312. Licata JM, Simpson-Holley M, Wright NT, Han Z, Paragas J, Harty RN. 2003. Overlapping motifs (PTAP and PPEY) within the Ebola virus VP40 protein function independently as late budding domains: involvement of host proteins TSG101 and VPS-4. J. Virol. 77:1812– 19 313. Liu J, Furukawa M, Matsumoto T, Xiong Y. 2002. NEDD8 modification of CUL1 dissociates p120(CAND1), an inhibitor of CUL1-SKP1 binding SCF ligases. Mol. Cell 10:1511–18 314. Cope GA, Suh GS, Aravind L, Schwarz SE, Zipursky SL, et al. 2002. Role of predicted metalloprotease motif of Jab1/Csn5 in cleavage of Nedd8 from Cul1. Science 298:608–11

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Figure 1 Representatives of HECT-type and RING-type E3 ligases. (A) The HECT-type E3 Itch promotes ubiquitination of JunB and affects IL-4 gene transcription. The WW domains of Itch recruit JunB, and Ub is transferred from E2 to the HECT domain and then to the substrate. (B) The RING-type E3 Cbl targets the TCR/CD3 complex for Ub conjugation through an adaptor’s role of Zap-70 to form Cbl, Zap-70, and the TCR/CD3 complex. Ub is directly transferred from E2 to the substrate.

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Figure 2 Protein ubiquitination in T cell anergy induction. TCR stimulation in the absence of co-stimulation or treatment of T cells with ionomycin results in an unbalanced activation of NFAT and the transcription of anergy-inducing genes. Some of these gene products turn out to be E3 Ub ligases like Cbl-b, Itch, or the Ub-binding protein, Tsg101 (V. Heissmeyer & A. Rao, submitted manuscript), which together induce the downmodulation of PLCγ–1 and PKCθ, and cause the T cell unresponsiveness. In anergized T cells, a novel RING-type E3 GRAIL is expressed and participates in T cell anergy induction, although the targets for this E3 remain unclear (160).

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CONTENTS FRONTISPIECE—Leonard A. Herzenberg and Leonore A. Herzenberg GENETICS, FACS, IMMUNOLOGY, AND REDOX: A TALE OF TWO LIVES INTERTWINED, Leonard A. Herzenberg and Leonore A. Herzenberg SELF- AND NONSELF-RECOGNITION BY C-TYPE LECTINS ON DENDRITIC CELLS, Teunis B.H. Geijtenbeek, Sandra J. van Vliet, Anneke Engering, Bert A. ’t Hart, and Yvette van Kooyk

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TRANSCRIPTIONAL CONTROL OF EARLY B CELL DEVELOPMENT, Meinrad Busslinger

UBIQUITIN LIGASES AND THE IMMUNE RESPONSE, Yun-Cai Liu LIGANDS FOR L-SELECTIN: HOMING, INFLAMMATION, AND BEYOND, Steven D. Rosen

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INTEGRINS AND T CELL–MEDIATED IMMUNITY, Jonathan T. Pribila, Angie C. Quale, Kristen L. Mueller, and Yoji Shimizu

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MULTIPLE ROLES OF ANTIMICROBIAL DEFENSINS, CATHELICIDINS, AND EOSINOPHIL-DERIVED NEUROTOXIN IN HOST DEFENSE, De Yang, Arya Biragyn, David M. Hoover, Jacek Lubkowski, and Joost J. Oppenheim

STARTING AT THE BEGINNING: NEW PERSPECTIVES ON THE BIOLOGY OF MUCOSAL T CELLS, Hilde Cheroutre THE BCR-ABL STORY: BENCH TO BEDSIDE AND BACK, Stephane Wong and Owen N. Witte

181 217 247

CD40/CD154 INTERACTIONS AT THE INTERFACE OF TOLERANCE AND IMMUNITY, Sergio A. Quezada, Lamis Z. Jarvinen, Evan F. Lind, and Randolph J. Noelle

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THE THREE ES OF CANCER IMMUNOEDITING, Gavin P. Dunn, Lloyd J. Old, and Robert D. Schreiber

AUTOIMMUNE AND INFLAMMATORY MECHANISMS IN ATHEROSCLEROSIS, Georg Wick, Michael Knoflach, and Qingbo Xu THE DYNAMIC LIFE OF NATURAL KILLER CELLS, Wayne M. Yokoyama, Sungjin Kim, and Anthony R. French

329 361 405

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THE ROLE OF COMPLEMENT IN THE DEVELOPMENT OF SYSTEMIC LUPUS ERYTHEMATOSUS, Anthony P. Manderson, Marina Botto, and Mark J. Walport

DROSOPHILA: THE GENETICS OF INNATE IMMUNE RECOGNITION AND RESPONSE, Catherine A. Brennan and Kathryn V. Anderson RAGS AND REGULATION OF AUTOANTIBODIES, Mila Jankovic,

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Rafael Casellas, Nikos Yannoutsos, Hedda Wardemann, and Michel C. Nussenzweig

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THE ROLE OF SUPPRESSORS OF CYTOKINE SIGNALING (SOCS) PROTEINS IN REGULATION OF THE IMMUNE RESPONSE, Warren S. Alexander and Douglas J. Hilton

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NATURALLY ARISING CD4+

REGULATORY T CELLS FOR IMMUNOLOGIC SELF-TOLERANCE AND NEGATIVE CONTROL OF IMMUNE RESPONSES, Shimon Sakaguchi PHOSPHOINOSITIDE 3-KINASE: DIVERSE ROLES IN IMMUNE CELL ACTIVATION, Jonathan A. Deane and David A. Fruman IMMUNITY TO TUBERCULOSIS, Robert J. North and Yu-Jin Jung MOLECULAR DEFECTS IN HUMAN SEVERE COMBINED IMMUNODEFICIENCY AND APPROACHES TO IMMUNE RECONSTITUTION, Rebecca H. Buckley PHYSIOLOGICAL CONTROL OF IMMUNE RESPONSE AND INFLAMMATORY TISSUE DAMAGE BY HYPOXIA-INDUCIBLE FACTORS AND ADENOSINE A2A RECEPTORS, Michail V. Sitkovsky, Dmitriy Lukashev, Sergey Apasov, Hidefumi Kojima, Masahiro Koshiba, Charles Caldwell, Akio Ohta, and Manfred Thiel

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T LYMPHOCYTE–ENDOTHELIAL CELL INTERACTIONS, Jaehyuk Choi, David R. Enis, Kian Peng Koh, Stephen L. Shiao, and Jordan S. Pober

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IMMUNOLOGICAL MEMORY TO VIRAL INFECTIONS, Raymond M. Welsh, Liisa K. Selin, and Eva Szomolanyi-Tsuda

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CENTRAL MEMORY AND EFFECTOR MEMORY T CELL SUBSETS: FUNCTION, GENERATION, AND MAINTENANCE, Federica Sallusto, Jens Geginat, and Antonio Lanzavecchia CONTROL OF T CELL VIABILITY, Philippa Marrack and John Kappler

745 765

ASTHMA: MECHANISMS OF DISEASE PERSISTENCE AND PROGRESSION, Lauren Cohn, Jack A. Elias, and Geoffrey L. Chupp

789

CD1: ANTIGEN PRESENTATION AND T CELL FUNCTION, Manfred Brigl and Michael B. Brenner

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CHEMOKINES IN INNATE AND ADAPTIVE HOST DEFENSE: BASIC CHEMOKINESE GRAMMAR FOR IMMUNE CELLS, Antal Rot and Ulrich H. von Andrian

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INTERLEUKIN-10 AND RELATED CYTOKINES AND RECEPTORS, Sidney Pestka, Christopher D. Krause, Devanand Sarkar, Mark R. Walter, Yufang Shi, and Paul B. Fisher

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INDEXES

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Subject Index Cumulative Index of Contributing Authors, Volumes 12–22 Cumulative Index of Chapter Titles, Volumes 12–22

ERRATA An online log of corrections to Annual Review of Immunology chapters may be found at http://immunol.annualreviews.org/errata.shtml

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Annu. Rev. Immunol. 2004. 22:129–56 doi: 10.1146/annurev.immunol.21.090501.080131 c 2004 by Annual Reviews. All rights reserved Copyright ° First published online as a Review in Advance on September 15, 2003

LIGANDS FOR L-SELECTIN: Homing, Inflammation, and Beyond

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Steven D. Rosen Department of Anatomy and Program in Immunology, University of California, San Francisco, San Francisco, California 94143-0452; email: [email protected]

Key Words leukocyte trafficking, HEV, endothelium, glycosylation, sulfation ■ Abstract Understanding the molecular basis of lymphocyte homing to lymphoid organs was originally a problem of concern only to immunologists. With the discovery of L-selectin and its ligands, interested scientists have expanded to include glycobiologists, immunopathologists, cancer biologists, and developmental biologists. Going beyond its first discovered role in homing to lymph nodes, the L-selectin system is implicated in such diverse processes as inflammatory leukocyte trafficking in both acute and chronic settings, hematogenous metastasis of carcinoma cells, effector mechanisms for inflammatory demyelination of axons, and implantation of the early mammalian embryo. This review focuses on the ligands for L-selectin that are found on vascular endothelium, leukocytes, carcinoma cells, and at various extravascular sites. The discovery of selectins and their ligands has validated the long-predicted hypothesis that carbohydrate-directed cell adhesion is relevant in eukaryotic systems. Emphasis will be given to the carbohydrate and sulfation modifications of the ligands, which enable recognition by L-selectin. The rapid “homing” of labeled cells into the lymph nodes presumably had its basis in the special affinity of small lymphocytes for the endothelium of the postcapillary venules. Gowans & Knight (1)

DEFINING THE PROBLEM In the 1950s and 1960s, James Gowans at the Sir William Dunn School of Pathology at Oxford University discovered that lymphocytes recirculate from the blood into lymphoid organs (“homing”) and back to the blood (1). These landmark studies provided the first enunciation of the role of lymphocyte recirculation in immune surveillance; namely, the process enables small numbers of specific lymphocytes to be brought into contact with antigen in regional lymphoid organs, which underlies primary sensitization of na¨ıve lymphocytes and restimulation of memory cells (2– 4). The quote given above comes from the seminal study in which Knight & Gowans 0732-0582/04/0423-0129$14.00

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(1) determined that the route of lymphocyte entry into lymph nodes is through postcapillary venules in the cortex “which are remarkable for the height of their endothelium.” These vessels are now commonly referred to as “high endothelial venules” (HEV), and the cells comprising them are called “high endothelial cells” (HEC). HEV are not unique to lymph nodes but are found in all secondary lymphoid organs with the exception of the spleen (2). Gowans & Knight (1) noted that the walls of HEV contain many small lymphocytes in various stages of extravasation. The restriction of infiltrating cells to this class of leukocyte led to their prediction of a “special affinity” between the endothelium and the small lymphocytes. In 1976, it became possible to approach the molecular basis of the special affinity through the development of an in vitro adhesion assay for lymphocyte-HEV binding. Overlaying viable lymphocytes onto cryostat-cut sections of lymph node, Stamper & Woodruff (5) observed highly specific adherence of exogenous lymphocytes to profiles of HEV (Figure 1). Taking a monoclonal antibody strategy to decipher the molecular basis of this interaction, Gallatin et al. (6) discovered a cell surface antigen on lymphocytes (gp90MEL-14) as the target of a functionblocking antibody (MEL-14). The subsequent cloning of this molecule led to the identification of L-selectin (CD62L), a type I membrane protein with a Ctype lectin at the amino terminus, an EGF domain, two short consensus repeats, a transmembrane domain, and a short cytoplasmic tail (7). The presence of the lectin domain validated earlier cell biological work that had shown that gp90MEL functions as a calcium-dependent lectin-like receptor that recognizes specific carbohydrate-based ligands on lymph node HEV (8–10). A definitive role for L-selectin in lymphocyte homing to lymph nodes was subsequently established by gene targeting (11). The other members of the selectin family (E- and P-selectin) have the same overall structural organization as L-selectin and also function in

Figure 1 The Stamper-Woodruff in vitro adhesion assay. A cryostat-cut section of a mouse lymph node is shown with exogenously added lymphocytes attached to a profile of an HEV, shown in a longitudinal view. The exogenous lymphocytes are above the plane of the section. The interaction measured by this assay accurately reflects the activity of L-selectin and its HEV-expressed ligands. The discovery of the L-selectin adhesion system emerged from studies with this assay. This experiment was performed by Mark Singer.

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leukocyte-endothelial interactions as C-type lectins (12–14). P-selectin is on activated platelets and endothelial cells. E-selectin is restricted to activated endothelium. It is now recognized that L-selectin is essential for homing of na¨ıve lymphocytes to all HEV-bearing secondary lymphoid organs (2). Homing to secondary lymphoid organs occurs through a cascade of steps, which involves the step-wise action of adhesion and signaling receptors. For na¨ıve lymphocytes and some memory cells, L-selectin serves a primary adhesion receptor by mediating the tethering and rolling of lymphocytes along the apical aspects of HEV. The most fully elucidated adhesion cascade is for homing of na¨ıve lymphocytes to peripheral lymph nodes (PN) in mouse (4). First, L-selectin mediates the tethering and rolling of lymphocytes along the apical aspects of HEV. Second, HEV-associated chemokines such as CCL21 (SLC) engage specific G-protein couple receptors on lymphocytes (CCR7 in the case of SLC), which leads to the activation of LFA-1 on the lymphocyte. Firm arrest of the lymphocyte occurs when LFA-1 interacts with ICAMs on the HEV. Finally, the lymphocyte transmigrates into the lymph node parenchyma. The combinatorial usage of adhesion and signaling receptors provides a paradigm to explain the selective homing of effector/memory lymphocytes to anatomically distinct lymphoid compartments (2, 4). Generalization of this “cascade” or multistep model also accounts for the exquisite spatiotemporal specificity of inflammatory leukocyte trafficking by which leukocyte populations are selectively targeted with precise timing to particular vascular beds (2, 15). L-selectin is broadly distributed on most leukocytes in the blood. Beyond its general role in lymphocyte homing to secondary lymphoid organs, L-selectin is now implicated in many instances of inflammatory leukocyte trafficking (16, 17). Although its best understood function is as a primary adhesion receptor for ligands on the vascular endothelium, L-selectin also mediates leukocyte-leukocyte interactions during inflammatory reactions. Moreover, leukocyte-carcinoma cell interactions mediated through L-selectin promote tumor metastasis. Further expanding the functional repertoire of L-selectin, recent studies have revealed that it has important extravascular functions. The purpose of this review is to summarize the current knowledge about the ligands engaged by L-selectin during normal and pathological processes. Several classes of ligands have been identified with distinct posttranslational modifications and strategies for binding. The structures of the molecules and the enzymes responsible for the their posttranslational modifications will be reviewed.

HEV-EXPRESSED LIGANDS IN LYMPH NODES AND TONSILS Early Work Gesner & Ginsburg (18) were the first to suggest that cell surface carbohydrates serve as recognition determinants in lymphocyte homing. They observed that treatment of lymphocytes with mixed glycosidases, probably including a sialidase

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activity, reduced their homing to lymph nodes and spleen but increased their accumulation in the liver. It is now appreciated that the accumulation of enzyme-treated lymphocytes in the liver was not due to inactivation of a normal homing mechanism but rather the activation of a liver clearance pathway. Ironically, sialic acid determinants were later shown to be critical elements of L-selectin ligands on HEV (9). The pivotal finding was that sialidase treatment of lymph node sections completely abrogates the binding of lymphocytes to HEV. A further intriguing finding was that HEV very avidly incorporate 35S-SO4 into macromolecular components, suggesting an important function of sulfated molecules in the process of lymphocyte homing (19). As detailed below, these early observations have now been rationalized by structural analysis of actual ligands.

Biochemical Identification of Ligands The first HEV-expressed ligands to be identified were GlyCAM-1, CD34, and podocalyxin (7, 20–22). Notably, all are sialomucins, a characteristic that generalizes to most other ligand candidates. Mucins are glycoproteins with multiple O-linked (via Ser or Thr) glycans. Whereas CD34 and podocalyxin are a type I membrane protein (Figure 2), GlyCAM-1 is a secreted protein that is found at high levels in plasma. GlyCAM-1 is also expressed in lactating mammary gland and milk in several species. However, milk GlyCAM-1 does not react with L-selectin (7). The human homologue of GlyCAM-1 is also expressed at the mRNA level in lactating mammary gland but not in lymphoid organs (23). CD34 and podocalyxin are broadly expressed on the vascular endothelium, as well as on hematopoietic

Figure 2 The CD34 family of sialomucins. All three of these glycoproteins exhibit L-selectin ligand activity when they possess the appropriate posttranslational modifications. Endoglycan differs from the other two in having an acidic amino region that contains two tyrosine sulfates. In addition, endoglycan is modified with chondroitin sulfate glycosaminoglycan (GAG) chains. The potential sites for GAG chain addition are the “SG” pairs. The two tyrosines (“Y”) in the acidic domain of endoglycan are modified by sulfation. The transmembrane regions, cysteine-containing regions, and C-terminal cytoplasmic tails are denoted by “M,” “C-C,” and “CT,” respectively. In addition to the overall structural similarity among the three glycoproteins, there is considerable sequence homology in the cytoplasmic tails.

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precursor cells (24, 25). L-selectin-reactive forms of podocalyxin and CD34 are present in the HEV of tonsils in human, whereas nonreactive forms are found in noninflamed vessels (21, 22, 26). A second approach to the identification of HEV-expressed ligands has relied on a widely used mAb known as MECA-79 (27). This antibody strongly stains lymph node HEV in mouse, blocks lymphocyte attachment to HEV in the StamperWoodruff in vitro adherence assay, and inhibits short-term lymphocyte homing to lymph nodes. As revealed by intravital microscopy, MECA-79 effectively blocks the tethering and rolling of lymphocytes along HEV, thus preventing the initiation of the recruitment cascade (28). MECA-79 and an L-selectin-IgG chimera immunoprecipitate the same complex of proteins from mouse lymph nodes and human tonsils (29). In fact, the function-blocking activity of MECA-79 is explained by overlap of its sulfated carbohydrate epitope with the L-selectin recognition determinant (Figure 3 and see below). PNAd, or peripheral lymph node addressin, is

Figure 3 The structure of a disulfated biantennary O-glycan found in HEV-derived GlyCAM-1 from mouse (56). The upper arm is the core 2 branch and the lower arm is the core 1 extension. Both arms are capped by 6-sulfo sLex (indicated by boxes shown in panel A), which is likely to be the minimal recognition determinant for Lselectin. Panel B shows the MECA-79 epitope. This figure was modified from one kindly provided by Carolyn Bertozzi.

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a widely used term to designate the complex of MECA-79-reactive glycoproteins within HEV (2). For mouse lymph nodes and human tonsils, there are four or more distinct members of this complex, including the aforementioned GlyCAM-1 (mouse), CD34 (mouse and human), and podocalyxin (human). Recently, endomucin, another type I membrane sialomucin, was identified as a member of the PNAd complex in mouse and human (30). MAdCAM-1, as isolated from mesenteric lymph nodes, is also a PNAd component, presumably attributable to its short mucin domain (31). It also belongs to the Ig superfamily and serves as a counterreceptor for α4β7 in the homing of lymphocytes to gut-associated lymphoid organs and tissues (2). MAdCAM-1 is not expressed in PN HEV. Other members of the PNAd complex, for example the >200 kd component, have not yet been molecularly identified, although they are susceptible to degradation by a mucindegrading enzyme (O-sialoendoglycoprotease, or OSGE) (22). Furthermore, it should be noted that human tonsillar HEV express L-selectin ligands that are insensitive to OSGE and lack MECA-79 reactivity (32). These nonmucin ligands also remain to be defined. Rolling studies performed in the parallel plate flow chamber have established that the entire PNAd complex as well as its individual members can support tethering and rolling of lymphocytes via L-selectin under physiological flow conditions (21, 22). Null mice have been generated for GlyCAM-1 (26) and CD34 (33) with no obvious abnormality in homing to lymph nodes. It is strongly suspected that the HEV-expressed sialomucins are functionally redundant such that the loss of one member is compensated by the activity of the others. In contrast, significant deficiencies in homing are seen when specific posttranslational modifications shared by these ligands are eliminated by gene targeting (see below). Thus, there is a not a strict requirement for a particular core protein but rather for a set of specific posttranslational modifications. The situation is strikingly different for P-selectin in that its principle leukocyte ligand is a single sialomucin called PSGL-1 (34, 35). Further description of PSGL-1 is provided below.

Biophysics of Selectin-Ligand Interactions For most eukaryotic cells, changes in cell adhesion to other cells or extracellular matrix takes minutes to hours. In contrast, leukocytes whose functions depend on rapid deployment over large distances develop adhesive interactions quickly, and the interactions are usually readily reversible. An extreme example of rapid kinetics is the rolling interaction of blood-borne leukocytes with the vascular endothelium. Here, within seconds of contact, the leukocyte is converted from a free-moving cell to a rolling cell propelled by the blood flow (2). The rolling interaction with the endothelium involves the rapid formation of bonds at the leading edge of the leukocyte and rapid bond dissociation at the trailing edge. From in vitro flow chamber measurements and intravital observations, L-selectin is specialized to mediate fast rolling, as compared to the other two selectins or the α4 integrins (36, 37). In vitro, rolling via L-selectin is about 7–12-fold faster than rolling through

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E- or P-selectin at comparable substrate densities. This faster rolling is correlated with a faster unstressed koff, which is 7–9-fold faster for L-selectin than for the other two selectins. This faster rate of bond dissociation predicts that the rate of tether bond formation, kon, must also be faster for L-selectin in order to maintain stable rolling. L-selectin-mediated rolling exhibits a shear threshold phenomenon in which a minimum wall shear is required for rolling, after which the number of rolling increases and then decreases (38). This behavior is believed to limit the inappropriate interaction of leukocytes with one another in the center of vessels (low shear) or with the vessel wall in low-flow vessels. Rolling via L-selectin is also very stable in that rolling velocity plateaus with increasing wall shear stress (39); this characteristic minimizes variation in the velocity of rolling leukocytes with fluctuations in wall shear stress and provides sufficient time for the leukocytes to be exposed to activating stimuli present on the vessel wall.

Recognition Determinants for L-Selectin and MECA-79 All three selectins recognize sialyl Lewis x (sLex) (Table 1) but with relatively low affinity (40, 41). By NMR spectroscopy, the binding of sLex to L-selectin IgG fusion occurs with a Kd of 3.9 µM (42). Sialylation and fucosylation of the tetrasaccharide are required for binding of sLex to L-selectin (26, 41). An important line of evidence that sLex is actually a component of L-selectin ligands comes from the use of sLex-reactive mAbs. Several of these antibodies stain HEV in human lymphoid organs and in some cases block L-selectin dependent adherence of lymphocytes to HEV in in vitro adherence assays (26). sLex-reactive antibodies also stain capillaries and venules at sites of inflammation (24). In settings of sustained inflammation, the positive vessels frequently are high-walled and are referred to as HEV-like (26, 43). Vessels in nonlymphoid tissues under normal circumstances generally show little if any reactivity with these antibodies (24). The avid incorporation of 35S-SO4 incorporation by HEV mentioned above prompted the original investigation of the possible sulfation of the ligands associated with these vessels (20). In fact, HEV-expressed forms of L-selectin ligands

TABLE 1 Nomenclature and structure of complex carbohydrates Name

Structure

sLex

Siaα2 → 3Galβ1 → 4[Fucα1 → 3]GlcNAc

6-sulfo sLex

Siaα2 → 3Galβ1 → 4[Fucα1 → 3][SO3 → 6]GlcNAc

0

6 -sulfo sLex

Siaα2 → 3[SO3 → 6]Galβ1 → 4[Fucα1 → 3]GlcNAc

6-sulfo LacNAc

Galβ1 → 4[SO3 → 6]GlcNAc

Core 1

Galβ1 → 3GalNAc

Core 2

Galβ1 → 3[GlcNAcβ1 → 6]GalNAc

Extended core 1

GlcNAcβ1 → 3Galβ1 → 3GalNAc

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are sulfated, as directly shown in mouse and human systems (20, 44, 45). Moreover, sulfation is, in fact, essential for L-selectin binding (46) and also for the MECA-79 epitope (29). Structural investigation of mouse GlyCAM-1 found sulfation at C-6 of GlcNAc (i.e., GlcNAc-6-SO4) (47). Importantly, this modification occurs in sLex to yield 6-sulfo sLex (Table 1) (47). In the simplest O-glycans of GlyCAM-1, 6-sulfo sLex occurs as a capping group on the core 2 branch (upper arm in Figure 3) (47). 6-sulfation of sLex enhances its interaction with L-selectin in cell-free assays (26, 48). Also, changing sLex to 6-sulfo sLex on the surface of transfected cells increases binding by L-selectin (49–51). Two mAbs, G72 and G152, recognize 6-sulfo sLex in a sulfation- and sialic acid–dependent manner (52). These antibodies strongly stain HEV in human lymphoid organs and competitively inhibit the binding of L-selectin to these vessels. Taken together, these findings qualify 6-sulfo sLex as a minimal recognition determinant for L-selectin. The original studies of mouse GlyCAM-1 found significant levels of Gal-6sulfate within its O-glycans and inferred the existence of a 60 -sulfo sLex capping structure (Table 1) (47). By contrast, the ligands on human lymph node or tonsillar HEV in humans lack detectable Gal-6-sulfation and 60 -sulfo sLex (44, 45, 52). Whether or not Gal-6-sulfation enhances the interaction of sLex with L-selectin is controversial (26, 53). Furthermore the existence of an enzymatic route for the synthesis of 60 -sulfo sLex is in question (54). Conceivably, Gal-6-sulfation in other structural contexts contributes to ligand activity in the murine system (55). The fact that many of the O-glycans of GlyCAM-1 possess multiple sulfation modifications (47) poses challenges for future structural and functional analyses. The structural elucidation of the MECA-79 epitope has provided further insights into the structure of L-selectin ligands (56). The critical structure is 6-sulfated N-acetyllactosamine (6-sulfo LacNAc) on an extended core 1 O-glycan (Table 1, Figure 3). This oligosaccharide is found in the O-glycans of both native and recombinant GlyCAM-1. In its fully substituted form, the structure is modified with α2 → 3 sialylation on galactose and α1 → 3 fucosylation on GlcNAc, thus providing the 6-sulfo sLex determinant as a capping group. Interestingly, sialylation and fucosylation are dispensable for the MECA-79 epitope, whereas they are required for optimal binding by L-selectin. Native GlyCAM-1 from murine lymph nodes exhibits biantennary O-glycans, both of which are capped by 6-sulfo sLex. The lower arm is the extended core 1 glycan containing the MECA-79 epitope, and the upper arm is the core 2 branch. Mass spectrometry analysis of human tonsillar CD34 is consistent with the existence of the sulfated extended core 1 structure (Figure 3) (44). The dual presentation of the capping group in the biantennary O-glycan potentiates the L-selectin ligand activity of recombinant GlyCAM-1 as compared to forms of GlyCAM-1 in which 6-sulfo sLex is presented only on a single branch (56). This result indicates that both branches are capable of engaging L-selectin. Biacore measurements have shown that the monovalent interaction of L-selectin with native GlyCAM-1 occurs with a Kd of 108 µM, whereas the interaction of oligomeric L-selectin has a much higher affinity (57). Clustering of L-selectin on the cell surface, as is known to occur for P-selectin (35), may allow it to more effectively engage arrays of 6-sulfo sLex on mucin scaffolds, thus promoting

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TABLE 2 Enzymes implicated in the key posttranslational modifications of PNAd for L-selectin binding Structure

Enzyme

References

Core 2 branch

Core2GlcNAcT-I

60

β1 → 4-linked Gal

β4GalT-IV

71

Extended core 1

β3GlcNAcT-3

56

GlcNAc-6-sulfate

HEC-GlcNAc6ST and GlcNAc6T-1

67, 68

α2 → 3-linked Sia

ST3Gal-III, ST3Gal-IV or ST3Gal-VI

70

α1 → 3-linked Fuc

FucT-VII and FucT-IV

54

adhesive interactions through avidity effects. Indirect evidence for clustering of L-selectin has been presented (58).

Enzymes Involved in Posttranslational Modifications The essential role of glycans in the function of HEV-expressed ligands has stimulated considerable interest in the identification of the glycosyltransferases and sulfotransferases involved in their elaboration (59). Table 2 summarizes the known and suspected participation of cloned enzymes in ligand biosynthesis. The relevant enzymes are all type II transmembrane proteins, each with amino-terminal tail in the cytosol, a transmembrane domain, and a larger catalytic domain in the golgi/ER lumen. Glycosyltransferases catalyze the transfer of nucleotide donor sugars to acceptor structures, whereas sulfotransferases catalyze the formation of sulfate esters on acceptor glycans or tyrosines utilizing the high energy sulfate donor PAPS (30 -phosphoadenosine 50 -phosphosulfate) (59). The core 2 branch on the O-glycans of PNAd mucins, such as GlyCAM-1, requires the action of a core 2 β1 → 6-N-acetylglucosaminotransferase (Core2GlcNAcT), which adds GlcNAc in a β1 → 6 linkage to GalNAc in core 1 structures. For ligand formation in mouse lymph nodes, the relevant enzyme of this class is Core2GlcNAcT-I (60). The genetic deletion of this enzyme eliminates the formation of core 2-linked 6-sulfo sLex (56). However, substantial ligand activity and full MECA-79 reactivity persist in the HEV of these mice, apparently because of the extended core 1 glycan, which allows for the presentation of the 6-sulfo sLex determinant. The core 1 extension enzyme in mouse HEV is β3GlcNAcT-3, a member of the family that adds GlcNAc in a β1 → 3 linkage to Gal (61). This enzyme shows a restricted pattern of expression at the mRNA level that includes intestine, colon, placenta, and tonsillar HEV (56). A strong prediction is that null mice for this enzyme will not express MECA-79 reactivity on lymph node HEV. Mice that are doubly deficient in β3GlcNAcT-3 and Core2GlcNAcT-I are predicted to be devoid of 6-sulfo sLex on both arms (Figure 3) and to show a severe homing deficiency.

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Considerable progress has been made in defining the enzymes responsible for the 6-sulfo sLex capping group, which is thought to be directly engaged by the L-selectin lectin domain. Genetic studies in mouse have clearly shown that α1 → 3 fucosylation of GlcNAc is necessary for lymph node HEV ligand function and that FucT-VII is the principal enzyme involved (41, 54, 62). Thus, FucT-VII null mice show a 80%–90% reduction of lymphocyte homing to peripheral lymph nodes, the loss of staining of HEV by an L-selectin/IgM chimera, and markedly reduced ligand activity of isolated GlyCAM-1. A small contribution to ligand function is attributable to another fucosyltransferase, FucT-IV. Whereas mice that are FucTIV null show no loss of homing or impairment of ligand function, mice that are null for both FucTs show profound deficits in both activities, exceeding the effects observed in FucT-VII null mice. Further evidence for the relevance of FucT-VII is that this enzyme can act on 6-sulfo α2→3 sialylated N-acetyllactosamine to form 6-sulfo sLex in vitro (62). Coinciding with a general interest in elucidating the entire sulfotransferase gene family has been the more focused objective of identifying the GlcNAc-6-Osulfotransferases (GlcNAc6STs) involved in the formation of L-selectin ligands. Six members of the subfamily of GlcNAc6STs have been cloned and characterized (63, 64). One of these, known principally as HEC-GlcNAc6ST or LSST (L-selectin ligand sulfotransferase) has received the most attention because of its highly restricted expression in lymph node and tonsillar HEV (49, 65). The enzyme is also referred to as GST-3, CHST4, or GlcNAc6ST-2. In combination with exogenously provided cDNAs (FucT-VII, Core2GlcNAcT-I) and endogenous enzymes (α2 → 3 sialyltransferases), HEC-GlcNAc6ST promotes the L-selectin ligand activity of GlyCAM-1 and CD34 (49, 65, 66). Importantly, HEC-GlcNAc6ST contributes to the formation of the 6-sulfo sLex epitope in transfected cells (49) and the MECA79 epitope when β3GlcNAcT-3 cDNA (core 1 extension enzyme) is included (56). A critical in vivo role for HEC-GlcNAc6ST was established through the analysis of gene-targeted mice (67). First, in vitro binding of lymphocytes to lymph node HEV and luminal staining of HEV by an L-selectin chimera are eliminated in the null mice. Additionally, MECA-79 reactivity of HEV is greatly diminished, with the residual staining being most apparent on the abluminal aspect of these vessels. The ability of lymphocytes to home to null lymph nodes is reduced to 50% of that in wild-type mice, but the residual homing remains entirely L-selectin dependent. An excellent candidate to account for the remaining MECA-79 reactivity in the null mice is another member of the GlcNAc-6-O-sulfotransferase family, namely GlcNAc6ST-1, also known as GST-2 or CHST2 (68). Like HECGlcNAc6ST, this enzyme promotes the formation of L-selectin ligand activity, the MECA-79 epitope, and 6-sulfo sLex determinant in transfected cells (50). Moreover, the enzyme is expressed in lymph node HEV, although its tissue expression is much broader than that of HEC-GlcNAc6ST. Galactose-6-O-sulfation (55) and other ligand-generating strategies (69) also have to be considered as potential contributing factors to the residual ligands. Although sialylation was the first recognized posttranslational modification required for L-selectin ligands (9), its enzymatic basis remains unresolved. Six

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mammalian genes are known to add α2 → 3 sialylation to Gal (ST3Gal-I through VI) (70). Of these, three (ST3Gal-III, ST3Gal-IV, and ST3Gal-VI) can sialylate N-acetyllactosamine (Galβ1 → 4GlcNAc) in vitro and thus are candidates for involvement in the formation of sLex. The collaborative involvement of more than one sialyltransferase is indicated for the formation of ligands for E- and P-selectin (70). A similar scenario is likely to hold for L-selectin. Finally, the identification of the β1 → 4 galactosyltransferase (β4GalT) involved in the formation of the 6-sulfo sLex recognition determinant has received recent attention. It is clear that this action of this enzyme must follow the 6-sulfation of GlcNAc because the GlcNAc6STs act on GlcNAc only when it is terminal (64). Among the seven cloned β4GalTs, the relevant enzyme appears to be β4GalT-IV, as it is the only family member that efficiently adds Gal to the appropriate GlcNAc6-SO4-terminated glycans (71). Moreover, the broad distribution of this enzyme includes relatively strong expression in lymph nodes. Gene targeting has established that β4GalT-I makes a major contribution to the formation of P-selectin ligand activity on monocytes and neutrophils, whereas it has no detectable role in the elaboration of L-selectin ligands on HEV (72). Establishing a definitive role for β4GalT-IV in lymphocyte homing awaits a similar approach. In view of the foregoing discussion and the known acceptor preferences of the enzymes, a plausible scheme for the synthesis of 6-sulfo sLex would be the sequential action of the following enzymes on a GlcNAc-terminated acceptor: (A) HEC-GlcNAc6ST or GlcNAc6T-1; (B) β4GalT-IV; (C) α2 → 3 sialyltransferase (ST3Gal-III, ST3Gal-IV, or ST3Gal-VI); and (D) FucT-VII (54).

L-SELECTIN LIGANDS ON OTHER VASCULAR BEDS HEV-Expressed Ligands in Mucosal Lymphoid Organs Peyer’s patches (PP), one component of gut-associated lymphoid tissue, are found in the wall of the small intestine and participate in mucosal immune defense. Application of the Stamper-Woodruff assay to mouse PP failed to reveal the involvement of L-selectin in lymphocyte homing to this organ (6). Subsequently, in vivo homing studies and intravital microscopy established that naive lymphocytes tether and roll on PP HEV via L-selectin whereas activated/memory populations utilize α4β7 for these steps (73). Although L-selectin mediated rolling is faster in PP HEV than in PN HEV, efficient chemokine-mediated arrest is achieved because the rolling of naive lymphocytes is slowed through the braking action of the α4β7-MAdCAM-1 system. Very limited information is available about the nature of L-selectin ligands in mouse PP HEV. These molecules do not belong to the PNAd complex since administration of the MECA-79 mAb does not inhibit lymphocyte homing to PP, and the relatively weak staining of HEV by this antibody is predominantly in an abluminal pattern (for some strains of mice but not all) (27). Antibody blockade studies implicate MAdCAM-1 as a potential L-selectin ligand at this site, presumably through carbohydrate determinants presented by its mucin domain (73).

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Gene targeting experiments have yet to be performed to substantiate this possibility. Core2GlcNAcT-I-deficient mice show only a slight impairment in ligand activity within PP HEV (74). However, FucT-VII-deficient mice show a ∼60% deficiency in homing to PP, consistent with the known participation of L-selectin in this process (62). From these results, it is plausible that the PP HEV luminal ligand is based on sLex presented on an N-linked chain or on an extended core 1 O-glycan. It should be noted that in others species (sheep, rabbit, and pig), MECA-79 staining of PP HEV is intense, comparable to that of lymph node HEV (75). Thus, in these cases, MECA-79-reactive molecules are likely to be the predominant ligands engaged by L-selectin. Bronchus-associated lymphoid tissue (BALT) is a mucosal lymphoid organ that is morphologically and functionally related to PP (76). It is somewhat surprising that the adhesion cascades are very different for these two anatomic sites. Thus, the L-selectin/PNAd system predominates in the homing of lymphocytes to mouse BALT in correspondence with strong staining of HEV by MECA-79 (76). The homing of memory lymphocytes to BALT relies on the α4β1-VCAM-1 adhesion pair rather than the α4β7-MAdCAM-1 system utilized in PP. In mouse nasal-associated lymphoid tissue, another example of a mucosal lymphoid organ, the L-selectin/PNAd system also makes a substantial contribution to lymphocyte adherence to HEV (77).

Induction of MECA-79+ Vessels at Sites of Chronic Inflammation Extralymphoid tissues are supplied with lymphocytes that perform surveillance and effector functions. Excessive recruitment of lymphocytes to these tissues results in the formation of chronic inflammatory lesions, which can cause disease. When inflammation persists for sustained periods, the inflammatory infiltrates frequently demonstrate features of lymphoid organs, including the compartmentalization of B and T cells, and the presence of dendritic cells and HEV-like vessels (78). Depending on the inflamed organ, these vessels express PNAd and/or MAdCAM-1. The overall process, referred to as lymphoid organ neogenesis, is observed in several common autoimmune diseases (e.g., rheumatoid arthritis, multiple sclerosis, thyroiditis, diabetes, and chronic inflammatory bowel disease) (78, 79). Lymphoid aggregates can also be induced experimentally in transgenic mice through the expression of various chemokines (e.g., CXCL13 and CCL21) or cytokines (e.g., LTαβ) at ectopic sites (78). Investigation of one of these models has shown a strong correlation between the expression of HEC-GlcNAc6ST protein in HEVlike vessels and MECA-79 staining (80). In other examples of chronic inflammation, infiltrates are more diffuse, lacking an organized lymphoid structure. Psoriatic skin lesions are generally of this character (81), and about half of the infiltrates in rheumatoid arthritis fall into this category (82a). MECA-79+ vessels, with either an HEV-like character or flatwalled, are frequently seen in a variety of inflamed sites (26, 43, 83). Renkonen

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and coworkers (24) have carried out systematic surveys in humans, involving large numbers of independent samples. In asthma, thyroiditis, heart and kidney allograft rejection, ulcerative colitis, and psoriasis, MECA-79 reactivity is present on a substantial proportion of CD34+ vessels in the infiltrates. Similarly, Salmi et al. (82b) determined that this epitope is present on a subpopulation of synovial vessels in the majority of chronic arthritis patients. In several mouse models of inflammation, MECA-79 staining of HEV-like vessels has been confirmed to reflect L-selectin ligand activity. Thus, the staining has been correlated with positive reactivity with an L-selectin/IgG chimera (84) or L-selectin-dependent binding of lymphocytes in the Stamper-Woodruff assay (85). Most convincing has been the demonstration that an L-selectin mAb and MECA-79 both effectively inhibit short-term lymphocyte homing to the inflamed organs (86, 87). Substantiation of the importance of the PNAd complex in pathogenesis awaits the use of MECA-79 or a related antibody in a model of chronic inflammatory disease.

Ligands Associated with Acutely Inflamed Vessels Many studies have demonstrated an involvement of L-selectin in the recruitment of leukocytes to sites of acute inflammation (16). The standard approaches have been based on use of function-blocking antibodies or by exploiting L-selectin-deficient mice. For example, in the classic model of thioglycollate-induced inflammation in the peritoneum, the absence of L-selectin results in a significant reduction in the number of neutrophils, macrophages, and lymphocytes recruited between 24 and 48 h (88). L-selectin mAbs are protective in multiple models of ischemiareperfusion injury and hemorrhagic shock (17), thus establishing the relevance of L-selectin to actual disease processes. A humanized antibody against L-selectin is currently under development by Scil Biomedicals (http://www.scil.de) for the treatment of multi-organ failure following severe trauma. Intravital microscopy has allowed the visualization of L-selectin-dependent interactions of leukocytes with acutely inflamed vessels. The most thoroughly studied system has been the mouse cremaster muscle, in which surgical exteriorization induces rolling of leukocytes in venules (37). Initially, the rolling of granulocytes is exclusively due to P-selectin but by 1 h postsurgery shows a codependency between L-selectin and P-selectin. In TNF-α treated preparations, L-selectin cooperates with E- and P-selectin to mediate rolling. Other systems have been described in which L-selectin predominates in mediating rolling. For example, Lselectin transfectants lacking ligands for E- or P-selectin roll in mesenteric venules of rat (89). More physiologically, the rolling of na¨ıve T cells in the cremaster preparation is almost exclusively dependent on L-selectin (81). It is now clear that leukocyte rolling on the vascular endothelium is more complicated than just the primary interaction of the two cell types. This possibility was initially suggested by in vitro observations showing that neutrophils can roll on endothelial-adherent neutrophils (90). This process is mediated through

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L-selectin on the rolling cells. Alon et al. (91) further observed L-selectin-dependent interleukocyte tethering events that enhance the accumulation of neutrophils (in “strings”) on several different adhesive substrata. The term secondary tethering (91), or secondary capture (92), have been coined for this phenomenon. High resolution imaging in mice has now confirmed the in vivo relevance of secondary capture and the molecular basis for it. Eriksson et al. (92) observed that free-flowing cells can tether on cells already rolling on vascular endothelium, converting the former cells into rolling cells. This phenomenon occurs on venules after surgical trauma, on arterial vessels after cytokine exposure, and on atherosclerotic lesions in the aorta. Secondary tethering can account for 20%–50% of the overall rolling flux. Importantly, the leukocyte-leukocyte interactions are completely dependent on Lselectin, whereas the primary interactions between leukocytes and endothelium are L-selectin independent (92). These new findings can rationalize the functional synergy between L-selectin and the vascular selectins discussed above. The nature of the L-selectin ligands operative in the acute settings of inflammation has been a subject of some interest for many years. MECA-79 staining of acutely inflamed vessels have not been reported. In the search for candidate molecules, various L-selectin ligand activities have been described on different types of cultured endothelium. These include a heparan sulfate-based activity on arterial endothelium (93), a sulfation-dependent ligand on TNF-α stimulated microvascular endothelial cells (94), and a sulfation- and sLex-dependent (but MECA-79-unreactive) ligand on TNF-α stimulated HUVEC (95). One molecularly defined ligand candidate is endoglycan (Figure 2) (96). It is found on vascular endothelium as well as leukocyte subpopulations. The appropriately modified recombinant protein can function as an L-selectin ligand (69). See the next section for a complete description of this molecule. Thus far, evidence is lacking on the in vivo relevance of these ligand candidates. The recent appreciation of the role of L-selectin in the secondary capture phenomenon has focused attention on leukocyte-expressed PSGL-1 as the relevant Lselectin ligand in acute inflammatory settings rather than an endothelial-expressed molecule. Antibody blockade of PSGL-1 or genetic deletion of this molecule eliminates the L-selectin-dependent component of rolling in the cremaster muscle model (97). Consistent with the findings of Eriksson et al. (92), L-selectin-dependent rolling events are attributable to secondary tethers to endothelial-adherent leukocytes or to fragments thereof (97).

LEUKOCYTE LIGANDS FOR L-SELECTIN PSGL-1 Antibody blockade and genetic deletion studies have established that PSGL-1 is the major leukocyte ligand for both P- and L-selectin (98–101). This sialomucin is a type I transmembrane protein that is broadly expressed on leukocytes (34). P- and L-selectin bind to the extreme amino-terminal region of PSGL-1,

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which is exposed after biosynthetic processing (35). Extensive studies have defined the posttranslational modifications of PSGL-1 that enable its binding to the selectins (35, 102–105). Essential are 3 tyrosine sulfate moieties (Tyr-46, Tyr-48, and Tyr-51) and a single O-glycan (Thr-58) bearing sLex on a core 2 branched O-glycan. All three tyrosine sulfates contribute to the ligand activity for L- and P-selectin, although the relative importance of the individual tyrosine sulfates differs for the two. Interestingly, the monovalent affinity of the aminoterminal fragment for L-selectin is about eightfold lower than for P-selectin (Kds of 5 µM versus 650 nM) (104). However, this affinity is 20-fold stronger than that reported for GlyCAM-1 (57). As is the case for L-selectin-mediated rolling on PNAd elements (see above), leukocytes require a minimum shear stress in order to roll on PSGL-1 (104). This shear-threshold phenomenon would help to minimize leukocyte-leukocyte interactions in the center of vessels where shear is absent and promote interactions (secondary capture) near the wall where shear is highest (38). Considerable information is available about the enzymes that provide the essential posttranslational modifications to L-selectin ligands (i.e., principally PSGL-1) on leukocytes. The available information is summarized in Table 3. Interestingly, GlcNAc-6-sulfation of PSGL-1 has a dramatic impact on its Lselectin ligand activity. Thus, PSGL-1 modified with 6-sulfo sLex, as imparted by transfection with FucT-VII and GlcNAc6ST-1, is a much superior L-selectin ligand than the sLex-modified form (106). Moreover, the amino-terminal tyrosine sulfates are rendered dispensable for its ligand activity. In contrast, P-selectin ligand activity is only marginally enhanced by the 6-sulfation of sLex while maintaining a critical dependency on tyrosine sulfation. These results indicate that L-selectin prefers ligands (PSGL-1 or other mucins) based on 6-sulfo sLex rather than sLex/Tyr sulfation, whereas the reverse appears to be true for P-selectin. The key question is whether 6-sulfo sLex actually decorates ligands on leukocytes. Staining of granulocytes by a 6-sulfo sLex-specific mAb has not been reported, although a small subpopulation of CD4 memory T cells is positive (107). Differentiated NK cells express a sulfated lactosamine epitope (PEN5) on PSGL-1 (108). This epitope appears to confer L-selectin binding activity, which is

TABLE 3 Enzymes implicated in the key posttranslational modifications of leukocyte ligands for L-selectin Structure

Enzyme

References

Core 2 branch

Core2GlcNAcT-I

60

β1 → 4-linked Gal

β4GalT-I

72

Tyrosine sulfate

TPST-1/TPST-2

105

α2 → 3-linked Sia

ST3Gal-IV

70

α1 → 3-linked Fuc

FucT-VII

60

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independent of the amino-terminal tyrosine sulfates. Although PEN5 is suspected to involve GlcNAc-6-sulfate, its structure and relationship to 6-sulfo sLex remain to be defined.

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Other Ligands A variety of experiments point to the existence of PSGL-1 independent ligands on leukocytes. For example, neutrophil-neutrophil interactions that form under shear stress are completely dependent on L-selectin but are incompletely inhibited (60%) by a PSGL-1 mAb (109). Similarly, the rolling of myeloid cells on an L-selectin substratum is partially blocked by PSGL-1 antibodies, whereas rolling on a Pselectin substratum is totally inhibited (99). A detergent extract of HL60 retains Lselectin ligand activity after immunodepletion of PSGL-1. As this residual activity is sensitive to both sialidase and OSGE, a sialomucin character is indicated. Endoglycan (EG) is a member of the CD34 family of sialomucins that also includes CD34 and podocalyxin (Figure 2). Although its tissue distribution is incompletely defined at this point, it is known to be present on leukocytes subpopulations, hematopoietic precursors, and vascular endothelium (96). Like CD34 and podocalyxin, endoglycan possesses a mucin domain. However, in distinction, it possesses an amino terminal domain of 174 amino acids with an abundance of acidic residues and two tyrosine sulfates (Figure 2). Endoglycan exhibits striking parallels with PSGL-1 (69). Both form disulfide bond-dependent heterodimers in SDS gels. There is significant homology in a critical 9 amino acid span in the acidic region, including identity at the residues corresponding to Tyr 51 (Tyr-118 in EG) and Thr 58 (Thr-124 in EG) in PSGL-1. The acidic domain, when modified with FucT-VII, supports rolling of Jurkat T cells through L-selectin. The ligand activity depends on the two tyrosine sulfates and sLex on core 2-linked O-glycans (predominantly Tyr-124). Whether leukocyte-expressed endoglycan functions as ligand for E- and P-selectin awaits further studies. In view of its expression on vascular endothelium, the role of endoglycan as an endothelial ligand for L-selectin also merits attention. Finally, it is very noteworthy that endoglycan carries several chondroitin sulfate chains. This class of glycosaminoglycan chains, if appropriately sulfated, can impart binding to both L-selectin and chemokines (110), raising further functional possibilities for this molecule. Chrondroitin sulfate-modified ligands for L-selectin have been reported on cultured HEC from rat lymph node (111).

“BEYOND”: LIGANDS IN SURPRISING PLACES Tumor Metastasis Tumor cells frequently exhibit altered cell surface glycosylation (112). The cell surface expression of sLex/sLea epitopes (both of which are recognition determinants for selectins) is positively correlated with tumor progression and metastasis in humans (113). Furthermore, human carcinoma cell lines, such as LS180, express sialomucins that can serve as L- and P-selectin ligands (114). The vivo

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relevance of these findings has been explored in mouse models of metastasis (115, 116). Utilizing sialomucin-based ligands on LS180 cells, L-selectin and P-selectin synergistically facilitate metastasis in immunodeficient mice. Similarly, the lung metastasis of a mouse adenocarcinoma cell in syngeneic mice is critically dependent on these selectins. In this case, the P-selectin ligands on the carcinoma cells are predominantly sulfated glycolipids (e.g., sulfatide), whereas the L-selectin ligand is carried by a combination of sulfated glycolipids, sialomucins, and glycosaminoglycans. P-selectin appears to act first in the metastatic process, probably by mediating the interaction of activated platelets with the carcinoma cells. Acting in subsequent steps, L-selectin may provide the platelet-carcinoma emboli with a leukocyte “coat.” The increased size of the aggregates could facilitate mechanical trapping of the emboli in the microvasculature; alternatively, the leukocyte layer could bridge the emboli to the vascular endothelium through L-selectin-mediated primary or secondary capture events. A related mechanism may explain why ectopic expression of L-selectin in carcinoma cells induces their metastasis to lymph nodes (117). The “commandeering” of selectin mechanisms by metastasizing cancer cells merits further study (118). Novel therapeutic approaches for the treatment of hematogenous metastasis may result.

Perivascular and Extravascular Ligands Streeter et al. (27) in their original description of the MECA-79 antibody noted that the epitope is found on abluminal aspects of HEV in addition to blood-exposed luminal regions. When sensitive immunohistochemical techniques are used, a reticular pattern of staining is observed, which emanates from the HEV and extends for a considerable distance into the parenchyma of the lymphoid organ (Figure 4). One

Figure 4 The reticular pattern of MECA-79 staining around HEV. Shown is a mouse lymph node section stained with MECA-79. The staining was performed using a fluorescently labeled second antibody. The epitope is present on both the luminal and abluminal aspects of HEV and extends into the lymph node parenchyma in a reticular pattern. The image was provided by Durwin Tsay.

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provocative possibility is that these reticular ligands serve as tracks for lymphocytes, facilitating their dispersal from the HEV. Alternatively, these ligands could stimulate signaling in lymphocytes. Ligation of L-selectin on the surface of leukocytes activates signaling pathways that modulate integrin-mediated adhesivity and chemoattractant receptivity of the cells (119–122). Intriguingly, L-selectin ligands have been detected on efferent lymphatic vessels in lymph nodes, suggesting that L-selectin may be involved in exiting of lymphocytes from lymph nodes (123). Further study is needed to delineate the contributions of L-selectin to lymphocyte migration within the parenchyma of lymphoid organs. Studies by Hickey et al. (124) support a role for L-selectin in extravascular migration of leukocytes in an acute inflammatory setting. Superfusing the mouse cremaster muscle preparation with a chemoattractant (platelet activating factor or KC) induces emigration of leukocytes. In the absence of L-selectin or with this molecule functionally neutralized, the distance that extravasated leukocytes migrate is reduced by 50% or more. The nature of the postulated perivascular or interstitial ligands is open to speculation. Proteoglycans are candidates, since certain forms of chondroitin sulfate and heparan sulfate proteoglycans exhibit L-selectin ligand activity (125–127). In a rat kidney model of inflammation, interstitial sulfatide has been implicated as an L-selectin ligand for infiltrating mononuclear cells. (128). It is noteworthy that sulfatide, as distinct from PNAd elements, mediates L-selectin-dependent adhesive interactions under static conditions (129). This property is consistent with ligand function in the extravascular compartment where shear forces would be minimal (see below).

Ligands on Myelin In 1979, Woodruff adapted her in vitro adhesion assay to brain sections and showed that lymphocytes selectively adhere to white matter regions of the central nervous system (Figure 5) (130). After the discovery of L-selectin, it was shown that Lselectin is required for this interaction (131, 132). Ligands were directly demonstrated with an L-selectin fusion protein as a histochemical probe. The ligands are present on myelin sheaths of axons in the CNS but not in the peripheral nervous system. In contrast to HEV ligands, the myelin ligands are sialic acid–independent and are extractable with organic solvents. A prominent candidate for the activity is sulfatide, which is a major constituent of myelin sheaths and is known to bind to L-selectin (see above). From their results, Huang et al. (131) speculated that L-selectin may play a role in the targeting of leukocytes to myelinated axons during demyelinating diseases. Recent experiments of Grewal et al. (133) in a model of experimental allergic encephalomyelitis (EAE) have provided incentive to revisit this hypothesis. Transgenic mice with a T cell receptor specific for myelin basic protein (MBP) exhibit rapid onset of paralysis and demyelination after immunization with an MBP peptide. When the mice are put on an L-selectin null background, the animals fail to develop damage to myelin and do not show clinical signs of EAE. This protection is seen even though neither antigen activation of CD4 cells

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Figure 5 In vitro adhesion of lymphocytes to white matter region of brain. The Stamper-Woodruff assay was performed with a section of mouse cerebellum. The darkly staining cells over the white matter tract (W) are adherent exogenous lymphocytes. Very few lymphocytes bind to the granular layer (G) or the molecular layer (M). The white matter region contains myelinated axons. Similar binding to other white matter regions of the CNS is seen. The binding to these regions requires L-selectin. The ligand is present on myelin sheaths of CNS axons.

nor leukocyte recruitment (T cells, B cells, and macrophages) into the CNS is compromised by the absence of L-selectin. Remarkably, EAE could be induced in L-selectin null animals by the adoptive transfer of wild-type macrophages. These experiments argue that the destruction of myelin during the effector phase of EAE requires L-selectin on extravasated macrophages. Whether L-selectin engagement of a myelin ligand is involved in this pathogenic process remains to be determined. Of great interest is whether L-selectin is a contributing factor to the effector phase of disease in other cases of inflammatory demyelination.

Implantation The first example of the presence of L-selectin on a nonhematopoietic cell is the remarkable finding that the human blastocyst-stage embryo, as well as trophoblasts, express this receptor in a functional form (134). Furthermore, uterine epithelium (human but not mouse) upregulates MECA-79-reactive determinants during the receptive period for implantation. That the ligand-receptor system might be functional at the fetal/maternal interface was shown through the application of the Stamper-Woodruff adhesion assay to endometrial biopsies. Trophoblasts interact

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with luteal-phase uterine epithelium (receptive) and much less so to follicular phase tissue (nonreceptive). The interaction is inhibited by L-selectin and MECA79 mAbs. As reviewed above, GlcNAc6ST-1 is one of the enzymes than can provide the sulfation modification recognized by MECA-79. Interestingly, gene profiling of endometrium shows that the expression of mRNA for this enzyme is upregulated during the window of implantation but is diminished in women with endometriosis, an infertility condition (135). Clearly, the L-selectin system will receive considerable attention from investigators who study implantation, placentation, and their disorders.

FUTURE PERSPECTIVES The study of L-selectin and its ligands will remain an active area for many years to come. Major structural and mechanistic questions remain as to the nature of the receptor ligand interactions and how these molecular interactions are translated into cellular interactions. Considerable efforts will be required to elucidate the full complement of ligand scaffolds and the posttranslational modifications involved in the vascular and extravascular ligand functions detailed in the present review. A second major theme for future work will be the continued investigation of the diverse and expanding functions for L-selectin. Further understanding of how Lselectin participates in the processes of inflammatory trafficking, metastasis, CNS demyelination, and implantation is likely to generate new opportunities for the treatment and diagnosis of human disorders. ACKNOWLEDGMENTS This work in the author’s lab is supported by grants from the NIH (R37GM23547 and GM57411), Sandler Foundation, and the Dana Foundation. The Annual Review of Immunology is online at http://immunol.annualreviews.org

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cell function and migration. Two sides of the same coin. N. Engl. J. Med. 343:1020– 34 5. Stamper H, Woodruff J. 1976. Lymphocyte homing into lymph nodes: in vitro demonstration of the selective affinity of recirculating lymphocytes for highendothelial venules. J. Exp. Med. 144: 828–33 6. Gallatin W, Weissman I, Butcher E. 1983. A cell-surface molecule involved

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18. Gesner BM, Ginsburg V. 1964. Effect of glycosidases on the fate of transfused lymphocytes. Proc. Natl. Acad. Sci. USA 52:750–55 19. Andrews P, Ford W, Stoddart R. 1980. Metabolic studies of high-walled endothelium of postcapillary venules in rat lymph nodes. CIBA Symp. 71:211–30 20. Imai Y, Singer MS, Fennie C, Lasky LA, Rosen SD. 1991. Identification of a carbohydrate-based endothelial ligand for a lymphocyte homing receptor. J. Cell Biol. 113:1213–21 21. Puri KD, Finger EB, Gaudernack G, Springer TA. 1995. Sialomucin CD34 is the major L-selectin ligand in human tonsil high endothelial venules. J. Cell Biol. 131:261–70 22. Sassetti C, Tangemann K, Singer MS, Kershaw DB, Rosen SD. 1998. Identification of podocalyxin as an HEV ligand for L-selectin: parallels to CD34. J. Exp. Med. 187:1965–75 23. Rasmussen LK, Johnsen LB, Petersen TE, Sorensen ES. 2002. Human GlyCAM1 mRNA is expressed in the mammary gland as splicing variants and encodes various aberrant truncated proteins. Immunol. Lett. 83:73–75 24. Renkonen J, Tynninen O, Hayry P, Paavonen T, Renkonen R. 2002. Glycosylation might provide endothelial zip codes for organ-specific leukocyte traffic into inflammatory sites. Am. J. Pathol. 161:543– 50 25. McNagny KM, Pettersson I, Rossi F, Flamme I, Shevchenko A, et al. 1997. Thrombomucin, a novel cell surface protein that defines thrombocytes and multipotent hematopoietic progenitors. J. Cell Biol. 138:1395–407 26. Rosen SD. 1999. Endothelial ligands for L-selectin: from lymphocyte recirculation to allograft rejection. Am. J. Pathol. 155: 1013–20 27. Streeter PR, Rouse BTN, Butcher EC. 1988. Immunohistologic and functional characterization of a vascular addressin

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124. Hickey MJ, Forster M, Mitchell D, Kaur J, De Caigny C, Kubes P. 2000. L-selectin facilitates emigration and extravascular locomotion of leukocytes during acute inflammatory responses in vivo. J. Immunol. 165:7164–70 125. Kawashima H, Li YF, Watanabe N, Hirose J, Hirose M, Miyasaka M. 1999. Identification and characterization of ligands for L-selectin in the kidney. I. Versican, a large chondroitin sulfate proteoglycan, is a ligand for L-selectin. Int. Immunol. 11:393–405 126. Wang L, Brown JR, Varki A, Esko JD. 2002. Heparin’s anti-inflammatory effects require glucosamine 6-O-sulfation and are mediated by blockade of L- and Pselectins. J. Clin. Invest. 110:127–36 127. Kawashima H, Watanabe N, Hirose M, Sun X, Atarashi K, et al. 2003. Collagen XVIII, a basement membrane heparan sulfate proteoglycan, interacts with L-selectin and monocyte chemoattractant protein-1. J. Biol. Chem. 278:13069–76 128. Shikata K, Suzuki Y, Wada J, Hirata K, Matsuda M, et al. 1999. L-selectin and its ligands mediate infiltration of mononuclear cells into kidney interstitium after ureteric obstruction. J. Pathol. 188:93– 99 129. Alon R, Feizi T, Yuen C-T, Fuhlbrigge RC, Springer TA. 1995. Glycolipid ligands for selectins support leukocyte tethering and rolling under physiologic flow conditions. J. Immunol. 154:5356–66 130. Kuttner B, Woodruff J. 1979. Selective adherence of lymphocytes to myelinated areas of rat brain. J. Immunol. 122:1666–68 131. Huang K, Geoffroy JS, Singer MS, Rosen SD. 1991. A lymphocyte homing receptor (L-selectin) mediates the in vitro attachment of lymphocytes to myelinated tracts of the central nervous system. J. Clin. Invest. 88:1778–83 132. Huang K, Kikuta A, Rosen SD. 1994. Myelin localization of a central nervous system ligand for L-selectin. J. Neuroimmunol. 53:133–41

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133. Grewal IS, Foellmer HG, Grewal KD, Wang H, Lee WP, et al. 2001. CD62L is required on effector cells for local interactions in the CNS to cause myelin damage in experimental allergic encephalomyelitis. Immunity 14:291–302 134. Genbacev OD, Prakobphol A, Foulk RA, Krtolica AR, Ilic D, et al. 2003. Trophoblast L-selectin-mediated adhesion Annu. Rev. Immunol. 2004.22:129-156. Downloaded from arjournals.annualreviews.org by HINARI on 09/01/07. For personal use only.

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at the maternal-fetal interface. Science 299:405–8 135. Kao LC, Germeyer A, Tulac S, Lobo S, Yang JP, et al. 2003. Expression profiling of endometrium from women with endometriosis reveals candidate genes for disease-based implantation failure and infertility. Endocrinology 144:2870– 81

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Annual Review of Immunology Volume 22, 2004

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CONTENTS FRONTISPIECE—Leonard A. Herzenberg and Leonore A. Herzenberg GENETICS, FACS, IMMUNOLOGY, AND REDOX: A TALE OF TWO LIVES INTERTWINED, Leonard A. Herzenberg and Leonore A. Herzenberg SELF- AND NONSELF-RECOGNITION BY C-TYPE LECTINS ON DENDRITIC CELLS, Teunis B.H. Geijtenbeek, Sandra J. van Vliet, Anneke Engering, Bert A. ’t Hart, and Yvette van Kooyk

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TRANSCRIPTIONAL CONTROL OF EARLY B CELL DEVELOPMENT, Meinrad Busslinger

UBIQUITIN LIGASES AND THE IMMUNE RESPONSE, Yun-Cai Liu LIGANDS FOR L-SELECTIN: HOMING, INFLAMMATION, AND BEYOND, Steven D. Rosen

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INTEGRINS AND T CELL–MEDIATED IMMUNITY, Jonathan T. Pribila, Angie C. Quale, Kristen L. Mueller, and Yoji Shimizu

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MULTIPLE ROLES OF ANTIMICROBIAL DEFENSINS, CATHELICIDINS, AND EOSINOPHIL-DERIVED NEUROTOXIN IN HOST DEFENSE, De Yang, Arya Biragyn, David M. Hoover, Jacek Lubkowski, and Joost J. Oppenheim

STARTING AT THE BEGINNING: NEW PERSPECTIVES ON THE BIOLOGY OF MUCOSAL T CELLS, Hilde Cheroutre THE BCR-ABL STORY: BENCH TO BEDSIDE AND BACK, Stephane Wong and Owen N. Witte

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CD40/CD154 INTERACTIONS AT THE INTERFACE OF TOLERANCE AND IMMUNITY, Sergio A. Quezada, Lamis Z. Jarvinen, Evan F. Lind, and Randolph J. Noelle

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THE THREE ES OF CANCER IMMUNOEDITING, Gavin P. Dunn, Lloyd J. Old, and Robert D. Schreiber

AUTOIMMUNE AND INFLAMMATORY MECHANISMS IN ATHEROSCLEROSIS, Georg Wick, Michael Knoflach, and Qingbo Xu THE DYNAMIC LIFE OF NATURAL KILLER CELLS, Wayne M. Yokoyama, Sungjin Kim, and Anthony R. French

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THE ROLE OF COMPLEMENT IN THE DEVELOPMENT OF SYSTEMIC LUPUS ERYTHEMATOSUS, Anthony P. Manderson, Marina Botto, and Mark J. Walport

DROSOPHILA: THE GENETICS OF INNATE IMMUNE RECOGNITION AND RESPONSE, Catherine A. Brennan and Kathryn V. Anderson RAGS AND REGULATION OF AUTOANTIBODIES, Mila Jankovic,

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Rafael Casellas, Nikos Yannoutsos, Hedda Wardemann, and Michel C. Nussenzweig

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THE ROLE OF SUPPRESSORS OF CYTOKINE SIGNALING (SOCS) PROTEINS IN REGULATION OF THE IMMUNE RESPONSE, Warren S. Alexander and Douglas J. Hilton

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REGULATORY T CELLS FOR IMMUNOLOGIC SELF-TOLERANCE AND NEGATIVE CONTROL OF IMMUNE RESPONSES, Shimon Sakaguchi PHOSPHOINOSITIDE 3-KINASE: DIVERSE ROLES IN IMMUNE CELL ACTIVATION, Jonathan A. Deane and David A. Fruman IMMUNITY TO TUBERCULOSIS, Robert J. North and Yu-Jin Jung MOLECULAR DEFECTS IN HUMAN SEVERE COMBINED IMMUNODEFICIENCY AND APPROACHES TO IMMUNE RECONSTITUTION, Rebecca H. Buckley PHYSIOLOGICAL CONTROL OF IMMUNE RESPONSE AND INFLAMMATORY TISSUE DAMAGE BY HYPOXIA-INDUCIBLE FACTORS AND ADENOSINE A2A RECEPTORS, Michail V. Sitkovsky, Dmitriy Lukashev, Sergey Apasov, Hidefumi Kojima, Masahiro Koshiba, Charles Caldwell, Akio Ohta, and Manfred Thiel

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T LYMPHOCYTE–ENDOTHELIAL CELL INTERACTIONS, Jaehyuk Choi, David R. Enis, Kian Peng Koh, Stephen L. Shiao, and Jordan S. Pober

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IMMUNOLOGICAL MEMORY TO VIRAL INFECTIONS, Raymond M. Welsh, Liisa K. Selin, and Eva Szomolanyi-Tsuda

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CENTRAL MEMORY AND EFFECTOR MEMORY T CELL SUBSETS: FUNCTION, GENERATION, AND MAINTENANCE, Federica Sallusto, Jens Geginat, and Antonio Lanzavecchia CONTROL OF T CELL VIABILITY, Philippa Marrack and John Kappler

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ASTHMA: MECHANISMS OF DISEASE PERSISTENCE AND PROGRESSION, Lauren Cohn, Jack A. Elias, and Geoffrey L. Chupp

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CD1: ANTIGEN PRESENTATION AND T CELL FUNCTION, Manfred Brigl and Michael B. Brenner

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CHEMOKINES IN INNATE AND ADAPTIVE HOST DEFENSE: BASIC CHEMOKINESE GRAMMAR FOR IMMUNE CELLS, Antal Rot and Ulrich H. von Andrian

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INTERLEUKIN-10 AND RELATED CYTOKINES AND RECEPTORS, Sidney Pestka, Christopher D. Krause, Devanand Sarkar, Mark R. Walter, Yufang Shi, and Paul B. Fisher

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Subject Index Cumulative Index of Contributing Authors, Volumes 12–22 Cumulative Index of Chapter Titles, Volumes 12–22

ERRATA An online log of corrections to Annual Review of Immunology chapters may be found at http://immunol.annualreviews.org/errata.shtml

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INTEGRINS AND T CELL–MEDIATED IMMUNITY

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Jonathan T. Pribila, Angie C. Quale, Kristen L. Mueller, and Yoji Shimizu Department of Laboratory Medicine and Pathology, Center for Immunology, Cancer Center, University of Minnesota Medical School, Minneapolis, Minnesota 55455; email: [email protected], [email protected], [email protected], [email protected]

Key Words extracellular matrix, chemokine, signal transduction, dendritic cell, immunological synapse ■ Abstract Integrin receptors mediate adhesive events that are critical for a specific and effective immune response to foreign pathogens. Integrin-dependent interactions of lymphocytes and antigen-presenting cells (APCs) to endothelium regulate the efficiency and specificity of trafficking into secondary lymphoid organs and peripheral tissue. Within these sites, integrins facilitate cell movement via interactions with the extracellular matrix, and promote and stabilize antigen-specific interactions between T lymphocytes and APCs that are critical for initiating T cell–activation events. In this review, we discuss the role of integrins in T cell–mediated immunity, with a focus on how these receptors participate in lymphocyte recirculation and T cell activation, how antigen stimulation regulates integrin activity, and how integrins define functionally unique subsets of T cells and APCs.

INTRODUCTION Efficient recognition of foreign pathogens by T cells requires adhesive interactions between T cells and other cell types, such as endothelial cells and antigenpresenting cells (APCs), and with components of the extracellular matrix (ECM). These contacts are dynamic, in most cases transient, and subject to an unusually high degree of regulation. Integrins are αβ heterodimeric cell surface receptors that are major mediators of these adhesive interactions, which are essential for T cell recirculation, migration into inflammatory sites, and recognition of foreign antigens (1, 2). In mammals, the integrin family consists of 18 α subunits and 8 β subunits that combine to form 24 different integrin αβ pairs (Figure 1). The ligand specificity for each integrin differs, and therefore the spectrum of integrins expressed by a given cell type determines, to a large extent, how efficiently that cell can interact with a given microenvironment. The constellation of integrins expressed by circulating cells, such as lymphocytes, is particularly critical because they encounter a wide array of microenvironments as they 0732-0582/04/0423-0157$14.00

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Figure 1 Integrin receptors. A total of 18 α subunits and 8 β subunits combine to form 24 different integrins. Integrins in the circle are particularly relevant to T cell–mediated immunity.

recirculate through the body. In this review, we highlight how integrins participate in T cell–mediated immune responses by regulating the circulatory behavior of T cells and APCs, and the efficiency of antigen-specific interactions of T cells with APCs.

INTEGRINS AND LYMPHOCYTE RECIRCULATION The constant movement of na¨ıve T cells through lymph nodes (LNs) ensures that the immune system exposes as many T cells as possible to rare, foreign peptideMHC (pMHC) complexes in an environment conducive to optimal stimulation of na¨ıve T cells (1). The interaction of na¨ıve T cells with high endothelial venules (HEVs) is critical for efficient T cell recirculation through LNs. On na¨ıve T cells, L-selectin—the CCR7 chemokine receptor—and the LFA-1 integrin mediate distinct and sequential steps in T cell–HEV interactions: initial tethering of T cells to endothelium, activation, and the subsequent formation of stable adhesive contacts (Figure 2).

Tethering and Reversible Rolling Under conditions of shear flow, the initial interaction of T cells with endothelium is characterized by a rolling behavior of the T cell on the endothelial surface. Lselectin is uniquely suited to mediating transient adhesive interactions that result in rolling, as this receptor forms rapid but weak interactions with specific carbohydrate epitopes on the endothelium (3). Like L-selectin, α4 integrins mediate lymphocyte rolling (4–6), particularly in the absence of a selectin contribution (6). Lymphocyte rolling mediated by α4β1 does not appear to require high-affinity interactions with VCAM-1 because mutations that reduce α4β1 affinity support rolling but not firm adhesion (4). Recent evidence also suggests that α4β1 integrin-mediated rolling on VCAM-1 may be regulated by a very rapid (<0.1 second) induction of α4 integrin clustering by chemokines (5).

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Figure 2 Integrin receptors mediate adhesive interactions essential to lymphocyte recirculation and T cell–APC interactions. T cell interactions with endothelium and T cell interactions with APCs in secondary lymphoid tissues both involve sequential, discrete steps that begin with brief, unstable interactions that are converted by an activation signal to stable, firm, integrin-dependent contacts. The figure depicts receptors expressed on na¨ıve T cells that have been implicated in the sequence of events that are critical for successful T cell extravasation into secondary lymphoid tissue and T cell interactions with antigen-laden APCs (see text for further details).

LFA-1 can also support rolling on both purified ICAM-1 and endothelial cells under shear flow (7–10). Although LFA-1/ICAM-1 interactions are not involved in initial tether formation, they appear to optimize L-selectin-mediated rolling by decreasing the velocity with which lymphocytes move over the endothelium (7, 10). The ability of LFA-1 to mediate rolling is dependent on weak interactions with ICAM-1 because mutations that either increase the lateral mobility of LFA-1 integrin in the membrane or increase the affinity of LFA-1 for ICAM-1 eliminate lymphocyte rolling in favor of firm adhesion to ICAM-1 (8, 9).

Activation and Stable Arrest The transient tethering and rolling of lymphocytes along the endothelium enhances the likelihood of sufficient lymphocyte stimulation to induce firm integrinmediated adhesion. Stimulation of rolling T cells by chemokines that are localized on the endothelial surface via interactions with apical proteoglycans results in rapid, but transient, increases in integrin adhesiveness (5, 11). As with other signals that modulate integrin activity, chemokines induce changes in integrin functional activity via two distinct, but complementary, mechanisms: conformational

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changes that alter integrin ligand binding affinity and changes in integrin lateral mobility that result in integrin clustering and increased avidity of cell adhesion. Although a vast majority of integrins on the cell surface exist in a low affinity state on unstimulated T cells, a small subset of integrins that are in a high-affinity state are particularly critical for spontaneous T cell arrest on endothelium (4). In addition, chemokines induce a rapid and transient increase in β1 and β2 integrin affinity that correlates with adhesion to endothelial ligands (12, 13). Structural studies of the inserted (I) domain of the αL subunit of LFA-1 have also demonstrated that the transition from LFA-1-mediated rolling to LFA-1-mediated stable adhesion can be mediated by conformational changes that result in increased LFA-1 affinity (9). Thus, increases in LFA-1 affinity are sufficient to promote firm adhesion under shear flow. Chemokines also regulate integrin function by altering the lateral mobility of integrins within the cell membrane, thereby facilitating integrin clustering (5, 13–15). Stimulation of primary na¨ıve T cells with the chemokines CCL19, CCL21, or CXCL12 induces changes in LFA-1 avidity that are sensitive to inhibitors of the lipid kinase phosphatidylinositol 3-kinase (PI 3-K) (13). In addition, CXCL12 induces α4β1 integrin clustering and results in either the transient tethering or the firm adhesion of cells to integrin ligands (5). The concentration of integrin ligand determines the relative contribution of affinity and avidity to changes in integrin-mediated adhesion under shear flow. At low ligand concentrations, avidity changes are critical, as blocking increased integrin avidity with PI 3-K inhibitors prevents lymphocyte arrest under shear flow (13). However, at high-ligand concentrations, affinity changes are sufficient to mediate chemokine-dependent firm adhesion (13). Although chemokines play a central role in inducing stable arrest of T cells on endothelium, other receptor signals may also participate. Integrin activation may be regulated, in part, through L-selectin-ligand interactions because L-selectin ligation increases the avidity of β2 integrin-mediated adhesion (16). The α4β1 integrin also modulates LFA-1 integrin–mediated migration (17) through a mechanism that involves binding of paxillin to the integrin α4 cytoplasmic tail (18). Thus, tethering mediated by α4 integrins may provide signals that enhance LFA-1dependent adhesion and migration. In addition, a recent study demonstrated that presentation of insulin by pancreatic endothelial cells is critical for the adhesion of insulin-specific CD8 T cells to endothelial cells and for homing of these cells to pancreatic islets (19). Thus, trafficking of effector cells to peripheral tissue sites may be enhanced by such cross-presentation of antigen by endothelial cells.

Diapedesis Following firm attachment to the endothelial surface, lymphocytes must crawl through interendothelial junctions and cross the underlying basement membrane in order to successfully enter tissue, a process referred to as diapedesis, transmigration, or extravasation (20). Studies utilizing inhibitory antibodies and β2

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integrin–deficient T cell clones have demonstrated that LFA-1 mediates T cell transendothelial migration in response to several chemokines (21, 22). The transmigration process involves LFA-1 interactions with ICAM-1, as well as with the immunoglobulin superfamily member JAM-1, a new LFA-1 ligand that is expressed at the tight junctions of resting endothelium (23). LFA-1-dependent interactions with JAM-1 support both firm adhesion and transmigration, and this appears to be dependent in part on the activation state of the endothelial cell, as JAM-1 redistributes to the endothelial cell surface upon cytokine stimulation. Other nonintegrin receptors that are localized to interendothelial junctions, including CD31 (20) and CD99 (24), are likely the major receptors mediating diapedesis, and it now appears that, similar to tethering and stable arrest, diapedesis involves the sequential contribution of multiple receptor-ligand interactions. The α4β1 integrin also participates in T cell diapedesis (22), although its relative contribution to this process is dependent on cytokine activation of the endothelial cells, which enhances expression of the α4β1 ligand VCAM-1 and chemokine stimulation of the T cells (22). It should be noted that much of the work implicating β2 and β1 integrins in diapedesis has utilized experimental systems where the effects of blocking integrin function likely inhibited adhesion, which is required for successful diapedesis. Thus, it is difficult to precisely define the contribution of integrins specifically to the transmigration process in some of these studies.

Lymphocyte Movement in Lymph Nodes Following diapedesis, na¨ıve T cells enter the T cell–rich paracortical regions of LNs, where a network of reticular fibers extends from the capsule through the T cell–rich cortex and into the medulla (25, 26). Collagen types I, III, and IV form the core of these fibers and provide strength to the LN (25, 27, 28; JT Pribila, AA Itano, KL Mueller, Y Shimizu, submitted). These core fibers are surrounded by a meshwork of elastin, fibronectin, laminin-1, laminin-α3, tenascin, vitronectin, and several proteoglycans including heparan sulfate and keratan sulfate (25, 27, 30, 31). However, a majority of these fibrous cords are ensheathed by a layer of fibroblastic reticular cells (FRCs) that are interconnected by tight junctions (25). The FRCs likely limit exposure of T cells to ECM in LNs, as only approximately 10% of the ECM network is exposed to the cellular compartment of the LN (32). This structure likely enhances cell-cell contacts within the LN microenvironment. Recent studies using intravital two photon scanning laser microscopy have provided critical insight into lymphocyte behavior within the LN (33–36). In both explanted LNs and intact inguinal LNs of anesthetized mice, T cells exhibit a very high rate of random motility, averaging 11 µm per min (35, 36). In the absence of antigen, relatively short interactions occur between CD4 T cells and dendritic cells (DCs). However, a high percentage of T cells rapidly form stable interactions with antigen-laden DCs that last at least 15 h (34). At 36–48 h following antigen exposure, when T cells display evidence of activation, T cells dissociate from

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DCs and again move rapidly within the LN. Thus, like T cell interactions with endothelium, T cell interactions with APCs in LNs are characterized by short, relatively unstable initial interactions that can be converted into more stable, longterm interactions if an appropriate activation signal, in this case antigen, is delivered to the T cell (Figure 2).

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THE LFA-1 INTEGRIN AND T CELL–APC INTERACTIONS A stable interaction between a T cell and APC is required to elicit the signaling cascades necessary for T cell activation and effector function (33, 34, 36). The TCR and MHC molecules alone cannot mediate this stable interaction owing to the low affinity of TCR interaction with pMHC, the small size of the TCR and MHC molecules, and the relatively low abundance of MHC expressing cognate antigen. The LFA-1 integrin, expressed on the T cell surface, and its ligand, ICAM-1, expressed on the surface of the APC, are key mediators of this interaction (37–39), and TCR stimulation promotes stable T cell–APC contact by rapidly enhancing LFA-1 functional activity (see below).

T Cell Scanning In the absence of antigen, T cells move rapidly within the LN, forming transient contacts with APCs that allow T cells to “scan” APCs for the presence of cognate antigen. Chemokine gradients present in the LN microenvironment may promote T cell scanning of APCs by activating LFA-1 because CXCL12 enhances antigenindependent T cell conjugation with DCs (40). Chemokine-stimulated increases in LFA-1 affinity are both extremely rapid and transient, characteristics that would support T cell scanning of APCs. However, imaging studies show that T cells within the LN move in a random rather than directed fashion (33, 36). The scanning process itself may promote integrin activation and facilitate transient interactions between T cells and APCs. The encounter of na¨ıve CD4 T cells with class II MHC-presenting self-peptide in the periphery promotes polarization of the TCR and signaling molecules, such as ZAP-70, to sites of T cell–APC contact (41). Although LFA-1 distribution was not assessed in these studies, this tonic level of activation may polarize LFA-1 or shift the conformational equilibrium toward high-affinity LFA-1 that facilitates T cell scanning. Antigen-independent interactions between na¨ıve T cells and DCs can lead to some T cell responses, including calcium signaling (42). Because calcium mobilizers enhance LFA-1 activity in T cells (43), low levels of antigen-independent calcium signaling may promote T cell scanning by modulating LFA-1 activity. Although these studies support a role for LFA-1 in T cell scanning of APCs, no direct evidence exists to suggest that T cell scanning requires integrins. Other nonintegrin adhesion molecules mediating low-affinity interactions, such as DCspecific ICAM-3 grabbing nonintegrin (DC-SIGN) and ICAM-3, are equally

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attractive candidates because they can form transient adhesive interactions and do not require activation to mediate adhesion (44).

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LFA-1 and the Immunological Synapse An external ring of LFA-1 (and the integrin-associated cytoskeletal protein talin) surrounding a central TCR-rich region is a structural hallmark of a mature immunological synapse (IS), which forms during antigen-dependent interactions with APCs (45–47). Furthermore, studies using planar lipid bilayers have established that the IS can form when a T cell interacts with only pMHC complexes and ICAM-1 (46). During the initial stages of T cell activation, LFA-1 is localized in the center of the T cell–APC contact site while the TCR localizes primarily to the periphery (46–48). Rapid clustering of LFA-1 coupled with its central localization within the contact site suggests that LFA-1-mediated adhesion is needed to stabilize T cell–APC contact, resulting in larger numbers of engaged TCRs and activation of signaling cascades required for T cell activation. This is supported by colocalization of the TCR and activated tyrosine kinases Lck and ZAP-70 in the periphery of the IS (47, 48), which suggests that signaling cascades necessary for T cell activation are initiated while LFA-1 and ICAM-1 are clustered in the center of the T cell–APC contact site. T cell commitment to proliferation and effector function requires sustained T cell–APC interaction (36, 47, 49) and extended interactions of a single T cell with an APC have been observed in ex vivo LN cultures (34, 36). In the mature IS, the TCR moves to the center of the T cell–APC contact site while LFA-1 translocates to the periphery (47, 48). Whereas the TCR is largely absent from the IS after 1 h of conjugation, clustered LFA-1 is present up to at least 4 h (47, 48, 50). The kinetics of LFA-1 localization to the IS correlate with the minimum amount of conjugation time necessary for T cell proliferation to occur (47, 51), suggesting that prolonged localization of LFA-1 may facilitate molecular engagements at the T cell–APC contact site that result in signaling events necessary for complete T cell activation. Recent insights into the structural basis of integrin-mediated adhesion also suggest an active role for LFA-1 in T cell–APC interactions. The negatively charged glycocalyx favors repulsion of the T cell from the APC. The major components of the glycocalyx, such as CD43 and CD45, extend at least 45 nm from the cell surface and span approximately 30% of the T cell surface area (52), whereas the TCR-pMHC complex extends only 15 nm from the cell surface (53, 54). Integrins are capable of adopting both open and closed conformations that are regulated by intracellular as well as extracellular stimuli (55). Integrins exhibit low ligandbinding affinity in the closed conformation, due in large part to a bend in the middle of the α and β subunits that brings the ligand binding site to within 5 nm of the cell surface (56, 57). This closed conformation likely would not efficiently promote T cell–APC interactions because the low-affinity integrin is unlikely to span the glycocalyx. In the open conformation, the two subunits straighten and the integrin

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displays high affinity for its ligand (55). The high-affinity integrin now extends approximately 20 nm from the cell surface and thus would likely be more effective in supporting T cell–APC interactions. Analysis of the I domain of LFA-1 bound to ICAM-1 also revealed that an intermediate conformational affinity state exists, where the αL and β2 subunits are partially bent (58). Thus, integrins are likely to exist in an allosteric equilibrium between these different conformational states. Antigen-dependent signaling through the TCR may shift the equilibrium toward the most open conformation, thereby promoting T cell–APC interaction. It is also important to note that factors such as the differentiation state of the T cell, the type of APC, and the microenvironment where the T cell is interacting with the APC affect the initiation, maintenance, and functional consequences of IS formation. Memory T cells express generally higher levels of LFA-1 and other integrins than do na¨ıve T cells, and thus memory T cells have enhanced basal and TCR-dependent integrin function (1). These differences in integrin function between na¨ıve and memory T cells likely affect both the T cell scanning process and IS formation. Furthermore, effector T cells have elevated integrin activity when compared to resting memory T cells, and they likely interact with collagen and other ECM proteins in peripheral tissue. We currently know little about the role of integrins in initiating interactions between effector T cells and target cells in peripheral microenvironments.

Integrins as Costimulatory Receptors In addition to mediating adhesion to cell surface and ECM ligands, integrins generate a diverse array of intracellular signals. In T cells, LFA-1 and several β1 integrins can provide costimulatory signals for TCR-induced T cell activation (59, 60). Differences in the regulation of IL-2 production following TCR stimulation by integrins and CD28 demonstrate the unique costimulatory properties of these molecules. In CD4 T cells, LFA-1-mediated costimulation modulates IL-2 transcription, whereas CD28 costimulation alters IL-2 levels by stabilizing IL-2 mRNA (61). In addition, although both LFA-1 and CD28 induce the activation of PI 3-K in CD8 T cells, PI 3-K activity is required only for LFA-1-meditated costimulation (62). A promising candidate protein that may couple LFA-1 to changes in IL-2 transcription is JAB1, which interacts with LFA-1 (63) and is a known coactivator of the c-Jun transcription factor. Integrin engagement on T cells increases the nuclear fraction of JAB1, resulting in increased AP-1 activity (63). This suggests that LFA-1 modulates the transcriptional activity of AP-1 by regulating the nuclear localization of JAB1. Upon T cell activation, both β1 and β2 integrins move into cholesterol-rich, detergent-insoluble areas in the cell membrane called lipid rafts (64). Although the importance of lipid rafts to integrin signaling is unclear, they likely facilitate the interaction of integrins with a subset of cytoplasmic and transmembrane proteins that are either constitutively or inducibly associated with rafts (65). For example, β1 integrin ligation on T cells induces activation of the src kinase fyn (66), which

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is constitutively localized to lipid rafts. Fyn associates with the adapter proteins SH2 domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76), Crk-L, and adhesion- and degranulation-promoting adapter protein (ADAP) (66, 67), and both Crk-L and ADAP regulate integrin-dependent adhesion and migration (68–71). Because the Fyn/ADAP/SLP-76 complex is critical to the regulation of TCR-induced IL-2 production (72), these molecules may participate in integrin-mediated costimulation. CD3/TCR stimulation coupled with LFA-1 cross-linking also induces tyrosine phosphorylation of focal adhesion kinase (73), which constitutively associates with human enhancer of filamentation (74), a Crk-associated substrate that enhances β1 integrin-mediated costimulation when overexpressed in T cells (75).

REGULATION OF INTEGRIN FUNCTION BY THE TCR Stimulation of the CD3/TCR results within minutes in a transient increase in the functional activity of both LFA-1 and β1 integrins that is not dependent on increased expression of integrins on the T cell surface. Integrin activation is one of the earliest functional responses of T cells that encounter with pMHC and dramatically alters the migratory behavior of T cells (76). In addition, TCR-dependent activation of LFA-1 increases T cell sensitivity to antigen by stabilizing T cell interactions with APCs. TCR-dependent changes in integrin functional activity involve cytoskeletal-dependent integrin clustering that enhances the avidity of cell adhesion (14). Although TCR stimulation can also enhance integrin affinity (77), much less is currently known about how the TCR controls integrin affinity and how integrin affinity changes contribute to enhanced integrin-mediated adhesion following TCR stimulation.

Signaling Pathways Regulating TCR-Dependent Integrin Activation The proximal signaling events triggered by the TCR have been extensively characterized (78), and many of these signaling intermediates have been implicated in TCR-dependent regulation of integrin activity (Figure 3). Studies utilizing peripheral human T cells and genetic variants of the Jurkat T cell line, together with pharmacological inhibitors and dominant-negative signaling constructs, have identified important functions for Lck, ZAP-70, Itk, and PI 3-K in CD3/TCR-mediated integrin activation (39, 77, 79–82). Although ZAP-70 kinase activity is essential for CD3/TCR-mediated activation of β1 integrin function, a precise role for the ZAP-70 substrates LAT and SLP-76 has not been clearly established (81). The role of PI 3-K in regulating integrin activity appears to involve Itk, as binding of the pleckstrin homology domain of Itk to the PI 3-K lipid product PI(3,4,5)-P3 is important in membrane recruitment and subsequent activation of Itk. In addition, overexpression of just the pleckstrin homology domain of Itk inhibits TCR signaling to integrins (80).

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Because ZAP-70 phosphorylates LAT, and Itk associates with LAT following TCR stimulation and regulates PLC-γ 1 activity, a function for PLC-γ 1 in TCR-dependent integrin activation seems likely. A PLC inhibitor does, in fact, block integrin-mediated adhesion of mouse T cells and T cell–conjugate formation with APCs (39, 83). Furthermore, defects in PLC-γ 1 phosphorylation in anergic T cells are associated with defects in integrin activation in these cells (83). Signaling responses downstream of PLC-γ 1 are also important in regulating integrin activity in T cells, as intracellular calcium mobilizers and phorbol esters can enhance β1 and β2 integrin-mediated adhesion independently of the TCR (43, 84). Constitutively active forms of conventional PKC isotypes α, βI, and βII, and the novel isotype δ, but not the atypical isotype PKCζ , also enhance the basal adhesion of a LFA-1-expressing pro B cell line to ICAM-1 (85). In addition, TCR-mediated activation of integrins is blocked by PKC inhibitors (37, 39, 86). Studies with knockout mice have identified ADAP as a novel effector of integrin activation in T cells. Previously known as SLP-76-associated protein of 130 kDa (SLAP-130) and Fyn-T-binding protein (Fyb), ADAP is an intracellular adapter protein that becomes tyrosine phosphorylated following TCR stimulation and associates with SLP-76 (87), Fyn (88), and a number of proteins implicated in cytoskeletal rearrangement including the Ena/VASP family member protein Ev1, Wiskott-Aldrich syndrome protein, and the adapter protein Nck (89). Whereas ADAP is dispensable for T cell development, mature T cells from ADAP-deficient mice exhibit defective proliferative responses and are unable to efficiently activate β1 and β2 integrins following CD3/TCR stimulation (70, 71). This defect in integrin activation is associated with defective CD3-induced LFA-1 clustering in ADAP-deficient T cells. Although the mechanism by which ADAP regulates integrin activity is currently unknown, ADAP also associates with the adapter protein src kinase-associated phosphoprotein of 55 kDa (SKAP55), and overexpression of SKAP55 enhances CD3/TCR-mediated increases in adhesion to ICAM-1 and fibronectin, conjugate formation, and LFA-1 clustering (90). Regulation of integrin activity by SKAP55 appears to be dependent on its interaction with ADAP, as constructs lacking the SKAP55 SH3 domain, which binds to ADAP, do not enhance conjugate formation. Integrin activation and integrin-dependent conjugate formation induced by TCR stimulation is also impaired in T cells isolated from mice lacking expression of Vav1 (82, 91), a guanine nucleotide exchange factor for the GTPases Rac-1 and Rac-2 (92). GTPases regulated by Vav1 have also been implicated in integrin activation. Constitutively active Rac constructs induce cell spreading and enhance basal adhesion of nonlymphoid and lymphoid cells to fibronectin and ICAM-1 (85, 93, 94). Similarly, thymocytes from transgenic mice expressing the active form of Rac-1 show increased basal adhesion to fibronectin (95). These studies suggest that Rac-1 activation is sufficient to enhance integrin activity, but a role for Rac-1 in TCR-dependent activation of integrins is less clear. A role for other Rho family GTPases in controlling integrin activity in T cells is also not well

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characterized. Although constitutively active forms of Rho and Cdc42 do not induce cell spreading or enhance adhesion to fibronectin or ICAM-1 (85, 93, 94), thymocytes from transgenic mice expressing active RhoA do show enhanced basal adhesion to fibronectin (96). In contrast, Rho inhibitors are reported to actually increase basal adhesion to ICAM-1 (97). More compelling evidence that GTPases regulate TCR signaling to integrins has come from the analysis of Rap1, a GTPase that was first identified by its ability to revert the morphological phenotype of Ras-transformed fibroblasts (98). Constitutively active Rap1 potently enhances basal LFA-1 integrin-mediated adhesion to ICAM-1 (85, 99). Rap1 activity is also enhanced in Cbl-b-deficient mice, owing to enhanced interactions between Crk-L and the Rap1 guanine nucleotide exchange factor C3G. Consequently, both basal LFA-1 function and CD3-induced increases in LFA-1 function are enhanced in Cbl-b-deficient T cells (100). A dominant-negative form of Rap1 or SPA-1, a Rap1 GTPase-activating protein, inhibits increased integrin activity induced by stimulation of the TCR (101), the CD31 antigen (102), and several cytokine and chemokine receptors (94, 103). Although these studies suggest a central function for Rap1 in the regulation of integrin function by multiple activating signals, it should be noted that TCR stimulation does not enhance integrin function in anergic T cells (83), even though anergy has been associated with enhanced Rap1 activity (104). There is no clear consensus on whether Rap1 mediates changes in integrin functional activity via effects on integrin affinity or integrin clustering. LFA-1 is constitutively clustered on thymocytes from transgenic mice expressing active Rap1, but there is no enhanced binding of soluble ICAM-1 (99). In contrast, active Rap1 expression in a pro B cell line expressing LFA-1 results in enhanced soluble ICAM-1 binding and increased expression of an antibody epitope indicative of conformational changes in LFA-1 (85). Rap1 activity is enhanced in Cbl-bdeficient T cells, and there is enhanced soluble ICAM-1 binding in these cells in the absence of stimulation (100). However, LFA-1 clustering is enhanced in these cells only following CD3 stimulation (100). Rap1 antagonists also block increases in β1 and β2 integrin function induced by PMA stimulation (105), which enhances integrin function via effects on integrin clustering, and by divalent cations and unique integrin-specific antibodies that induce conformational changes that enhance integrin affinity (106). However, inhibitory effects of Rap1 antagonists on PMA-induced activation of β2 integrin function have not been consistently observed (101). Ultimately, the identification of Rap1 effectors critical to Rap1-dependent regulation of integrin function will be essential. Katagiri et al. recently identified a novel protein, designated RapL, that associates with Rap1 following TCR or chemokine stimulation (107). RapL overexpression enhances LFA-1-dependent adhesion to immobilized as well as soluble ICAM-1 and induces cell polarization and LFA1 clustering. Expression of active Rap1 enhances the association of RapL with LFA-1, suggesting a potential mechanism by which RapL facilitates Rap1dependent effects on LFA-1 function (107).

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Integrin Structure and Activation of Integrin Function Recent studies of the cytoplasmic and transmembrane domains of the αIIb and β3 integrin subunits (2, 108) suggest an intimate connection between conformational changes that lead to increased integrin affinity and mechanisms of integrin clustering that lead to enhanced avidity of cell adhesion. Interaction between the αIIb and β3 subunit cytoplasmic domains (109, 110) restrains the αIIbβ3 integrin in an inactive state. Mutation of key residues that disrupt a putative salt bridge linking the αIIb and β3 cytoplasmic domains results in constitutively active αIIbβ3 integrin (111). This suggests that intracellular signals that enhance integrin activity ultimately result in separation of the integrin α and β subunit cytoplasmic tails. Activation-dependent separation of the integrin tails may involve competitive displacement of the α-β subunit association by proteins such as talin, which binds to integrin β subunits and colocalizes with LFA-1 in the IS. The phosphotyrosine binding-like (PTB) domain of talin binds to the β3 integrin cytoplasmic domain via a tyrosine residue (Y747) in a NPXY motif that is conserved among multiple integrin β subunit tails (112, 113). The interaction of talin with the β3 tail blocks the interaction of the αIIb tail with β3 (110), and binding of talin to the β3 tail results in integrin activation (112, 113). This suggests that proteins that interact with integrin cytoplasmic domains may mediate integrin activation via changes in the spacing between the integrin α and β tails. Structural studies of LFA-1 suggest a similar mechanism of regulation by the αL and β2 cytoplasmic domains (114). In addition, talin binding to integrin β tails requires exposure of the talin PTB domain, which can occur upon cleavage with calpain, an enzyme that has been implicated in calcium-dependent regulation of LFA-1 activity in T cells (43). Structural studies also show that isolated αIIb transmembrane helices can form homodimers and isolated β3 transmembrane helices can form homotrimers. These homomeric interactions would most likely occur when the integrin is active and the α and β tails are physically separated (55, 56, 108). Thus, activation-dependent conversion to a high-affinity integrin may be accompanied by integrin clustering mediated by transmembrane sequences that result in homomeric associations between integrin subunits (108). Two mutations in the β3 transmembrane helix have been identified that lead to a constitutively active integrin that is clustered on the cell surface (108).

INTEGRINS AS MARKERS OF T CELL AND DENDRITIC CELL SUBSETS The specificity by which integrins direct cell trafficking and retention within peripheral tissue makes them important markers of both T cells and DCs. Whereas na¨ıve T cells express uniform levels of β1 and β2 integrins, memory T cells can be divided into subsets based on differential integrin expression (1). A majority of memory T cells (>80%) express high levels of β1 integrins, but not α4β7

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or αEβ7 integrins, and recirculate through nonmucosal tissue. Inflammatory cytokines induce VCAM-1 expression on the endothelium of nonmucosal tissue and preferentially recruit α4β1-bearing memory T cells to these sites. In contrast, two other subsets of memory T cells are defined by low levels of β1 integrin expression and by the differential expression of β7 integrins (αEβ7HIα4β7LO and αEβ7LOα4β7HI) (1, 115).

α4β7 and αEβ7 Integrins and Tissue-Specific Localization of T Cells Integrin α4β7 is expressed on a distinct subset of memory CD4 and CD8 T cells (115–117), and it directs the trafficking of effector and memory T cells to intestinal sites of inflammation via interactions with mucosal addressin cell adhesion molecule (MAdCAM-1) (1, 6, 115, 117–119). Although the importance of α4β7 to intestinal trafficking is clear, the factors that determine whether a na¨ıve T cell will become α4β7HI or α4β7− are not fully known. The site of initial antigen exposure can define the phenotype of the memory population, as CD4 T cells primed in intestinal lymphoid organs increase α4β7 expression, whereas those primed in cutaneous LNs lose α4β7 within two days of systemic immunization (120). Furthermore, intestinal DCs preferentially induce expression of α4β7 compared to peripheral DCs, regardless of the source of T cells (121). These studies suggest that the site of antigen exposure can differentially regulate integrin expression and, thereby, regulate the type of effector and memory T cell to which na¨ıve T cells give rise. Intraepithelial lymphocytes (IELs) are a distinct subset of memory T cells defined by expression of αEβ7 integrin (122, 123), which specifically binds to the epithelial-specific cadherin, E-cadherin (124, 125), and is critical to IEL retention between intestinal epithelial cells (1, 122) and to IEL effector function (126). Mice lacking αE integrin have dramatically reduced numbers of intestinal and vaginal IELs as well as decreased numbers of lamina propria T cells (127). However, αEβ7 is not important for generating or maintaining T cells in Peyer’s patches, as there are normal numbers of T cells in αE-deficient mice (127). In addition to IELs, the αEβ7 integrin is expressed on CD4+CD25+ regulatory T cells (TREG), as well as an uncharacterized subset of CD4+CD25− TREG (128). Integrin αEβ7 expression on TREG correlates with CTLA-4 expression, suppression of T cell proliferation in vitro, and protection against colitis in a severe combined immunodeficient model (128). However, other studies show that αEβ7-specific mAbs actually ameliorate existing immunization-induced colitis in IL-2 deficient mice, primarily by preventing the localization of CD4 T cells to the lamina propria (129). Because there are a reduced number of lamina propria T cells in αE-deficient mice, αEβ7 may regulate the localization of a specific subset of TREG to the lamina propria. Mice lacking αE are also predisposed to the development of inflammatory skin lesions (130), consistent with a role for αEβ7 integrin in localization or functional regulation of TREG.

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Collagen-Binding Integrins and Effector T Cell Function The α1β1 and α2β1 integrins mediate cell adhesion to collagen and were originally identified as “very late activation” antigens expressed on activated T cells following several weeks of in vitro culture (131). Although resting na¨ıve and memory T cells lack expression of α1β1 and α2β1 and do not adhere to collagen in vitro, α1β1 is expressed on T cells isolated from the intestinal lamina propria (132). In addition, infiltrating T cells in arthritis and other inflammatory conditions express α1β1 and exhibit activation-dependent adhesion to collagen (133). Thus, α1β1 (and likely α2β1) are the major collagen receptors on T cells, and the highly regulated expression of these integrins suggests a unique function for collagen in T cell function. Studies in mice with blocking antibodies and α1 integrin-deficient mice demonstrate a role for α1β1 and α2β1 in both delayed-type and contact hypersensitivity models, as well as a model of collagen antibody–induced arthritis (134). The α1β1 integrin is expressed on infiltrating leukocytes, including T cells and subsets of monocytes and neutrophils, and antiα1 and antiα2 antibody treatment is associated with decreased leukocyte infiltration. Similar findings regarding α1β1 function have also been reported in two models of experimental colitis (135, 136) and are consistent with the reduced numbers of IELs in α1-deficient mice (137). Together, these studies directly implicate α1β1 and α2β1 in the function of effector T cells and suggest a critical function for T cell interactions with collagen in peripheral tissue (138).

Differential Expression of Multiple Integrins on Murine DC Subsets Integrins also define murine DCs and DC subsets (Figure 4). CD11c, the αX subunit of the αXβ2 integrin, was the first murine DC marker to be identified (139) and has been instrumental in the identification and characterization of DC subsets in the LN, spleen, and thymus (140–142). Although originally identified as a myeloidspecific antigen, the αM subunit of the αMβ2 (MAC-1; CR3) integrin, CD11b, distinguishes CD8α-negative myeloid DCs from CD8α-positive lymphoid DCs (140). In peripheral LNs from normal mice, lymphoid DCs, but not myeloid DCs, express the α1, α6, and αE integrin subunits (JT Pribila, AA Itano, KL Mueller, Y Shimizu, submitted; 143). Other integrin subunits, including αL, α4, and α5 are expressed at comparable levels on skin-derived lymphoid and myeloid DCs in the mouse (JT Pribila, AA Itano, KL Mueller, Y Shimizu, submitted). The α4 integrin subunit is also a maturation marker on monocyte-derived human DCs (144). The α1β1 and αEβ7 integrins are also expressed on a subset of CD40HICD8α INT skin-derived DCs in peripheral LNs (JT Pribila, AA Itano, KL Mueller, Y Shimizu, submitted). When compared to other skin-derived DCs, α1β1+αEβ7+ skinderived DCs exhibit an enhanced ability to interact with T cells in the absence of antigen and a reduced ability to acquire soluble antigen in vivo. Skin-derived DCs also exhibit α1β1 integrin-dependent adhesion to collagen and interact more

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Figure 4 Integrin expression on murine DCs. Integrins are important phenotypic markers of functionally distinct subsets of DCs in peripheral LN of normal mice (JT Pribila, AA Itano, KL Mueller, Y Shimizu, submitted; 140, 142). These differences in integrin expression are also associated with differential adhesion of DC subsets to ECM components. The α1β1 and αEβ7 integrins are not expressed on Langerhans cells in the skin, which suggests that expression of these integrins is induced on a subset of skin-derived DCs after they have migrated to peripheral LNs (JT Pribila, AA Itano, KL Mueller, Y Shimizu, submitted).

efficiently with collagen and fibronectin than myeloid and lymphoid DCs, even though lymphoid DCs express comparable levels of α1β1, α4β1, and α5β1 integrins. These findings may be particularly relevant to DC function in LNs, as α1β1+ DCs colocalize in vivo with collagen, which is found in the reticular network that limits the diffusion of soluble antigens in LNs (26). Because the uptake of soluble antigen by skin-derived DCs resident in draining LNs is critical to the initial activation of naive T cells (28), DCs capable of adhering to these ECM fibers are uniquely situated to serve as the critical APCs that initiate T cell activation. The role of integrins in DC recruitment into LNs is incompletely understood. DCs and DC precursors interact with endothelium in a manner similar to lymphocytes, except that DC-SIGN expressed on DCs mediates tethering and rolling via interaction with ICAM-2 on endothelium (145). Blood-borne DCs, which enter the LN via HEVs, utilize both β1 and β2 integrins to adhere to human umbilical vein endothelial cells (146). The migration of Langerhans cells to LNs involves both LFA-1 (147, 148) and α6 laminin-binding integrins (149). Although the α1β1 and αEβ7 integrins are expressed on a subset of skin-derived DCs resident in LNs, these integrins are not expressed on Langerhans cells in the skin (JT Pribila, AA Itano, KL Mueller, Y Shimizu, submitted), and α1β1 is not required for the migration of skin-derived DCs to the LN (134).

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CONCLUSIONS In this review, we have focused on the role of integrins in T cell–mediated immunity. However, the impaired immune response in patients with leukocyte adhesion deficiency-1, where genetic mutations impair β2 integrin subunit expression (150), vividly illustrates the vital role that integrins play in virtually every aspect of immune system function. The identification of several cases of a novel form of LAD-1 characterized by loss not of integrin expression but of the ability of activation signals to enhance integrin function has provided additional evidence regarding the importance of integrin activation to immune system function (150). Further analysis of how integrins participate in the immune response will clearly facilitate ongoing efforts to utilize integrins as therapeutic targets for treatment of diseases such as inflammatory bowel disease, asthma, and multiple sclerosis. Because global loss of integrin function will have unwanted immunosuppressive effects, the challenge ahead lies in capitalizing on basic research findings discussed in this review to devise clinically effective therapies.

ACKNOWLEDGMENTS This work is supported by NIH grants AI31126 and AI38474 (Y.S.), the Harry Kay Chair in Biomedical Research (Y.S.), a University of Minnesota Doctoral Dissertation Fellowship (J.T.P.), NIH training grant T32 HL07741 (A.C.Q.), and NIH training grant T32 AI007313 (K.L.M.). The Annual Review of Immunology is online at http://immunol.annualreviews.org

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142. Ruedl C, Koebel P, Bachmann M, Hess M, Karjalainen K. 2000. Anatomical origin of dendritic cells determines their life span in peripheral lymph nodes. J. Immunol. 165:4910–16 143. Kilshaw PJ. 1993. Expression of the mucosal T cell integrin α M290β7 by a major subpopulation of dendritic cells in mice. Eur. J. Immunol. 23:3365–68 144. Puig-Kroger A, Sanz-Rodriguez F, Longo N, Sanchez-Mateos P, Botella L, et al. 2000. Maturation-dependent expression and function of the CD49d integrin on monocyte-derived human dendritic cells. J. Immunol. 165:4338–45 145. Geijtenbeek TB, Krooshoop DJ, Bleijs DA, Van Vliet SJ, Van Duijnhoven GC, et al. 2000. DC-SIGN-ICAM-2 interaction mediates dendritic cell trafficking. Nat. Immunol. 1:353–57 146. Brown KA, Bedford P, Macey M, McCarthy DA, LeRoy F, et al. 1997. Human blood dendritic cells: binding to vascular endothelium and expression of adhesion molecules. Clin. Exp. Immunol. 107:601– 7 147. Ma J, Wang J-H, Guo Y-J, Sy M-S, Bigby M. 1994. In vivo treatment with antiICAM-1 and anti-LFA-1 antibodies inhibits contact sensitization-induced migration of epidermal Langerhans cells to regional lymph nodes. Cell. Immunol. 158:389–99 148. Xu H, Guan H, Zu G, Bullard D, Hanson J, et al. 2001. The role of ICAM-1 molecule in the migration of Langerhans cells in the skin and regional lymph node. Eur. J. Immunol. 31:3085–93 149. Price AA, Cumberbatch M, Kimber I, Ager A. 1997. α6 integrins are required for Langerhans cell migration from the epidermis. J. Exp. Med. 186:1725– 35 150. Shimizu Y. 2003. Disabling multiple integrins from the inside out. J. Clin. Invest. 111:23–24

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Figure 3 Signaling pathways implicated in TCR signaling to integrins. A large array of intracellular proteins, including tyrosine, serine/threonine and lipid kinases, adapter proteins, guanine nucleotide exchange factors, GTPases, and cytoskeletal proteins, are involved in increases in integrin function that occur following TCR stimulation. Potential relationships between these various signaling pathways are shown, but for many of these intracellular mediators, the biochemical basis by which they mediate integrin activation remains undefined.

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CONTENTS FRONTISPIECE—Leonard A. Herzenberg and Leonore A. Herzenberg GENETICS, FACS, IMMUNOLOGY, AND REDOX: A TALE OF TWO LIVES INTERTWINED, Leonard A. Herzenberg and Leonore A. Herzenberg SELF- AND NONSELF-RECOGNITION BY C-TYPE LECTINS ON DENDRITIC CELLS, Teunis B.H. Geijtenbeek, Sandra J. van Vliet, Anneke Engering, Bert A. ’t Hart, and Yvette van Kooyk

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TRANSCRIPTIONAL CONTROL OF EARLY B CELL DEVELOPMENT, Meinrad Busslinger

UBIQUITIN LIGASES AND THE IMMUNE RESPONSE, Yun-Cai Liu LIGANDS FOR L-SELECTIN: HOMING, INFLAMMATION, AND BEYOND, Steven D. Rosen

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INTEGRINS AND T CELL–MEDIATED IMMUNITY, Jonathan T. Pribila, Angie C. Quale, Kristen L. Mueller, and Yoji Shimizu

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MULTIPLE ROLES OF ANTIMICROBIAL DEFENSINS, CATHELICIDINS, AND EOSINOPHIL-DERIVED NEUROTOXIN IN HOST DEFENSE, De Yang, Arya Biragyn, David M. Hoover, Jacek Lubkowski, and Joost J. Oppenheim

STARTING AT THE BEGINNING: NEW PERSPECTIVES ON THE BIOLOGY OF MUCOSAL T CELLS, Hilde Cheroutre THE BCR-ABL STORY: BENCH TO BEDSIDE AND BACK, Stephane Wong and Owen N. Witte

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CD40/CD154 INTERACTIONS AT THE INTERFACE OF TOLERANCE AND IMMUNITY, Sergio A. Quezada, Lamis Z. Jarvinen, Evan F. Lind, and Randolph J. Noelle

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THE THREE ES OF CANCER IMMUNOEDITING, Gavin P. Dunn, Lloyd J. Old, and Robert D. Schreiber

AUTOIMMUNE AND INFLAMMATORY MECHANISMS IN ATHEROSCLEROSIS, Georg Wick, Michael Knoflach, and Qingbo Xu THE DYNAMIC LIFE OF NATURAL KILLER CELLS, Wayne M. Yokoyama, Sungjin Kim, and Anthony R. French

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THE ROLE OF COMPLEMENT IN THE DEVELOPMENT OF SYSTEMIC LUPUS ERYTHEMATOSUS, Anthony P. Manderson, Marina Botto, and Mark J. Walport

DROSOPHILA: THE GENETICS OF INNATE IMMUNE RECOGNITION AND RESPONSE, Catherine A. Brennan and Kathryn V. Anderson RAGS AND REGULATION OF AUTOANTIBODIES, Mila Jankovic,

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Rafael Casellas, Nikos Yannoutsos, Hedda Wardemann, and Michel C. Nussenzweig

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THE ROLE OF SUPPRESSORS OF CYTOKINE SIGNALING (SOCS) PROTEINS IN REGULATION OF THE IMMUNE RESPONSE, Warren S. Alexander and Douglas J. Hilton

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NATURALLY ARISING CD4+

REGULATORY T CELLS FOR IMMUNOLOGIC SELF-TOLERANCE AND NEGATIVE CONTROL OF IMMUNE RESPONSES, Shimon Sakaguchi PHOSPHOINOSITIDE 3-KINASE: DIVERSE ROLES IN IMMUNE CELL ACTIVATION, Jonathan A. Deane and David A. Fruman IMMUNITY TO TUBERCULOSIS, Robert J. North and Yu-Jin Jung MOLECULAR DEFECTS IN HUMAN SEVERE COMBINED IMMUNODEFICIENCY AND APPROACHES TO IMMUNE RECONSTITUTION, Rebecca H. Buckley PHYSIOLOGICAL CONTROL OF IMMUNE RESPONSE AND INFLAMMATORY TISSUE DAMAGE BY HYPOXIA-INDUCIBLE FACTORS AND ADENOSINE A2A RECEPTORS, Michail V. Sitkovsky, Dmitriy Lukashev, Sergey Apasov, Hidefumi Kojima, Masahiro Koshiba, Charles Caldwell, Akio Ohta, and Manfred Thiel

531 563 599

625

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T LYMPHOCYTE–ENDOTHELIAL CELL INTERACTIONS, Jaehyuk Choi, David R. Enis, Kian Peng Koh, Stephen L. Shiao, and Jordan S. Pober

683

IMMUNOLOGICAL MEMORY TO VIRAL INFECTIONS, Raymond M. Welsh, Liisa K. Selin, and Eva Szomolanyi-Tsuda

711

CENTRAL MEMORY AND EFFECTOR MEMORY T CELL SUBSETS: FUNCTION, GENERATION, AND MAINTENANCE, Federica Sallusto, Jens Geginat, and Antonio Lanzavecchia CONTROL OF T CELL VIABILITY, Philippa Marrack and John Kappler

745 765

ASTHMA: MECHANISMS OF DISEASE PERSISTENCE AND PROGRESSION, Lauren Cohn, Jack A. Elias, and Geoffrey L. Chupp

789

CD1: ANTIGEN PRESENTATION AND T CELL FUNCTION, Manfred Brigl and Michael B. Brenner

817

CHEMOKINES IN INNATE AND ADAPTIVE HOST DEFENSE: BASIC CHEMOKINESE GRAMMAR FOR IMMUNE CELLS, Antal Rot and Ulrich H. von Andrian

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INTERLEUKIN-10 AND RELATED CYTOKINES AND RECEPTORS, Sidney Pestka, Christopher D. Krause, Devanand Sarkar, Mark R. Walter, Yufang Shi, and Paul B. Fisher

929

INDEXES

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Subject Index Cumulative Index of Contributing Authors, Volumes 12–22 Cumulative Index of Chapter Titles, Volumes 12–22

ERRATA An online log of corrections to Annual Review of Immunology chapters may be found at http://immunol.annualreviews.org/errata.shtml

981 1011 1018

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Annu. Rev. Immunol. 2004. 22:181–215 doi: 10.1146/annurev.immunol.22.012703.104603 First published online as a Review in Advance on January 12, 2004

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MULTIPLE ROLES OF ANTIMICROBIAL DEFENSINS, CATHELICIDINS, AND EOSINOPHIL-DERIVED NEUROTOXIN IN HOST DEFENSE∗ De Yang,1 Arya Biragyn,2 David M. Hoover,3 Jacek Lubkowski,3 and Joost J. Oppenheim4 1

Basic Research Program; 3Macromolecular Crystallography Laboratory, SAIC-Frederick; 4Laboratory of Molecular Immunoregulation, Center for Cancer Research; National Cancer Institute at Frederick, Frederick, Maryland 21702; 2 Laboratory of Immunology, Gerontology Research Center, National Institute of Aging, Baltimore, Maryland 20892; email: [email protected]

Key Words antimicrobial, chemotaxis, dendritic cells, GPCR, immune response ■ Abstract Mammals generate a diverse array of antimicrobial proteins, largely represented by defensins or cathelicidins. The direct in vitro microbicidal activity of antimicrobial proteins has long been considered an important innate immune defense, although the in vivo relevance has only very recently been established for certain defensins and cathelicidins. Mammalian defensins and cathelicidins have also been shown to have multiple receptor-mediated effects on immune cells. Beta-defensins interact with CCR6; murine β-defensin-2 in addition activates TLR4. Cathelicidins act on FPRL1-expressing cells. Furthermore, several defensins have considerable immunoenhancing activity. Thus, it appears that mammalian antimicrobial proteins contribute to both innate and adaptive antimicrobial immunity.

INTRODUCTION Mammals are constantly exposed to a myriad of microorganisms, yet individuals rarely become infected because of the barrier function of the skin and epithelia that prevent microbial entry based on mechanical obstruction and the presence of antimicrobial substances. If the barrier is breached, invading pathogens are contained and ultimately eliminated by the host immune system. Mammals have evolved two kinds of immunity: innate, nonclonal and nonspecific; and adaptive, inducible and antigen-specific (1, 2). Innate immunity represents the first line of constitutively pre-existing host defense that is rapidly mobilized following the ∗ The U.S. Government has the right to retain a nonexclusive, royalty-free license in and to any copyright covering this paper.

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detection of microbial invasion. The effector branch of innate immunity consists of two major components: the recruitment and/or activation of leukocytes (e.g., phagocytic granulocytes, monocytes/macrophages, etc.) capable of combating the invading pathogens and the release and/or activation of a variety of extracellular humoral mediators (e.g., complement, cytokines, antimicrobial substances, etc.). Adaptive immunity is induced when lymphocytes are activated in response to antigen (Ag) presented by antigen-presenting cells (APCs), in particular dendritic cells (DCs) (1, 3). The T cell antigen receptors recognize antigenic epitopes bound to the major histocompatibility complex (MHC) on the surface of APCs. CD8+ T cells, once activated after recognition of antigenic epitopes bound to the MHC class I, differentiate into cytotoxic T cells that directly kill cells infected by intracellular pathogens. The complex of MHC class II and antigenic epitope triggers the activation of CD4+, generating T-helper cells that, by producing various cytokines, promote B cell activation and enhance the efficiency of phagocytes to eliminate pathogens. B cell activation leads to the production of antigen-specific antibodies that neutralize pathogen-derived toxins, block the infectivity of invading pathogens, and promote their opsonization and elimination by phagocytes. Thus, innate and adaptive immune responses work in concert to eliminate microbial invaders. Antimicrobial substances comprise microbicidal chemicals (e.g., hydrogen peroxide, nitric oxide, etc.) and a wide variety of host gene-encoded antimicrobial proteins. Almost half a century ago, a crude protein fraction of polymorphonuclear leukocytes with antimicrobial properties was described and named “phagocytin” (4), the prologue for investigating antimicrobial components of inflammatory leukocytes. The subsequent exploration of the functional capabilities of defined proteins and peptides in inflammation paralleled the evolving methodologies of protein identification and purification, and molecular biology. In the early1960s, lysozyme was found to have the bacteriolytic activity toward Grampositive bacteria (5). The bactericidal effect of lactoferrin was discovered in 1977 (6). Study of antimicrobial activity in neutrophil lysates of rabbit and guinea pig identified the so-called arginine-rich basic antibacterial proteins that migrated faster than lysozyme toward the cathode (7). In the early 1980s, these arginine-rich basic antimicrobial proteins from rabbit lung macrophages and granulocytes and structurally similar peptides from human granulocytes were purified and named “defensins” (8–10). In the late 1980s, another type of antimicrobial proteins termed histatins were purified (11). The 1990s witnessed the discovery of constitutive βdefensins (12, 13), Paneth cell α-defensins (14–16), inducible β-defensins (17, 18), cathelicidins (19, 20), θ-defensin (21), and many others proteins with antimicrobial activities (22–24). Since then, the genomic organization, regulation of expression, structure, microbicidal activity, and mechanisms of many mammalian antimicrobial proteins have been investigated and reviewed extensively (20, 25–30). Although sporadic reports suggested that certain antimicrobial proteins might have direct effects on host monocytes (31, 32), only in 1996 were human

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neutrophil-derived α-defensins demonstrated to be chemotactic for human T lymphocytes not only in vitro but also in vivo (33). This finding nurtured the investigation of potential chemotactic effects of other antimicrobial proteins and led to the detection of the chemotactic activities of human β-defensins and cathelicidin and identification of receptors that mediate their chemotactic activities on leukocytes (34, 35). Over the past 10 years, mammalian antimicrobial proteins have been reported to have numerous biological activities that promote host defense (28, 36–46). In this review, we discuss defensins in detail and also briefly outline the multiple effects of cathelicidins and eosinophil-derived neurotoxin (EDN) on host immune cells and their resultant roles in innate and adaptive antimicrobial immunity.

DEFENSIN Genes, Expression, and Regulation CLASSIFICATION AND STRUCTURE There are two major subfamilies of defensins in vertebrates (Figures 1A and 1B): α-defensins (47, 48), whose six cysteines are linked 1–6, 2–4, 3–5, and β-defensins (49, 50), linked 1–5, 2–4, 3–6. Because cysteines 5 and 6 are always adjacent to one another, the two subfamilies are structurally very similar. The canonical sequence of α-defensins in humans is x1–2CXCRx2–3Cx3Ex3GxCx3Gx5CCx1–4, where x represents any amino acid residue. Owing to their initial isolation from neutrophil primary (azurophilic) granules, human α-defensin-1 ∼ 4 are conventionally called human neutrophil peptides (HNP1 ∼ 4) (10, 51). Human α-defensin-5 ∼ 6 are products of Paneth cells, often referred to as human defensin-5 (HD5) and -6 (HD6) (15, 16). The canonical sequence for human β-defensins is x2–10Cx5–6(G/A)xCX3–4Cx9–13Cx4–7CCxn. Human β-defensin-1 (HBD1) was initially isolated from human plasma (13), βdefensin-2 (HBD2) was purified from psoriatic scales (18), β-defensin-3 (HBD3) was identified simultaneously from psoriatic scales and by bioinformatics (52–54), and β-defensin-4 (HBD4) was recently identified solely by genomics (55). The pace at which new defensin genes are being discovered has increased dramatically with the advent of genomics-based open-reading frame searches (53–56). The third subfamily, θ-defensins, is derived from two α-defensins prematurely truncated by stop codons present between the third and fourth cysteine residues. The translated products are shortened to nonapeptides, covalently dimerized by disulfide linkages, and cyclized via new peptide bonds between the first and ninth residues (21). The resulting structure (Figure 2C) is a β-hairpin stabilized by three disulfide bonds (57). As only one pseudogene may encode a human θ -defensin, there is no true consensus for sequence (58). A new and growing family of proteins with strong homology to β-defensins is expressed in the testis and epididymis. One of this family, termed HE2/EP2, has at least 6 ∼ 9 splice variants (59). Three of the variants contain β-defensin motifs (54, 59) of which one is bactericidal (60). Another epididymis-specific protein,

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Figure 1 Alignment of human α-defensins (A) and selected β-defensins (B). Experimentally determined signal peptides are shown in white with black highlighting, predicted signal peptides are shown in white with gray highlighting, HNP proregions are shown in black with gray highlighting, and conserved residues are shown in bold. Sequences were selected only for those proteins that have been purified or whose mRNA has been detected. A 46 amino acid insert between the signal peptides and the defensin domains, indentical in EP2C and EP2D, is not shown. Signal sequences were predicted by neural networks using the software SignalP v2.0.

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termed ESC42, also contains a β-defensin motif, although it is not clear whether this protein has defensin-like activity (56, 61). The distinct splicing mechanism of HE2/EP2 may indicate convergent evolution from an unrelated gene toward that of β-defensin-like products (60). The backbone of the tertiary structures of monomeric α- and β-defensins (Figure 2A,B) is termed the defensin-like fold, consisting of three antiparallel

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Figure 2 Structures of defensins. (A) HNP3 monomer. (B) HBD2 monomer. (C) RTD-1 from macaque. Disulfides are shown as ball-and-stick models, and the N and C termini are labeled for HNP3 and HBD2. One end of the cyclic molecule RTD-1 is disordered and is not displayed in the figure. The structures were made using the software Ribbons.

β-sheets constrained by three disulfide bridges (48, 50, 62–69). The archetype for the defensin-like fold is HNP3 (PDB: 1DFN) (48). Additionally, the sheet is sometimes flanked by one or two α-helices, as seen in β-defensins (64, 68, 69). In solution, most α- and β-defensins are monomeric, although HNP1, HNP3, and HBD3 form homodimers (48, 68), and HBD2 can even form higher-order oligomers (64). The molecular structures of representative α- and β-defensins are shown in Figures 1 and 2. Mammalian defensins show significant structural similarity to insect defensins (70). The evolution of defensins likely followed the standard model of gene evolution: duplication of the ancestral gene, followed by mutation and natural selection based on the needs of the organism. This has been proposed for both α-defensins (71) and mammalian β-defensins (71–74). Based on sequence homologies, there is a closer relationship between vertebrate β-defensins and insect defensins than between vertebrate α- and β-defensins (71). Furthermore, it is likely that α-defensins are a relatively new set of genes distinct from their progenitors because (a) αdefensins as a group are much more homologous than β-defensins, (b) α-defensins

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exist only in mammals and are expressed in a small range of tissues, and (c) their genes are located in a very tight region of a single chromosome and present in variable nondeterminable multiple copies. GENOMIC STRUCTURE The gene for HNP1, HDEFA1, was first localized to chromosome 8 (75), followed by HNP3 gene, HDEFA1A (76). HDEFA1 and HDEFA1A (Figure 3) are almost identical (hence often referred to as HDEFA1/1A) except for one point mutation in the genome that leads to the conversion of the first amino acid residue from alanine in HNP1 to aspartic acid in HNP3 (Figure 1A). HDEFA1/1A has multiple copies that are inherited unequally, giving rise to individuals with either two or three copies of either HNP1 and/or HNP3 (77). The genes for HNP4 (78), HD5 and HD6 (79), and HBD1 ∼ 2 (74, 80, 81) are all mapped to the same chromosomal location, 8p23 (Figure 3). Analysis of this chromosomal region in detail has turned up genes for HBD3 (53, 54), HBD4 (55), and two new defensins of unknown activity, HBD5 and HBD6 (82). Because the gene for HNP2 has never been found, it is likely that HNP2 is generated from HNP1 and/or HNP3 by proteolytic processing (75–77). The genomic structure of HNP1, 3, and 4 (Figure 3) consists of three exons, with exon I, II, and III encoding the 50 -untranslated region (50 -UTR), the preproregion, and the mature peptide plus the 30 -UTR, respectively (76, 78). The HD5 and

Figure 3 The genomic location/organization, transcription, translation, and posttranslational processing of human α- and β-defensins. The short arm of human chromosome 8 is shown at the top. The intervening sequences between defensin genes are not drawn to scale. The circle on the right indicates the centromere. HDEFA/B, human α/β-defensin gene. UTR, untranslated region.

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HD6 genes (Figure 3) have two exons, with exon I containing the 50 -UTR and preproregion, and exon II containing mature protein and 30 -UTR (79). The genomic structure of HBD1 ∼ 3 is similar to that of HD5 and HD6 (Figure 3), except that a portion of preproregion is present on the second exon (53, 74, 83). HBD4 and HBD6 show the same genomic structure as the β-defensin family, except that the internal intron is much larger (55, 82). The genomic structure of HBD5 is similar to the α-defensin family, except that a preproregion is encoded across the first two exons, rather than on only the second exon (82). EXPRESSING CELLS AND TISSUES The expression pattern of defensins varies greatly among different species; for example, human neutrophils have 4 α-defensins, bovine neutrophils contain 13 β-defensins (BNDB) (12), whereas mouse neutrophils lack defensins (84). In humans, HNP1 ∼ 4 are predominantly synthesized in promyelocytes and stored in the primary granules of neutrophils (10, 51). Recently, HNP1 has also been found to be expressed by NK and T cells (85). HD5 and HD6 are expressed by Paneth cells of intestine, placenta, aminion, chorion, and by nasal and bronchial epithelial cells (15, 16, 86, 87). HBD1 ∼ 6 are expressed by epithelial cells lining tissues facing the external environment, including keratinocytes (18, 52–55, 82, 83, 88, 89). REGULATORY SITES AND CORRESPONDING TRANSCRIPTION FACTORS The production of defensins can be either constitutive or inducible (Table 1). Neutrophilderived (e.g., HNP1 ∼ 4 and BNDB1 ∼ 13), Paneth cell–derived (e.g., HD5 ∼ 6 and mouse cryptidins), and β-defensin-1 are constitutively expressed (10, 12, 13, 15, 16, 51, 89–93). The promoter regions of HDEFA1/1A contain the binding sites for the myeloid factor PU.1 (94) and C/EBP-α (95) that control its constitutive transcription in promyelocytes. The transcription factors responsible for the constitutive expression of Paneth cell–derived defensins and β-defensin-1 are unknown. The expression of constitutive defensins can be modulated; for example, G-CSF can increase expression of HNP-1 ∼ 3 in neutrophils (96). HBD1 has recently been shown to be more highly expressed by peripheral blood leukocytes in response to LPS or dead bacteria (97). Expression of HBD1 is apparently downregulated during Shigella infections (potentially by bacterial DNA), which may contribute to the promotion of bacterial adherence and invasion (98). Most of the epithelial-derived β-defensins are induced by proinflammatory stimuli (17, 18, 83, 90, 99, 100). HBD2 is inducible by bacteria, LPS, TNFα, IL-1, or even L-isoleucine (18, 97, 100, 101) in an NF-κB-dependent manner (83, 101). In addition to multiple NF-κB binding sites, many regulatory elements including the binding sites for AP-1, AP-2, and NF-IL-6 exist in the promoter region of the HBD2 gene (102). The expression of HBD3 is induced in primary keratinocytes and tracheal epithelial cells by TNFα and by heat-inactivated Pseudomonas aeruginosa and Staphylococcus aureus (52). In fetal lung explants and gingival keratinocytes it is induced by IL-1β (54). However, IFNγ , but not TNFα, induces the expression of HBD3 in the cultured keratinocyte cell line HaCaT (53). The expression of HBD4

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TABLE 1 Cell sources and regulation of mammalian defensins, cathelicidins, and EDN∗

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Defensin Conventional name

Type

Cell source

Synthesis

Release

HNP1 ∼ 4

α

Neutrophils CD8 T cells

Constitutive Inducible

Degranulation Secretion?

HD5 ∼ 6

α

Paneth cells

Constitutive

Degranulation

Mouse cryptidin

α

Paneth cells

Constitutive

Degranulation

HBD1

β

Keratinocytes and epithelial cells

Constitutive and inducible

Secretion

HBD2 ∼ 4

β

Keratinocytes and epithelial cells

Inducible

Secretion

BNDBs

β

Neutrophils

Constitutive

Degranulation

Bovine TAP

β

Epithelial cells

Inducible

Secretion

RTD-1

θ

Neutrophils, monocytes

Constitutive

Degranulation

Cathelicidins

Neutrophils, keratinocytes, epithelial cells, mast cells, and monocytes/macrophages

Constitutive and inducible

Degranulation or secretion

EDN

Eosinophils, neutrophils, macrophages, and placental epithelial cells

Constitutive and inducible

Degranulation or secretion

∗ Abbreviations: EDN, eosinophil-derived neurotoxin; HNP, human neutrophil peptide; HD, human defensin; HBD, human β-defensin; BNDB, bovine neutrophil-derived β-defensin; TAP, tracheal antimicrobial peptide; RTD-1, rhesus theta defensin-1.

in cultured epithelial cells was induced to a limited extent by heat-inactivated P. aeruginosa, and markedly by heat-inactivated Streptococcus pneumoniae or PMA (55). POSTTRANSLATIONAL MODIFICATION Defensins are translated as larger precursor polypeptides consisting of the prepiece, the propiece (often anionic), and the mature peptide (Figures 1 and 3). Posttranslational modifications include the proteolytic removal of the preproregion. The prepiece is a typical signal peptide (highly hydrophobic), and is proteolytically cleaved in the Golgi body. Cleavage of the propiece differs for different defensins. For HNP1 ∼ 4, the propiece is also proteolytically removed in the Golgi body, and the mature peptide is sorted to the primary granules of neutrophils for storage (103, 104). HD5 is stored in granules of Paneth cells and released as the proform (105, 106). Removal of the propiece of HD5 occurs extracellularly and is mediated by trypsin (107). The cleavage of propieces of cryptidins (mouse Paneth cell–derived α-defensins) also occurs extracellularly, but by using another protease, matrilysin (37). The enzyme(s)

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responsible for the removal of the propiece of β-defensin is unknown, although the mature form is secreted onto the surface and immediate surroundings of epithelial cells. Further processing by removal of individual amino acids from the N terminus of mature peptide has been seen for both α- (107, 108) and β-defensins (88). The variable processing of defensins generates multiple forms differing in N-terminal truncation, a mechanism that may diversify the biological activity of antimicrobial peptides (33, 88).

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Defensins as Effectors and Regulators of Innate Immunity DIRECT ANTIMICROBIAL ACTIVITY Defensins have mutiple host defense functions (Table 2). All defensins characterized so far have direct antimicrobial effect (27, 30, 109). All mammalian defensins, including α-, β-, and θ-subtypes, have the capacity to kill a wide variety of Gram-positive and Gram-negative bacteria, fungi, and some parasites in vitro, especially when examined under low concentrations of salt and plasma proteins (9, 10, 13, 18, 52, 53, 55, 91). The direct antimicrobial activity of defensins is dose-dependent and can usually be observed in micromolar range. The mechanism(s) by which defensins kill microorganisms is not completely understood. The interaction of defensins with target microorganisms results in the destabilization and disruption of their cell membranes, leading to an increase in permeability and leakage of small molecules (110). The polar topology of defensins with spatially separated charged and hydrophobic regions allows them to insert themselves into the microbial cell membrane that contains more negatively charged phospholipids than mammalian cell membrane (111). This interaction is generally believed to cause the formation of multiple pores in the microbial cell membrane (112). Alpha-defensins are able to inactivate certain enveloped viruses (113). HNP1 ∼ 3 have recently been identified as the nonchemokine molecules responsible for the anti-HIV activity produced by CD8 T cells of HIV-nonprogressors (114), a finding in line with an earlier report showing that HNP1 ∼ 3 can inhibit HIV replication (115). Monkey θ-defensin and retrocyclin, an artificial human θ -defensin rescued from the pseudogene by correcting the mutated stop codon, also exibit considerable in vitro anti-HIV activity (58). The anti-HIV activity of α- or θ -defensins is effective for both M- and T-tropic HIV strains, but the mechanistic basis is not completely understood (58, 114). θ -defensin has recently been shown to bind with high affinity to glycoproteins and glycolipids such as gp120, CD4, and galactosylceramide, which may be partly responsible for inhibiting HIV infection of CD4+ T cells (116). The direct microbicidal activity of most defensins [except HBD3 (52) and θ defensin (21)] in vitro is often blunted by physiological concentration of salt (e.g., 150 mM NaCl), increasing concentrations of divalent cations, and serum proteins, although the magnitude of inhibition depends on the target bacteria (88, 100, 110, 117–119). Therefore, it has been speculated that the microbicidal activity of defensins may be restricted to sequestered environments where the salt and serum protein concentrations are low, such as the surface of epithelium or skin and the

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TABLE 2 Diverse activities of mammalian defensins∗

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Activity relevant to immunity Defensin

Representative

In vitro

In vivo

α-defensin

HNP1 ∼ 3 HD5 Cryptidins

Microbicidal activity Antiviral activity Chemotactic activity Promoting phagocytosis

Recruiting immune cells Inducing cytokines Enhancing Ag-specific humoral and cellular immune responses Conferring resistance to bacterial invasion

Degranulating mast cells Stimulating the production of cytokines and chemokines Regulating complement activation Inhibiting ACTH receptor and glucocorticoid production β-defensin

HBD1 ∼ 4 mBD2 ∼ 3

Microbicidal activity Chemotactic activity using CCR6 Degranulating mast cells Stimulating the production of cytokines and prostaglandins Inducing dendritic cell maturation through TLR4 (only mBD2)

θ-defensin

RTD-1

Microbicidal Antiviral

Enhancing Ag-specific humoral and cellular immune responses Conferring resistance to bacterial invasion

Unknown

∗ Abbreviations: HNP1 ∼ 3, human neutrophil peptide 1 ∼ 3; HD5, human defensin 5; HBD1 ∼ 4, human β-defensin 1 ∼ 4; mBD2 ∼ 3, mouse β-defensin 2 ∼ 3; RTD-1, rhesus theta defensin 1.

phagosomes of neutrophils. However, evidence showing the physiologic relevance of the microbicidal activity of defensins has emerged in recent years (Table 2). In one study where HNP1 ∼ 3 were mixed with bacteria in the presence of lung tissue, defensins demonstrated more potent bactericidal activity (120), suggesting that the antimicrobial activity of defensins is effective under physiologic settings. Using a simple mouse model, HBD2 has been shown to have in vivo antimicrobial activity (121). More convincing evidence has been obtained for some defensins using transgenic or knockout models. For example, inactivation of the gene for matrilysin, an enzyme required for the generation of mature mouse Paneth cell α-defensins, leads to the deficiency of functional Paneth cell α-defensins and an increase in susceptibility of mice to oral challenge with Salmonella typhimurium (37). Knockout of a single defensin, mouse β-defensin-1, results in delayed clearance of Haemophilus influenzae from the lung (40) and increased colonization by Staphylococcus species in the bladder (41). More recently, HD5 has been shown to have antibacterial activity, using transgenic mice overexpressing HD5 gene (43). Compared with cryptidins, HD5 is more potent against murine S. typhimurium.

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Transgenic HD5 mice were fully protected from orally administered murine S. typhimurium, which killed 100% of the wild-type mice (43). CHEMOTACTIC EFFECTS OF DEFENSINS ON PHAGOCYTIC AND MAST CELLS Phagocytes, including neutrophils and monocytes/macrophages, constitute the first line of effector cells of innate antimicrobial host defense after the entry of pathogen(s) into the host. For phagocytes to combat invading pathogens, they need to be recruited to sites of bacterial entry. Leukocyte recruitment occurs along gradients of chemotactic factors, including chemokines and other chemoattractants (122, 123). Many defensins examined to date are leukocyte chemoattractants at nanomolar concentrations (Table 3). In 1989, HNP1 ∼ 3 were reported to be chemotactic for monocytes (31). HBD3 and 4 are also chemotactic for monocytes/macrophages (53, 55, 124, 125), whereas HBD2 chemoattracts mast cells (126), which may promote phagocyte recruitment indirectly. Notably, several mammalian defensins also function as chemoattractants for DCs (discussed later in detail). DCs are also phagocytic and participate in innate antimicrobial immunity (127) in at least two ways. First, DC precursor cells and DCs can directly phagocytize and kill pathogens (127). Second, DCs, particularly upon activation, produce numerous mediators including cytokines, chemokines, and antimicrobial peptides (128) that participate in innate antimicrobial immunity. The capacity of various defensins to chemoattract phagocytes, mast cells, and DCs suggests that they can potentially

TABLE 3 The chemotactic target cells of defensins, cathelicidin, and EDN∗ T lymphocytes

DCs

CD4 Defensin

PMN

MC

Mo/Mφ

CD45RA

CD45RO

CD8

iDCs

mDCs

HNPm & 1

−

nt

−

+

−

+

+

−

HNP2

−

nt

−

+

+

−

HBD1

−

nt

−

−

+

+

+

−

HBD2

−

+

−

−

+

+

+

−

HBD3

−

nt

+

+

+

−

HBD4

nt

nt

+

nt

nt

mBD2 & 3

−

nt

(+)

nt

+

LL-37

+

+

+

+

−

−

PR-39

+

nt

−

−

nt

nt

Bac7

+

nt

+

−

nt

nt

EDN/mEAR2

−

nt

−

−

+

+

∗

−

Abbreviations: HNPm, a mixture of HNP1 ∼ 3; HNP1 or 2, human neutrophil peptide 1 or 2; HBD1, 2, and 3, HBD1, 2, 3, and 4, human β-defensin 1, 2, 3, and 4; mBD2 & 3, mouse β-defensin 2 and 3; EDN/mEAR2, eosinophil-derived neurotoxin/mouse eosinophil-associated ribonuclease 2; PMN, polymorphonuclear leukocytes (neutrophils); MC, mast cells; Mo/Mφ, monocytes/macrophages; DCs, dendritic cells; iDCs or mDCs, immature or mature DCs; nt, not tested.

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contribute either directly or indirectly to the mobilization of host defense in response to pathogen entry. Defensins and chemokines not only overlap in chemotactic activity, but evidence is emerging that they share antimicrobial activity as well. Truncated forms of CXC chemokine CXCL7 with antimicrobial effects were initially isolated from platelet α-granules and named thrombocidins (129, 130). IFNγ -inducible ELR− CXC chemokines (including CXCL9 ∼ 11) were found to have defensin-like bactericidal activity (131). Based on the structural features shared by β-defensins and CCL20 (63, 64, 132), we showed that CCL20 has potent antibacterial activity (132, 133). CCL20 was also found to permeabilize the bacterial cell membrane and to be secreted by epithelial cells of the airway in response to proinflammatory stimuli in large quantity (approximately 170 ng/ml) (134). Screening of 30 human chemokines revealed that about two thirds of human chemokines have antibacterial activity (133). Together with the identification of the antimicriobial activity of CCL28 (135), it appears that many chemokines demonstrate defensin-like antimicrobial activity. INDUCTION OF INFLAMMATORY MEDIATORS Human, rabbit, and guinea pig αdefensins induce mast cell degranulation and histamine release (136, 137). Recently, HBD2 has also been shown to activate rat mast cells, resulting in the release of histamine and prostaglandin D2 (138). HNP1 ∼ 3 can augment the expression and/or production of CXCL8 and CXCL5 by bronchial epithelial cells (139–141). Because mast cell granule products increase neutrophil influx (142, 143) and CXCL8 is a potent neutrophil chemotactic factor (122, 123), defensins are likely to indirectly promote the recruitment of phagocytic neutrophils to inflammatory sites. Degranulation of the recruited neutrophils releases more defensins (33, 144) and consequently generates more CXCL8 and CXCL5, both of which result in a positive feedback loop. Furthermore, HNP1 ∼ 3 have been reported to increase the production of TNFα and IL-1 while decreasing the production of IL10 by monocytes (145). Increased levels of proinflammatory factors (IL-1, TNFα, and histamine) and suppressed levels of IL-10 at the site of microbial infection are likely to amplify local inflammatory responses. Intratracheal instillation of HNP1 ∼ 3 into mice led to the production of TNFα, MCP-1, and MIP-2 (146), providing in vivo support for the capacity of α-defensins to stimulate the production of inflammatory mediators. REGULATION OF THE FUNCTIONS OF PHAGOCYTES AND COMPLEMENT SYSTEM

Once recruited to the site of infection, phagocytes become activated and work with a variety of effector molecules to destroy microbial invaders. Guinea pig αdefensins are reported to induce neutrophil activation, as evidenced by enhanced expression of adhesion molecules including ICAM-1, CD11b, and CD11c by neutrophils (147). Upregulation of adhesion molecules on phagocytes not only facilitates their recruitment, but also promotes their activation, leading to enhanced microbicidal activity (122, 148, 149). In addition, human α-defensins can directly

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activate phagocytes to enhance phagocytosis (150) and to induce the production of reactive oxygen intermediates, which are potent bactericidal molecules (120). Moreover, human α-defensins can bind to complement C1q to either enhance (151) or suppress (152) the activation of the classical pathway of complement in vitro, depending on the experimental conditions. Presumably, α-defensins exhibit similar effects in vivo and therefore participate in regulating the function of complement system. Certain α-defensins have also been reported to inhibit the production of immunosuppressive adrenal steroid hormones, perhaps by blocking the ACTH receptor (153, 154). During systemic infections, α-defensin levels in plasma can reach up to 100 µg/ml, a concentration sufficient to interfere with the production of adrenal glucocorticoids (155, 156). Because glucocorticoids are potent immunosuppressive mediators, α-defensins may also enhance systemic antimicrobial immunity in vivo by inhibiting the production of glucocorticoids. Collectively, defensins are vital contributors to innate host antimicrobial defense. Although data from experiments using knockout and transgenic mice are often interpreted as being a result of the direct antimicrobial activity of defensins, it is more likely that the in vivo contribution of defensins to antimicrobial defense depends on their capabilities to directly kill or inactivate microorganisms; to enhance phagocytosis; to promote the recruitment of phagocytes, mast cells, and DCs; to enhance production of proinflammatory cytokines; to suppress antiinflammatory or immunosuppressive mediators; and to regulate complement activation (Figure 4).

Defensins as Enhancers of Adaptive Immunity INTERACTION OF DEFENSINS WITH G PROTEIN–COUPLED RECEPTOR(S) ON iDCs

The initiation of adaptive antimicrobial immune response begins at the sites of microbial entry where microbial Ags are taken up by immature DCs (iDCs) (1, 3, 157, 158). While processing Ags, iDCs undergo a maturational process in response to endogenous mediators and microbial products to become mature DCs (mDCs) with the capacity to migrate to secondary lymphoid organs and to stimulate Agspecific na¨ıve T cells (3, 158). Thus, recruitment to, and maturation of, DCs at sites of microbial entry are critical for the induction of adaptive antimicrobial immune responses. Indeed, one hallmark of the early phase of infection is the recruitment of iDCs to the inflammatory sites (158–160). Defensins have been found to be direct chemoattractants for iDCs (Table 2). For example, HNP1 ∼ 3 are selectively chemotactic for human iDCs generated from human CD34+ DC precursor cells (161). HBD1 and 2 are also selectively chemotactic for human iDCs, but not mDCs (34). In addition to being chemotactic for monocyte/macrophage (53), HBD3 also attracts iDCs (124). Similar to HBDs, mouse β-defensin 2 (mBD2) and mBD3, but not their proforms, are chemotactic for iDCs, but not mDCs, generated from mouse bone marrow progenitor cells (44). Since defensins are usually released in large quantities in response to inflammatory and microbial stimuli, they may contribute to the recruitment of iDCs to the sites of microbial entry.

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The chemotactic activity of HBD1 ∼ 3 and mBD2 and 3 for iDCs is mediated by the chemokine receptor CCR6 (34, 44), which is also the receptor for the CC chemokine CCL20 (123, 162). The chemotaxis of monocytes by HBD3 must use a receptor other than CCR6 because monocytes do not express functional CCR6 (124, 162). Although the chemotactic receptor(s) for HNP1 ∼ 3 have not yet been identified, they must be a Giα-protein-coupled receptor(s) because their chemotactic activity can be inhibited by pretreatment of target cells with pertussis toxin (33, 161). Despite the lack of sequence homology between β-defensins and CCL20 (13, 18, 52, 53, 163, 164), they each interact with CCR6. The tertiary structures of both HBD2 and CCL20, determined by either X-ray crystallography or nuclear magnetic resonance (64, 69, 132, 165), possess a core folding of three antiparallel β-strands. Thus, BD2 can be structurally considered a simplified form of CCL20 lacking the C-terminal α-helix (69, 165). The Asp4-Leu9 motif in BD2 resembles the Asp5-Leu8 motif of CCL20, which is considered to be responsible for specific interaction with CCR6 (165), providing a structural basis for the capacity of βdefensins and CCL20 to interact with the same receptor (124, 165). STIMULATION OF DC MATURATION BY mBD2 In addition to its chemotactic effect on CCR6-expressing iDCs (44), mBD2 has the unique capacity to promote the phenotypic and functional maturation of murine DCs (42). Treatment of mouse DCs with mBD2 upregulates the expression of costimulatory molecules (CD40, CD80, and CD86), MHC class II, and chemokine receptor CCR7. In addition, mBD2-treated DCs develop the capacity to activate na¨ıve T cells since they induced a greater allogeneic mixed lymphocyte reaction than untreated DCs or DCs treated with promBD2. Furthermore, mBD2-matured DCs exhibit a Th1-polarizing cytokine profile with the production of proinflammatory cytokines IL-12, IL-1α, IL1β, and IL-6 (42). Because activated APCs, particularly mDCs, are responsible not only for the elicitation of Ag-specific immune responses, but also determination of Th1/Th2 polarization of T and B cells (3, 158), the capacity of mBD2, but not mBD3, to induce the production of a Th1-polarizing cytokine profile suggests that different defensins may regulate the type of immune responses (42, 44). The capacity of mBD2 to stimulate DC maturation is mediated by Toll-like receptor 4 (TLR4) based on several lines of evidence (42). Most critically, mBD2 cannot stimulate the maturation of iDCs derived from C3H/HeJ or C57BL10ScNcr mice (both lack functional TLR4). Furthermore, mBD2 can activate NF-κB in HEK293 cells transfected with TLR4 and MD-2, but not in untransfected HEK293 cells. Thus, mBD2, in addition to interacting with CCR6 (44), functions as an endogenous ligand of TLR4 signaling (42). DIRECT EFFECTS ON T LYMPHOCYTES Both α- and β-defensins function as chemoattractants for T lymphocytes (Table 3). HNP-1 and -2 are chemotactic for peripheral blood T cells both in vitro and in vivo, as tested using a human/SCID

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chimeric model (33). Subsequent study indicates that HNP1 ∼ 3 are chemotactic for CD4+/CD45RA+ and CD8+ T cells (161). On the other hand, HBD2 is chemotactic for CD4+/CD45RO+ T cells expressing CCR6 (34). The T cell– chemoattracting effect of defensins suggests that they may contribute to the recruitment of both CD4+ and CD8+ effector T cells to sites of microbial infection. An early report shows that HNP1 ∼ 3, in particular HNP2, can selectively inhibit the catalytic activity of PKC without affecting the binding of this enzyme to Ca2+, its substrate, or phosphatidylserine (a cofactor) (166). HNP1 ∼ 3 are present in the nucleus of human peripheral blood T cells (167). These findings suggest that defensins may profoundly regulate the functions of T lymphocytes. The T-cell chemotactic and microbicidal activities of HNP1 are differentially regulated in the airway (168). The airway epithelial cells secrete or express on their surface arginine-specific ADP-ribosyltransferase-1, which modify HNP1 in vivo by ADP-ribosylating Arg14 of HNP1. The modification greatly decreases its antimicrobial activity, but does not affect the T-cell chemotactic activity of HNP1 (168). ENHANCEMENT OF Ag-SPECIFIC IMMUNE RESPONSE IN VIVO The effects of defensins on DCs and T lymphocytes predicts that both α- and β-defensins may contribute to the induction of adaptive antimicrobial immunity (Table 2). The in vivo immunoenhancing activity of human α-defensins has been demonstrated in several studies. The earliest study showed that HNP1 ∼ 3 could enhance Ag-specific immune responses to simultaneous intranasal administration of ovalbumin (OVA) into C57BL/6 mice. Compared to immunization with OVA alone, coadministration of HNP1 ∼ 3 enhanced the systemic production of OVA-specific serum IgG antibody and the generation of IFNγ , IL-5, IL-6, and IL-10 by OVA-specific CD4+ T cells, providing the first evidence that α-defensins can promote both humoral and cellular adaptive immune responses (36). The immunoenhancing activity of α-defensins was further demonstrated in a study in which intraperitoneal injection of HNP1 ∼ 3 together with KLH or B-cell lymphoma idiotype Ag into mice was shown not only to augment the serum levels of Ag-specific IgG, but also to enhance the resistance of immunized mice to tumor challenge (169). A recent study of the immunoenhancing effect of individual HNP, indicated that the in vivo immunoenhancing role varies among defensins (170). The capacity of β-defensins to enhance Ag-specific immune responses has been demonstrated by the use of a DNA vaccine approach (42, 44). When mBD2 and mBD3 were fused with B-cell lymphoma epitope sFv38 (lymphoma-specific VH and VL fragments, an idiotypic Ag) and used as DNA vaccines to immunize mice, not only did the mice generate potent humoral immune responses against otherwise nonimmunogenic sFv38, but they also developed antitumor immunity (42, 44). Since the induction of antitumor protection in this model relies on the generation of tumor-specific cellular immunity (171), it seems that β-defensins can promote both humoral and cellular Ag-specific immune responses. In line with the fact that mBD2 and mBD3 share the same receptor with mCCL20, fusion

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of mCCL20 with sFv38 also induced Ag-specific humoral and cellular immune responses (44). Using a similar approach with a different Ag, mBD2 was also demonstrated to induce both antibody and CTL responses to gp120, an envelope protein of HIV (172). In these studies, the immunoenhancing activity of the fusion construct of mDB2, mBD3, and mCCL20 depends on their interaction with CCR6 because the fusion constructs of promBD2 or mutated mCCL20 and target Ags, which were not able to interact with CCR6 to induce chemotaxis, failed to enhance immune responses to target Ags (42, 44, 172). In addition, fusion of mBD2, mBD3, or mCCL20 with target Ags was critical because immunization of the mice with a mixture of unfused target Ags and chemotactic ligands (either β-defensins or mCCL20) was not effective in inducing Ag-specific immune responses (44, 172). These characteristics are also true for the fusion constructs of other chemokine ligands such as MCP-3 (44, 171, 172). Therefore, besides promoting the recruitment of iDCs (or other Ag-presenting cells), another mechanism for chemotactic ligands such as β-defensins to promote Ag-specific immune responses may be the promotion of Ag uptake and processing following chemokine receptor-mediated internalization of the fused target Ags. When another even weaker B cell-lymphoma idiotypic Ag, sFv20, was used as the antigenic moiety in the fusion constructs, only mBD2, but not mBD3, could induce protective antitumor immunity (42, 44). The difference between mBD2 and mBD3 in this case may be due to the fact that only mBD2, but not mBD3, can induce phenotypic and functional maturation of DCs (42). The importance of DC maturation in the induction of adaptive immune responses has recently been demonstrated by a similar observation that linkage of Ag with anti-DEC205 mAb to facilitate efficient antigen uptake and processing by iDCs induces efficient Ag-specific immune responses only if a maturational signal is provided (173, 174). Moreover, IL-6 production by mBD2-treated DCs may also contribute to the induction of anti-sFv20 (42) as IL-6 contributes to the activation of adaptive immune response by overcoming the suppressive effect of CD4+ CD25+ regulatory T cells (175). Very recently, HBD1 and HBD2 were also investigated using the intranasal immunization model (36). In comparison with mice immunized with only OVA, mice immunized with a mixture of OVA and HBD1 or HBD2 generated significantly higher OVA-specific serum IgG antibody, confirming that human βdefensins have in vivo immunoenhancing activity (170). How can α- and β-defensins promote in vivo adaptive immunity to microbial Ags in the context of infection? Several scenarios can be envisaged (Figure 4). First, defensins potentially promote Ag uptake and processing by DCs. This can be achieved at least in two ways: the chemotactic recruitment of iDCs to sites of infection, and consequent facilitation of microbial Ag delivery to iDCs. Following the killing of microorganisms, defensins may still bind to a portion of antigenic microbial cell membrane to form “dead microbe-defensin” complexes. Such “defensin-Ag” complexes may be subject to defensin receptor-mediated internalization, and thus deliver microbial Ag(s) to iDCs more efficiently. In addition, defensins promote Ag presentation by inducing DC maturation directly or indirectly.

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Although only mBD2 has been found to directly induce DC maturation so far, the possibility that additional defensin(s) with such activity will be identified is high given the recent realization that over 30 β-defensin genes are present in both humans and mice (56). Defensins induce production of TNFα and IL-1 by monocytes/macrophages (145), which are inducers of DC maturation (3, 158), and should contribute indirectly to DC maturation during microbial infection. Furthermore, defensins may also facilitate the chemotactic recruitment of memory CD4+ and/or CD8+ T cells to infected tissue, thus contributing to the effector phase of adaptive antimicrobial immune responses.

CATHELICIDIN Cathelicidin represents another major group of mammalian antimicrobial proteins found in many mammalian species (20, 25–27, 176). All cathelicidin proteins (Figure 5) contain an N-terminal putative signal peptide (preregion), a conserved cathelin-like domain (proregion), and a C-terminal microbicidal domain (hence the name cathelicidin) (20). About 35 cathelicidin members have been identified in various mammalian species; humans and mice, however, generate only one cathelicidin, called hCAP18 (19, 177–179) and CRAMP (180), respectively.

Gene, Expression, and Regulation Cathelicidin genes (Figure 5) consist of four exons (45, 181–183). The first three exons encode the N-terminal preproregion consisting of a putative signal peptide

Figure 5 The genomic organization, expression, and processing of cathelicidins and their activities. The last exon is not drawn to scale as it varies greatly among different cathelicidins.

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(29 ∼ 30 a.a.) and the cathelin-like domain (94 ∼ 114 a.a.). The last exon encodes the cleavage site and the C-terminal antimicrobial domain, which varies remarkably in size (12 ∼ 97 a.a.). Cathelicidins are usually stored in the granules of neutrophils as an inactive proform (cathelin-like domain + antimicrobial domain) and undergo processing to mature peptide during or after secretion by appropriate proteases. For example, human cathelicidin/hCAP18 is cleaved by elastase (184) or proteinase 3 (185) to liberate its C-terminal antimicrobial domain, which is called “LL-37” because this peptide begins with two leucine residues and has 37 amino acid residues (19, 177–179, 184). In cattle and pigs, the processing of cathelicidins seems to be mediated exclusively by elastase (186, 187). The C-terminal antimicrobial peptides of cathelicidins are also markedly variable in structure. Most of this group of antimicrobial peptides have an α-helical conformation (e.g., hCAP18/LL37, rabbit CAP18, mouse CRAMP, etc.) (184, 188, 189). Some cathelicidins (e.g., porcine PR-39, bactenecin 5, etc.) are proline/arginine-rich, showing an extended α-helical structure like polyproline (190, 191). Pig protegrins, on the other hand, have β-sheet structures (192, 193). Cathelicidins are constitutively expressed in a variety of tissues such as bone marrow, thymus, liver, spleen, testis, stomach, and intestine in a developmentally regulated manner (180, 194, 195). At the cellular level, cathelicidins are most abundant in granules of neutrophils of various species (20, 176, 178); however, they are also expressed by other cell types either constitutively or in an inducible manner (176, 177, 196). For example, hCAP18/LL-37 is expressed by various epithelial cells and keratinocytes (177, 196, 197), monocytes, NK cells, B cells, and γ δT cells (85), and is induced in keratinocytes in response to inflammatory stimuli (188, 194) or injury (196). Very recently, cathelicidins have been found to be present in both mouse and human mast cells, and the expression can also be upregulated by bacterial components such as LPS or lipoteichoic acid (198). Several potential regulatory motifs have been found at the promoter regions of cathelicidin genes, such as the consensus binding sites for NF-κB, NF-IL-6, acute phase response factor, and IFNγ response element (182, 184, 188, 194, 199). The expression of LL-37 by colon epithelial cells is upregulated by short chain fatty acids in an Erk (extracellular signal regulated protein kinase)–dependent manner (200).

Roles of Cathelicidins in Host Antimicrobial Immunity DIRECT ANTIMICROBIAL ACTIVITY The N-terminal prepiece of cathelicidins is a classical signal peptide. The cathelin-like domain has long been considered to neutralize the cationic antimicrobial domain so that the whole molecule is maintained in an inactive form during intracellular transport and storage to avoid potential intracellular cytotoxicity (20, 176). However, a recent study found that the cathelin-like domain not only inhibits the protease activity of cathepsin L, a cysteine protease, but also demonstrates potent antibacterial activity (201). The Cterminal antimicrobial peptides of cathelicidins are microbicidal against a broad spectrum of microorganisms, including bacteria, fungi, and parasites, with a wide overlap in specificity, but they exhibit significant differences in potency from one

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another (20, 176). Similar to defensins, the mechanism of cathelicidin-mediated microbial killing depends on the formation of ion channels or pores in the microbial cell membrane (176). CHEMOTACTIC ACTIVITY Several cathelicidins are chemotactic for various leukocytes. ProBac7, a bovine cathelicidin, is chemotactic for monocytes/macrophages (125). PR-39, one member of the porcine cathelicidins, can induce chemotaxis of pig neutrophils (202). Recently, LL-37 has been found to be chemotactic for neutrophils, monocytes (35, 85), and mast cells (203). Cathelicidins generated at the sites of microbial entry form chemotactic gradients, which are likely to result in the recruitment of phagocytes. In addition to inducing chemotaxis, PR-39 can mobilize intracellular Ca2+ in pig neutrophils (202), whereas LL-37 can induce Ca2+ mobilization in phagocytes (35), suggesting that cathelicidins are endogenous activators of phagocytes. The capacity of LL-37 to induce Ca2+ mobilization in monocytes can be cross-desensitized by ligands specific for human formyl peptide receptor-like 1. This finding led to the identification of FPRL1 as a receptor for LL-37 (35). INDUCTION OF EXPRESSION OR RELEASE OF INFLAMMATORY MEDIATORS LL-37 enhances the expression of a variety of genes by macrophages (204). Of particular interest is the upregulation of the chemokines CXCL8 and CCL2 and their corresponding receptors, CXCR2 and CCR2, by LL-37 (204). CXCR2 is expressed by neutrophils, monocytes, and T cells, whereas CCR2 is expressed by monocytes and iDCs (122, 123, 158). Therefore, LL-37 may indirectly facilitate the recruitment of phagocytes, iDCs, and T cells to inflammatory sites through the induction of chemokines and their corresponding receptors. Furthermore, LL-37 can degranulate mast cells, leading to the release of proinflammatory mediators such as histamine and prostaglandins (138). The capacity of LL-37 to chemoattract human peripheral blood T cells (35, 85) indicates that it can participate in the recruitment of effector T cells to sites of microbial infection, thereby contributing to adaptive antimicrobial immunity. NEUTRALIZATION OF BACTERIAL ENDOTOXIN Killing of bacteria by antimicrobial peptides, phagocytes, and complement system result in the release of bacterial components, such as endotoxin from Gram-negative bacteria and lipotechoic acid from Gram-positive bacteria. These bacterial components, if allowed to enter the circulation, have a detrimental outcome such as septic shock by inducing the production of high levels of systemic proinflammatory cytokines, including TNFα, IL-1β, and IL-6. Many of the cathelicidins, including LL-37, SMAP-29, Bac 2A-NH2 (a linear form of Bac 2A), and indolicidin, bind LPS with high affinity and neutralize its biological activities (19, 28, 179, 189, 204). In addition, the activity of lipotechoic acid can also be inhibited by cathelicidins (204). This property has pathophysiological relevance because both rabbit CAP18106–142, intact or truncated LL-37 (a 27-residue LPS-binding fragment corresponding to hCAP18109–135), can protect

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galactosamine-sensitized mice from LPS-mediated lethality (19, 204, 205). This protection has also been demonstrated by overexpression of LL-37 in mice through adenovirus-mediated gene transfer (206). Therefore, cathelicidins can serve as buffers of LPS and LTA, reducing the severity of host inflammatory responses to bacteria that can lead to lethal conditions such as septic shock, and this activity of cathelicidins can be considered one aspect of host innate antimicrobial defense. ANGIOGENESIS AND WOUND HEALING Certain cathelicidins have angiogenic effect. PR-39 can enhance angiogenesis in vitro and stimulate the formation of functional vasculature in vivo (207). This effect is thought to be mediated by inhibiting the ubiquitin-proteasome-dependent degradation of hypoxia-inducible factor-1α (207). LL-37 also stimulates angiogenesis (208). Similar to its chemotactic activity, the angiogenic activity of LL-37 is mediated by FPRL1 expressed on endothelial cells (208). PR-39 can induce the production of syndecan-1 and -4, major components of cell coat (209). LL-37 can stimulate re-epithelialization of skin wounds, and the wound repair can be inhibited by LL-37-specific neutralizing antibody (210). Thus, cathelicidins are potentially important for wound healing. IN VIVO ROLES OF CATHELICIDINS The participation of LL-37 in host antimicrobial defense has been demonstrated by in vivo studies showing that adenoviral vector–targeted systemic overexpression of LL-37 in mice results in decreased bacterial load and mortality of experimental mice following challenge with P. aeruginosa or E. coli (38, 206). Moreover, knockout of Cnlp, the mouse gene encoding CRAMP, results in increased susceptibility of the mice to infection by Group A Streptococcus (39). Furthermore, mice deficient for CRAMP show greatly decreased vascularization during skin wound repair (208).

EDN EDN, one of the four eosinophil-granule-derived cationic proteins, belongs to the ribonuclease superfamily (211). EDN was purified to homogeneity in 1981 as a protein of 18.4 kDa (212). Its cDNA, cloned in 1989, has an open reading frame encoding a 134-amino acid mature polypeptide with 4 intrachain disulfide bridges and a 27-residue amino-terminal hydrophobic leader sequence (213). Its threedimensional structure, solved by X-ray crystallography, shows a typical RNase folding, which is a V-shaped α + β-type polypeptide with the active-site cleft in the middle (214). The secondary structural elements consist of six β-strands and four α-helices. The tertiary structure is organized into two lobes, each consisting of three antiparallel β-strands and one α-helix, and with two α-helices located between the two lobes. The gene for EDN localizes to 14q24–q31 and contains two exons and one small intron (230 bases) in the 50 untranslated region, with the second exon encoding the whole mature protein (215). Although EDN is a single-copy gene, another form containing four additional amino acids (Ser-LeuHis-Val) on the N terminus originally considered as part of the signal sequence

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has also been identified, suggesting alternative splicing or different posttranscriptional modification (216, 217). The transcription of EDN gene is controlled by elements located at the intron and proximal promoter, including binding sites for AP-1, NF-ATp, PU.1, and C/EBP (218–220). EDN is stored in eosinophil granules or expressed by liver, spleen, neutrophils, and activated monocytes/macrophages (211, 221, 222). EDN is not antibacterial and its role(s) in host defense is unknown. In the late 1990s, EDN was found to have in vitro antiviral activity, in particular against respiratory syncytial virus (22), which thus marked it as one member of host gene-coded antimicrobial proteins. Recently, EDN has also been shown to be responsible, in part, for the HIV-1-inhibitory activities in the supernatant of allogeneic mixed lymphocyte reaction (223). EDN has recently been found to selectively chemoattract both human and mouse DCs (224). Mouse eosinophil-associated RNase 2 (mEAR2), one of a cluster of divergent orthologs of human EDN (211, 225), was also chemotactic for human and mouse DCs (224). In agreement with its DC chemotactic activity, EDN induced the activation of p42/44 Erk in DCs (224). Furthermore, injection of mEAR2 into the air pouches of mice resulted in the recruitment of DCs into the air pouches, indicating that EDN/mEAR2 acts as a DC chemoattractant in vivo (224). Most recently, EDN was found to be able to activate human dendritic in vitro, leading to the production of a variety of cytokines, chemokines, growth factor, and soluble receptors (D. Yang, Q. Fu, Q. Chen, D.L. Newton, H.F. Rosenberg, et al., submitted). Most of the mediators induced by EDN are proinflammatory, such as IL-6, TNFα, and many chemokines. Furthermore, EDN also induced the maturation of dendritic cells. Therefore, EDN can act as potent activators for human dendritic cells. Given the critical roles of DC recruitment, maturation, and IL-6 in the induction of Ag-specific immune response (3, 157, 158, 175), EDN is therefore another host gene-coded antimicrobial protein that potentially contributes to the induction and/or regulation of both innate and adaptive antimicrobial immunity.

CONCLUDING REMARKS Based on in vitro and animal model studies, it has become evident that many mammalian antimicrobial proteins (e.g., defensins, cathelicidins, EDN, etc.) have, in addition to their well-recognized direct antimicrobial activities, additional roles in initiating and amplifying host innate and adaptive immune responses against microbial invasion. However, their contribution to human antimicrobial immunity needs to be further explored. One study of the expression of human antimicrobial proteins by morbus Kostmann patients with normal level of neutrophils (as a result of G-CSF treatment) has shown that HNP1 ∼ 3 are greatly reduced and LL-37 is absent in patients’ plasma and saliva (226). The abnormal expression of α-defensins and LL-37 correlates with the occurrence of periodontal infectious disease in patients with morbus Kostmann, providing the strongest evidence to date

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that defensins and cathelicidins are important in human antimicrobial immunity (226). New antimicrobial proteins keep emerging. Recent genomic surveys have revealed defensin-like genes in five separate syntenic clusters on four chromosomes (56, 82). The antimicrobial and immunomodulatory activities of these antimicrobial peptides have not yet been evaluated. Most of the known immunomodulatory effects of antimicrobial proteins overlap with other humoral components such as cytokines and chemotactic factors of the immune system. Additional studies are needed to distinguish their relative contribution to host antimicrobial immunity from that of other mediators using appropriate knockout or transgenic models. The receptor(s) utilized by antimicrobial proteins (e.g., EDN) to signal gene activation in target cells remains to be identified. Attempts to engineer antimicrobial peptides or proteins into clinically applicable antibiotics have been widespread (227). Such therapeutic effort may be complicated by their immunomodulatory activities, and any engineered products need to be evaluated to avoid potential undesirable immunomodulatory effects. Conversely, antimicrobial proteins or their modified forms have the potential to be developed into therapeutic agents with both antibiotic and immunoenhancing activities. ACKNOWLEDGMENTS This project has been funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. NO1-CO-12,400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The Annual Review of Immunology is online at http://immunol.annualreviews.org

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171. Biragyn A, Tani K, Grimm MC, Weeks S, Kwak LW. 1999. Genetic fusion of chemokines to a self tumor antigen induces protective, T-cell dependent antitumor immunity. Nat. Biotechnol. 17:253– 58 172. Biragyn A, Belyakov IM, Chow Y-H, Dimitrov DS, Berzofsky JA, Kwak LW. 2002. DNA vaccines encoding human immunodeficiency virus-1 glycoprotein 120 fusions with proinflammatory chemoattractants induce systemic and mucosal immune responses. Blood 100:1153– 59 173. Hawiger D, Inaba K, Dorsett Y, Guo M, Mahnke K, et al. 2001. Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. J. Exp. Med. 194:769–80 174. Bonifaz L, Bonnyay D, Mahnke K, Rivera M, Nussenzweig MC, Steinman RM. 2002. Efficient targeting of protein antigen to the dendritic cell receptor DEC-205 in the steady state leads to antigen presentation on major histocompatibility complex class I products and peripheral CD8+ T cell tolerance. J. Exp. Med. 196:1627– 38 175. Pasare C, Medzhitov R. 2003. Toll pathway-dependent blockade of CD4+ CD25+ T cell-mediated suppression by dendritic cells. Science 299:1033–36 176. Ramanathan B, Davis EG, Ross CR, Blecha F. 2002. Cathelicidins: microbicidal activity, mechanisms of action, and roles in innate immunity. Microbes Infect. 4:361–72 177. Agerberth B, Gunne H, Odeberg J, Kogner P, Boman HG, Gudmundsson GH. 1995. FALL-39, a putative human peptide antibiotic, is cysteine-free and expressed in bone marrow and testis. Proc. Natl. Acad. Sci. USA 92:195–99 178. Cowland JB, Johnsen AH, Borregaad N. 1995. hCAP-18, a cathelin/probactenecin-like protein of human neutrophil specific granules. FEBS Lett. 368:173–76

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Figure 4 Schematic illustration of the potential mechanisms by which defensins enhance host innate and adaptive antimicrobial immunity. When the integrity of skin or epithelial barrier is breached, microorganisms invading the host stimulate the release of a-defensins from neutrophils (recruited by microbial fMLP) and b-defensins from epithelial cells (Ep, including keratinocytes). Defensins promote innate antimicrobial immunity through at least five ways. For the enhancement of adaptive antimicrobial immunity, defensins potentially enhance the recruitment of iDCs to sites of infection. After killing of microorganisms, defensins may form a “dead microbe-defensin” complex to facilitate Ag uptake by targeting Ag to iDCs through defensin receptor–mediated internalization. In addition, defensins can enhance the maturation of iDCs to mDCs directly or indirectly by inducing the production of DC-maturing cytokines such as TNF and IL-1. Furthermore, defensins may also contribute to the effector phase of adaptive antimicrobial immunity by facilitating the recruitment of effector T cells to infected tissues. Other antimicrobial proteins including chemokines (not illustrated here) may have similar roles.

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CONTENTS FRONTISPIECE—Leonard A. Herzenberg and Leonore A. Herzenberg GENETICS, FACS, IMMUNOLOGY, AND REDOX: A TALE OF TWO LIVES INTERTWINED, Leonard A. Herzenberg and Leonore A. Herzenberg SELF- AND NONSELF-RECOGNITION BY C-TYPE LECTINS ON DENDRITIC CELLS, Teunis B.H. Geijtenbeek, Sandra J. van Vliet, Anneke Engering, Bert A. ’t Hart, and Yvette van Kooyk

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TRANSCRIPTIONAL CONTROL OF EARLY B CELL DEVELOPMENT, Meinrad Busslinger

UBIQUITIN LIGASES AND THE IMMUNE RESPONSE, Yun-Cai Liu LIGANDS FOR L-SELECTIN: HOMING, INFLAMMATION, AND BEYOND, Steven D. Rosen

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INTEGRINS AND T CELL–MEDIATED IMMUNITY, Jonathan T. Pribila, Angie C. Quale, Kristen L. Mueller, and Yoji Shimizu

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MULTIPLE ROLES OF ANTIMICROBIAL DEFENSINS, CATHELICIDINS, AND EOSINOPHIL-DERIVED NEUROTOXIN IN HOST DEFENSE, De Yang, Arya Biragyn, David M. Hoover, Jacek Lubkowski, and Joost J. Oppenheim

STARTING AT THE BEGINNING: NEW PERSPECTIVES ON THE BIOLOGY OF MUCOSAL T CELLS, Hilde Cheroutre THE BCR-ABL STORY: BENCH TO BEDSIDE AND BACK, Stephane Wong and Owen N. Witte

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CD40/CD154 INTERACTIONS AT THE INTERFACE OF TOLERANCE AND IMMUNITY, Sergio A. Quezada, Lamis Z. Jarvinen, Evan F. Lind, and Randolph J. Noelle

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THE THREE ES OF CANCER IMMUNOEDITING, Gavin P. Dunn, Lloyd J. Old, and Robert D. Schreiber

AUTOIMMUNE AND INFLAMMATORY MECHANISMS IN ATHEROSCLEROSIS, Georg Wick, Michael Knoflach, and Qingbo Xu THE DYNAMIC LIFE OF NATURAL KILLER CELLS, Wayne M. Yokoyama, Sungjin Kim, and Anthony R. French

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THE ROLE OF COMPLEMENT IN THE DEVELOPMENT OF SYSTEMIC LUPUS ERYTHEMATOSUS, Anthony P. Manderson, Marina Botto, and Mark J. Walport

DROSOPHILA: THE GENETICS OF INNATE IMMUNE RECOGNITION AND RESPONSE, Catherine A. Brennan and Kathryn V. Anderson RAGS AND REGULATION OF AUTOANTIBODIES, Mila Jankovic,

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Rafael Casellas, Nikos Yannoutsos, Hedda Wardemann, and Michel C. Nussenzweig

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THE ROLE OF SUPPRESSORS OF CYTOKINE SIGNALING (SOCS) PROTEINS IN REGULATION OF THE IMMUNE RESPONSE, Warren S. Alexander and Douglas J. Hilton

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NATURALLY ARISING CD4+

REGULATORY T CELLS FOR IMMUNOLOGIC SELF-TOLERANCE AND NEGATIVE CONTROL OF IMMUNE RESPONSES, Shimon Sakaguchi PHOSPHOINOSITIDE 3-KINASE: DIVERSE ROLES IN IMMUNE CELL ACTIVATION, Jonathan A. Deane and David A. Fruman IMMUNITY TO TUBERCULOSIS, Robert J. North and Yu-Jin Jung MOLECULAR DEFECTS IN HUMAN SEVERE COMBINED IMMUNODEFICIENCY AND APPROACHES TO IMMUNE RECONSTITUTION, Rebecca H. Buckley PHYSIOLOGICAL CONTROL OF IMMUNE RESPONSE AND INFLAMMATORY TISSUE DAMAGE BY HYPOXIA-INDUCIBLE FACTORS AND ADENOSINE A2A RECEPTORS, Michail V. Sitkovsky, Dmitriy Lukashev, Sergey Apasov, Hidefumi Kojima, Masahiro Koshiba, Charles Caldwell, Akio Ohta, and Manfred Thiel

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T LYMPHOCYTE–ENDOTHELIAL CELL INTERACTIONS, Jaehyuk Choi, David R. Enis, Kian Peng Koh, Stephen L. Shiao, and Jordan S. Pober

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IMMUNOLOGICAL MEMORY TO VIRAL INFECTIONS, Raymond M. Welsh, Liisa K. Selin, and Eva Szomolanyi-Tsuda

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CENTRAL MEMORY AND EFFECTOR MEMORY T CELL SUBSETS: FUNCTION, GENERATION, AND MAINTENANCE, Federica Sallusto, Jens Geginat, and Antonio Lanzavecchia CONTROL OF T CELL VIABILITY, Philippa Marrack and John Kappler

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ASTHMA: MECHANISMS OF DISEASE PERSISTENCE AND PROGRESSION, Lauren Cohn, Jack A. Elias, and Geoffrey L. Chupp

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CD1: ANTIGEN PRESENTATION AND T CELL FUNCTION, Manfred Brigl and Michael B. Brenner

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CHEMOKINES IN INNATE AND ADAPTIVE HOST DEFENSE: BASIC CHEMOKINESE GRAMMAR FOR IMMUNE CELLS, Antal Rot and Ulrich H. von Andrian

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INTERLEUKIN-10 AND RELATED CYTOKINES AND RECEPTORS, Sidney Pestka, Christopher D. Krause, Devanand Sarkar, Mark R. Walter, Yufang Shi, and Paul B. Fisher

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INDEXES

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Subject Index Cumulative Index of Contributing Authors, Volumes 12–22 Cumulative Index of Chapter Titles, Volumes 12–22

ERRATA An online log of corrections to Annual Review of Immunology chapters may be found at http://immunol.annualreviews.org/errata.shtml

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Annu. Rev. Immunol. 2004. 22:217–46 doi: 10.1146/annurev.immunol.22.012703.104522 c 2004 by Annual Reviews. All rights reserved Copyright ° First published online as a Review in Advance on October 15, 2003

STARTING AT THE BEGINNING: New Perspectives on the Biology of Mucosal T Cells

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Hilde Cheroutre Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121; email: [email protected]

Key Words lymphopoiesis, intestine, thymus, epithelial cells, immune regulation ■ Abstract The gastrointestinal tract is the central organ for uptake of fluids and nutrients, and at the same time it forms the main protective barrier between the sterile environment of the body and the outside world. In mammals, the intestine has further evolved to harbor a vast load of commensal bacteria that have important functions for the host. Discrimination by the host defense system of nonself from self can prevent invasion of pathogens, but equivalent responses to dietary or colonizing bacteria can lead to devastating consequences for the organism. This dilemma imposed by the gut environment has probably contributed significantly to the evolutionary drive that has led to sophisticated mechanisms and diversification of the immune system to allow for protection while maintaining the integrity of the mucosal barrier. The immense expansion and specialization of the immune system is particularly mirrored in the phylogeny, ontogeny, organization, and regulation of the adaptive intraepithelial lymphocytes, or IEL, which are key players in the unique intestinal defense mechanisms that have evolved in mammals.

INTRODUCTION The intestine of higher vertebrates is a major T cell organ. Three defined anatomical compartments contain T lymphocytes. The gut-associated lymphoid tissues (GALT), including Peyer’s patches (PP) and mesenteric lymph nodes (MLN), harbor T cells in organized lymphoid structures. T cells residing in the GALT have the most in common with peripheral lymph node T cells. In the other two compartments, T lymphocytes are scattered among nonlymphoid cell types. These include T cells distributed within the lamina propria (lamina propria lymphocytes, or LPL). Additionally, numerous intraepithelial lymphocytes (IEL) reside on the other side of the basement membrane from the lamina propria. IEL are found as single cells between the intestinal epithelial cells, with about one lymphocyte for every four to nine epithelial cells in the small intestine. It has been estimated, based on immunohistology, that the IEL of the mouse small intestine alone amount to almost 50% of the total T cell number in all lymphoid organs (1), although the number 0732-0582/04/0423-0217$14.00

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that can be purified is somewhat less. Additionally, the T cells residing in these different intestinal compartments are significantly different from conventional T cells as well as from one another in terms of ontogeny, phenotype, and function, and it is therefore evident that the IEL provide qualitatively and quantitatively major contributions to the biology of the mucosal and systemic immune systems. This review discusses the biology of IEL, with an emphasis on the subsets that express an αβ TCR. Although they are heterogeneous, as a group IEL exhibit a number of properties that distinguish them from peripheral T cells. The distinct nature and complexity of IEL is undoubtedly dictated by their unique location at the critical interface between the intestinal epithelial barrier and the gut lumen.

THE IMMUNE FUNCTION ORIGINATED IN THE GUT Host defense by specialized immune mechanisms arose hundreds of millions of years ago from the nondefensive, food-absorbing mechanism of phagocytosis by single-cell organisms. With the evolution of complex, multicellular organisms, differentiation and specialization became apparent, and food-absorbing cells became distinct from other cell types. The initial “gastral layer” of phagocytic cells first appeared in Metazoans and showed much homology with the gastrointestinal epithelial cell layer of the higher vertebrates. When the function of phagocytosis assumed its defensive role, protection of the organism from self-destruction initiated the first immune recognition. Defensive phagocytosis most likely only occurred in the absence of self-recognition, established via inhibitory antiself receptors. This self-recognition-based defense system had much in common with inhibitory NK receptors, which are regulated by recognition of self-MHC class I molecules. In fact, NK-like receptors appeared before T and B cell antigen receptors, as evidenced by the finding of a homolog of the C94/NKR-P1 NK-type receptor in the urochordate Botryllus (2). The origin of the adaptive immune system probably goes back to the gastrointestinal regions of the first “jawed” fish in the Placoderms species some 500 mya. The intestine as a central primary immune organ is evident in primitive vertebrates including the sea lamprey and hagfish (3, 4), but this is less apparent in higher vertebrates. The dominant evolutionary drive that led to the expansion and specialization of immune defense mechanisms coincided with the increasing complexity of the organism itself and the constant race to keep up with the evolving and increasing number of pathogens. This could have been the evolutionary selection for the acquisition of the ancestral RAG gene for antigen-receptor gene recombination, which is likely to have arisen from an ancient bacterial transposon (5). A particularly strong selective pressure might have been imposed on the multiple tasks of the digestive tract with the dietary changes concurring with the emergence of the jaw function and the migration of these early vertebrates from water to land. This might have led to the first need for compartmentalization of the intestinal tract (6). The mechanisms controlling this differentiation and specialization of

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the gastrointestinal tract are poorly understood, but homeobox-containing genes, such as Hox-1.4 (7) and Hox-3 (8), have been implicated in this differentiation process.

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THE EVOLUTION OF THE THYMUS Although the gastrointestinal tract has retained some of its ancestral ability for lymphopoiesis, particularly for B-lymphocytes, the thymus has evolved as the primary lymphoid organ for T cell development. The appearance of the thymus seems to coincide with the sudden appearance of a family of MHC antigen-presenting molecules and expanding repertoires of adaptive T and B cell antigen receptors. This dramatically increased the capacity of the immune system to cope with the staggering demand for recognition of nonself external molecules, and with the complexity of the organism itself, as well as the need to control for neoplasm. Paradoxically, this sudden expansion also increased the potential of self-destruction by the immune system, and strategies to educate immune cells became a necessity (9). The evolutionary origin of the thymus is unknown, but several phylogenetic as well as ontogenetic facts suggest a connection to the gastrointestinal tract. In humans, the primordial thymus develops from the anterior portion of the embryonic gut tube (the pharyngeal pouches). At one point during gestation, the third pair of pouches buds off the gut epithelium (endodermis) and forms a sac-like epithelial protrusion that bends toward the digestive tract. This becomes the thymus rudiment. As the thymus compartment grows, it pushes into the mesoderm that surrounds the primordial gut, and some of the mesenchymal tissue becomes incorporated into the thymus tissue. Subsequentially, it becomes colonized by bone marrow– derived lymphocyte precursors, macrophages, and DCs, all mesodermal in origin. The thymus epithelium further develops and differentiates from the gut endoderm, but only with the stimulus from mesenchymal cells. The lymphocyte precursors interact with the epithelium in a two-way fashion, whereby the epithelial cells induce lymphoid differentiation, and at the same time they themselves differentiate further by the stimulus of developing lymphoid cells (10, 11). As a result, the thymus tissue becomes organized and a clear cortex and medulla are formed. Unlike the typical layer of gut epithelium cells with tight connections and limited intercellular spaces, the thymic epithelial cells are loosely connected. Nevertheless, desmosomes or tight junctions remain and are witnesses of their epithelial origin (12, 13). It has been suggested recently that thymus epithelium is composed of a variety of cells with different antigen-presenting capacity and which display a mosaic of ectopically expressed self-antigens (14). Speculations have been put forward that this developmental plasticity of the thymus organ may be important for the generation of self-tolerance to some tissue-specific antigens, and we propose here that this ectopic expression of organ-specific self-antigens is equally important for the selection in the thymus of self-specific T cells that are plentiful among the IEL (discussed below).

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Thymocyte precursors are believed to arrive in the subcapsullar region of the thymic cortex, where the initial events of conventional positive selection occur. The selected thymocytes subsequently move to the medulla for further maturation and differentiation, and eventually they exit the thymus. The thymus organ involutes later in life, when a peripheral repertoire of mature TCRαβ + T cells and memory T cells is established and the need for newly generated na¨ıve T cells is no longer desirable. As a consequence in older animals, the remnant lymphopoietic capacity of the gut occasionally becomes more apparent (15).

MODERN TIMES: MUCOSAL T CELL SUBSETS IN MAMMALS Mammalian IEL are almost exclusively T cells, but they have diverse phenotypes with regard to TCR and coreceptor expression, as well as the expression of other cell surface molecules. Unlike peripheral T cells, however, all the diverse populations of IEL display an antigen-experienced phenotype. Nevertheless, the locations and pathways the various IEL subsets follow to encounter antigens, and the nature of these antigens, distinguish them from one another. There are three broad categories of IEL: the subset of γ δTCR+ IEL and two distinct subsets of αβTCR+ IEL, those that express one of the conventional TCR coreceptors, CD4 or CD8αβ, and those that lack coreceptor expression and are double negative (DN). A common feature of all IEL subsets is the unique capacity to express CD8αα, a characteristic of the activated nature of the mucosal T cells and their adaptation to the gut environment. The ratio of γ δ to αβ TCRs in IEL varies among species. In mice, a significant portion of the IEL in the small intestine expresses a γ δTCR, and they predominate in young animals at three weeks of age, after which both TCRγ δ + and TCRαβ + IEL increase in numbers (16). They are less prevalent in the large intestine (17, 18), and in humans TCRγ δ + IEL are a relatively small (∼10%) population (19), but their numbers increase significantly during coeliac disease (20). γ δ TCRs generally do not recognize processed peptides presented by MHC class I or class II molecules (21, 22), and γ δ TCRs share properties with both adaptive receptors encoded by rearranging genes and invariant NK-like receptors. Similar to the self-based NK receptors, some γ δTCRs can interact directly with self-MHC molecules such as the mouse T10 and T22 molecules (23) and human MIC molecules (24), which are not loaded with processed antigens. The specificity of most mouse γ δTCR IEL, however, is unknown. γ δT cells are also capable of sensing stressed cells by a direct recognition of stress-induced self-proteins. The human MHC class I–like molecules MICA and MICB are examples of such inducible self-antigens. Stressed intestinal epithelial cells and some epithelial tumors induce their expression, and MIC molecules can be recognized by Vδ1+ γ δ TCRs that are most prevalent among IEL (25, 26). The NK receptor NKG2D, which also binds to MICA and MICB (27), likewise is expressed by those γ δTCR IEL (28). It is thus possible that the rearranged receptors and the invariant receptors recognize the same molecules,

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providing an opportunity for cross-talk between these receptor systems. Mice do not have structural homologs of MICA and MICB, although they have NKG2D receptors and class I–like molecules, including REA-1 and H-60, that can bind to them (29, 30). The second major category of IEL are the αβTCR+ cells that express the typical TCR coreceptors, CD4 or CD8αβ, although the ratio of CD8αβ to CD4 is much higher on these cells compared with the spleen cells. Conventional αβTCR+ cells will migrate from the GALT and peripheral lymphoid tissues to the intestinal epithelium upon antigen stimulation in the periphery (31); these are essentially tissue-seeking effector or memory cells. Specialized M cells in the follicleassociated epithelium continuously sample the gut lumen and transport antigens without processing to the subepithelium and GALT (32). Local dendritic cells (DCs) then process and present these antigens and further distribute them via the thoracic duct (TD) into the bloodstream. Peripheral na¨ıve TCRαβ + T cells reactive to the specific antigens will then undergo activation and proliferation locally and migrate as antigen-experienced lymphocytes via the TD to the gut, from where they can seed the whole length of the small intestinal epithelium (33). Repeated identical antigenic stimulation progressively narrows the TCR repertoire of these conventional IEL, which consequently have an oligoclonal TCR repertoire (33). These cells, which have a memory function, have been shown to be protective against oral infections with several pathogens (34–38). Gut-seeking, antigen-experienced T cells have some differences from those in the spleen, including an initial dependence upon CD40-CD40L interactions (36), effector function that can readily be measured in vitro (38), and longer survival than the memory cells in the spleen (38). It has recently become apparent, however, that antigen-experienced T cells migrate to a variety of tertiary sites, including the lung, liver, and intestine (39). This has led to the concept that there are two types of memory T cells that can be distinguished by expression of CCR7 and other molecules (40). Central memory cells are localized to lymphoid organs, whereas effector memory cells are found in the effector organs. Although it is not fully understood what the specific signals are that determine the localization of these conventional T cells activated in the periphery to the intestinal epithelium, integrins containing a β7 subunit are important, and β7deficient mice have greatly reduced numbers of T cells throughout the mucosa (41–43). Chemokines are also likely to play an important role. The chemokine CCL25 (TECK) is produced by epithelial cells in the small intestine, but not by those in the large intestine (44, 45), and its receptor CCR9 likewise is found predominantly on small intestine IEL and LPL (46). Recent data suggest that this chemokine may be involved in the selective homing of conventional T cells to the small intestine (47), although the in vivo blocking of CCL25 with antibodies (48), or the analysis of CCR9−/− mice (49), indicated only modest decreases in IEL. It is therefore likely that there is redundancy in this chemokine/chemokinereceptor system. Nevertheless, the exposure to antigens that are present in mucosal lymphoid structures is important for the migration of conventional peripheral

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T cells to mucosal tissues. CD4+ T cells activated in peripheral lymph nodes have low expression of the α 4β 7 integrin important for homing to the intestine, whereas those activated in intestinal lymphoid structures selectively express high levels of α 4β 7 and migrate in response to CCL25 (50). Similarly, for CD8+ T cells, it has been shown that activation with DCs from PP induces α 4β 7 and CCL25 responsiveness, whereas activation of splenic or lymph node DC does not (51), suggesting an imprinting of a mucosal-seeking phenotype by PP DCs. The third category of IEL includes TCR αβ + DN cells, and the more numerous CD8αα single positive (SP) IEL. Like the γ δTCR IEL, the expression of a number of surface proteins characteristic of conventional T cells are reduced or lacking on these cells, including Thy-1 (52), CD28 (53), and CD2 (54). On the other hand, they exclusively express NK receptors and they have been dubbed “gut NKT cells” (55). Additionally, and typical of NKT cells, cells that express a canonical human Vα7.2-Jα33 or mouse Vα19-Jα33 TCR have been identified among the mucosal lymphocytes, particularly among the LPL. These mucosal-associated invariant T cells are selected and/or restricted by a nonclassical class I molecule, MR1 (56). The invariant TCR α chain and reactivity to a nonpolymorphic class I molecule are features similar to the CD1d-dependent NKT cells, suggesting that this MR1-reactive population might constitute an intestinal-specific NKT cell subset. CD8αα IEL preferentially use the invariant signaling component FcεRIγ chain (57, 58), which also is a subunit of the multimeric Fcγ RIII A (CD16) complex displayed by NK cells. The FcεRIγ chain is expressed as part of their CD3 complex, either as a homodimer or as a heterodimer together with CD3ζ . The presence of a different TCR signaling module, as well as the absence of coreceptor molecules and accessory/costimulatory molecules such as CD2 or CD28, indicate that the TCR-mediated selection and activation events for CD8αα TCRαβ + IEL are likely to be different from conventional T cells. Although CD8αα SP TCRαβ + IEL express an oligoclonal TCR repertoire, this repertoire does not overlap with the one expressed by the CD8αβ TCRαβ + IEL (59, 60). Furthermore, although potentially self-reactive TCRs are depleted from the peripheral repertoire during negative selection, these TCRs accumulate among the CD8ααSP TCRαβ + IEL (1). This implies that the CD8αα SP TCRαβ + IEL have not been submitted to conventional negative selection, and that the gut-specific CD8αα + IEL must have originated under distinct selection pressure with a distinct ontogeny.

T CELL LYMPHOPOIESIS AND THE INTESTINE Even before TCRs had been discovered, based on the presence of IEL in neonatally thymectomized mice, Fichtelius postulated that the small intestine is a “first-level,” or primary, lymphoid organ (61). Direct evidence for in situ development of T cells within the gut epithelium was provided by Ferguson & Parrott, who engrafted fetal small intestine tissue under the kidney capsule of athymic mice (62). They showed

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that host lymphocytes developed to some extent in the intestinal grafts. With improved technology and new tools, other approaches were taken to provide further evidence to demonstrate and characterize T cell lymphopoiesis in the absence of a functional thymus. Although the results from a number of experiments provided evidence for an extrathymic origin for some IEL (63–65), in no case could it be demonstrated that functional TCRαβ + T cells had been subjected to a positive selection process. The results showed that the extrathymic pathway of development was inefficient and mostly skewed to the TCRγ δ + population. Consistent with this thymus dependence, thymic transplant gives rise to IEL in chickens (66, 67), neonatal thymectomy causes a drastic decrease in IEL in mice (68), and early thymectomy results in decreased IEL in Xenopus (69). Congenitally athymic (nu/nu) nude mice, which have a mutation in the winged-helix transcription factor, Whn, that is required for differentiation of thymic epithelial cells (70), have greatly reduced TCRαβ + IEL, although there is a residual γ δTCR+ IEL population (71). The level of TCRαβ and CD3 expression on the few TCRαβ + T cells in nude mice is low, and the percentage of splenocytes expressing CD4 or CD8αβ is greatly variable among individual nude mice (72). Furthermore, the repertoire of αβ TCRs in nude mice is pauciclonal (73, 74) and often shows extreme bias toward certain Vβs (73). In minor lymphocyte-stimulating (Mls)-1a or I-E+ strains, T cells expressing a Vβ6 or Vβ11 TCR are present in the periphery, whereas thymocytes expressing these TCRs in euthymic mice of the same strains are deleted during the process of negative selection in the thymus (73, 75). This provides further evidence that the TCRαβ + T cells that develop in the absence of a thymus do not undergo the selection events characteristic of thymic development. Evidence for lymphocyte development in the adult human intestine is scarce (76). mRNA for RAG-1 and RAG-2 could be isolated from IEL but not from LPL (77) while terminal deoxynucleotidyl transferase was undetectable (78). Nevertheless, adult IEL TCRβ mRNAs contain numerous N region additions (79, 80), indicating that any role in situ for RAG in building an IEL-specific TCRαβ repertoire must be very small. Human fetal intestine contains T cells in the LP and epithelium from 12 to 14 weeks into gestation (81), but the fetal thymus is already exporting T cells at this stage of gestation. Immunohistochemical staining of tissue sections of fetal intestine indicates that approximately 50% of the CD3+ IEL express CD8αα +, whereas the rest are predominantly DN cells. The LP also contains numerous CD3+ cells, but CD4+ T cells outnumber the CD8+ LPL regardless of gestation age, and there are large numbers of DN cells as well (76). The majority of fetal IEL already express an activated phenotype, and unlike adult IEL, they are actively proliferating. It is unlikely that IEL in the fetal intestine have migrated there as effectors in response to nonself antigens. Together with the fact that fetal IEL, unlike IEL of the adult intestine, display a very diverse TCR Vβ repertoire (76), it seems logical to suggest that fetal IEL represent a na¨ıve repertoire. The antigen-experienced phenotype of the fetal IEL together with the fact that most fetal CD8+ IEL express CD8αα (82) is consistent with the finding in mice that CD8αα TCRαβ + IEL have acquired this phenotype during self-agonist-based

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selection in the thymus (discussed below). In summary, the evidence from several species is consistent with a thymic origin of all or most IEL, and it is also consistent with the hypothesis that efficient positive selection of T cells occurs only in the thymus.

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LYMPHOCYTE PRECURSORS AND THE INTESTINE Although abundant data support a thymic origin for IEL, the intestine retains some vestigial function in lymphopoiesis. In an immunohistochemical search for anatomical sites of lymphopoiesis within the gut, small clusters of lymphoid precursors called cryptopatches (CP) were discovered within the LP compartment adjacent to the epithelial crypts in the small intestine in mice (83). Similar structures in other species have been ambiguously described (84). In nude mice, none of these clusters contain CD3+ TCR+ cells, and the c-kit+ cells located there were negative for expression of CD3, B220, Mac-1, Gr-1, and TER 119 (lin−) (83). Transplantation of CP subsets isolated from athymic nude mice to irradiated severe combined immune deficient (SCID) recipient mice indicated a lymphopoietic capacity for the c-kit+ CP subset (83). Most c-kit+ CP cells also expressed the IL-7R (85), and in both IL7Rα −/− mice and common cytokine receptor γ -chaindeficient mice (CRγ −/−), formation of CP was defective (86). γ δTCR+ IEL, which are dependent on IL7-R signaling for their development, were also absent in these CP-deficient strains. Consistent with a CP-independent origin, however, αβ TCR+ IEL were still present in the CP-deficient strains but absent in athymic nude CRγ −/− mice (86). TCR− IEL isolated from these athymic CRγ −/− mice have characteristics resembling B220+ fetal liver progenitors (87). Furthermore, although the adoptive transfer of CP cells to SCID recipient mice suggested the presence of T cell precursors, when transferred to whole-lobe fetal thymic organ cultures, CP cells showed no such capacity (83). T cell precursor activity can be revealed among IEL as well. Co-culture of CD3−CD8−Ig−CD45+ IEL with newborn thymic stromal cells, which had been depleted of CD45+ thymocytes, led to the generation of DP (CD4+, CD8β +) and SP CD4+ or CD8αβ + cells (88). DP cells that were generated from these co-cultures of intestinal progenitors and thymic stromal cells expressed αβTCRs, whereas DN cells expressed either αβTCRs or γ δTCRs. Furthermore, a significant amount of the T cells expressed NK markers (88). A subset of the TCR− putative progenitors expresses low levels of CD45 (CD45low). Cells with this phenotype are abundant among the epithelial cells of nude mice. The CD45low subset also expressed markers typical of immature thymic precursors, such as CD44high, CD16, CD24 (heat-stable antigen), c-kit, CD127 (IL-7Rα), and CD122 (IL-2/15Rβ) but lacked CD25 (IL2Rα). The presence of the IL-7Rα and IL-2/15-Rβ is consistent with a role for IL-7 and IL-15 in the ontogeny of IEL (89, 90). Cocultures of these CD45low CD3−CD8− cells isolated from nude mice with thymic stromal cells from normal mice also led readily to the development of DP, SP, and DN T cells similar to the developmental stages of thymocytes (88).

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Studies on lymphopoiesis within the intestine are hampered by the dominant presence of mature T cells in the adult gut, as opposed to mostly immature precursors in the thymus. Using multiple lineage markers, progenitor cells isolated from CPs and IEL were further characterized and divided into six types (91, 92). Bone marrow from nude mice was transferred to thymectomized RAG-2−/− and CRγ −/− double-deficient recipient mice to establish the sequence of appearance of these precursors during lymphoid development (92). CP lin− cells showed very little evidence for T cell commitment, but they expressed GATA-2, a transcription factor found in pluripotent hematopoietic progenitor cells (93). It is therefore possible that CP cells represent predominantly precursors of other hematopoietic cells. Using several gene mutations that affect T cell differentiation, including preTα −/−, TCRα −/−, and CD3ε−/−, it was shown that none of these mutations affected the CP cells, further demonstrating that these cells are not committed to the T cell lineage (92). IEL progenitors were more committed to the T cell pathway, and the TCRα −/− mutation led to accumulation of DP IEL. On the other hand, TCRδ −/− did not block the cells at the DP stage, and it is thus more likely that TCRγ δ IEL developed before the DP stage. Such a scenario is typical of the developmental pathway for γ δ T cells in the thymus (See Figure 1). Pre-Tα mRNA, uniquely expressed by the precursors committed to the TCRαβ lineage in the thymus, was extremely low among the Lin− gut cells, further supporting the notion that T cell precursors in the gut are predominantly committed to the TCRγ δ T cell lineage (92). To determine if the extrathymic pathway of T cell development is active in euthymic mice, transgenic mice that carry a reporter gene (green fluorescent protein, or GFP) driven by the RAG-2 promoter were analyzed (15). Cells expressing high levels of GFP in these mice indicate recent transcription of RAG-2, reflecting TCR and Ig gene rearrangements (94). Using this reporter system, it was shown that athymic mice show receptor rearrangements predominantly in the MLN and PP. CP cells did not express RAG-2, indicating that rearrangements of TCR genes did not occur in these cells. Mature cells migrated from the MLN to the TD, and eventually to the gut mucosa. Interestingly, this pathway was totally suppressed in euthymic mice, except under conditions of severe lymphopenia. Nevertheless, in euthymic TCRβ −/− mice, which only have mature γ δ T cells, GFP+ cells were present in MLN and PP (15). This indicated that the lack of extrathymic T cell development in euthymic mice is not due merely to the presence of a thymus, but rather the thymusderived TCR αβ T cells themselves actively down-modulate lymphopoiesis in the gut. The suppression is less pronounced in older mice where newly generated TCRαβ T cells are much reduced due to the involution of the thymus (15).

CD8αα TCRαβ IEL ARE SELF-REACTIVE Conventional selection of TCRαβ T cells in the thymus is central in establishing self-MHC restriction (95–98) and self-tolerance (99, 100). The na¨ıve TCRαβ repertoire in the periphery is thus imprinted by the selective interactions of TCRs

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with self-antigens/MHC during this selection process in the thymus (101). The affinity/avidity-based model for selection proposes that TCR signal strength is central to the outcome of thymic selection, with intermediate TCR signal strength resulting in positive selection (Figure 2) and further maturation of the CD4+CD8αβ + double positive (DP) immature thymocytes to the SP mature stage (102). Strong TCR-mediated selection signals delete those TCRs from the repertoire of conventional T cells (see Figure 2). The CD8αα TCRαβ IEL subset, however, is governed by different avidity requirements than those outlined above for conventional T cells. In MHC class II, I-E+ mice bearing the Mls-1a allele of the Mls locus, T cells expressing TCRs (Vβ6, Vβ8.1, or Vβ11) reactive to the endogenous retroviral superantigen of the Mtv-7 provirus are deleted from the conventional repertoire while these TCR are present, and in some cases at frequencies higher than the nondeleting strain, in the CD8αα TCRαβ IEL subset (1). The notion that CD8αα TCRαβ IEL do not follow the rules of conventional selection was also apparent in TCRαβ transgenic mice that also express the cognate antigen recognized by the TCR transgene. H-Y TCR transgenic mice, with a TCR that recognizes a Y chromosome-encoded Smcy peptide presented by Db, provide a paradigm for these types of studies. When the TCR transgene was crossed on a RAG−/− background (103), it was shown that CD8αβ SP thymocytes matured in the thymus and populated the peripheral tissues of H-Y antigen-negative female mice. There were few IEL in these female mice, however, which is consistent with the belief that conventional T cells migrate to the intestine only upon antigen stimulation. This stimulation might be provided to some extent by endogenous peptides of the kind that are responsible for the homeostatic maintenance of na¨ıve T cells in the periphery. The H-Y TCR+ T cells are unusual in that they do not undergo this type of homeostatic maintenance in female mice (104, 105), perhaps reflecting the low affinity of this TCR for endogenous peptides in female mice. In sharp contrast, male H-Y TCR transgenic mice developed large numbers of TCR+ IEL, and they predominantly expressed CD8αα, despite deletion of conventional CD8αβ H-Y TCR+ T cells (103, 106, 107). The active generation of the CD8αα TCRαβ IEL under deleting conditions for the conventional TCRαβ T cells clearly demonstrated that a different outcome pertained to the CD8αα TCRαβ IEL with regard to self-recognition during selection. Similar observations were made in a number of other TCR transgenic systems expressing endogenous cognate antigen, including the 2C TCR system recognizing Ld as an alloantigen (108), and in double transgenic mice expressing a transgenic TCR and the cognate antigen as a transgene, including OT-I/RIPmOVA (107) and F5 TCR transgenic mice expressing influenza virus nucleoprotein (NP) peptides as transgenes (109). The selection of these CD8αα + IEL is most effective in the presence of highaffinity self-antigens. This was demonstrated using the clonotypic TCR F5. The NP68 peptide is recognized by the F5 TCR with high affinity and induces profound deletion of thymocytes in vitro, whereas the peptide NP34 is a peptide recognized with lower affinity. NP68-F5 TCR double transgenic mice generated large numbers

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of CD8αα TCRαβ + IEL (109). Likewise, CD8αα IEL expressing the 2C TCR were readily generated in mice expressing the Ld high-affinity ligand, whereas CD8αβ + T cells developed when the low-affinity ligand presented by H-2Kb was present. Similarly, H-Y TCR+ CD8αα IEL were more efficiently generated in Db/b homozygous male mice than in their Db/d heterozygous counterparts (110). The expression of CD8αα on these IEL does not necessarily imply MHC class I restriction of the TCR. A similar, high-affinity self-antigen-dependent development of CD8αα expressing IEL also was observed using several MHC class II–restricted TCR transgenic systems (107, 111). These observations indicate that CD8αα does not function as a traditional TCR coreceptor and that selection of the CD8αα TCRαβ IEL might occur in a coreceptor-independent fashion. This was also supported by the observation that CD8αα H-Y TCR+ IEL are actively generated in male mice that are deficient for CD8β expression, whereas the female H-Y TCR transgenic mice on the CD8β −/− background failed to generate mature H-Y TCR transgenic T cells (107). Although CD8αα is most likely not directly involved as an MHC-interacting coreceptor in the selection of self-antigen-reactive TCRs, all CD8αα TCRαβ IEL depend on some kind of MHC class I expression for their development and/or homeostasis. CD8αα TCRαβ IEL, but not TCRγ δ IEL, are drastically reduced in β2-microglobulin-deficient mice (112–114). By contrast, CD8αα TCRαβ IEL are present in mice deficient for the transporter associated with Ag processing (TAP) gene, whereas conventional CD8αβ + MHC class I restricted T cells are nearly absent in these mice (112). The classical MHC class I molecules are highly TAP-dependent for their cell-surface expression, although some nonclassical class I molecules, including the thymic leukemia (TL) antigen and CD1d are not (115, 116). Similar to the TAP−/− mice, animals deficient for the classical class I molecules (Kb−/−Db−/−) efficiently generated CD8αα TCRαβ IEL, whereas the population of conventional CD8αβ-T cells was greatly reduced (117–119). The somewhat more efficient generation of CD8αα TCRαβ IEL in Kb−/−Db−/−mice, as compared with the TAP−/− mice, led to the suggestion that TAP-independent and TAP-dependent nonclassical class I molecules could promote the generation of the CD8αα TCRαβ IEL. It has been reported that mice deficient in the nonclassical MHC class I molecule, Qa-2, which is for the most part TAP dependent (120), were much less efficient in generating the CD8αα IEL, suggesting Qa-2 reactivity for some CD8αα TCRαβ IEL (121). By comparing BALB/c mice with the Qa2null Bailey substrain (BALB/cByJ), we were unable to confirm these findings (L. Gapin, M. Kronenberg & H. Cheroutre, unpublished data). The general rule that emerges from these studies is that CD8αα TCRαβ IEL are self-reactive, but they are not selected for self-reactivity to a single self-antigen or a single antigen-presenting molecule. It is difficult, however, to estimate the fraction of these cells that is reactive to classical class I molecules, nonclassical class I molecules, or MHC class II molecules, considering that in the absence of one specificity, cells with another specificity may be expanded. The diverse specificities of these cells, together with their requirement for β2m, indicates that

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a function mediated by an MHC class I molecule other than peptide presentation to a TCR is required for the selection of CD8αα TCRαβ IEL.

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CD8αα TCRαβ IEL ARE THYMUS DERIVED The efficient generation of the CD8αα TCRαβ IEL, under conditions that caused negative selection in the thymus of CD8αβ T cells, was consistent with the view that the CD8αα-expressing cells were generated extrathymically. As discussed above, studies on the lymphopoietic capability of the small intestine indicated that IEL could develop locally in the absence of a functional thymus. Nonetheless, the local T cell development in the gut was biased toward the development of γ δ T cells. This, together with the drastic reduction of CD8αα TCRαβ IEL in nude mice and mice that were neonatally thymectomized, suggested that the thymus is required to efficiently generate all TCRαβ T cells, including the IEL. This is also supported by the observation that thymus grafts from normal mice efficiently generated CD8αα-expressing TCRαβ IEL in recipient nude mice (122). Interestingly, it was shown that the different subsets were generated with different kinetics, and that whereas fetal thymus grafts or grafts from mice up to weaning age predominantly repopulated the intestine of the recipient mice with CD8αα TCRαβ T cells, thymus grafts from older mice were more efficient in generating the conventional TCRαβ T cell subsets (122). This was not necessarily due to the reduced ability of the adult thymus to generate CD8αα TCRαβ IEL. Rather, it could result from the suppression of the selection and/or expansion of CD8αα TCRαβ IEL by the increasing population of conventional TCRαβ T cells. Support for this hypothesis is provided by the demonstration that adult thymus grafts isolated from male H-Y TCR donor mice on a RAG−/− background readily and efficiently repopulated the intestine of RAG−/− recipient mice with mature H-Y TCR transgenic CD8αα IEL (107). It is possible that in the absence of conventional positive selection, as in the case of the male H-Y TCR transgenic mice on a RAG−/− background, the generation of CD8αα TCRαβ IEL will continue as long as a functional thymus is present.

AGONIST SELECTION: A NOVEL PATHWAY OF T CELL DIFFERENTIATION Although it is thought that negative selection is a major tool for the immune system to eliminate self-reactivity from the T cell repertoire (123), the death of autoreactive cells is not all encompassing. New evidence suggests that an agonist-based positive selection pathway permits the immune system to preserve and specifically select for self-reactive TCRs (Figure 1) (107). As outlined above, strong correlative evidence indicates that self-agonists are required to promote the development of CD8αα + IEL. Consistent with active selection for high-affinity-based TCRs, it was found that among the selected TCR+ thymocytes in male H-Y TCR transgenic

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mice on a RAG+ background, with the potential to edit their TCR to escape negative selection, there was no evidence for editing. On the other hand, on a nonselecting background, numerous thymocytes underwent editing of the TCRα chain (124). Similar high-affinity selection conditions have been described for CD4+ CD25+ regulatory T cells (125) and NKT cells, including those that express an invariant Vα14 TCR and are CD1d reactive (126), and those with other specificities (127, 128). Some of these agonist-selected T cell subsets have regulatory functions, suggesting that agonist selection enables the immune system to make use of T cells that recognize self to control the responses of nonself reactive T cells. The development and selection of self-reactive T cells is not an imperfection of the thymic selection mechanism, or a mere escape of these cells from conventional negative selection to create anergic or nonfunctional T cells. Evidence suggests that T lymphocytes selected by self-agonists require true ERK-dependent positive selection signals mediated by the TCR (107, 128). This was inferred by their requirement for the TCRα chain-connecting peptide domain or α-CPM. This unique motif appeared with the first ancestral TCRαβ receptor in jawed fish, and it has been conserved over 500 million years, underscoring its crucial function during TCRαβ T cell development (129). The α-CPM allows for efficient association of the CD3 subunits with the TCR, and imparts an ERK-mediated signaling function during thymocyte positive selection. TCR transgenic mice lacking the α-CPM motif have impaired positive selection of conventional TCRαβ T cells while negative selection still occurs (130). When TCR/Ag double transgenic mice that also had a mutated α-CPM α chain were analyzed for the presence of CD8αα TCRαβ TCR transgenic IEL, we showed a much reduced population of these cells in the α-CPM mutant mice, demonstrating that agonist selection is also a true ERK-dependent positive selection process (107). Together with the lack of dependence on CD8β, these data indicate that the agonist-driven selection of CD8αα TCRαβ IEL is not an escape from conventional negative selection. The concept of agonist-based selection is complementary to, and not mutually exclusive from, the deletion of thymocytes during conventional negative selection. The TCRs that are eliminated from the pool of conventional T cells might specifically accumulate in the repertoire of agonist-selected T cells. Such a prediction would indeed be consistent with the accumulation of the cognate transgenic TCRs among the CD8αα IEL of double TCR/Ag transgenic mice (107) as well as with the accumulation of self-reactive TCRs among the CD8αα IEL in normal mice (1). Furthermore, it remains to be determined if at very high affinities, agonist selection is no longer possible and negative selection is completely dominant (Figure 2). The data from multiple TCR transgenic systems suggests, however, that an affinity in which only negative selection is found may be difficult to reach. As a result of the agonist-selection process, T lymphocytes differentiate into highly specialized cells with an antigen-experienced phenotype and regulatory functions. Mature agonist-selected T cells migrate preferentially to specific organs and tissues including the intestinal epithelium or liver, as opposed to the migration of conventional na¨ıve T cells, which predominantly migrate to defined lymphoid

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organs in the periphery (Figure 2). The factors that are responsible for the selective localization of CD4+ Treg to lymph nodes and spleen, Vα14 invariant NKT cells to the liver, and CD8αα TCRαβ IEL remain to be determined.

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AGONIST SELECTION AND SELF-ANTIGENS IN THE THYMUS If self-reactive T cells were primordial, then the thymus might have evolved initially to accommodate the agonist selection of self-Ag-specific T cells reactive to polymorphic self-molecules. Recently, it has been shown that tissue-specific self-antigens are expressed by a subset of medullary thymic epithelial cells (131). The ectopic expression of these self-antigens is controlled by the transcriptional regulator, AIRE (132–134). The human autoimmune polyendocrinopathy syndrome type 1 is a multiorgan autoimmune disease resulting from loss-of-function mutations in the AIRE gene (132, 134), and AIRE-deficient mice also showed autoimmune disorders similar to the human disease. These observations suggested strongly that the AIRE-controlled ectopic expression of self-antigens in the thymus was central to establish self-tolerance (135). It was proposed that the absence of expression of these self-antigens during selection in the thymus resulted in the absence of effective negative selection and the appearance of uncontrolled autoreactive conventional TCRαβ T cells (132, 133). This was illustrated in a model system, in which TCR transgenic T cells specific for a hen egg lysozyme (HEL) peptide were crossed to transgenic mice expressing HEL under the control of the rat insulin promoter. The normal induction of thymic tolerance in the TCR transgenic T cells to the insulin promoter–driven HEL was abolished when these mice were crossed onto an AIRE-deficient background (133). We speculate that AIRE, and a transcription factor that controls AIRE expression (see below), might be required for the positive selection of self-specific CD8αα TCRαβ IEL as well as the negative selection of conventional T cells. The observation that agonist-positive selection of specialized T cells, including the CD8αα TCRαβ IEL, is based on recognition of self-Ag, and the fact that efficient agonist-driven positive selection occurs simultaneously with negative selection of conventional TCRαβ T cells, suggests that the autoimmune pathology linked with defects in AIRE mutant mice and humans might reflect impaired agonist selection in addition to defective negative selection. The absence of self-Ag-based agonist selection might lead to reduced regulation of conventional T cells by these selfantigen-specific IEL and other regulatory T cells. The regulatory role of CD8αα TCRαβ IEL is discussed below. It has been proposed that mouse CD1d reactive NKT cells with an invariant Vα14 rearrangement, referred to here as Vα14i NKT cells, are selected by glycolipid self-agonists (126). Similar to the CD8αα TCRαβ + IEL, these NKT cells have a natural memory phenotype, and interestingly, their IL-4 and IFNγ gene loci are in the open configuration (136) and they become active as these cells mature in the

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thymus. Although thymic epithelial cells are not required for the CD1d-mediated presentation of self-antigens during selection of Vα14i NKT cells, we and others have shown that a signaling pathway in a radio-resistant host cell, with the NFκB-inducing kinase (NIK) activating the NF-κB family transcription factor RelB, is required for Vα14i NKT cell differentiation (137, 138). Furthermore, evidence suggests that this signaling pathway is required in thymic medullary epithelial cells. Interestingly, RelB−/− mice also display a significant decrease in the number of IEL, including the CD8αα-expressing TCRαβ T cells (R. Shaikh, M. Kronenberg & H. Cheroutre, unpublished data) indicating that a RelB-dependent pathway is also crucial for the development, homing, or homeostasis of TCRαβ CD8αα IEL. The fact that these two agonist-selected T cell populations are defective in RelB−/− mice, while conventional T cells are numerous, has led us to speculate here that the agonist-dependent selection pathway is specifically impaired in the RelB−/− mice. Similar to the AIRE−/− mice, RelB−/− mice also failed to delete conventional T cells with a high affinity for self, and these mice also show a T cell–dependent autoimmune pathology (137, 139, 140). This suggests that the RelB-dependent contribution could be the same for both types of selection, the agonist-positive selection and the conventional negative selection. Interestingly, it has been shown that AIRE expression by thymic epithelial cells is RelB dependent, and RelB−/− mice show abnormal thymic medullary epithelial cells and complete absence of AIRE expression (134). It is thus possible that the autoimmunity displayed by RelB−/− mice could be attributed in part to the lack of RelB-dependent AIRE expression. Consequently, this would imply that defects in central tolerance, which lead to autoimmunity, are not solely the result of impaired conventional negative selection, but that concomitant defects in the process of agonist selection, and the resulting absence of self-specific CD8αα TCRαβ IEL and other agonist-dependent regulatory T cells, might contribute to the severity of autoimmune conditions that are particularly prevalent in the intestine.

AGONIST SELECTION AND DISTINCT FEATURES OF SIGNALING It is not understood what drives thymocyte precursors to the agonist-selection pathway or at what point in thymopoiesis precursors divert to the different selection pathways. We can only speculate that the quality of the TCR signal received during the initial selection events differentiates precursors along distinct ontogenetic pathways. Nearly all CD8αα TCRαβ IEL express the FcεRIγ chain as part of the CD3 complex, whereas conventional TCRαβ IELs express homodimers of CD3ζ or hetero dimers of CD3ζ and η (57), an alternatively spliced form of ζ . The genes for CD3ζ /η and FcεRIγ are related and genetically linked. Analyses of gene-deficient mice have indicated that CD3ζ /η is required for conventionally selected TCRαβ IEL (CD8β + or CD4), but less so for the agonist-selected CD8αα TCRαβ IEL, consistent with their usage of the FcεRIγ subunit (58, 141, 142).

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The differing composition of the TCR signaling components between agonistselected T cells and conventionally selected T cells suggests likely differences both in the downstream signaling cascades and in the developmental intermediates required to produce the different T cell types. Immature thymocytes at the DN stage initially express FcεRIγ as part of their CD3 complex (143), and upon transitioning to the immature DP stage they replace the FcεRIγ with CD3ζ /η. The fact that FcεRIγ is retained in the TCR complex of the CD8αα TCRαβ IEL, combined with the fact that these cells can be selected in a coreceptorindependent fashion, suggests the possibility that these agonist-selected T cells might be selected at the DN stage, deviating from the conventional pathway that requires a DP intermediate (see Figure 1). In many TCR/Ag double transgenic models that promote the development of the self-Ag-specific CD8αα TCRαβ IEL, the coreceptor-expressing thymocytes (DP) that proceed along the conventional pathway of selection are greatly reduced in number (107), indicating that the development of the precursors of these agonist-selected T cells could occur in a CD4/CD8αβ coreceptor–independent way. This was directly demonstrated using the class II restricted DO-TCR transgenic system. DN transgenic T cells are selected under agonist conditions on an I-Ab background. In H-2b CD4−/− mice expressing human CD2 under the control of the mouse CD4 promoter, selected mature DN DO-TCR transgenic T cells did not express the CD2 transgene, suggesting that the DO-TCR transgenic T cells had developed without passing the DP stage (144). The DN pathway was also suggested in a recent phenotypic analysis of thymocytes from H-Y TCR transgenic mice, where in the male transgenic mice the majority of the DN thymocytes have a mature phenotype, whereas the DN thymocytes from female transgenic mice are predominantly immature cells (111). The immediate precursors of DP thymocytes are the CD4− CD8αα + thymocytes (82). Although there are very few in normal adult mice, these precursors are numerous in the TCR/Ag double transgenic animals, and they constitute all the CD8+ thymocytes in the fetal thymus (82). Even though controversy exists as to what extent these CD8αα SP thymocytes are mature immune-competent cells, it was shown that TCR cross-linking of thymocytes at the CD8αα + SP stage interfered with their transition to the DP stage (145). Consistent with their development along an alternative selection pathway, as opposed to being a dead end, the CD4− CD8αα + immature thymocytes express high levels of antiapoptotic factors of the Bcl-2 family, and they lack DNA fragmentation (82). The difficulty in detecting these precursors in the thymus of normal adult mice could be due to very low numbers of these intermediates, or a different kinetics of their selection process with rapid export of newly matured cells.

AGONIST SELECTION AND CD8αα-TL INTERACTION Several factors, including the differential use of signaling molecules and the absence of coreceptor contributions, might influence the TCR signals received by the agonist-selected thymocytes. At the immature DN stage, however, where FcεRIγ

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is expressed and CD4 and CD8αβ coreceptors are not, other mechanisms must operate to allow for deviation of the immature precursors and maturation along the agonist selection pathway. CD8αα may provide a key for understanding this. The coordinate binding of CD4 or CD8αβ with class II– or class I–restricted TCRs, respectively, and their association with the p56lck tyrosine kinase, are two requirements for efficient positive selection. The coexpression of CD8αα with CD4 or CD8αβ, and the expression of CD8αα on MHC class II–restricted T cells, are inconsistent with a coreceptor function for CD8αα and suggest strongly that CD8αα expression mediates another function. A number of studies have demonstrated that CD8αα is inefficient as a TCR coreceptor, even though it is the α chain of the CD8 molecule that associates with p56lck (146, 147), and it is the CD8α chain ectodomain that interacts with the α3 domain of the heavy chain of class I molecules (148, 149). For example, CD8β −/− mice, which express CD4 and CD8αα at their DP immature thymocytes, do not efficiently select class I– restricted conventional T cells (150, 151). It has been shown that CD4 and CD8αβ associate with p56lck and help sequester it into lipid rafts together with the TCR, thus localizing the kinase in proximity of the TCR/CD3 complex (152). Furthermore, it was demonstrated using CD8α transfection of CD4+ class II–restricted T cells that expression of the coreceptor not involved in the activation complex sequesters active p56lck away from the activation complex, thus down-modulating the TCR-mediated signaling cascade (153). These observations are very consistent with the effects observed when endogenous CD8αα is expressed by T cells. Unlike CD8αβ, CD8αα is not internalized with the TCR from the surface of activated cells (154), and associated p56lck is inefficiently provided to the TCR complex in part because of the inability of CD8αα to effectively merge into lipid rafts. It is CD8β that promotes raft association of CD8 (155), although this can be partially overcome if CD8αα can bind to the antigen-presenting MHC class I molecule. The TL antigen, a nonclassical MHC class I molecule that is abundantly expressed on the epithelial cells of the small intestine in mice (156), is a specific ligand for CD8αα (157). TL, however, is not a typical antigen-presenting molecule, and TL transgene expression in the absence of classical class I expression in TAP−/− mice does not promote the selection of CD8 T cells in the periphery (H. Cheroutre, unpublished data). Furthermore, the crystal structure of TL demonstrates a narrowed and completely occluded groove that cannot present peptides (158). These observations suggest a function for this MHC class I molecule that is different from antigen presentation. Direct evidence for this was provided by demonstrating that the TL interaction with its receptor CD8αα expressed by IEL mediates profound modulation of TCR activation signaling resulting in reduced proliferation and cytotoxicity of the activated T cells while promoting specific cytokine production (157). Furthermore, the TL-CD8αα interaction can mediate survival and further differentiation of the antigen-stimulated T cells (L. Madakamutil & H. Cheroutre, unpublished data). The pronounced expression of this receptor-ligand pair on immature thymocytes besides the IEL suggests a possible function for CD8αα-TL not only in the maintenance and regulation of mature IEL, but also in the development and

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selection of CD8αα-expressing thymocytes. We speculate that the interaction of CD8αα on immature thymocytes with its ligand TL could mediate the survival during agonist selection in the thymus of CD8αα TCRαβ mucosal T cells.

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REGULATED IMMUNE RESPONSES IN THE INTESTINE All TCRαβ IEL subsets display functional and phenotypic traits of activated or memory T cells. Using adoptive transfer of na¨ıve TCRαβ transgenic lymph node T cells, it was shown that virus-encoded antigen, but not soluble antigens, could induce the generation of memory T cells in the LP and epithelium of the recipient mice (35–38). The mucosal memory T cells were retained locally and expressed specific adhesion molecules that differ from those expressed by memory T cells generated in the periphery (38). They showed functional characteristics of memory T cells, including rapid recall responses in in vivo and ex vivo lytic activity, which from a protective point of view are critical at interfaces such as the gut epithelium (38). These results therefore suggested that conventional T cells specific for nonself-antigens can differentiate into IEL following activation. These IEL represent a pool of antigen-specific memory T cells that can respond rapidly and effectively upon secondary exposure to their cognate antigen encountered in the intestine. IEL are surrounded by cells with antigen-presenting capability. Enterocytes have been shown to function as antigen-presenting cells (159–162), and DCs are widely spread throughout the LP and the intestinal epithelium. The epithelial DCs are specifically equipped to preserve the integrity of the epithelial barrier by expressing tight junction proteins, including occludin and claudin, which can establish rigid contact with the neighboring epithelial cells while protruding dendrites across the epithelium into the gut lumen (163). Furthermore, the antigendependent migration of conventionally selected T cells to the intestine also could be a protective measure to preserve an intact epithelial layer and prevent undesirable immune responses from nonself-specific na¨ıve T cells against nonpathogenic agents abundantly present in the gut. In this context, it is interesting to note that the intestinal epithelial cells lack significant expression of costimulatory molecules, including the B7-1 and B7-2 molecules, which are required for efficient antigenic stimulation of the na¨ıve T cells (164–166). Unlike the conventionally selected TCRαβ IEL, which have migrated from the periphery after encountering antigens in an organized lymphoid structure, there is no evidence that CD8αα TCRαβ IEL or their immediate precursors have resided in lymph nodes. We propose that agonist selection in the thymus imprints these cells with a “natural” memory phenotype during development, including expression of cell surface molecules typical of mature IEL. For example, these agonist-selected thymocytes can express the mucosal integrin, α Eβ 7, which can mediate binding to E cadherin expressed by the epithelial cells (167–168) and might function to direct these agonist-selected T cells effectively to the intestine and/or tether them to the epithelial cells.

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The intestine displays a pronounced tone of immune regulation. Nowhere else in the body is there more evidence that the immune system has evolved numerous mechanisms to prevent useless or self-destructive immune responses. The selfspecific IEL subset has been conditioned during agonist selection in the thymus to remain immune quiescent in the antigen-rich environment of the gut. Using T cells from TCR transgenic mice that also expressed the cognate antigen during selection, it was shown that the CD8αα TCR transgenic IEL that express a TCR specific for a self-antigen were not destructive to the epithelium (107). By contrast, in a transfer model of colitis induction, which is induced by the injection of na¨ıve (CD45RBhigh) CD4+ T cells into immune-deficient mice, it was shown that these self-specific CD8αα TCRαβ IEL exert a regulatory role not carried out by other IEL populations (169). These cells controlled the migration to the intestine and immune responses of the pathogenic CD4+ CD45RBhigh T cells, and the regulation by the CD8αα TCRαβ + donor IEL was contingent upon expression and recognition of their specific cognate self-antigen in the intestine of the recipient mice (169). The absence or defect of these self-specific regulatory IEL might be the underlining factor in the predisposition of the animal to uncontrolled immune responses and tissue destruction mediated by conventional T cells, as is observed in several models of experimental colitis. The TCRγ δ IEL were not shown to display suppressive regulatory activity in these transfer experiments, but these cells have been shown to secrete keratinocyte growth factor, which can stimulate repair of damaged epithelium and restore the integrity of the barrier (170). The intestinal epithelial cells themselves play a key role in the immune regulation by expressing distinct surface molecules and restriction elements and secreting factors that allow them to uniquely modulate and differentiate regulatory subsets of mucosal T cells. Immune-modulatory cytokines, in particular TGFβ and IL-10, have been implicated as interrelating key regulatory factors (171–173), with TGFβ serving as the primary anti-inflammatory agent to down-modulate Th1 mucosal immune responses (174). IEL express receptors for growth factors that epithelial cells secrete, including stem cell factor, IL-7, and IL-15. The gut epithelial cells likely also express cell surface molecules that are specific ligands for regulatory receptors expressed by the IEL. This was demonstrated by the interaction of the TL antigen on epithelial cells with CD8αα expressed by the majority of the IEL (157). When CD8αα is engaged by TL, it is able to modulate TCR signals, thereby adapting the immune response of the IEL to an environment where maintaining the integrity of the epithelial barrier is a high priority. Unlike the clonal expansion and cytolytic activity of peripheral activated CD8+ T cells, IEL activated in the presence of the TL-CD8αα interaction show reduced proliferation and cytotoxicity but enhanced cytokine production allowing for protection without destruction of the epithelial cell layer (157). It is likely that other receptor and ligand pairs expressed by IEL and epithelial cells also play an important role in regulating mucosal immune responses. Antibodies to the human biliary glycoprotein (CD66a), a carcinoembryonic Ag-related molecule, could block the cytolytic activity of human IEL (175). This molecule

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is expressed on epithelial cells as well as on IEL, and it can engage in homotypic interactions (176). Cross-linking of the α Eβ 7 integrin, which may provide a mimic of the E cadherin interaction with this integrin, increased the TCR-mediated activation of human IEL (177). IEL, particularly the CD8αα TCRαβ subset, have been shown to express activating and inhibitory NK receptors, including members of the Ly49 family, CD94/NKG2 and NKR-PI (55). Like CD66a in human IEL, some of these receptors have ITIM motifs and therefore could suppress overly exuberant IEL responses. Similar to the TL-CD8αα interaction, and perhaps to some of the other examples mentioned here, it is possible that these NK receptor-ligand interactions also deliver signals that can control and modify TCR activation signals in order to adapt IEL to provide protective functions without epithelial destruction. It is therefore likely that the TL-CD8αα interaction provides a paradigm for these types of lympho-epithelial immune-regulation in the intestine, and we are just at the beginning stages of understanding them.

CONCLUSION Mucosal T cells of higher vertebrates have uniquely evolved to adapt to the gutspecific environment that imposes extremely challenging conditions for defensive mechanisms. Through evolution, the mucosal immune system has diverted immensely to provide rapid and effective protection against innumerable pathogens concurrently with maintaining the integrity of the epithelial barrier, tolerating commensal micro-organisms, and allowing for efficient nutrient absorption. The evolution of the thymus as the organ responsible for αβTCR+ T cell education has relieved the intestine of much of its primordial function in lymphopoiesis. CD8αβ TCRαβ IEL are a subtype of conventional memory T cells reactive to foreign antigens. By contrast, CD8αα TCRαβ IEL are self-reactive natural memory T cells with diverse specificities. Self-specificity is selected for in the thymus—a developmental pathway that may endow these cells with the ability to regulate immune responses. T cell localization and function in the intestine is influenced by selection in the thymus, the site of antigen encounter in the periphery for conventional cells, integrin and chemokine receptor expression, and a dense network of invariant and adaptive receptor-ligand interactions that maintain a continuous communication between the mucosal T cells and their neighboring intestinal epithelial cells. ACKNOWLEDGMENTS I would like to thank Dr. Mitchell Kronenberg for critical reading of this manuscript and for the very enlightening discussions and numerous suggestions that significantly enriched and enhanced this article. I would also like to thank Marieke Cheroutre for her very important contribution to this work, and all my colleagues and especially Drs. Loui Madakamutil, Denise Gangadharan, Raziya Shaikh, and

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Laurent Gapin for sharing unpublished data. My special thanks also goes to Drs. Madakamutil and Gapin for the design of the figures. The author’s research was supported by NIH grants DK54451 and AI50263. This is manuscript number 595 of the La Jolla Institute for Allergy and Immunology. The Annual Review of Immunology is online at http://immunol.annualreviews.org

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intraepithelial lymphocytes in antigenbearing hosts. J. Exp. Med. 184:493– 503 Levelt CN, de Jong YP, Mizoguchi E, O’Farrelly C, Bhan AK, et al. 1999. Highand low-affinity single-peptide/MHC ligands have distinct effects on the development of mucosal CD8 alpha alpha and CD8 alpha beta T lymphocytes. Proc. Natl. Acad. Sci. USA 96:5628–33 Podd BS, Aberg C, Kudla KL, Keene L, Tobias E, Camerini V. 2001. MHC class I allele dosage alters CD8 expression by intestinal intraepithelial lymphocytes. J. Immunol. 167:2561–68 Guy-Grand D, Pardigon N, Darche S, Lantz O, Kourilsky P, Vassalli P. 2001. Contribution of double-negative thymic precursors to CD8 alpha alpha (+) intraepithelial lymphocytes of the gut in mice bearing TCR transgenes. Eur. J. Immunol. 31:2593–602 Sydora BC, Brossay L, Hagenbaugh A, Kronenberg M, Cheroutre H. 1996. TAPindependent selection of CD8+ intestinal intraepithelial lymphocytes. J. Immunol. 156:4209–16 Neuhaus O, Emoto M, Blum C, Yamamoto S, Kaufmann SH. 1995. Control of thymus-independent intestinal intraepithelial lymphocytes by beta 2microglobulin. Eur. J. Immunol. 25:2332– 39 Fujiura Y, Kawaguchi M, Kondo Y, Obana S, Yamamoto H, et al. 1996. Development of CD8 alpha alpha+ intestinal intraepithelial T cells in beta 2-microglobulinand/or TAP1-deficient mice. J. Immunol. 156:2710–15 Holcombe HR, Castano AR, Cheroutre H, Teitell M, Maher JK, et al. 1995. Nonclassical behavior of the thymus leukemia antigen: peptide transporter-independent expression of a nonclassical class I molecule. J. Exp. Med. 181:1433–43 Rodgers JR, Mehta V, Cook RG. 1995. Surface expression of beta 2-microglobulin-associated thymus-leukemia

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antigen is independent of TAP2. Eur. J. Immunol. 25:1001–7 Gapin L, Cheroutre H, Kronenberg M. 1999. Cutting edge: TCR alpha beta+ CD8 alpha alpha+ T cells are found in intestinal intraepithelial lymphocytes of mice that lack classical MHC class I molecules. J. Immunol. 163:4100–4 Park SH, Guy-Grand D, Lemonnier FA, Wang CR, Bendelac A, Jabri B. 1999. Selection and expansion of CD8 alpha/alpha(1) T cell receptor alpha/beta(1) intestinal intraepithelial lymphocytes in the absence of both classical major histocompatibility complex class I and nonclassical CD1 molecules. J. Exp. Med. 190:885–90 Das G, Janeway CA Jr. 1999. Development of CD8 alpha/alpha and CD8 alpha/beta T cells in major histocompatibility complex class I-deficient mice. J. Exp. Med. 190:881–84 Tabaczewski P, Stroynowski I. 1994. Expression of secreted and glycosylphosphatidylinositol-bound Qa-2 molecules is dependent on functional TAP-2 peptide transporter. J. Immunol. 152: 5268–74 Das G, Gould DS, Augustine MM, Fragoso G, Sciutto E, et al. 2000. Qa-2dependent selection of CD8 alpha/alpha T cell receptor alpha/beta(+) cells in murine intestinal intraepithelial lymphocytes. J. Exp. Med. 192:1521–28 Lin T, Matsuzaki G, Yoshida H, Kenai H, Omoto K, et al. 1996. Thymus ontogeny and the development of TCR alpha beta intestinal intraepithelial lymphocytes. Cell Immunol. 171:132–39 von Boehmer H, Teh HS, Kisielow P. 1989. The thymus selects the useful, neglects the useless and destroys the harmful. Immunol. Today 10:57–61 Buch T, Rieux-Laucat F, Forster I, Rajewsky K. 2002. Failure of HY-specific thymocytes to escape negative selection by receptor editing. Immunity 16:707–18 Jordan MS, Boesteanu A, Reed AJ,

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CHEROUTRE Petrone AL, Holenbeck AE, et al. 2001. Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist selfpeptide. Nat. Immunol. 2:301–6 Bendelac A. 1995. Positive selection of mouse NK1+ T cells by CD1expressing cortical thymocytes. J. Exp. Med. 182:2091–96 Legendre V, Boyer C, Guerder S, Arnold B, Hammerling G, Schmitt-Verhulst AM. 1999. Selection of phenotypically distinct NK1.1+ T cells upon antigen expression in the thymus or in the liver. Eur. J. Immunol. 29:2330–43 Capone M, Troesch M, Eberl G, Hausmann B, Palmer E, MacDonald HR. 2001. A critical role for the T cell receptor alphachain connecting peptide domain in positive selection of CD1-independent NKT cells. Eur. J. Immunol. 31:1867–75 Backstrom BT, Muller U, Hausmann B, Palmer E. 1998. Positive selection through a motif in the alphabeta T cell receptor. Science 281:835–38 Werlen G, Hausmann B, Palmer E. 2000. A motif in the alphabeta T-cell receptor controls positive selection by modulating ERK activity. Nature 406:422–26 Derbinski J, Schulte A, Kyewski B, Klein L. 2001. Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nat. Immunol. 2:1032– 39 Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, et al. 2002. Projection of an immunological self shadow within the thymus by the AIRE protein. Science 298:1395–401 Liston A, Lesage S, Wilson J, Peltonen L, Goodnow CC. 2003. AIRE regulates negative selection of organ-specific T cells. Nat. Immunol. 4:350–54 Zuklys S, Balciunaite G, Agarwal A, Fasler-Kan E, Palmer E, Hollander GA. 2000. Normal thymic architecture and negative selection are associated with AIRE expression, the gene defective in the autoimmune-polyendocrinopathy-

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candidiasis-ectodermal dystrophy (APECED). J. Immunol. 165:1976–83 Ramsey C, Winqvist O, Puhakka L, Halonen M, Moro A, et al. 2002. AIRE deficient mice develop multiple features of APECED phenotype and show altered immune response. Hum. Mol. Genet. 11:397–409 Matsuda JL, Gapin L, Baron JL, Sidobre S, Stetson DB, et al. 2003. Mouse V alpha 14i natural killer T cells are resistant to cytokine polarization in vivo. Proc. Natl. Acad. Sci. USA 100:8395–400 Elewaut D, Shaikh RB, Hammond KJ, De Winter H, Leishman AJ, et al. 2003. NIK-dependent RelB activation defines a unique signaling pathway for the development of V alpha 14i NKT cells. J. Exp. Med. 197:1623–33 Sivakumar V, Hammond KJ, Howells N, Pfeffer K, Weih F. 2003. Differential requirement for Rel/nuclear factor kappa B family members in natural killer T cell development. J. Exp. Med. 197:1613–21 DeKoning J, DiMolfetto L, Reilly C, Wei Q, Havran WL, Lo D. 1997. Thymic cortical epithelium is sufficient for the development of mature T cells in relB-deficient mice. J. Immunol. 158:2558–66 Valero R, Baron ML, Guerin S, Beliard S, Lelouard H, et al. 2002. A defective NFkappa B/RelB pathway in autoimmuneprone New Zealand black mice is associated with inefficient expansion of thymocyte and dendritic cells. J. Immunol. 169:185–92 Malissen M, Gillet A, Rocha B, Trucy J, Vivier E, et al. 1993. T cell development in mice lacking the CD3-zeta/eta gene. EMBO J. 12:4347–55 Simpson S, Hollander G, She J, Levelt C, Huang M, Terhorst C. 1995. Selection of peripheral and intestinal T lymphocytes lacking CD3 zeta. Int. Immunol. 7:287– 93 Rodewald HR, Moingeon P, Lucich JL, Dosiou C, Lopez P, Reinherz EL. 1992. A population of early fetal thymocytes

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expressing Fc gamma RII/III contains precursors of T lymphocytes and natural killer cells. Cell 69:139–50 Liu CP, Kappler JW, Marrack P. 1996. Thymocytes can become mature T cells without passing through the CD4+ CD8+, double-positive stage. J. Exp. Med. 184:1619–30 Hunig T. 1988. Cross-linking of the T cell antigen receptor interferes with the generation of CD4+8+ thymocytes from their immediate CD4−8+ precursors. Eur. J. Immunol. 18:2089–92 Turner JM, Brodsky MH, Irving BA, Levin SD, Perlmutter RM, Littman DR. 1990. Interaction of the unique N-terminal region of tyrosine kinase p56lck with cytoplasmic domains of CD4 and CD8 is mediated by cysteine motifs. Cell 60:755– 65 Shaw AS, Chalupny J, Whitney JA, Hammond C, Amrein KE, et al. 1990. Short related sequences in the cytoplasmic domains of CD4 and CD8 mediate binding to the amino-terminal domain of the p56lck tyrosine protein kinase. Mol. Cell Biol. 10:1853–62 Gao GF, Jakobsen BK. 2000. Molecular interactions of coreceptor CD8 and MHC class I: the molecular basis for functional coordination with the T-cell receptor. Immunol. Today 21:630–36 Norment AM, Salter RD, Parham P, Engelhard VH, Littman DR. 1988. Cellcell adhesion mediated by CD8 and MHC class I molecules. Nature 336:79– 81 Crooks ME, Littman DR. 1994. Disruption of T lymphocyte positive and negative selection in mice lacking the CD8 beta chain. Immunity 1:277–85 Fung-Leung WP, Kundig TM, Ngo K, Panakos J, De Sousa-Hitzler J, et al. 1994. Reduced thymic maturation but normal effector function of CD8+ T cells in CD8 beta gene-targeted mice. J. Exp. Med. 180:959–67 Wallace VA, Penninger J, Mak TW. 1993.

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CD4, CD8 and tyrosine kinases in thymic selection. Curr. Opin. Immunol. 5:235–40 Miceli MC, von Hoegen P, Parnes JR. 1991. Adhesion versus coreceptor function of CD4 and CD8: role of the cytoplasmic tail in coreceptor activity. Proc. Natl. Acad. Sci. USA 88:2623–27 Cawthon AG, Alexander-Miller MA. 2002. Optimal colocalization of TCR and CD8 as a novel mechanism for the control of functional avidity. J. Immunol. 169:3492–98 Arcaro A, Gregoire C, Boucheron N, Stotz S, Palmer E, et al. 2000. Essential role of CD8 palmitoylation in CD8 coreceptor function. J. Immunol. 165:2068–76 Hershberg R, Eghtesady P, Sydora B, Brorson K, Cheroutre H, et al. 1990. Expression of the thymus leukemia antigen in mouse intestinal epithelium. Proc. Natl. Acad. Sci. USA 87:9727–31 Leishman AJ, Naidenko OV, Attinger A, Koning F, Lena CJ, et al. 2001. T cell responses modulated through interaction between CD8alphaalpha and the nonclassical MHC class I molecule, TL. Science 294:1936–39 Liu Y, Xiong Y, Naidenko OV, Liu JH, Zhang R, et al. 2003. The crystal structure of a TL/CD8alpha alpha complex at ˚ resolution: implications for mod2.1 A ulation of T cell activation and memory. Immunity 18:205–15 Campbell N, Yio XY, So LP, Li Y, Mayer L. 1999. The intestinal epithelial cell: processing and presentation of antigen to the mucosal immune system. Immunol. Rev. 172:315–24 Hershberg RM, Cho DH, Youakim A, Bradley MB, Lee JS, et al. 1998. Highly polarized HLA class II antigen processing and presentation by human intestinal epithelial cells. J. Clin. Invest. 102:792–803 Hershberg RM, Framson PE, Cho DH, Lee LY, Kovats S, et al. 1997. Intestinal epithelial cells use two distinct pathways for HLA class II antigen processing. J. Clin. Invest. 100:204–15

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162. Hershberg RM, Mayer LF. 2000. Antigen processing and presentation by intestinal epithelial cells—polarity and complexity. Immunol. Today 21:123–28 163. Rescigno M, Urbano M, Valzasina B, Francolini M, Rotta G, et al. 2001. Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nat. Immunol. 2:361–67 164. Sanderson IR, Ouellette AJ, Carter EA, Walker WA, Harmatz PR. 1993. Differential regulation of B7 mRNA in enterocytes and lymphoid cells. Immunology 79:434– 38 165. Framson PE, Cho DH, Lee LY, Hershberg RM. 1999. Polarized expression and function of the costimulatory molecule CD58 on human intestinal epithelial cells. Gastroenterology 116:1054–62 166. Byrne B, Madrigal-Estebas L, McEvoy A, Carton J, Doherty DG, et al. 2002. Human duodenal epithelial cells constitutively express molecular components of antigen presentation but not costimulatory molecules. Hum. Immunol. 63:977– 86 167. Cepek KL, Shaw SK, Parker CM, Russell GJ, Morrow JS, et al. 1994. Adhesion between epithelial cells and T lymphocytes mediated by E-cadherin and the alpha E beta 7 integrin. Nature 372:190–93 168. Schon MP, Arya A, Murphy EA, Adams CM, Strauch UG, et al. 1999. Mucosal T lymphocyte numbers are selectively reduced in integrin alpha E (CD103)deficient mice. J. Immunol. 162:6641–49 169. Poussier P, Ning T, Banerjee D, Julius M. 2002. A unique subset of self-specific intraintestinal T cells maintains gut integrity. J. Exp. Med. 195:1491–97

170. Boismenu R, Havran WL. 1994. Modulation of epithelial cell growth by intraepithelial gamma delta T cells. Science 266:1253–55 171. Asseman C, Mauze S, Leach MW, Coffman RL, Powrie F. 1999. An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J. Exp. Med. 190:995– 1004 172. Asseman C, Powrie F. 1998. Interleukin 10 is a growth factor for a population of regulatory T cells. Gut 42:157–58 173. Annacker O, Asseman C, Read S, Powrie F. 2003. Interleukin-10 in the regulation of T cell-induced colitis. J. Autoimmun. 20:277–79 174. Fuss IJ, Boirivant M, Lacy B, Strober W. 2002. The interrelated roles of TGF-beta and IL-10 in the regulation of experimental colitis. J. Immunol. 168:900–8 175. Morales VM, Christ A, Watt SM, Kim HS, Johnson KW, et al. 1999. Regulation of human intestinal intraepithelial lymphocyte cytolytic function by biliary glycoprotein (CD66a). J. Immunol. 163:1363– 70 176. Watt SM, Teixeira AM, Zhou GQ, Doyonnas R, Zhang Y, et al. 2001. Homophilic adhesion of human CEACAM1 involves N-terminal domain interactions: structural analysis of the binding site. Blood 98:1469–79 177. Sarnacki S, Begue B, Buc H, Le Deist F, Cerf-Bensussan N. 1992. Enhancement of CD3-induced activation of human intestinal intraepithelial lymphocytes by stimulation of the beta 7-containing integrin defined by HML-1 monoclonal antibody. Eur. J. Immunol. 22:2887–92

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Figure 1 IEL are a diverse population of T cells. IEL consist of three major subsets: the TCRgd T cells that are thymus derived and develop along the DN pathway; the conventional CD4 or CD8ab TCRab IEL that have matured in the thymus along the conventional selection pathway and migrate as antigen-experienced T cells to the intestine; and the CD8aa TCRab IEL that have matured and differentiated in the thymus along the agonist-selection pathway and independent of coreceptor expression. The agonistselection process directs their migration as self-antigen-experienced T cells to the intestine.

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Figure 2 Thymic selection is determined by TCR signal strength. Conventional positive selection occurs under conditions of intermediate TCR signal strength received upon recognition of self-MHC and self-antigen. Agonist selection occurs under strong signal strength conditions that otherwise delete thymocytes along the conventional negative selection pathway. Conventional selected mature T cells migrate to the intestine upon agonistic nonself activation signals received in the periphery.

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CONTENTS FRONTISPIECE—Leonard A. Herzenberg and Leonore A. Herzenberg GENETICS, FACS, IMMUNOLOGY, AND REDOX: A TALE OF TWO LIVES INTERTWINED, Leonard A. Herzenberg and Leonore A. Herzenberg SELF- AND NONSELF-RECOGNITION BY C-TYPE LECTINS ON DENDRITIC CELLS, Teunis B.H. Geijtenbeek, Sandra J. van Vliet, Anneke Engering, Bert A. ’t Hart, and Yvette van Kooyk

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TRANSCRIPTIONAL CONTROL OF EARLY B CELL DEVELOPMENT, Meinrad Busslinger

UBIQUITIN LIGASES AND THE IMMUNE RESPONSE, Yun-Cai Liu LIGANDS FOR L-SELECTIN: HOMING, INFLAMMATION, AND BEYOND, Steven D. Rosen

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INTEGRINS AND T CELL–MEDIATED IMMUNITY, Jonathan T. Pribila, Angie C. Quale, Kristen L. Mueller, and Yoji Shimizu

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MULTIPLE ROLES OF ANTIMICROBIAL DEFENSINS, CATHELICIDINS, AND EOSINOPHIL-DERIVED NEUROTOXIN IN HOST DEFENSE, De Yang, Arya Biragyn, David M. Hoover, Jacek Lubkowski, and Joost J. Oppenheim

STARTING AT THE BEGINNING: NEW PERSPECTIVES ON THE BIOLOGY OF MUCOSAL T CELLS, Hilde Cheroutre THE BCR-ABL STORY: BENCH TO BEDSIDE AND BACK, Stephane Wong and Owen N. Witte

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CD40/CD154 INTERACTIONS AT THE INTERFACE OF TOLERANCE AND IMMUNITY, Sergio A. Quezada, Lamis Z. Jarvinen, Evan F. Lind, and Randolph J. Noelle

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THE THREE ES OF CANCER IMMUNOEDITING, Gavin P. Dunn, Lloyd J. Old, and Robert D. Schreiber

AUTOIMMUNE AND INFLAMMATORY MECHANISMS IN ATHEROSCLEROSIS, Georg Wick, Michael Knoflach, and Qingbo Xu THE DYNAMIC LIFE OF NATURAL KILLER CELLS, Wayne M. Yokoyama, Sungjin Kim, and Anthony R. French

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THE ROLE OF COMPLEMENT IN THE DEVELOPMENT OF SYSTEMIC LUPUS ERYTHEMATOSUS, Anthony P. Manderson, Marina Botto, and Mark J. Walport

DROSOPHILA: THE GENETICS OF INNATE IMMUNE RECOGNITION AND RESPONSE, Catherine A. Brennan and Kathryn V. Anderson RAGS AND REGULATION OF AUTOANTIBODIES, Mila Jankovic,

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Rafael Casellas, Nikos Yannoutsos, Hedda Wardemann, and Michel C. Nussenzweig

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THE ROLE OF SUPPRESSORS OF CYTOKINE SIGNALING (SOCS) PROTEINS IN REGULATION OF THE IMMUNE RESPONSE, Warren S. Alexander and Douglas J. Hilton

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REGULATORY T CELLS FOR IMMUNOLOGIC SELF-TOLERANCE AND NEGATIVE CONTROL OF IMMUNE RESPONSES, Shimon Sakaguchi PHOSPHOINOSITIDE 3-KINASE: DIVERSE ROLES IN IMMUNE CELL ACTIVATION, Jonathan A. Deane and David A. Fruman IMMUNITY TO TUBERCULOSIS, Robert J. North and Yu-Jin Jung MOLECULAR DEFECTS IN HUMAN SEVERE COMBINED IMMUNODEFICIENCY AND APPROACHES TO IMMUNE RECONSTITUTION, Rebecca H. Buckley PHYSIOLOGICAL CONTROL OF IMMUNE RESPONSE AND INFLAMMATORY TISSUE DAMAGE BY HYPOXIA-INDUCIBLE FACTORS AND ADENOSINE A2A RECEPTORS, Michail V. Sitkovsky, Dmitriy Lukashev, Sergey Apasov, Hidefumi Kojima, Masahiro Koshiba, Charles Caldwell, Akio Ohta, and Manfred Thiel

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T LYMPHOCYTE–ENDOTHELIAL CELL INTERACTIONS, Jaehyuk Choi, David R. Enis, Kian Peng Koh, Stephen L. Shiao, and Jordan S. Pober

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IMMUNOLOGICAL MEMORY TO VIRAL INFECTIONS, Raymond M. Welsh, Liisa K. Selin, and Eva Szomolanyi-Tsuda

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CENTRAL MEMORY AND EFFECTOR MEMORY T CELL SUBSETS: FUNCTION, GENERATION, AND MAINTENANCE, Federica Sallusto, Jens Geginat, and Antonio Lanzavecchia CONTROL OF T CELL VIABILITY, Philippa Marrack and John Kappler

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ASTHMA: MECHANISMS OF DISEASE PERSISTENCE AND PROGRESSION, Lauren Cohn, Jack A. Elias, and Geoffrey L. Chupp

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CD1: ANTIGEN PRESENTATION AND T CELL FUNCTION, Manfred Brigl and Michael B. Brenner

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CHEMOKINES IN INNATE AND ADAPTIVE HOST DEFENSE: BASIC CHEMOKINESE GRAMMAR FOR IMMUNE CELLS, Antal Rot and Ulrich H. von Andrian

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INTERLEUKIN-10 AND RELATED CYTOKINES AND RECEPTORS, Sidney Pestka, Christopher D. Krause, Devanand Sarkar, Mark R. Walter, Yufang Shi, and Paul B. Fisher

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INDEXES

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Subject Index Cumulative Index of Contributing Authors, Volumes 12–22 Cumulative Index of Chapter Titles, Volumes 12–22

ERRATA An online log of corrections to Annual Review of Immunology chapters may be found at http://immunol.annualreviews.org/errata.shtml

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Annu. Rev. Immunol. 2004. 22:247–306 doi: 10.1146/annurev.immunol.22.012703.104753 c 2004 by Annual Reviews. All rights reserved Copyright °

THE BCR-ABL STORY: Bench to Bedside and Back Stephane Wong1 and Owen N. Witte2 Annu. Rev. Immunol. 2004.22:247-306. Downloaded from arjournals.annualreviews.org by HINARI on 09/01/07. For personal use only.

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Molecular Biology Interdepartmental PhD Program/UCLA, 2Howard Hughes Medical Institute/David Geffen School of Medicine at UCLA, Los Angeles, California 90095-1662; email: [email protected]; [email protected]

Key Words tyrosine kinase, leukemia, Imatinib mesylate, inhibitor mechanism, signal transduction ■ Abstract The twenty-first century is beginning with a sharp turn in the field of cancer therapy. Molecular targeted therapies against specific oncogenic events are now possible. The BCR-ABL story represents a notable example of how research from the fields of cytogenetics, retroviral oncology, protein phosphorylation, and small molecule chemical inhibitors can lead to the development of a successful molecular targeted therapy. Imatinib mesylate (Gleevec, STI571, or CP57148B) is a direct inhibitor of ABL (ABL1), ARG (ABL2), KIT, and PDGFR tyrosine kinases. This drug has had a major impact on the treatment of chronic myelogenous leukemia (CML) as well as other blood neoplasias and solid tumors with etiologies based on activation of these tyrosine kinases. Analysis of CML patients resistant to BCR-ABL suppression by Imatinib mesylate coupled with the crystallographic structure of ABL complexed to this inhibitor have shown how structural mutations in ABL can circumvent an otherwise potent anticancer drug. The successes and limitations of Imatinib mesylate hold general lessons for the development of alternative molecular targeted therapies in oncology.

IDENTIFICATION OF THE CHROMOSOMAL ABNORMALITY AND CELLULAR ORIGIN OF THE HUMAN DISEASE CHRONIC MYELOGENOUS LEUKEMIA (CML) The Philadelphia (Ph) Chromosome is Associated with CML In 1845, the pathologists Bennet, Craigie, and Virchow independently described the disease chronic myelogenous leukemia (CML) (1–3). In 1960, a major clue to the cause of CML was provided by Nowell & Hungerford’s landmark discovery of the Philadelphia (Ph) chromosome and its association with the disease CML (4). They examined leukemic cells from chronic phase CML and other leukemia patients. Surprisingly, the cells of all seven CML patients showed a consistent “minute chromosome” abnormality, which they named the Philadelphia (Ph) chromosome (4). Other leukemias did not show any chromosomal abnormalities (4). 0732-0582/04/0423-0247$14.00

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Figure 1 Timeline of major ABL oncogenesis findings.

This discovery was the first demonstration of a chromosomal rearrangement being consistently linked to a specific cancer (Figure 1) and sparked searches for associations of additional chromosomal aberrations with specific forms of cancer. Numerous abnormalities have been subsequently identified and associated with cancer (reviewed in 5). In retrospect, it was fortunate that Nowell & Hungerford analyzed mainly chronic phase CML patient samples for chromosomal abnormalities, where the Ph chromosome is now known to be present in over 90% of CML cases (6). Had they analyzed samples from patients with adult B-ALL, where the Ph chromosome accounts for only 10% to 15% of such cases, the association of a specific chromosomal abnormality with a specific disease might not have been as apparent (7). Chronic phase CML has a consistent, relatively indolent presentation in patients, with an increase in immature and mature myeloid elements and retention of hematopoietic differentiation (8). This unique and consistent phenotype of chronic phase CML enabled Nowell & Hungerford to easily and accurately identify these patients. The phenotypes of accelerated and blast crisis CML is much more diverse and aggressive than chronic phase CML. Both accelerated and blast phases are characterized by a severe reduction in cellular differentiation, with a displacement of mature cells by immature blasts (8). In blast crisis, more than 50% of patients enter a myeloid blast stage resembling acute myeloblastic leukemia (AML) (8). A pre-B blast stage similar to acute lymphoid leukemia (B-ALL) accounts for 30% of patients (8), and erythroid blasts develop in 10% of patients (8). Rarely do T cell blasts (T-ALL) evolve (9, 10). The pleiotropic and aggressive phenotypes of blast crisis suggest that different oncogenic abnormalities could lead to the transition of chronic phase CML to blast phase CML. Numerous oncogenic events have been associated with blast crisis; these include trisomy 8, i(17q) (11, 12), loss of p53 function (13, 14), MYC amplification (12), RB (RB1) deletion/rearrangement (15), and p16INK4A (CDKN2) rearrangement/deletion (16). Loss of p53 function has been exclusively linked with

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myeloid and not lymphoid blast crisis, which suggests that p53 signaling is critical for the regulation of normal myelopoiesis (13). Over 80% of blast phase CML cases have definable genetic aberrations in addition to the Ph chromosome (11).

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The Philadelphia Chromosome is Present in the Hematopoietic Stem Cell The transition from a predominantly myeloid disease in chronic phase CML to alternative lineages in blast crisis raised the question of which cell types contained the Ph chromosome. Fialkow and colleagues examined different cell types in chronic phase CML patients for the presence of the Ph chromosome (17, 18). Surprisingly, both granulocytes and erythroid lineage cells from chronic phase CML patients contained the Ph chromosome, even though only myeloid cells are expanded during chronic phase CML (17, 18). The presence of the Ph chromosome in granulocyte and erythroid lineages suggested that the Ph chromosome is either generated in multiple cell types or originates in a hematopoietic stem cell (HSC) from which it is passed down to other cell lineages. Fialkow and colleagues addressed the cellular origin of Ph+ cells by examining whether different lineage Ph+ cells were of polyclonal or monoclonal origin. Female CML patients heterozygous for the Glucose-6-Phosphate Dehydrogenase (G-6-PD) isoenzymes were examined for expression of a specific G-6-PD form in Ph+ cells. During the process of X-chromosome inactivation during embyrogenesis, one X chromosome is inactivated in each HSC, resulting in expression of a single G-6-PD isoenzyme type per HSC. Fialkow and colleagues demonstrated that individual CML patients expressed the same G-6-PD isoenzyme in Ph chromosome-positive granulocytic and erythroid lineage cells, whereas nonleukemic patient granulocytes expressed both enzymes (17, 18), substantiating the clonal and stem cell origin of CML (Figure 1). Subsequent purification of HSCs and different lineage–restricted cells from CML patients by cell surface markers has confirmed the presence of the Ph chromosome in the HSC (reviewed in 19, 20). The discovery of a clonal HSC origin of CML suggested that elimination of Ph+ HSCs and replacement of these cells with normal HSCs should be an effective therapy. Currently, this type of treatment regimen, using chemotherapy followed by bone marrow transplantation, is the only curative procedure for CML (reviewed in 21).

DISCOVERY OF A NOVEL TYROSINE KINASE ACTIVITY REQUIRED FOR ABELSON MURINE LEUKEMIA VIRUS (A-MULV)-INDUCED CELLULAR TRANSFORMATION AND LEUKEMOGENESIS A-MuLV Generates Lymphosarcomas Our understanding of the oncogenic activity generated from the Ph chromosome unexpectedly came in large part from studies of the Abelson murine leukemia virus

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(A-MuLV). Inoculation of the Moloney Leukemia Virus (M-MuLV) into neonatal mice had been reported to generate thymomas (reviewed in 22). To determine whether this virus was capable of generating lymphomas of other cellular tropisms, Abelson & Rabstein destroyed the T cell compartment of mice with the steroid prednisolone prior to injecting animals with M-MuLV (23; reviewed in 24). Of 153 MLV-infected mice, one developed a distinct type of lymphosarcoma (23; reviewed in 24). This Abelson murine leukemia virus (A-MuLV) reproducibly generated thymic-independent lymphomas (23, 25, 26). Differences between A-MuLV and M-MuLV were noted by subsequent in vitro studies in which A-MuLV but not M-MuLV transformed NIH 3T3 cells (27) and lymphoid cells (28) (Figure 1). The direct in vitro B lymphoid transformation system developed by Rosenberg & Baltimore has proven exceptionally important for the studies of hematopoietic transformation and immune system development.

A-MuLV Expresses a Unique Chimeric Fusion Gene Product Gag-Abl To identify the unique transforming components in A-MuLV not present in MMuLV, the nucleic acid composition of both viruses were compared. Heteroduplex and endonuclease restriction digest analyses of A-MuLV RNA hybridized with MMuLV DNA indicated that A-MuLV encoded 50 and 30 sequences identical to the M-MuLV genome and a unique 3.6-kB fragment not present M-MuLV (29). Using this 3.6-kB insert sequence as a cDNA probe, it was demonstrated that the unique coding region of A-MuLV was cellular in origin (29). In parallel with viral genomic analysis, the unique protein components in AMuLV were analyzed using tryptic peptide analysis of [35S] methionine-labeled AMuLV and M-MuLV proteins and antibodies immunoreactive against major viral proteins. A 120-kD A-MuLV polyprotein contained p15, p12, and part of p30 Gag proteins in common with M-MuLV (30–32). The remaining 80–100-kD protein component in A-MuLV was unique (30, 31). To identify the unknown component in A-MuLV, sera specific for A-MuLV but not M-MuLV were obtained from mice that showed tumor regression upon A-MuLV transformed cell line challenge (reviewed in 24; 33). The tumor regressor sera reacted with the C terminus of A-MuLV, whereas the N terminus of A-MuLV reacted with Gag antibodies (33–35). The same tumor regressor sera cross-reacted with a normal cellular protein NCP 150, later named c-Abl (33, 36). These results demonstrated that A-MuLV encoded a chimeric fusion gene product Gag-Abl with the N-terminal Gag protein originating from M-MuLV and the C-terminal Abl protein being of cellular origin (Figures 1, 2A). Subsequently, A-MuLV was shown to encode a 160-kD chimeric protein. The initially identified 120-kD fusion protein contained an in-frame 789 base pairs (263 amino acids) deletion (Figure 2A). Both proteins were equally potent at transforming cells (reviewed in 24).

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Tyrosine Kinase Activity is Essential for Gag-Abl Cellular Transformation The connection of the field of protein kinases and its significance to oncogenic transformation came from a critical observation by Collett & Erikson demonstrating that the protein kinase activity of the Rous Sarcoma Virus (RSV) SRC protein was connected to its transforming potency (37). This finding led to the question of whether other oncoproteins such as Gag-Abl possessed protein kinase activity. Immunoprecipitates of Gag-Abl proteins were shown to possess kinase activity and the P120 Gag-Abl protein itself was autophosphorylated (38, 39). Furthermore, of several variant strains of A-MuLV, the only strain (P92td) that was biologically inactive for cellular transformation had no detectable kinase activity (40). This result linked genetic variations in the Gag-Abl gene product to changes in enzyme activity and biological potency. In the late 1970s, cellular kinase activities were known to predominantly utilize serine and theonine residues as phosphate acceptors (41). However, in vitro autophosphorylated Gag-Abl had undetectable levels of phospho-serine and phosphothreonine (42). Alternative Gag-Abl protein phosphorylations on lysine, histidine, and acidic residues were ruled out based on chemical stabilities and reactivities (42). Further, no evidence of a protein–nucleic acid linkage was observed (42). Evaluation of Gag-Abl as a tyrosine-specific kinase was influenced from two types of prior studies. First, poliovirus RNA was shown to be linked to a small protein via a phosphoester linkage through a tyrosine residue (43), and second, the DNA topoisomerase (ω protein) involved in unwinding DNA superhelical turns was shown to utilize a phosphoester linkage to a tyrosine residue as a transient intermediate in the reaction between enzyme and DNA (44). Immunoprecipitated Gag-Abl autophosphorylated in vitro with 32γ -ATP and Gag-Abl harvested from cells labeled with 32P-orthophosphate were shown to contain phosphotyrosine when protein samples were hydroloyzed in acid at 110◦ C for only several hours instead of the customary 24-h period (42) (Figure 1). Phosphotyrosine has a limited half-life in acid at high temperatures, and extended hydrolysis converted the label to free phosphate. Hunter & Sefton independently discovered that the protein kinase activity associated with pp60Src of RSV specifically phosphorylated tyrosine residues (45). These combined observations led to the concept that tyrosine kinase activity might regulate both leukemias and solid tumors induced by oncogenic retroviruses. Aberrant tyrosine kinase regulation has been subsequently linked with cancer development in many systems, validating these early findings that deregulated tyrosine kinase activity is associated with malignant transformation (reviewed in 5). After the initial discovery of Gag-Abl tyrosine kinase activity, different experimental approaches provided further support for ABL tyrosine kinase activity being critical to Gag-Abl–induced cellular transformation. Within the next two years, it was shown that transformation-defective mutants of Gag-Abl, similar to its cellular homolog c-Abl (Abl NCP150), lacked the heightened tyrosine kinase activity

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present in transforming variants of Gag-Abl (34, 35). Subsequent improvements in kinase activity assays led to the discovery that c-Abl also possesses tyrosine kinase activity, albeit at a much lower specific activity than Gag-Abl (46). Random amino acid insertions into the tyrosine kinase domain, but not other regions of Gag-Abl, were shown to abrogate tyrosine kinase activity and cellular transformation (47). In addition, temperature-sensitive GAG-ABL mutants at nonpermissive temperatures were unable to transform NIH 3T3 and lymphoid cells due to inhibited tyrosine ←−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− Figure 2 Generation of chimeric ABL oncogenes. (A) Generation of A-MuLV. The exact mechanism of A-MuLV formation is not clear. One possible mechanism involves recombination between M-MuLV viral RNA and Abl RNA via one or multiple steps to eventually generate the A-MuLV retrovirus. Another possible mechanism involves the integration of the M-MuLV genome into the abl genome at exon 3 to generate the replication defective Gag-Abl. Gag-Abl encodes a myristoylated fusion protein containing N-terminal p15, p12, and 21 amino acids of p30 from the M-MuLV Gag sequences combined with Abl exonic sequences starting from exon 3 onwards encoding the SH2 = src homology domain 2, SH1 = src homology tyrosine kinase domain, NLS = nuclear localization domains, DNA = DNA binding sites, and ACTIN = F and G actin binding sites. The A-MuLV genome encodes a 120-kD or 160-kD chimeric protein, both shown to contain elevated ABL tyrosine kinase activity and to induce cellular transformation, with the smaller initially identified form containing an inframe deletion of 789 base pairs (263 amino acids) in the Abl sequence of A-MuLV. U5 = unique to 50 sequences; U3 = unique to 30 sequences; R = repeated sequence. (B) Locations of breakpoints in BCR and ABL genes and structure of derived chimeric proteins. Three breakpoint regions within the BCR genome are responsible for generating the predominant BCR-ABL fusion proteins. The minor breakpoint cluster (m-bcr) spans 54-kb and results in an e1a2 7.0 mRNA that generates p185BCR-ABL. The major breakpoint cluster (M-bcr) spans 5.8 kb and results in either a b2a2 or b3a2 8.5 kb mRNA producing p210BCR-ABL. A third breakpoint located at the 30 end of the gene (µ-bcr) generates a c3a2 9.0 kb mRNA forming p230BCR-ABL. Regardless of the exact breakpoint in ABL, BCR sequences are most often fused to ABL exon a2 in the hybrid transcript. BCR protein domains include: OLIGO = oligomerization; A and B = A and B boxes; S/TKINASE = serine/threonine kinase; DBL/CDC24 = Dbl homology; PH = Pleckstrin homology; RACGAP = Rac GTPase. ABL protein domains include MYR = myristoylation signal; CAP = CAP hydrophobic residues; SH3 = src homology 3; and remaining ABL domains as described in Figure 2A. (C) Two forms of TEL-ABL are generated in human leukemias. TEL-ABL containing the first 4 exons of TEL and exon 2 of ABL onwards generates a p145TEL-ABLfusion protein encoding the first 154 amino acids of TEL and 1104 residues of ABL. TEL-ABL containing the first 5 exons of TEL and exon 2 of ABL onwards generates a p180TEL-ABL fusion protein encoding the first 336 amino acids of TEL and 1104 residues of ABL. Both chimeric proteins encode the SAM/PNT = SAM/pointed helix-loop-helix oligomerization domain of TEL and identical ABL domains to BCR-ABL (Figure 3B).

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kinase activity (48). However, it was still unclear whether the murine Gag-Abl oncoprotein and its biological transforming activity related to human cancer.

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IDENTIFICATION OF THE GENETIC PRODUCT OF THE HUMAN PH CHROMOSOME AND ITS UNEXPECTED RELATIONSHIP TO THE MURINE GAG-ABL ONCOPROTEIN The Ph Chromosome Gene Product, BCR-ABL, Possesses Deregulated Tyrosine Kinase Activity Diverse experimental approaches were crucial to the identification of the Ph chromosome product. The advent of quinacrine fluorescence and Giemsa banding enabled Rowley and colleagues to show that the Ph chromosome resulted from a reciprocal translocation between the long arms of chromosomes 9 and 22 t(9;22)(q34;q11) (49). Another 9 years passed after the identification of the chromosome arms involved in the Ph chromosomal translocation before key studies from several investigators including Heisterkamp, Groffen, Stephenson, and Canaani, led to the definitive characterization of the Ph chromosome structure and its mRNA product (Figures 1 and 2B). Chromosome mapping studies demonstrated that the human ABL gene mapped to chromosome 9 (50). This gene was shown to be translocated to the Ph chromosome in CML cells (51–53). An ABL probe reacted with an ∼8-kb mRNA present in Ph-positive but not in control cells, suggesting that the ABL gene is part of the Ph chromosome product (54). Work from our laboratory independently identified ABL as part of the protein product of the Ph chromosome. ABL is highly conserved among species and ABLantisera generated from murine Gag-Abl studies effectively cross-reacted with human ABL. Murine Abl-antisera were shown to immuno-react with a large 210-kD protein present in the Ph+ K562 cell line and not control cell lines, providing evidence that part of the ABL protein is expressed in the Ph chromosome protein product (55). This was further confirmed by preparing antibodies against GST-ABL fusion determinants and demonstrating antibody reactivity towards the 210-kD protein in the CML cell line K562 and primary CML bone marrow cell lysates (56, 57). Could the human Ph chromosome product possess elevated ABL tyrosine kinase activity similar to murine Gag-Abl required for cellular transformation? Using ABL-antisera generated from Gag-Abl studies, the Ph chromosome P210 protein product was shown to have similar tyrosine kinase activity to Gag-Abl with respect to autophosphorylation, trans-phosphorylation, and kinase inhibition by antisera against the tyrosine kinase region of ABL (55, 58, 59) (Figure 1). Furthermore, similar to Gag-Abl, a mutation in the Ph chromosome protein that specifically inactivated the tyrosine kinase activity of ABL inhibited cellular transformation, demonstrating that, like Gag-Abl, the Ph chromosome protein product requires ABL tyrosine kinase activity for its oncogenic function (60).

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Breakpoints along the Ph chromosome were found to occur within the breakpoint cluster region (BCR) gene, suggesting that BCR might also be affected by the translocation that creates the Ph chromosome (61). BCR was shown to be part of the unique Ph chromosome mRNA product not present in control cells (62). cDNA cloning of this Ph chromosome mRNA product demonstrated sequence homology to the BCR gene at the 50 end of the mRNA (62–65). Later, the unique Ph chromosome protein product was shown to cross-react with BCR-specific antiserum, demonstrating that this protein expressed at least part of BCR (56). Reactivity with both BCR and ABL probes to the unique mRNA product of the Ph chromosome demonstrated that this Ph chromosome mRNA was composed of BCR-ABL (56, 64, 66) (Figure 1). Later, through sequence analysis, the BCRABL transcript was shown to contain the first 13 to 14 BCR exons and exons 1a or a2 through a11 of ABL (reviewed in 67) (Figures 1, 2B). This generated a large mRNA product that after splicing, encoded an 8.5-kB BCR-ABL chimeric transcript (reviewed in 67). BCR-ABL was shown to be the 210-kD chimeric protein product of the Ph chromosome in K562 cells by coimmunoprecipitation of the protein with an ABL antiserum and detection of a 210-kD product with either ABL- or BCR-specific antibodies (56) (Figures 1, 2B).

Additional Forms of BCR-ABL are Preferentially Associated with Specific Human Leukemias A new association of the Ph chromosome with B-ALL was subsequently discovered. Advances in chromosome mapping and molecular biology enabled the specific B-ALL Ph chromosome gene product with its chromosome breakpoints and mRNA sequence to be analyzed and compared with that of CML samples. Initial Ph+ B-ALL studies showed that a smaller 7.0 kb mRNA as opposed to a CML Ph chromosome 8.5 kb mRNA product was formed (68, 69). Furthermore, the BCR-ABL protein product in B-ALL samples was 185/190-kD (henceforth referred to as p185BCR-ABL) as opposed to the 210-kD BCR-ABL protein product (henceforth referred to as p210BCR-ABL) in CML samples (68–71). The differences in the Ph chromosome gene product in B-ALL versus CML were due to differences within the BCR breakpoints. The translocation giving rise to the Ph chromosome in B-ALL was localized within the minor breakpoint cluster region (m-bcr) in BCR (71–75), whereas in CML, the translocation site was within the major breakpoint cluster region (M-bcr) in BCR (61, 62, 76) (Figure 2B). These studies showing a high but absolute correlation between the p210BCR-ABL form and CML, and p185BCR-ABL with B-ALL suggested that specific forms of BCR-ABL may play a role in the etiology of each leukemia. P210BCR-ABL is associated with over 90% of CML cases, approximately 33% of adult B-ALL cases with the Ph chromosome (reviewed in 77) and, on occasion, acute myeloid leukemias (AML) (reviewed in 78) and myelomas (79). P185BCR-ABL is associated with the remaining 66% of adult B-ALL cases, with the Ph chromosome not associated with p210BCR-ABL (67, 78), 3% of atypical CML cases with

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monocytosis (80), and in some AML cases (81) and lymphomas (82). In addition, a third form of BCR-ABL, p230BCR-ABL was identified as being mainly associated with neutropenic CML (83) as well as some cases of CML (84) (Figure 2B). These findings demonstrate a preferential association between different BCR-ABL forms and distinct leukemias. This correlation is not absolute as some cases of Ph+ BALL are associated with p210BCR-ABL expression. Furthermore, although the Ph chromosome is detected in HSCs in CML patients, in B-ALL patients, it is not clear whether the Ph chromosome is present in HSCs, or whether it is restricted to the lymphoid lineage (85, 86). These findings suggest that differences in target cells and BCR-ABL isoforms can contribute to the type of leukemia formed.

BCR-ABL Transcripts are Detected in Some Healthy Individuals Using highly sensitive two-step RT-PCR, BCR-ABL mRNAs were detected in leukocytes of healthy individuals (87, 88). Depending on the specific sets of primers used to amplify the BCR-ABL transcript, between ∼30% to ∼70% of healthy individuals had detectable levels of BCR-ABL expression in their white blood cells (87, 88). The amount of cells bearing the BCR-ABL transcript in these people was extremely low, with an estimated incidence of 1–10 cells per 108 white blood cells (88). Many of the BCR-ABL transcripts formed in these healthy cells encoded for nonfunctional or truncated proteins (88). However, BCR-ABL transcripts that might encode for a functional BCR-ABL protein were detected in some leukocytes of healthy individuals (88). Why the BCR-ABL positive cells that encode for a functional BCR-ABL protein do not generate leukemia in these individuals is not known. One possibility is that the origin of the BCR-ABL transcripts is a cell type more mature than HSCs/progenitors and that these cells cannot be expanded sufficiently to generate CML. Alternatively, the BCR-ABL clones may have originated from a HSC/progenitor that has subsequently been inactivated, thereby limiting the expansive capabilities of these BCR-ABL–expressing cells. Healthy individuals, unlike untreated CML patients, have high-avidity cytotoxic T lymphocytes (CTL) capable of selectively killing CML cells owing to recognition of a proteinase 3 self-peptide or a BCR-ABL junction peptide highly expressed in leukemic cells (89; reviewed in 90). Most individuals with BCR-ABL–expressing cells may possess BCR-ABL-specific high-avidity CTLs that can destroy most Phpositive cells, preventing an expansion that could result in CML. Therapy aimed at generating specific CTL killing of BCR-ABL-expressing cells has had limited success in treating CML patients, however, due to the rapid loss or complete absence of high-avidity CTLs against leukemic cells in these patients (reviewed in 90). Discovering the mechanism by which healthy individuals maintain highavidity CTLs with specificity against Ph-positive cells may lead to the development of successful immunotherapy against CML. The alternative reciprocal translocation gene product ABL-BCR has been detected in Ph chromosome-positive leukemias but is thought not to play a role in

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BCR-ABL–induced leukemogenesis and is not discussed further in this review (91, 92).

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The TEL (ETV6)-ABL Oncoprotein is Associated with Rare Human Leukemias Another form of chimeric ABL fusion gene product, TEL (ETV6)-ABL, was identified in rare cases of human ALL, AML, and CML (93–96). Two TEL-ABL forms have been associated with these leukemias. One form encodes the first 4 exons of TEL and the other encodes the first 5 exons of TEL, both being fused to ABL from exon 2 onwards (Figure 2C). As in BCR-ABL and GAG-ABL, TEL-ABL possesses activated ABL tyrosine kinase activity, essential for its transformation properties (94).

MECHANISM OF ABL TYROSINE KINASE ACTIVATION Crystal Structure of the N-Terminal Myristoylation, cap, SH3, SH2, and SH1 Kinase Domains of ABL Reveal a Three-Step Mechanism of ABL Tyrosine Kinase Activation Myristoylation of Gag-Abl on the glycine residue of Gag is essential for Gag-Abl association with the plasma membrane and transformation of NIH 3T3 fibroblasts (97). Although BCR-ABL is not myristoylated, attachment of a Gag myristoylation sequence to the N terminus of BCR-ABL enhances its transformation properties (98). These results suggested that myristoylation of ABL oncoproteins could augment cellular transformation by bringing mitogenic and antiapoptotic proteins such as RAS and PI3K, which associates with the plasma membrane, into close proximity for activation by ABL. Alternatively, myristoylation of ABL oncoproteins could favor the folding of the ABL tyrosine kinase domain toward an active conformation, thereby enhancing ABL tyrosine kinase activation and oncogenesis. These findings raised the question of the effect of myristoylation in ABL activation. There are two isoforms of ABL; isoform 1b is myristoylated on its second glycine residue, a site absent in all chimeric ABL oncoproteins (numbering of ABL is based on isoform 1b throughout text) (99) (Figure 3). Surprisingly, loss of myristoylation in ABL resulting from mutation of the second glycine residue to an alanine, dramatically enhanced its tyrosine kinase activity compared to wildtype ABL (100). This result is in contrast to Gag-Abl findings where loss of myristoylation was shown to suppress Gag-Abl transforming abilities (97). Kuriyan and Superti-Furga examined whether ABL myristylation contributed to the generation of a structurally inactive form of ABL and whether demyristylation led to ABL tyrosine kinase activation in the context of both human and murine ABL structures comprised of the N-terminal myristoylation, cap, SH3, SH2, and SH1 kinase domains of ABL. Collaboratively, the groups demonstrated that a

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Figure 3 Three-step mechanism of ABL tyrosine kinase activation (taken from 104). ABL is maintained in a closed inactive conformation by the “latching” of the N-terminal myristoyl group or N-terminal cap hydrophobic residues to a deep hydrophobic pocket in the ABL tyrosine kinase domain. This “latching” of the N terminus of ABL to its kinase domain places the SH2 and SH3 domains of ABL on the backside of the large and small lobes of the kinase respectively, “clamping” the structure together. This “clamp” sequesters the activation loop of the kinase, preventing its orientation to an active conformation and tyrosine 412 phosphorylation, required for full activation of the kinase. ABL activation requires an “unlatching” of the myristoyl group or hydrophobic residues in the ABL tyrosine kinase domain. Attachment of phosphotyrosine and proline-rich proteins to the SH2 and SH3 domains, respectively, could open up the kinase and expose the activation loop outwards leading to tyrosine 412 phosphorylation and full activation of the kinase.

nonmyristolyated peptide corresponding to the N terminus of ABL was unable to bind to an inactive conformation of the ABL tyrosine kinase domain, whereas the corresponding myristolyated peptide was able to complex with the inactive conformation of ABL (100, 101). These results suggested that ABL myristolyation contributed to the maintenance of an inactive conformation and that loss of ABL myristoylation may promote the conversion of ABL from an inactive to an active state (Figures 1, 3). The N-terminal myristoyl group of ABL binds to a deep hydrophobic pocket in the kinase domain, keeping ABL in a closed inactive conformation (100, 101) (Figure 3). Although ABL isoform 1a and BCR-ABL are not myristoylated, it was suggested that the hydrophobic residues in the cap domain of ABL, present in both forms of ABL, may substitute for the myristoyl latching function (100, 101). The N-terminal myristoyl group of ABL latching to its kinase domain was shown to place the SH2 and SH3 domains of c-ABL on the backside of the large and small lobes of the tyrosine kinase domain, respectively. Clamping of the SH2 and SH3 domains within the kinase domain lobes obstructed ATP binding (100, 101) (Figure 3). Addition of increasing concentrations of tyrosine phosphorylated peptides specific to ABL SH2 domain binding led to a dose-dependent opening up of the ABL structure and activation of ABL tyrosine kinase activity (100, 101).

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Mutations in the SH2 and SH3 regions that disrupted the clamping of the ABL kinase lobes also generated active forms of ABL (100, 101). An SH3 domain mutation abolished clamping to the catalytic domain and led to ABL activation (102). This effect was reversed by a reciprocal mutation in the corresponding catalytic domain residue (102). These findings support the role of the SH3 domain in stabilizing the inactive conformation of ABL. The third step leading to full ABL tyrosine kinase activation involved an outward reorientation of the activation loop away from the protein and phosphorylation on tyrosine 412 (100, 101) (Figure 3). Phosphorylation of this site enhances the in vitro kinase activity of Abl by 2- to 3.3-fold (103). Abl inefficiently autophosphorylated this site, which required expression of the Src tyrosine kinase Hck for its phosphorylation (103). This general latching, clamping, and sequestration of the activation loop is very similar to the overall mechanism of maintaining SRC in an inactive state (100, 101; reviewed in 104). The up-regulated ABL tyrosine kinase activity of chimeric ABL oncoproteins is most likely the result of disruptions in these ABL inhibitory processes. The lack of a myristoyl group in BCR-ABL and TEL-ABL, for example, may favor a more open conformation of the ABL kinase domain, leading to the heightened tyrosine kinase activity detected in these chimeric ABL oncoproteins compared with ABL.

MECHANISMS OF TYROSINE KINASE UP-ACTIVATION IN CHIMERIC ABL ONCOPROTEINS Oligomerization Contributes to ABL Tyrosine Kinase Activation and Cellular Transformation BCR-ABL, TEL-ABL, and Gag-Abl all contain oligomerization motifs and form oligomers (94, 105; reviewed in 24). This commonality suggests that oligomerization may be a general mechanism for ABL tyrosine kinase activation. ABL, on the other hand, does not contain oligomerization domains and is not predicted to utilize oligomerization to regulate its tyrosine kinase activity. Deletion of the oligomerization motifs in BCR-ABL and TEL-ABL greatly suppresses tyrosine kinase activity and cellular transformation (94, 105–107) (Table 1). Substitution of the BCR oligomerization motif in BCR-ABL with an unrelated yeast transcription factor GCN4 leucine zipper oligomerization sequence was able to maintain a high level of BCR-ABL tyrosine kinase activity and transforming ability (108). However, attachment of alternative oligomerization motifs, such as GST (109), GAG (107), and BCR oligomerization sequences 1 through 63 (105) to ABL, generated chimeric fusion proteins with modest tyrosine kinase activity and cellular transformation abilities compared to BCR-ABL. These constructed ABL oligomers possessed higher levels of tyrosine kinase activity compared with ABL and transformed certain cell lines, demonstrating that ABL

− (105, 107, 114) ↓ (120, 121) − (107, 119) + (112) ↓ (120−123) ↓ (60, 120, 121) − (60)

↓/− (105, 107, 114, 172) + (114, 121, 128) ↓/− (107) + (112, 113, 319) + (121, 122, 128) + (60, 121, 128) − (60)

Oligomerization

Y177-GRB2 site

A + B boxes

SH3

SH2

412Y P site

SH1 kinase

− (60)

− (169, 170)

ND

LL (173)

+ (319)

ND

− (114, 127, 175)

− (114)

ND

ND

+ (174)

ND

ND

+ (175)

LL (172)

− (169, 170)

ND

ND

ND

ND

LL (114)

LL (114)

T-ALL

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+ = positive; − = negative; ↓ = greatly reduced.

T-ALL = acute T-cell leukemia; LL = long latency; ND = not done.

− (60)

↓ (60, 121)

+ (121)

+ (112)

− (107, 119)

+ (121)

− (107, 114)

B-ALL

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+ (60, 121, 128)

+ (121, 123, 128, 320)

+ (113)

− (128)

+ (121, 128)

↓/− (105, 114)

CML-like

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TABLE 1 BCR-ABL domain requirements for tyrosine kinase activation, in vitro cellular transformation, and in vivo leukemogenesis

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oligomerization can be sufficient to activate ABL tyrosine kinase to levels required for cellular transformation.

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Inactivation of the SH3 Domain Up-Regulates ABL Tyrosine Kinase Activity Leading to Cellular Transformation A direct correlation between the highest levels of ABL tyrosine phosphorylation and the greatest level of cellular transformation has been established such that the level of tyrosine kinase activity and transformation in Gag-Abl > p185BCR-ABL > p210 BCR-ABL (110). A major difference in the ABL structure of Gag-Abl compared to BCR-ABL is the absence of a functional SH3 domain in Gag-Abl (reviewed in 24) (Figure 2). This suggested that the SH3 domain may be a negative regulator of ABL tyrosine kinase activity. Further evidence for a negative function of the SH3 domain was demonstrated in the crystal structure of ABL, where contacts between the SH3 domain and the tyrosine kinase domain kept ABL in an inactive conformation (100–102) (Figure 3). Deletion of the SH3 domain in ABL greatly up-regulates its tyrosine kinase activity, leading to transformation in certain cell types (99, 111). Removal of the SH3 domain in BCR-ABL also enhances BCR-ABL cellular transformation (112, 113), and deletion of the SH3 domain in a transformation defective BCR-ABL oligomerization domain-deleted clone largely restored the tyrosine kinase activity and transforming abilities of the clone (113, 114). A random mutagenesis schema identified ABL point mutants within the SH3 domain with heightened catalytic and transforming activities. Surprisingly, these mutations were not at residues predicted to obstruct clamping of the SH3 domain with the tyrosine kinase domain leading to ABL activation. These ABL mutants were defective at binding PxxP ligands (115). These results suggest that the SH3 domain could negatively regulate ABL tyrosine kinase activity when ABL is in an open conformation by interacting with proline-rich proteins that suppress ABL catalytic activity (Figure 3). The ABL interactor proteins (ABI) contain PxxP motifs that bind to the SH3 domain of c-ABL (116). Expression of ABI suppressed Gag-Abl transformation (117), and BCR-ABL expression degraded ABI proteins (118). These results suggest that ABI proteins could act as negative regulators of ABL transformation via interaction with the SH3 domain of ABL during its open conformation. The SH3 domain may serve as a dual negative regulator of kinase activity in both the active and inactive conformations of ABL.

BCR A and B Boxes are Required for BCR-ABL Activation and Cellular Transformation Crystallographic analyses of ABL activation have demonstrated that addition of phospho-peptides that bind to the SH2 domain of ABL opens up the inactive conformation of ABL, leading to its activation in a dose-dependent manner (see section on Mechanism of ABL Tyrosine Kinase Activation; 100). Deletion of BCR A and B boxes in BCR-ABL that bind to the SH2 domain of ABL inhibit

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BCR-ABL tyrosine kinase activity and cellular transformation (107, 119). These findings suggest that BCR A and B box regions may bind to the SH2 domain of ABL, preventing the SH2 domain from clamping to the large tyrosine kinase lobe, and maintaining BCR-ABL in an open active conformation. However, a reciprocal deletion of the SH2 domain predicted to reduce the chances of ABL from adopting an inactive conformation, based on ABL crystallographic data (see section on Mechanism of ABL Tyrosine Kinase Activation; 100, 101), does not lead to BCRABL activation, but rather its suppression in the context of fibroblast transformation (120–123). This is most likely due to the role of the SH2 domain in interacting with critical transforming signaling molecules when BCR-ABL is in an active conformation to induce fibroblast transformation. These findings suggest that the SH2 domain can have a positive or negative role in BCR-ABL transformation depending on the structural conformation of the tyrosine kinase.

DOMAIN AND SIGNALING REQUIREMENTS FOR BCR-ABL–INDUCED IN VITRO CELLULAR TRANSFORMATION ABL Tyrosine Kinase Activity is Essential for Oncogenic Signaling of Multiple BCR-ABL Domains The Y177 residue in the BCR portion of BCR-ABL complexes with the GRB2 adaptor protein linking BCR-ABL to the RAS-MAPK pathway (124–126) (Table 2). GAB2 is a scaffolding adaptor that binds to GRB2 in a BCR-ABL complex (127) (Table 2). BCR-ABL expression in GAB2 knockout cells shows greatly diminished in vitro cellular transformation coincident with a decrease in RAS-ERK activation (127). These results suggest that the GRB2-GAB2 complex could be a dominant RAS signaling component. Mutation of tyrosine 177 to phenylalanine suppressed the ability of BCR-ABL to transform Rat1 fibroblast cells (120, 121) (Table 1). However, expression of the BCR-ABL Y177F mutant maintained high levels of ABL tyrosine kinase activity and was sufficient to render cytokine-dependent hematopoietic cell lines growth factor independent (121, 128) (Table 1). Mutation in the FLVRES motif of the ABL SH2 domain or deletion of the SH2 domain in BCR-ABL prevented its association with tyrosine phosphorylated proteins such as p62DOK (121, 129, 130) and suppressed BCR-ABL transformation of fibroblasts (120–123) (Table 1). However, as in the case of the BCR-ABL Y177F mutant, expression of either BCR-ABL SH2 mutant led to high levels of ABL tyrosine kinase activity and transformation of hematopoietic cell lines (121, 123, 128) (Table 1). Without tyrosine kinase activity, the GRB2 binding site was unable to complex with its signaling molecule or regulate signaling cascades leading to heightened BCR-ABL activation (131). BCR-ABL regions such as the GRB2 binding site

VEGF (344) BACHS (348) C/EBPα (350) C/EBPε (350)

JNK (140, 151) p38MAPK (159) STAT5 (174, 179) NFκB (317, 318) c-MYC (335) BCL-XL (159, 352) BCL-2 (354, 355) BAD (147, 357) TRAIL (359) AATYK (359)

ERK1/2 (140, 174) c-MYC (335) RIN1 (340) RAC (343)

G2A (334)

GM-CSF (169, 170) G-CSF (324)

IL-3Rβc (330)

PTPIB (341)

SHP-1 (336)

SHIP2 (325)

SHIP1 (325, 326)

Phosphatases

c-CBL (337, 338)

PAXILLIN (331, 332)

CRKL (327, 328)

Cytoskeletal

DNA-PK (274) DNAPOLβ (267) RAD5I (345)

BRCA1 (273)

XPB (271)

DNA repair

SHC (121, 125) p62DOK (129, 130) c-CBL (337, 338)

GAB2 (127)

GRB4 (333)

GRB2 (124, 125)

Adaptors

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CK2α (351) PKCι (353) JAK2 (356) VAV (358) p53 (156, 360) MDM2 (360) BAGE

LYN (323, 339) HCK (339, 342) FPS/FES (346, 347) GCKR (349)

ABI-2 (118)

ABI-1 (118)

Others

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bold italic text = primary cells; plain text = cell lines.

AKT (141, 174)

IL-3 (320, 324)

p27KIP (322, 329)

PI3K (146, 323)

RAS (140, 141)

Hematopoietic factors

CYCLIN D2 (321, 322)

Apoptosis

Mitogens

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TABLE 2 BCR-ABL regulates a diverse range of signaling molecules and pathways

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and SH2 domain need to work in concert with up-regulated ABL tyrosine kinase activity to heighten the cellular transforming ability of BCR-ABL. The functional dependence of these domains on ABL tyrosine kinase activity reinforces the critical role of activated tyrosine kinase in BCR-ABL–induced cellular transformation. BCR-ABL augments cellular adhesion to fibronection in a tyrosine kinase– independent manner (132). The cytoskeletal interacting F-actin and proline-rich CRKL binding domains of BCR-ABL are also capable of functioning in BCRABL tyrosine kinase inactive clones (133, 134). These results suggest that F-actin and proline-rich regions may mediate BCR-ABL tyrosine kinase–independent functions leading to enhanced cellular adherence. Deletion of these cytoskeletal interacting regions only marginally reduces BCR-ABL–induced foci formation and is dispensable for cytokine-independent growth of hematopoietic cell lines (123, 134, 135). These findings suggest that BCR-ABL cytoskeletal tyrosine kinase–independent functions are likely to be dispensable for BCR-ABL–induced oncogenesis.

BCR Serine/Threonine Kinase Activity is Dispensable for BCR-ABL Induced In Vitro Oncogenesis BCR is a serine/threonine kinase capable of transphosphorylating serine residues on histones and caesin (136). A cysteine pair of residues within amino acids 298– 333 was demonstrated to be essential for BCR serine/threonine kinase activity (136). Surprisingly, expression of a BCR-ABL mutant containing a deletion spanning this BCR region was competent in transforming cells (119). BCR-ABL inhibits the serine/threonine kinase activity of BCR via tyrosine phosphorylation of BCR residue 360 (137). Expression of a serine phosphorylated BCR peptide greatly reduced BCR-ABL tyrosine phosphorylation and interfered with the growth of BCR-ABL expressing cell lines, whereas expression of a BCR 360 tyrosine phosphorylated peptide had no such effects (138). Recently, BCR kinase activity has been shown to enhance BCR binding to the scaffolding protein AF-6, which led to a suppression of RAS-ERK activity (139). These results suggest that BCR-ABL may suppress BCR serine/threonine kinase activity via tyrosine 360 phosphorylation, thereby preventing BCR from negatively affecting BCR-ABL tyrosine kinase activity, RAS activation, and BCR-ABL–induced cellular transformation.

BCR-ABL Regulates a Diverse Range of Signaling Molecules of which RAS Activation Appears to be Critical for BCR-ABL–Induced Cellular Transformation BCR-ABL expression regulates a variety of signaling molecules ranging from mitogens, antiapoptotic proteins, hematopoietic factors, and cytoskeletal components, to negative regulators such as phosphatases (Table 2). Multiple studies of RAS activation have demonstrated that BCR-ABL expression leads to an increase in the amount of GTP loaded onto RAS (128, 140–143). Inactivation

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of RAS signaling via expression of dominant negative forms of RAS or addition of farnesyl transferase inhibitors severely suppresses BCR-ABL–induced cell growth and focus formation (144, 145). These results indicate that activation of the RAS pathway is critical and potentially essential to BCR-ABL–induced oncogenesis. However, it is unclear whether the majority of signaling molecules regulated by BCR-ABL expression contribute to its transforming properties. The antiapoptotic molecule PI3K is activated upon BCR-ABL induction (141, 146) and suppression of the PI3K pathway by expression of dominant negative AKT or addition of the PI3K inhibitor LY 294002 suppressed BCR-ABL–induced cytokine-independent growth (147) and colony formation (141). However, in other reports, activation of the PI3K downstream substrate AKT was shown to be minimal (148), with expression of dominant negative AKT or addition of LY 294002 being unable to reverse BCR-ABL–induced cellular transformation (148, 149). The mitogen MAPK ERK1/2 is activated or phosphorylated at its activation site upon BCR-ABL expression in the cell lines 32D and BaF3 (140, 143). Addition of the ERK1/2 inhibitor PD 98059 suppressed BCR-ABL–induced cell expansion in the Ph-positive K562 cell line (150). However, BCR-ABL expression did not activate ERK1/2 in the 293T human kidney epithelial cell or cytokine-dependent DAGM cell lines (151) and addition of the ERK1/2 inhibitor PD 98059 did not suppress cell growth of Ph-positive cell lines EM2, BV173, and ALL-1 (152). These sets of apparently opposing data on the requirement of ERK1/2 activation in BCR-ABL cellular transformation utilized different cellular systems. BCR-ABL expression may regulate different sets of signaling molecules required to induce cellular transformation, depending on its cellular context.

IN VITRO SYSTEMS TO STUDY BCR-ABL EFFECTS IN MULTIPOTENT PROGENITOR CELLS Multipotent hematopoietic progenitors are a cell population receptive to BCRABL expression and generate an abnormal expansion of mature myeloid cells, a clinical feature of chronic phase CML (153, 154). Alternative in vitro cellular systems have been developed to study BCR-ABL in the cellular context of hematopoietic progenitors. Infection of 5-fluorouracil-treated bone marrow cells depleted of cycling cells and enriched for HSCs/progenitors with a retrovirus expressing BCR-ABL was shown to expand cells predominantly of the myeloid lineage (155) (Figure 1). The pluripotent FDCP-Mix cell line has been used to demonstrate that growth factor independence of myeloid cells required long-term BCR-ABL expression (156). Chronic BCR-ABL expression in human CD34+ multipotent progenitors via retroviral transduction delayed apoptosis induced by serum and cytokine withdrawal (153). Embryonic stem (ES) cell-derived multipotent progenitors expressing BCR-ABL via retroviral transduction or tetracycline regulation expanded blast cells (157, 158).

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We have examined a set of signaling molecules shown to be regulated by BCR-ABL expression from cell line studies in the cellular context of ES-derived hematopoietic progenitors. The majority of these signaling molecules were not altered by acute BCR-ABL expression in this cellular context (159). The proapoptotic molecule p38MAPK was suppressed and the antiapoptotic molecule BCL-XL was up-regulated upon BCR-ABL expression coincident with the antiapoptotic effect of BCR-ABL in these progenitors (159) (Table 2). A gene microarray study has identified numerous signaling molecules regulated by BCR-ABL expression in Ph-positive multipotent progenitors (160) (Table 2). The contribution of these signaling molecules to Ph-positive leukemias awaits examination in BCR-ABL– induced in vivo leukemia animal models.

MURINE MODELS OF ABL ONCOGENESIS Deregulated Tyrosine Kinase Activity is Necessary for ABL-Induced Leukemias To confirm predictions based on initial GAG-ABL studies that expression of ABL forms with deregulated tyrosine kinase activity is sufficient to generate cancer in vivo, animal models expressing different ABL forms needed to be developed. An early transgenic study driving expression of a created trimeric bcr-gag-abl construct off an immunoglobulin heavy-chain enhancer (Eµ) or a myeloproliferative sarcoma virus (MPSV) promoter generated lymphomas in mice (161). Transgenic mice expressing p185BCR-ABL from a metallothionein-1 promoter (MT) developed acute leukemias (162) (Figure 1). Retroviral transduction of p210BCR-ABL expression into bone marrow cells transplanted into mice demonstrated that p210BCR-ABL expression induced multiple hematopoietic neoplasms including CML, ALL, erythroid leukemia, mast cell leukemia, T lymphoma, and macrophage tumors (reviewed in 163) (Figure 1). Different cell culture infection conditions and mouse strains affected the type of neoplasm induced by BCR-ABL expression. In fact, injection of BCR-ABL virus directly into the mouse thymus exclusively generated T lymphomas (164). These results validated earlier predictions that different forms of ABL oncoproteins with deregulated ABL tyrosine kinase activity could generate cancer in vivo and revealed that the target hematopoietic cell type expressing the ABL oncogene played a key role in determining the type of hematological disease generated. In 1990, several groups demonstrated that p210BCR-ABL expression could induce a CML-like disease in mice (165, 166) (Figure 1). The experimental strategy was to enrich for HSC/progenitor expression of p210BCR-ABL, the same target cell population from which human CML originates. Mice were treated with 5-fluorouracil (5-FU) to kill cycling cells and enrich for HSC/progenitor populations. Quiescent HSC/progenitors were induced to cycle with cytokine mixtures and these cells were subsequently infected with retroviral vectors encoding p210BCR-ABL. Lethally

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irradiated mice reconstituted with this p210BCR-ABL–infected cell population generated a CML-like disease.The CML-like disease was transplantable into secondary and tertiary recipients, demonstrating that the target cell type from which the disease originates is a HSC (165, 167). The correlation between highest levels of ABL tyrosine kinase activity and greatest level of cellular transformation was extended to the rate of leukemia development with Gag-Abl > p185BCR-ABL > p210 BCR-ABL (166, 168). This infection condition coupled with improved retroviral technology is still the main CML-like mouse model used today to study BCR-ABL leukemogenesis (169, 170). Using this CML-like model, it was shown that a tyrosine kinase inactive p210BCR-ABL mutant could not generate a CML-like disease (169, 170). This contrasts to the situation in Drosophila where expression of kinase-active or kinase-defective ABL forms were shown to be effective at rescuing ABL-defective animals to wild-type, fertile flies (171).

Multiple BCR-ABL Domains Contribute to the Type and Latency of Leukemia Deletion of the oligomerization domain previously shown to severely suppress BCR-ABL tyrosine kinase activity and in vitro cellular transformation (see section on Domain and Signaling Requirements for BCR-ABL-Induced in Vitro Cellular Transformation) inhibited BCR-ABL from generating a CML-like disease in vivo (114) (Table 1). However, this BCR-ABL mutant was able to generate B cell leukemia/lymphoma (172) and T-ALL (114) with a significantly longer latency period than wild-type BCR-ABL (Table 1). Restoration of the tyrosine kinase activity in this BCR-ABL mutant by deleting the SH3 domain rescued the ability of the mutant to generate an aggressive CML-like disease (114). This direct correlation of enhanced ABL tyrosine kinase activation with leukemia severity again displays the dominant role of ABL tyrosine kinase activity in BCR-ABL oncogenesis. Inactivation of the SH2 domain previously shown to maintain high levels of ABL tyrosine kinase activity (see section on Domain and Signaling Requirements for BCR-ABL-Induced in Vitro Cellular Transformation) delayed the development of a BCR-ABL–induced CML-like disease compared with wild-type BCR-ABL (173, 174) (Table 1). However, the mutation did not affect the ability of BCR-ABL to induce B-ALL (174) (Table 1). These results demonstrate that a functional SH2 domain contributes to, but is not required for BCR-ABL to generate a CML-like disease and is dispensable for BCR-ABL–induced B-ALL. Expression of the Y177F BCR-ABL mutant shown to retain elevated levels of tyrosine kinase activity (see section on Domain and Signaling Requirements for BCR-ABL-Induced in Vitro Cellular Transformation) was unable to generate a lethal CML-like disease and instead developed a long-latency fatal lymphoid leukemia in mice (114, 127, 175) (Table 1). The Y177 site in BCR-ABL is complexed with GRB2 and GAB2, which can lead to RAS activation (see section

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on Domain and Signaling Requirements for BCR-ABL-Induced in Vitro Cellular Transformation; 127). RAS activation and expression of the GAB2 scaffolding adaptor is crucial for BCR-ABL–induced in vitro cellular transformation (see section on Domain and Signaling Requirements for BCR-ABL-Induced in Vitro Cellular Transformation). These findings suggest that BCR-ABL activation of RAS via its Y177 site interaction with GRB2 and GAB2 may be critical in the generation of CML (see 176 for a detailed review on domain requirements for BCR-ABL–induced leukemias).

The Significance of the RAS Pathway in BCR-ABL Cellular Transformation has been Confirmed in Murine Leukemogenesis Models In vivo administration of the RAS inhibitor SCH66336 suppressed p190BCR-ABL– induced B-ALL in 80% of mice for over 200 days, whereas 100% of control animals succumbed to leukemia from 18–103 days (177). GAB2-deficient BCRABL expressing progenitors with severely reduced RAS-MAPK activation were unable to generate a BCR-ABL–induced CML-like disease unlike control cells (B. Neel & R. Van Etten, personnal communication). These results suggest that GAB2 may be a critical signaling molecule connecting BCR-ABL to RAS activation and leukemogenesis. IL-3 up-regulation (170, 178), p62DOCK phosphorylation (129, 130), and STAT5 activation (179, 180) have all been demonstrated following BCR-ABL induction in numerous cell types (Table 2). However, knockouts of these signaling molecules did not prevent BCR-ABL–induced leukemias, and only in the case of p62 DOCK was there a minor delay in leukemogenesis (181–183). These findings suggest that it may be difficult to identify individual signaling molecules critical for BCR-ABL–induced leukemia.

BCR-ABL Expression is Required for the Development and Maintenance of a BCR-ABL–Induced Leukemia A transgenic BCR-ABL tetracycline-regulatable B-ALL mouse model demonstrated that continual BCR-ABL expression was required for the establishment and maintenance of a BCR-ABL–induced leukemia (184). This is in agreement with a BCR-ABL tetracycline-regulatable ES in vitro differentiation system where continual BCR-ABL expression was shown to be required for the expansion of progenitor and myeloid cells (148). Temperature-sensitive Gag-Abl and BCRABL mutants at nonpermissive temperatures were unable to transform NIH 3T3 and lymphoid cells owing to inhibited tyrosine kinase activity (48, 185) (see section on Discovery of Novel Tryosine Kinase Activity Required for Abelson Murine Leukemia Virus (A-MuLV)–Induced Cellular Transformation and Leukemogenesis).

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KNOCKOUT ANIMAL MODELS WITH CML PHENOTYPES

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Interferon Consensus Sequence Binding Protein (ICSBP)-Deficient Mice Develop a CML-Like Disease ICSBP is a transcription factor of the interferon regulatory factor (IRF) family, members of which regulate interferon (IFN)–stimulated gene expression (186). ICSBP knockout mice are 100% penetrant for a chronic phase CML-like disease by 10 to 16 weeks of age, of which 33% evolve into blast crisis by 50 weeks of age (187). The chronic stage disease in these mice is characterized by an elevation of neutrophils in hematopoietic tissues. Development of blast crisis is associated with a huge expansion of myeloblasts in the bone marrow and spleen, with B lymphoblasts being dominant in the blood and lymph nodes. ICSBP+/− mice have a lower penetrance of CML-like disease compared with ICSBP−/− mice, suggesting that development of CML by loss of ICSBP expression is dose dependent. The CML-like phenotype of ICSBP knockout mice prompted investigators to examine whether ICSBP expression was down-regulated in a p210BCR-ABL– induced leukemia. ICSBP down-regulation indeed correlated with the development of a p210BCR-ABL–induced CML-like disease in vivo (188). Moreover, enforced expression of ICSBP delayed the onset of a p210BCR-ABL–induced lethal CMLlike syndrome from 3 weeks to 5 weeks (188). However, ICSBP expression was unable to inhibit p210BCR-ABL–induced leukemogenesis. ICSBP is poorly active at regulating gene expression by itself (189) but is highly active when it is part of a multiprotein complex being bound to IRF-1 or IRF-2 and PU.1 (189). Overexpression of ISCBP as well as its partner(s) may be necessary to fully inhibit p210BCR-ABL–induced leukemogenesis. This has been shown in the myelomonocytic cell line U937 in which transfection of all three components (ICSBP, IRF-1, and PU.1) was required to produce a highly active transcriptional complex (189).

Lack of JunB Expression in the Myeloid Lineage Generates a CML-Like Disease in Mice JunB expression increases during myeloid differentiation (190, 191), suggesting it may play an important role in myelopoiesis. JunB knockout mice rescued from embryonic lethality via expression of JunB driven from a human ubiquitin promoter transgene (JunB−/− Ubi-junB) were shown to gradually develop elevated levels of mature myeloid cells in the blood, spleen, bone marrow, and lymph nodes beginning at 4 months of age concomitant with a reduction in JunB expression (192). These results suggested that down-regulation or loss of JunB expression contributed to the CML-like disease, which progressed to a syndrome resembling blast crisis in 16% of the mice. JunB expression inhibits cyclinD1 function by activating P16INK4a (193, 194). CyclinD1 overexpression complements BCR-ABL–induced transformation (195). Therefore, cyclinD1 up-regulation may be a common signaling event in myeloid

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leukemogenesis induced by both BCR-ABL expression and loss of JunB activity. Although JunB−/− Ubi-junB transgenic mice lose JunB expression in the myeloid compartment during disease progression, JunB expression is maintained in T cells, B cells, and erythrocytes. This suggests that loss of JunB expression in HSCs is not required for the induction of the myeloproliferative disorder. Transgenic mice engineered with restricted expression of BCR-ABL to common myeloid progenitors and their progeny via the MRP8 promoter were shown to develop a CML-like disease (196). These findings demonstrate that a genetic lesion restricted to myeloid progenitors and their progeny can induce a CML-like disease and raise the question as to the involvement of the HSC in CML beyond that of the cellular origin/target.

Loss of SH2-Containing Inositol-5-Phosphatase (SHIP) Expression Leads to a CML-Like Disease in Mice Targeted disruption of SHIP was shown to generate a massive expansion of myeloid elements in the spleen, bone marrow, and lungs that proved fatal in 50% of mice by 10 weeks of age (197). SHIP mRNA and protein levels are down-regulated upon induction of ABL oncoproteins p185BCR-ABL, p210BCR-ABL, or TEL-ABL and exogenous expression of SHIP was shown to suppress BCR-ABL–induced spontaneous transwell migration (198). Both SHIP−/− and BCR-ABL expressing hematopoietic progenitors are hyperresponsive to cytokines such as IL-3, leading to an increase in the number of CFU colonies generated in methylcellulose compared with control cells (197, 199). SHIP down-regulation may contribute to BCRABL–induced leukemogenesis by enhancing the responsiveness of hematopoietic progenitors toward cellular expansion under growth factor limiting conditions.

CML TREATMENTS PRIOR TO BCR-ABL MOLECULAR TARGETED THERAPY Most CML treatments prior to BCR-ABL molecular targeted therapy were aimed at destroying actively proliferating cell populations. Busulfan and hydroxyurea treatments globally inhibited the growth of normal and leukemic cells and generated hematological responses in chronic phase CML patients. However, the treatments were unable to selectively destroy Ph+ cells or inhibit the oncogenic activity of BCR-ABL. The treatments did not lead to cytogenetic remission in most patients but could delay the onset of blast crisis CML (reviewed in 200). Ablative chemotherapy with or without irradiation therapy to destroy leukemic and normal proliferating cells followed by allogenic transplantation of normal bone marrow cells was and currently remains the only curative treatment for CML (reviewed in 21). However, only ∼20% of CML patients are candidates for bone marrow transplantation, and 5-year disease-free survival in transplanted patients can vary from 30% to 80% (reviewed in 201, 202).

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Potential Signaling Pathways Regulated by IFN-α Treatment May Contribute to its Selectivity and Effectiveness as a CML Suppressor Interferon-α (IFN-α) treatment leads to both a hematological and cytogenetic response in many chronic phase CML patients (203). In a large study of 512 early chronic phase CML patients treated with IFN-α, 27% (140 out of 512) of patients achieved complete cytogenetic responses and 78% of those patients survived for greater than ten years with this treatment (204). The effectiveness of IFN-α at treating a significant portion of CML patients suggests that IFN-α therapy may have some selectively toward destroying Ph+ leukemic cells or inhibiting the oncogenic activity of BCR-ABL. However, up to 20% of CML patients do not tolerate IFN-α therapy because of toxicity problems (reviewed in 202). IFN-α activation leads to JAK1 phosphorylation followed by STAT1/2 translocation to the nucleus and activation of IFN-α responsive genes (reviewed in 205). This signal transduction cascade is perturbed in CML patient cells resistant to IFNα therapy with a lack of STAT1 expression (206). CML cell lines resistant to IFN-α treatment also suppress the JAK1-STAT1 activation pathway by expressing high levels of suppressor of cytokine signaling 3 (SOC3) (207), which in turn blocks JAK1-STAT1 (208, 209) and down-regulates IFN-α signaling (210). Activation of the JAK1-STAT1 pathway could be a plausible mechanism by which IFN-α treatment suppresses CML. IFN-α induced CML remission is correlated with the reappearance of ICSBP expression (211). High-avidity cytotoxic T lymphocytes (CTLs) against Ph+ cells in IFN-α−treated CML patients experiencing cytogenetic remission have been demonstrated (212). ICSBP expression in a BaF3 cell line expressing BCR-ABL suppressed leukemia development in mice due to the generation of a CD8 cytotoxic T cell response against the BCR-ABL–expressing cell line (213). Coincidentally, ICSBP knockout mice not only develop a CML-like disease, but they also have impaired T cell Th1 response with defective IFN-γ and IL-12 production and enhanced susceptibility to pathogens (187). These results suggest that ICSBP expression may be required to generate high-avidity CTLs and IFN-α treatment may suppress CML by generating high-avidity CTLs against Ph+ leukemic cells via ICSBP induction of IFN-γ and IL-12 production.

DEVELOPMENT OF MOLECULAR TARGETED THERAPY AIMED AT INHIBITING THE TYROSINE KINASE ACTIVITY OF ONCOPROTEINS Over 100 gain-of-function oncogenes have been defined that can contribute to carcinogenesis (reviewed in 5). Tyrosine kinases represent a large fraction of known dominant oncogenic proteins and were a prime target for the development of specific cancer inhibitors (reviewed in 5, 214). The human genome encodes 518

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serine/threonine and tyrosine kinases (215), all of which bind ATP in a highly conserved manner within their catalytic domains (216). This high degree of commonality among kinase ATP-binding regions suggested that it would be difficult to develop compounds that specifically inhibited a single or limited set of tyrosine kinases without having cross-reactivity toward others. The abundance of ATP in a cell raised another concern over the difficulty in developing inhibitors to be administered at concentrations that would effectively suppress oncogenic tyrosine kinases without cellular toxicity.

Identification of Naturally Occurring Compounds with Specific Inhibitory Activity Towards Tyrosine Kinases The first group of compounds tested for inhibitory activity against oncoproteins came from naturally occurring sources. Herbimycin A is a natural antibiotic originally isolated as an agent that reversed the transformation phenotype of RSVinfected rat kidney cells (217). Herbimycin A inhibits a wide range of tyrosine kinases including YES, FPS, ABL, ERBB, ROS (218), and RET (219) without affecting serine/threonine kinases such as protein kinase C (PKC) (220). Herbimycin A targeted protein tyrosine kinases for degradation via a 20S proteosome and ubiquitin-dependent mechanism (221). Genistein is an isoflavone compound isolated from soybeans that acts as an ATP competitive inhibitor toward the catalytic domain of different tyrosine kinases but not serine/threonine kinases (222). Erbstatin was isolated from Streptomyces (223) and shown to be a low-molecularweight substance that resembled tyrosine and blocked the kinase activity of different tyrosine kinases (reviewed in 224). These findings demonstrated that compounds with selectivity towards tyrosine kinases and not serine/threonine kinases could be generated. These naturally occurring compounds were also shown to inhibit Gag-Abl/BCR-ABL cellular transformation (218, 225, 226), suggesting that inhibition of deregulated ABL tyrosine kinase activity may be a viable therapeutic approach toward ABL-induced leukemias.

Development of Tyrphostins: Tyrosine Phosphorylation Inhibitors with Selectivity Toward Specific Tyrosine Kinases In 1988, Levitzki’s laboratory described the synthesis of a series of low-molecularweight protein tyrosine kinase inhibitors with progressive affinity for the epidermal growth factor receptor (EGFR) (227). The most potent of these tyrphostins inhibited the kinase activity of EGFR 1000-fold over that of insulin receptor kinase and suppressed EGF-dependent proliferation without affecting EGF-independent proliferation (227). This demonstrated that synthetic inhibitors could be engineered with selective activity towards specific tyrosine kinases (reviewed in 228). The first generation of tyrphostins was designed to resemble tyrosine and act as substrate inhibitors based on findings that the naturally occurring tyrosine kinase inhibitor erbstatin resembled tyrosine. The initial group of tyrphostins, however, covered a wide range of kinetic behavior: Some were substrate

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competitive inhibitors, some ATP competitive inhibitors, and some both substrate and ATP competitive inhibitors (reviewed in 228). Levitzki’s group further improved the selectivity and potency of tyrphostins against specific tyrosine kinases by converting one aromatic ring, largely substrate mimic inhibitors, into two-ring largely ATP mimic inhibitors (for details on the chemistry of tyrphostin development, see 228). Three tyrphostins were generated and shown to inhibit BCRABL tyrosine kinase activity, cellular transformation, and loss of stromal cell adhesion (229–231). These tyrphostins had a short serum half-life, and further modifications were required to generate an inhibitor with a longer serum halflife. Adaphostin was developed and proved to have a longer serum half-life, although selectivity toward BCR-ABL tyrosine kinase inhibition was greatly reduced (232). The tyrphostin inhibitor AG 490 was one of the first synthetic chemical compounds shown to inhibit the growth of human leukemic cells both in vitro and in vivo (233). The inhibitor blocked the growth of human B-ALL cells transplanted into mice by selectively suppressing JAK-2 activity and did not have deleterious effects on normal hematopoiesis in vivo (233). This finding demonstrated that it was possible to administer a tyrphostin at a dose sufficient to inhibit oncogenesis without lethal toxicities in an in vivo setting (for details of tyrphostins and their potential in clinical use, see 234, 235).

Development of the Small Molecule Inhibitor Imatinib Mesylate Investigators at Ciba-Geigy, now Novartis, originally initiated a random screening of archived inhibitors against protein kinase C-α (PKC-α). They identified the class of phenylamino-pyrimidines as being relatively selective ATP competitive inhibitors against PKC-α (reviewed in 234). Zimmermann, Buchdunger, Trexler, Lydon, and colleagues modified this class of compounds, which underwent highthroughput screenings to identify inhibitors against the platelet-derived growth factor receptor (PDGF-R) tyrosine kinase (234, 235) for the chemistry behind the development of phenylamino-pyrimidine inhibitors). CGP 53,716 was identified as a potent tyrosine kinase inhibitor against PDGF-R and suppressed tumor growth of PDGF-R-activated cell lines in vivo (236). Surprisingly, the CGP 53,716 compound not only suppressed PDGF-R tyrosine kinase activity but quantitatively inhibited Gag-Abl tyrosine kinase activity to a similar degree (236). PDGF-R belongs to the split tyrosine kinase domain type III receptor family, which includes members CSF-1R, c-KIT, and FLK2 (FLT3), whereby ∼100 residues separate two parts of the tyrosine kinase domain (reviewed in 237). ABL tyrosine kinase domain is contiguous and not separated by any intervening residues and is most similar to ARG at the primary amino acid analysis level (reviewed in 237). Primary sequence alignment of the tyrosine kinase domains of PDGF-R and ABL would not have predicted that the structure of these two tyrosine kinase domains be comparable enough to be selectively inhibited by CGP 53,716 without cross-inhibition to a broader range of tyrosine kinases (Figure 4). This result predicted the need to analyze three-dimensional structures of

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Figure 4 Tyrosine kinase phylogenetic tree containing Imatinib mesylate-sensitive members. Phylogenetic tree includes SRC family members YES, SRC, FYN, FGR, BLK, LCK, LYN, and HCK; ABL family members ABL (ABL1) and ARG (ABL2); PDGFR family members PDGFRα, PDGFRβ, CSF1R, KIT, and FLK2 (FLT3); VEGFR family members VEGFR1 (FLT1), 2 (FLT4), and 3 (KDR/FLK1). Imatinib mesylate exhibits high selectivity toward inhibiting the tyrosine kinase activity of ABL, ARG, KIT, and PDGFR (r). Primary sequence alignment by ClusterW multiple sequence alignment (http://clustalw.genome.ad.jp/) demonstrates that CSF1R and VEGFR family tyrosine kinases are more closely related to KIT and PDGFR than ABL and ARG. However, CSF1R and VEGFR family members are not inhibited by Imatinib mesylate at doses that effectively block ABL, ARG, KIT, and PDGFR kinase activity.

kinases to obtain more reliable predictions towards the specificity of engineered inhibitors. CGP 53,716 was much more potent at inhibiting v-ABL tyrosine kinase activity than a previously engineered class of benzopyranone derivatives from Geissler and colleagues in the same company (238). CGP 53,716 was further optimized for vABL tyrosine kinase inhibition and Imatinib mesylate (Gleevec, STI571, CGP 57148B) was generated (reviewed in 234, 235). Imatinib mesylate demonstrated high selectivity at inhibiting a small group of tyrosine kinases including PDGF-R (239), KIT (240, 241), ABL (242), and ARG (243). Druker and colleagues demonstrated that Imatinib mesylate could selectively inhibit BCR-ABL–induced in vitro cell growth and in vivo tumor formation in mice from cell lines expressing BCR-ABL but not from control cell lines (244) (Figure 1). Imatinib mesylate inhibited Ph+ cell growth but not normal cell growth in a dose-dependent manner (245, 246). This high selectively of Imatinib mesylate at suppressing BCR-ABL–induced cell expansion in vitro and in vivo along with Imatinib mesylate’s pharmacological properties (reviewed in 247) led to the testing of Imatinib mesylate in CML patients refractory to IFN-α therapy.

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IMATINIB MESYLATE TREATMENT IN CML PATIENTS

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Imatinib Mesylate Treatment Leads to Remission in Most Chronic Phase CML Patients Resistant to IFN-α Therapy In 1998, a phase 1 study of Imatinib mesylate treatment on chronic phase CML patients refractory or resistant to interferon-based therapy began. When these patients became nonresponsive to IFNα therapy, no treatment options proven to be effective against CML were available. Druker, Talpaz, Sawyers, and colleagues reported that 53 of 54 of patients had complete hematologic responses by 4 weeks of Imatinib mesylate treatment (248). Of the Imatinib mesylate-treated patients, 96% (51 of 54) maintained normal blood counts and complete hematological responses for over a year (248) (Figure 1). The success of Imatinib mesylate treatment on chronic phase CML patients in phase I studies led to large-scale phase II and phase III studies. Results of Imatinib mesylate-treated chronic phase patients resistant to IFNα therapy were equally remarkable in phase II studies. Kantarjian and colleagues reported that of 532 patients, 95% of those treated with 400 mg of Imatinib mesylate daily, achieved complete hematologic responses, and 89% did not show disease progression (249) (Figure 1). Even more impressive, in a randomized phase III study of 553 patients not previously treated with IFNα, only 1.5% of Imatinib mesylate–treated patients had disease progression (201) (Figure 1).

A High Percentage of Accelerated and Blast Phase CML Patients are Resistant to or Relapse from Imatinib Mesylate Treatment The high rate of remission in Imatinib mesylate-treated chronic phase CML patients treated led the phase I research group to expand their study and determine the effect of Imatinib mesylate therapy on blast crisis CML patients and Ph+ BALL patients. In myeloid blast crisis patients, 55% (21 out of 38 patients) were responsive to Imatinib mesylate treatment, with 11% achieving complete hematological response. However, only 18% of patients had responses lasting over a year. The remaining 20 Imatinib mesylate–treated patients with lymphoid blast crisis CML or Ph+ B-ALL had a similar lower level of disease suppression compared with Imatinib mesylate–treated chronic phase CML patients, with only 20% achieving complete hematological response (250). During the aggressive phase of CML blast crisis, numerous secondary genetic aberrations including duplication of the Ph chromosome are common (11). These findings suggest that failure of Imatinib mesylate treatment in blast phase CML patients could be due to either the presence of added oncogenic events beyond the Ph chromosome or a heightened level of BCR-ABL tyrosine kinase activity ineffectively suppressed by the dose of Imatinib mesylate administered. The high relapse rate in Imatinib mesylate–treated blast crisis CML patients (250) and the frequent occurrence of an additional Ph chromosome in advanced stages of CML disease (11) prompted subsequent phase II accelerated and blast

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crisis CML studies to examine if a higher dose of Imatinib mesylate would be more effective at treating CML patients at the acute phases of the disease. In both accelerated and blast crisis studies, 600 mg of daily Imatinib mesylate led to a higher percentage of patients with complete hematological response compared with 400 mg of Imatinib mesylate daily treatment (251, 252). In the accelerated phase study, Talpaz and colleagues reported that patients treated with 600 mg Imatinib mesylate daily had a statistically significant improvement in 12-month survival compared with 400 mg daily Imatinib mesylate–treated patients (78% versus 65%, respectively, and P = 0.014) (251). These results suggest that duplication of the Ph chromosome may be a mechanism by which accelerated and blast crisis leukemic cells express higher levels of BCR-ABL tyrosine kinase activity, thereby requiring higher doses of Imatinib mesylate for effective suppression of ABL tyrosine kinase. In a subsequent study, Imatinib mesylate treatment at a dose of 800 mg/daily led to severe pancytopenia in over half of CML patients who did not respond to Imatinib mesylate at 400 mg/day, and a dose reduction of Imatinib mesylate to 600 mg/day had to be implemented (253). This toxicity of Imatinib mesylate at a dose of 800 mg/day may limit the therapeutic applicability of Imatinib mesylate in treating CML patients expressing higher amounts of BCR-ABL.

MECHANISMS OF RESISTANCE TO IMATINIB MESYLATE TREATMENT BCR-ABL Tyrosine Kinase–Dependent Mechanisms of Imatinib Mesylate Resistance The majority of Imatinib mesylate–insensitive Ph+ patient cells continue to generate high levels of deregulated BCR-ABL tyrosine kinase activity even in the face of drug treatment (254–257). The presence of BCR-ABL mutants resistant to or with reduced sensitivity to Imatinib mesylate inhibition appears to be the most frequent mechanism by which CML patients relapse from Imatinib mesylate therapy (254, 255, 258) (Figures 1, 5). Some BCR-ABL–resistant mutants are highly resistant to Imatinib mesylate, whereas others have demonstrated a minor twofold or less enhancement of resistance to Imatinib mesylate (259). Genotyping BCR-ABL Imatinib mesylate–resistant clones from a patient and phenotyping the clone’s level of resistance to Imatinib mesylate may identify patients who could be effectively treated for CML with higher doses of Imatinib mesylate and define candidates who will need alternative treatments. BCR-ABL mRNA and protein levels have also been shown to be upregulated in a subpopulation of Imatinib mesylate–resistant leukemic cells, with amplification of the Ph chromosome being a likely mechanism (254, 256, 257). Expression of the multidrug resistance gene (MDR-1) encoding a P-glycoprotein (PGP) that suppressed Imatinib mesylate entry into the Ph+ K562 cell line has been demonstrated to be another mechanism by which BCR-ABL tyrosine kinase activity is maintained upon drug treatment (257, 260).

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Figure 5 BCR-ABL mutations resistant to Imatinib mesylate suppression span across regions in addition to the ABL tyrosine kinase domain. Bold italic font: mutations identified in patients that relapsed from Imatinib mesylate treatment (254, 255, 258, 259). Normal font: mutations discovered in BCR-ABL expressing BaF3 cells resistant to Imatinib mesylate inhibition of cellular transformation (265). ABL numbering based on isoform 1b.

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BCR-ABL Tyrosine Kinase–Independent Mechanisms of Imatinib Mesylate Resistance May Be Rare Events Over 80% of blast phase CML cases have definable additional genetic aberrations including trisomy 8, i(17q) (11, 12), loss of p53 function (13, 14, 261), MYC amplification (12), RB deletion/rearrangement (15), and p16INK4A rearrangement/deletion (16). These findings suggested that the high rate of relapse in blast crisis CML patients treated with Imatinib mesylate could be due to the acquisition of additional oncogenic events that render Ph+ leukemic cell growth independent of BCR-ABL tyrosine kinase activity. Surprisingly, the large majority of accelerated and blast crisis Ph+ leukemic cells from Imatinib mesylate–resistant CML patients maintained high levels of BCR-ABL tyrosine kinase activity, suggesting that the mechanism of Imatinib mesylate resistance in these cells depends on sustained deregulated BCR-ABL enzyme activity (254, 255, 258). These findings provide strong evidence that deregulated BCR-ABL tyrosine kinase activity is required for the maintenance of most cases of CML, irrespective of disease stage and presence of additional genetic aberrations (Figure 1). These results are in agreement with basic research findings using Gag-Abl and BCR-ABL inducible systems, which demonstrated that continual oncoprotein expression/tyrosine kinase activity was required for the establishment and maintenance of ABL-induced cellular transformation and leukemogenesis (48, 158, 184, 185). A Ph+ K562 cell line resistant to Imatinib mesylate suppression of cell growth was shown to express a form of BCR-ABL sensitive to Imatinib mesylate inhibition (262). Addition of Imatinib mesylate suppressed phosphorylation of BCR-ABL and several of its key substrates including STAT5, CRKL, and MAPK (262). The SRC family kinase LYN was highly expressed in this cell line (262). Suppression of LYN expression with antisense LYN oligonucleotides or inhibition of LYN kinase activity with the specific compound CGP 76030 abrogated cell growth of this cell line at concentrations that did not affect a control K562 cell line (262). This is a rare example whereby a Ph+ cell loses its dependence on deregulated BCR-ABL tyrosine kinase activity for oncogenic transformation.

MECHANISM OF ABL TYROSINE KINASE INHIBITION BY IMATINIB MESYLATE Imatinib Mesylate Inhibits ABL Tyrosine Kinase Activity by Displacing ATP and Trapping the Enzyme in an Inactive Conformation To determine how Imatinib mesylate achieves its high specificity at inhibiting BCR-ABL transformation, the crystal structure of the kinase domain of ABL complexed with Imatinib mesylate was resolved by Kuriyan’s and Zimmermann’s

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groups (235, 263, 264). Both groups showed that Imatinib mesylate bound to the inactive conformation of ABL in the region where the adenosine base of ATP would bind thereby obstructing ATP binding (numbering of c-ABL based on isoform 1b) (Figures 1, 6A). It was further demonstrated that Imatinib mesylate effectively inhibited the catalytic activity of ABL in its inactive conformation but not in its active conformation (263). A critical component in determining the inactive versus active conformation of tyrosine kinases is the orientation and phosphorylation status of residues in the activation loop of the kinase. During the transition from an inactive to an active conformation of the ABL tyrosine kinase, the activation loop is sharply reorientated from facing toward the protein to facing outward, accompanied by phosphorylation of tyrosine 412 leading to full kinase activity (see section on Mechanism of ABL Tyrosine Kinase Activation; Figure 3). A comparison of the three-dimensional structures of highly homologous tyrosine kinases (by primary sequence alignment) in their active form, revealed that ABL, Insulin receptor kinase (IRK), and hematopoietic cell specific kinase (HCK) have a similar overall structure and activation loop conformation (263, 264) (Figure 6C). However, although the overall crystal structures of the inactive kinase domains are comparable, the activation loop conformations were vastly different (263, 264) (Figure 6C). Kuriyan, Zimmermann, and colleagues propose that the high selectivity of Imatinib mesylate at inhibiting a small group of protein kinases is achieved by the specificity with which Imatinib mesylate recognizes unique structural motifs present in the inactive conformation of kinases such as the activation loop. By primary sequence analysis, KIT and PDGFR would be predicted to have a more divergent catalytic domain structure than SRC and IRK in relation to the ABL tyrosine kinase domain (Figure 4). Kuriyan and coworkers state that all the residues that contact Imatinib mesylate in the ABL kinase are identical or substituted in a conservative manner in the SRC-family tyrosine kinases (263, 264). However, Imatinib mesylate inhibits KIT, PDGFR, and ABL tyrosine kinase activity with comparable efficiencies and is largely ineffective in suppressing the tyrosine kinase activity of SRC and IRK (reviewed in 247). Zimmermann and colleagues are extrapolating a 3-D structure of KIT complexed with Imatinib mesylate based on 3-D interactions of ABL and Imatinib mesylate (235). They demonstrate that predicted key interactions between KIT and Imatinib mesylate directly parallel those of ABL and the drug (235).

Imatinib Mesylate and ABL Kinase Domain Interactions Can Only Account for a Portion of BCR-ABL Mutants Resistant to Imatinib Mesylate Treatment The initial search for BCR-ABL mutants resistant to Imatinib mesylate focused on the identification of mutants in the ABL kinase domain predicted to obstruct direct Imatinib mesylate binding. The Sawyers’ laboratory initially discovered the ABL

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kinase T334I mutant as the most frequent BCR-ABL mutant in CML blast crisis patients resistant to Imatinib mesylate therapy (254) (Figures 1, 5). The crystal structure of Imatinib mesylate complexed to the ABL kinase domain demonstrated that T334 provided a key hydrogen bond (H-bond) interaction for Imatinib mesylate association with ABL (235, 263, 264) (Figure 6D). The BCR-ABL T334I amino acid substitution would be predicted to prevent formation of the H-bond with Imatinib mesylate as well as generate steric hindrance for drug binding. This Imatinib mesylate BCR-ABL mutation validated 3-D structural findings of key Imatinib mesylate and ABL kinase domain contact points. Numerous additional BCR-ABL mutants resistant to Imatinib mesylate have subsequently been identified in CML patients (255, 258, 259) (Figures 1, 5). Some of these mutants occurred in distal N-terminal and C-terminal regions of the ABL kinase domain, not predicted to directly interact with Imatinib mesylate (Figure 5). Using a random mutagenesis approach, a range of BCR-ABL mutants outside of the ABL kinase domain, in the cap, SH3, and SH2 domains of ABL were identified as resistant to Imatinib mesylate inhibition (265) (Figure 5). These domains play pivotal roles in the transition from an inactive to active conformation of ABL (see section on Mechanism of ABL Tyrosine Kinase Activation). Since Imatinib mesylate binds to the inactive conformation of ABL, mutations in these ABL domains could be predicted to abrogate Imatinib mesylate binding. The BCR portion of BCR-ABL has not been reported to be sequenced in BCRABL clones resistant to Imatinib mesylate treatment. As discussed above, different regions of BCR are critical for BCR-ABL activation. These findings suggest that mutations in BCR that up-regulate BCR-ABL tyrosine kinase activity may also be relatively resistant to Imatinib mesylate. Some Imatinib mesylate–resistant patient samples with an activated BCR-ABL tyrosine kinase domain contain no mutations in the ABL kinase domain (266). Sequencing BCR-ABL in its entirety in these samples may identify novel mutations in unexpected regions of BCR-ABL that render the protein insensitive to Imatinib mesylate treatment.

BCR-ABL EXPRESSION MAY INCREASE THE RATE OF CELLULAR MUTAGENESIS LEADING TO THE EVOLUTION OF BCR-ABL MUTANTS RESISTANT TO IMATINIB MESYLATE TREATMENT BCR-ABL expression has been shown to enhance the frequency of spontaneous mutations by three- to fivefold in the BaF3 cell line (267) and by two- to threefold in the preleukemic p185BCR-ABL transgenic mouse stain (268). This BCR-ABL effect was dependent on its tyrosine kinase activity as administration of Imatinib mesylate to preleukemic p185BCR-ABL transgenic mice reduced the mutation rate in these mice (269). Some Imatinib mesylate–resistant BCR-ABL mutants occur

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prior to Imatinib mesylate therapy in CML patients (270). These results suggest that Imatinib mesylate suppression of BCR-ABL tyrosine kinase activity during the early stages of chronic phase CML may prevent/reduce the generation of BCRABL Imatinib mesylate–resistant mutants in treated patients. BCR-ABL expression has been shown to down-regulate proteins involved in DNA repair. Mutation in the xeroderma pigmentosum group B protein results in a human DNA repair disorder, and BCR-ABL expression inactivates this enzyme by binding to and phosphorylating the enzyme (271). BRCA1 deficiency in mice leads to heightened sensitivity to DNA double-strand breaks (272), and this protein is down-regulated upon BCR-ABL induction in multiple cell types (273). The DNA-dependent protein kinase (DNA-PK) complex, a major DNA repair system in mammalian cells involved in DNA double-strand breaks repair, was demonstrated to be down-regulated via proteasome-induced degradation in a dosedependent manner concommitant with increasing levels of BCR-ABL expression (274) (Table 2). Determining which DNA repair mechanism is largely responsible for the mutator phenotype present in BCR-ABL expressing cells may identify therapeutic approaches that could suppress the generation of Imatinib mesylate– resistant BCR-ABL mutants in CML patients.

PH+ CELL POPULATIONS THAT MAY NOT BE ELIMINATED BY IMATINIB MESYLATE THERAPY Ph+ HSCs May Not Be Eliminated by Imatinib Mesylate Treatment The origin of CML begins in a HSC [see section on Identification of the Chromosomal Abnormality and Cellular Origin of the Human Disease Chronic Myelogenous Leukemia (CML); 17, 18; reviewed in 19, 20], a target population that is largely quiescent (275), which either does not express BCR-ABL (276) or is unaffected by BCR-ABL expression (277). Quiescent Ph+ HSCs are insensitive to Imatinib mesylate treatment in vitro (278). These findings suggest that the Ph+ HSC may not be eliminated by Imatinib mesylate treatment in CML patients owing to its unresponsiveness to both the Ph chromosome and Imatinib mesylate. Life-long Imatinib mesylate therapy may be required to continually suppress leukemia development in CML patients. Expansion of Ph+ progenitors is inhibited by Imatinib meyslate (244). However, this cell population persists in Imatinib mesylate–treated CML patients (279). Although Imatinib mesylate therapy is able to suppress the oncogenic activity of wild-type BCR-ABL expression, the treatment is unable to destroy all Ph+ cell populations. As in Ph+ HSCs, the inability of Imatinib mesylate to eliminate Ph+ progenitors suggests that CML patients will require long-term Imatinib mesylate monotherapy, which may lead to the generation and selection of BCR-ABL escape mutants that are resistant to the inhibitor.

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REGIONS IN CML PATIENTS THAT DO NOT RECEIVE HIGH LEVELS OF IMATINIB MESYLATE COULD LEAD TO LEUKEMIA RELAPSE

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The Central Nervous System (CNS) May Not Receive Imatinib Mesylate at Concentrations High Enough to Suppress BCR-ABL–Induced Leukemogenesis Imatinib mesylate treatment was unable to prevent CNS leukemia in a BCR-ABL– induced CML-like mouse model (280) because Imatinib mesylate was unable to reach the CNS at concentrations high enough to effectively suppress BCRABL tyrosine kinase activity. A lymphoid CML blast crisis patient with excellent systemic response to Imatinib mesylate was shown to relapse due to a lymphoid leukemia in the CNS (281). The cerebrospinal fluid (CSF) had a 2-log lower level of Imatinib mesylate compared to the blood plasma. These results suggest that CML patients in remission with Imatinib mesylate could eventually relapse with CNS leukemia due to the inefficiency of Imatinib mesylate at crossing the blood-brain barrier. Imaging the location of CML cells in a patient along with the distribution of the drug Imatinib mesylate may help define locations in the body where drug delivery needs to be improved to effectively treat this disease. We have recently demonstrated the ability to noninvasively image the development of a BCR-ABL–induced B-ALL in a mouse model using positron emission tomography (PET) (282). PET imaging has been successfully used to image the progression of neurological diseases (283), and small molecule compounds have been created for imaging (284). Combining these technologies, it should be possible to identify key regions in the body that do not allow Imatinib mesylate to penetrate and to test CML treatments that may overcome this current limitation.

THERAPEUTIC OPTIONS FOR IMATINIB MESYLATE RESISTANT BCR-ABL LEUKEMIAS Alternative Small Molecule Inhibitors The small molecule inhibitors PD 166326, PD 173995, and PD 180970 belonging to the class of pyrido [2,3-d] pyrimidine compounds were shown to selectively suppress the tyrosine kinase activity of a small group of proteins including BCR-ABL (285–287). These compounds required about tenfold less drug compared with Imatinib mesylate to inhibit BCR-ABL tyrosine kinase activity at similar levels. Such inhibitors may be useful at treating Ph+ patients resistant to the highest doses of Imatinib mesylate because of high levels of BCR-ABL expression.

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Structural analysis of this class of compounds complexed to the ABL tyrosine kinase domain revealed that these inhibitors bound to ABL with the activation loop being extended outwards, suggesting an active conformation of the protein (Figures 1, 6B). Addition of the inhibitor PD 173995 to both phosphorylated and unphosphorylated forms of ABL demonstrated that the drug suppressed ABL tyrosine kinase activity in both active and inactive conformations (101, 264, 285). The differing structural requirements of this group of inhibitors compared to Imatinib mesylate at suppressing BCR-ABL tyrosine kinase activity suggested that this class of compounds may be able to inhibit Imatinib mesylate–resistant forms of BCR-ABL. PD 166326 and PD 180970 effectively inhibit cellular transformation induced by Imatinib mesylate–resistant BCR-ABL forms Y272F and E274K (287, 288). These inhibitors could be an effective treatment in patients harboring such BCR-ABL mutants. However, the Imatinib mesylate T334I–resistant BCRABL clone was resistant to both pyrido [2,3-d] pyrimidine inhibitors (287, 288). Interestingly, a corresponding ABL T334I mutation made in EGFR by converting threonine 766 to methionine led to severely decreased sensitivity of the EGFR mutant to a different class of 4-anilinoquinazoline inhibitor, highly effective at suppressing wild-type EGFR tyrosine kinase activity (289). 4-anilino-3-quinolinecarbonitrile SKI-606 compound with dual SRC and ABL specificity was shown to completely regress xenografts of Ph+ K562 cells in mice and block BCR-ABL tyrosine phosphorylation (290). Whether this small molecule compound belonging to a class of inhibitors different from either Imatinib mesylate or PD 166326–180970 is able to suppress the tyrosine kinase activity of the multidrug-resistant BCR-ABL T334I mutant awaits determination.

Inhibiting BCR-ABL mRNA Production Inhibition of BCR-ABL production at the mRNA level via antisense oligonucleotide, small-interfering RNA, peptide nucleic acid, or ribozyme expression of BCR-ABL junction sequences effectively suppresses BCR-ABL in vitro transformation (291–295). However, these strategies aimed at preventing the generation of BCR-ABL transcripts are limited by the lack of proven technologies to introduce sufficient amounts of such agents into a patient and thereby suppress leukemia.

Suppressing BCR-ABL Protein Levels Arsenic trioxide decreases BCR-ABL protein levels via inhibition of BCR-ABL translation (296) and 17-allylaminogeldanamycin degrades both wild-type and Imatinib mesylate–resistant BCR-ABL protein forms via inactivation of the Heat Shock protein 90 (HSP 90), which is required for proper folding of the BCRABL molecule (297–300). Whether these compounds have sufficient selectively at blocking BCR-ABL protein production without severely affecting normal protein translation awaits further study.

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Inhibiting BCR-ABL Tyrosine Kinase Activity Expression of a truncated BCR protein encoding amino acids 64–413 inhibits CML cell growth by inhibiting BCR-ABL tyrosine kinase activity (138, 301). Expression of a chimeric fusion protein encoding a BCR-ABL binding domain fused to an active phosphatase region was also demonstrated to suppress BCRABL tyrosine kinase activity as well as its in vitro and in vivo transformation properties (302). These systems further validated the concept that inhibition of BCR-ABL tyrosine kinase activity was a valuable approach to suppress BCRABL–induced oncogenesis. However, unlike small molecule inhibitors, there is no current delivery system of sufficient efficiency to administer these BCR-ABL inhibitory proteins uniformly into a patient’s leukemic cells.

Treatments that Obstruct Signaling Components Potentially Critical for BCR-ABL Oncogenesis Inhibition of the RAS pathway via expression of a GRB2-SOS peptide blocker or treatment with the farnesyl transferase inhibitor SCH 66336 effectively suppresses BCR-ABL–induced in vitro cellular growth and in vivo leukemogenesis (145, 177, 303). The farnesyl transferase inhibitor R115777 was used to treat 22 patients representing chronic, accelerated, and blast phases of CML (304). Seven patients responded favorably, with a reduction in their WBC count (304). However, the hematological response was transient, with a median duration of nine weeks (304). These apparently opposing results could be resolved if the farnesyl transferase inhibitor R115777 is inferior to SCH 66336 at inhibiting RAS activation in an in vivo setting. However, if it is shown that both farnesyl transferase inhibitors are equally potent at inactivating RAS and that SCH 66336 leads to the same poor therapeutic response in CML patients as R115777, the results will reaffirm gene knockout studies demonstrating the difficulty in identifying a single molecule essential for BCR-ABL–induced leukemogenesis (see section on Murine Models of ABL Oncogenesis). If an approach of inhibiting signaling pathways critical to BCRABL oncogenesis is taken, effective therapy against Imatinib mesylate–resistant Ph+ patients is likely to require inactivation of multiple and not individual signaling modules regulated by BCR-ABL expression.

CONCLUSION The BCR-ABL story demonstrated that identifying and selectively targeting the primary oncogenic event shown to be essential for the development of Ph+ leukemias was sufficient to suppress the cancer. The effectiveness of Imatinib mesylate at inhibiting the tyrosine kinase activity of BCR-ABL and its direct correlation to disease remission has broadened the testing of this inhibitor to treating cancers where the known dominant oncogenic activity has been demonstrated to be efficiently blocked by the drug. In a phase 1 study of gastrointestinal stromal

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tumors (GISTs), where the dominant oncogenic activity is mostly due to either KIT or PDGFR activation (305), treatment with Imatinib mesylate, which suppresses the tyrosine kinase activity of both these oncoproteins led to major responses in over 80% of patients (306). Imatinib mesylate is also being tested for the treatment of systemic mastocytosis, AML, and germ-cell tumors where KIT activation has been detected (307, 308) and in chronic myeloproliferative diseases such as hypereosinophilic syndrome and CML, where rearrangements of the PDGFRα or PDGFRβ occur (309–311). Other small-molecule inhibitors and antibodies are being developed and tested for the inhibition of selective oncogenic activities and their associated diseases. Activated FMS-like tyrosine kinase 3 (FLT3) is the most common molecular defect associated with AML (312) and several FLT3 inhibitors are in clinical testing (reviewed in 313). Acute promyelocytic leukemia patients associated with the PML-RARα fusion can now be effectively treated with all-trans-retinoic acid, which selectively blocks the activity of the chimeric oncoprotein leading to a 5-year disease-free survival of 75%–80% (reviewed in 314). A significant portion of Ph+ patients treated with Imatinib mesylateat the acute phases of the disease are resistant to the therapy. Most patients relapse from treatment due to expression of BCR-ABL mutant proteins with reduced or complete insensitivity to Imatinib mesylate suppression of ABL tyrosine kinase activity. This is also turning out to be the case in the treatment of systemic mastocytosis, AML, and germ-cell tumors where expression of a KIT D816V mutant resistant to Imatinib mesylate has been detected (307, 308). These findings suggest that a multidrug treatment approach similar to HIV combination therapy (reviewed in 315) will be necessary to prevent the development of escape oncoprotein mutants resistant to the inhibitors. The BCR-ABL T334I mutant is resistant to tyrosine kinase inhibition by different forms of ATP competitive compounds (see section on Therapeutic Options for Imatinib Mesylate-Resistant BCR-ABL Leukemias). This mutant may not be suppressible by any type of ATP competitive inhibitor. Multidrug therapy aimed at inhibiting BCR-ABL tyrosine kinase activity via different mechanisms such as blockade of oligomerization, inactivation of the BCR A and B boxes, or suppression of an active conformation of ABL could be required to effectively treat Ph+ leukemias. Suppression of BCR-ABL protein production via 17-AAG inhibition of HSP 90 has been shown to block cellular transformation by the multidrugresistant BCR-ABL T334I mutant and could be another therapeutic approach (300). Therapeutic approaches aimed at suppressing the leukemic activity of a Ph+ cell by Imatinib mesylate-like mechanisms are unlikely to destroy all cancerous cells in a patient and would most probably require life-long treatment. Eliminating the cellular origin of leukemia is the only curative approach for patients; in CML, this would require destroying the Ph+ HSC that is largely quiescent. AML quiescent HSCs have been shown to constitutively activate the NF-κB pathway and treatment of these leukemic cells with the proteosome inhibitor carbobenzoxyl-L-leucylL-L-leucinal, which prevents IκB degradation and NF-κB activation, severely

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reduces or completely abrogates the engraftment of these leukemia HSCs into NOD/SCIDs without affecting control HSCs (316). BCR-ABL expression has also been shown to activate the NF-κB pathway in hematopoietic cell lines (317, 318). Determining whether Ph+ quiescent HSCs also show constitutive NF-κB activation or contain other deregulated pathways may identify molecular targets whose inhibition could eliminate the leukemic stem cell. BCR-ABL expression has been shown to regulate a plethora of signaling molecules, and it is unclear whether inhibition of any single signal transduction pathway would be sufficient to block leukemogenesis. Suppression of multiple signaling molecules and pathways regulated upon BCR-ABL induction with a combination of low-toxicity selective drugs could be a therapeutic approach for Imatinib mesylate resistant patients. Alternatively, gene profiling of patient specimens against known oncoproteins where basic science findings suggest, may identify unexpected therapeutic targets. LYN upregulation, for example, was shown to replace the requirement of BCR-ABL activation in expanding a Ph+ cell line. This Imatinib mesylate–resistant cell line was sensitive to LYN inactivation and suppression of cellular transformation (262; see section on Mechanism of Resistance to Imatinib Treatment). The well-understood pathogenesis of Ph+ leukemias is turning out to be fertile ground for the testing of novel therapies. Defining the effectiveness of these treatment approaches against Imatinib mesylate–resistant patients may help guide the next wave of cancer therapeutics.

ACKNOWLEDGMENTS We are grateful to Drs. Benjamin Neel and Rick Van Etten (Harvard University, Cambridge) for providing unpublished results; Gregory Ferl (UCLA) for the generation of the tyrosine kinase phylogenetic tree containing Imatinib mesylate– sensitive members (Figure 4); Drs. John Colicelli and Emmanuel Beillard for helpful discussions and critical reading of the manuscript; and to Barbara Anderson for excellent preparation of the manuscript, tables, and figures. Work from this laboratory is supported by grants from the National Institutes of Health and the U.S. Department of Energy. ONW is an Investigator of the Howard Hughes Medical Institute. The Annual Review of Immunology is online at http://immunol.annualreviews.org

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major tyrosine-phosphorylated protein in neutrophils from patients with chronic myelogenous leukemia. J. Biol. Chem. 269:22925–28 ten Hoeve J, Arlinghaus RB, Guo JQ, Heisterkamp N, Groffen J. 1994. Tyrosine phosphorylation of CRKL in Philadelphia+ leukemia. Blood 84:1731– 36 Deininger MW, Vieira SA, Parada Y, Banerji L, Lam EW, et al. 2001. Direct relation between BCR-ABL tyrosine kinase activity and cyclin D2 expression in lymphoblasts. Cancer Res. 61:8005–13 Wilson-Rawls J, Xie S, Liu J, Laneuville P, Arlinghaus RB. 1996. P210 Bcr-Abl interacts with the interleukin 3 receptor beta(c) subunit and constitutively induces its tyrosine phosphorylation. Cancer Res. 56:3426–30 Salgia R, Uemura N, Okuda K, Li JL, Pisick E, et al. 1995. CRKL links p210BCR/ABL with paxillin in chronic myelogenous leukemia cells. J. Biol. Chem. 270:29145–50 Salgia R, Li J-L, Lo SH, Brunkhorst B, Kansas GS, et al. 1995. Molecular cloning of human paxillin, a focal adhesion protein phosphorylated by P210+BCR/ABL. J. Biol. Chem. 270:5039–47 Coutinho S, Jahn T, Lewitzky M, Feller S, Hutzler P, et al. 2000. Characterization of Grb4, an adapter protein interacting with Bcr-Abl. Blood 96:618–24 Weng Z, Fluckiger AC, Nisitani S, Wahl MI, Le LQ, et al. 1998. A DNA damage and stress inducible G protein-coupled receptor blocks cells in G2/M. Proc. Natl. Acad. Arts Sci. 95:12334–39 Stewart MJ, Litz-Jackson S, Burgess GS, Williamson EA, Leibowitz DS, Boswell HS. 1995. Role for E2F1 in p210 BCR-ABL downstream regulation of cmyc transcription initiation. Studies in murine myeloid cells. Leukemia 9:1499– 507 Bruecher-Encke B, Griffin JD, Neel BG, Lorenz U. 2001. Role of the tyrosine phos-

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phatase SHP-1 in K562 cell differentiation. Leukemia 15:1424–32 Andoniou CE, Thien CBF, Langdon WY. 1996. The two major sites of cbl tyrosine phosphorylation in abl-transformed cells select the crkL SH2 domain. Oncogene 12:1981–89 de Jong R, ten Hoeve J, Heisterkamp N, Groffen J. 1995. Crkl is complexed with tyrosine-phosphorylated Cbl in Ph-positive leukemia. J. Biol. Chem. 270:21468–71 Danhauser-Reidl S, Warmuth M, Druker BJ, Emmerich B, Hallek M. 1996. Activation of Src kinases p53/56lyn and p59hck by p210bcr/abl in myeloid cells. Cancer Res. 56:3589–96 Afar DEH, Han L, McLaughlin J, Wong S, Dhaka A, et al. 1997. Regulation of the oncogenic activity of BCR-ABL by a tightly bound substrate protein RIN1. Immunity 6:773–82 LaMontagne KR Jr, Flint AJ Jr, Franza BR, Pendergast AM, Tonks1 NK. 1998. Protein tyrosine phosphatase 1B antagonizes signalling by oncoprotein tyrosine kinase p210 bcr-abl in vivo. Mol. Cell. Biol. 18:2965–75 Klejman A, Schreiner SJ, NieborowskaSkorska M, Slupianek A, Wilson M, et al. 2002. The Src family kinase Hck couples BCR/ABL to STAT5 activation in myeloid leukemia cells. EMBO J. 21:5766–74 Skorski T, Wlodarski P, Daheron L, Salomoni P, Nieborowska-Skorska M, et al. 1998. BCR/ABL-mediated leukemogenesis requires the activity of the small GTPbinding protein Rac. Proc. Natl. Acad. Arts Sci. 95:11858–62 Mayerhofer M, Valent P, Sperr WR, Griffin JD, Sillaber C. 2002. BCR/ABL induces expression of vascular endothelial growth factor and its transcriptional activator, hypoxia inducible factor-1alpha, through a pathway involving phosphoinositide 3-kinase and the mammalian target of rapamycin. Blood 100:3767–75

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345. Slupianek A, Schmutte C, Tombline G, Nieborowska-Skorska M, Hoser G, et al. 2001. BCR/ABL regulates mammalian recA homologs, resulting in drug resistance. Mol. Cell 8:795–806 346. Ernst TJ, Slattery KE, Griffin JD. 1994. p210Bcr/Abl p160v-Abl induce an increase in the tyrosine phosphorylation of p93c-Fes. J. Biol. Chem. 269:5764– 69 347. Maru Y, Peters KL, Afar DE, Shibuya M, Witte ON, Smithgall TE. 1995. Tyrosine phosphorylation of BCR by FPS/FES protein-tyrosine kinases induces association of BCR with GRB-2/SOS. Mol. Cell. Biol. 15:835–42 348. Vieira SA, Deininger MW, Sorour A, Sinclair P, Foroni L, et al. 2001. Transcription factor BACH2 is transcriptionally regulated by the BCR/ABL oncogene. Genes Chromosomes Cancer 32:353–63 349. Shi CS, Tuscano JM, Witte ON, Kehrl JH. 1999. GCKR links the Bcr-Abl oncogene and Ras to the stress-activated protein kinase pathway. Blood 93:1338–45 350. Schuster C, Forster K, Dierks H, Elsasser A, Behre G, et al. 2003. The effects of BcrAbl on C/EBP transcription-factor regulation and neutrophilic differentiation are reversed by the Abl kinase inhibitor imatinib mesylate. Blood 101:655–63 351. Heriche JK, Chambaz EM. 1998. Protein kinase CK2alpha is a target for the Abl and Bcr-Abl tyrosine kinases. Oncogene 17:13–18 352. Amarante-Mendes GP, McGahon AJ, Nishioka WK, Afar DE, Witte ON, Green DR. 1998. Bcl-2-independent Bcr-Ablmediated resistance to apoptosis: protection is correlated with up regulation of Bcl-xL. Oncogene 16:1383–90

353. Jamieson L, Carpenter L, Biden TJ, Fields AP. 1999. Protein kinase Ciota activity is necessary for Bcr-Abl-mediated resistance to drug-induced apoptosis. J. Biol. Chem. 274:3927–30 354. Sanchez-Garcia I, Grutz G. 1995. Tumorigenic activity of the BCR-ABL oncogenes is mediated by BCL2. Proc. Natl. Acad. Arts Sci. 92:5287–91 355. Cambier N, Chopra R, Strasser A, Metcalf D, Elefanty AG. 1998. BCR-ABL activates pathways mediating cytokine independence protection against apoptosis in murine hematopoietic cells in a dosedependent manner. Oncogene 16:335–48 356. Xie SH, Wang Y, Liu JX, Sun T, Wilson MB, et al. 2001. Involvement of Jak2 tyrosine phosphorylation in Bcr-Abl transformation. Oncogene 20:6188–95 357. Salomoni P, Condorelli F, Sweeney SM, Calabretta B. 2000. Versatility of BCR/ABL-expressing leukemic cells in circumventing proapoptotic BAD effects. Blood 96:676–84 358. Matsuguchi T, Inhorn RC, Carlesso N, Xu G, Druker B, Griffin JD. 1995. Tyrosine phosphorylation of p95Vav in myeloid cells is regulated by GM-CSF, IL-3 and steel factor and is constitutively increased by p210BCR/ABL. EMBO J. 14:257–65 359. Ghaffari S, Jagani Z, Kitidis C, Lodish HF, Khosravi-Far R. 2003. Cytokines and BCR-ABL mediate suppression of TRAIL-induced apoptosis through inhibition of forkhead FOXO3a transcription factor. Proc. Natl. Acad. Sci. USA 100:6523–28 360. Trotta R, Vignudelli T, Candini O, Intine RV, Pecorari L, et al. 2003. BCR/ABL activates mdm2 mRNA translation via the La antigen. Cancer Cell 3:145–60

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Figure 6 Structures of active and inactive tyrosine kinases complexed to inhibitors Imatinib mesylate and PD 166326 (reprinted from (101, 264)). (A) Structure of the murine Abl kinase domain complexed to a myristoylated peptide and Imatinib mesylate solved at a resolution of 1.75 Å. Imatinib mesylate binds to Abl with the activation loop pointed toward the protein indicative of an inactive Abl tyrosine kinase conformation (101). Abl numbering based on isoform 1b. (B) Structure of the murine Abl kinase domain bound to myristic acid and the inhibitor PD 166326 solved at a resolution of 1.8 Å. Unlike Imatinib mesylate, PD 166326 binds to the Abl kinase domain with the activation loop orientated outward of the protein indicative of an active tyrosine kinase conformation (101). Abl numbering based on isoform 1b. (C) Conformational changes in the activation loop upon activation of protein kinases. Left: three tyrosine kinases ABL, Insulin receptor kinase (IRK), and hematopoietic cell specific kinase (HCK) in inactive states showing distinct conformations of the activation loop (black). Right: the crystal structure of LCK, which illustrates the conformation of the activation loop that all kinases bear upon activation by phosphorylation (264). (D) Schematic diagram of interactions between Imatinib mesylate and the ABL kinase domain. Inhibitor carbon atoms are colored green and magenta and ABL carbon atoms are colored brown. Interacting nitrogen atoms are colored blue, oxygen atoms red, chlorine atoms green, and sulfur atoms yellow. Hydrogen bonds between inhibitor and amino acids are indicated by dotted lines along with their distances, and residues making Van Der Waal interactions are surrounded by green dots. A total of 6 H-bonds and 15 Van Der Waal interactions occur between Imatinib mesylate and the ABL tyrosine kinase domain (264). ABL numbering based on isoform 1b.

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CONTENTS FRONTISPIECE—Leonard A. Herzenberg and Leonore A. Herzenberg GENETICS, FACS, IMMUNOLOGY, AND REDOX: A TALE OF TWO LIVES INTERTWINED, Leonard A. Herzenberg and Leonore A. Herzenberg SELF- AND NONSELF-RECOGNITION BY C-TYPE LECTINS ON DENDRITIC CELLS, Teunis B.H. Geijtenbeek, Sandra J. van Vliet, Anneke Engering, Bert A. ’t Hart, and Yvette van Kooyk

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TRANSCRIPTIONAL CONTROL OF EARLY B CELL DEVELOPMENT, Meinrad Busslinger

UBIQUITIN LIGASES AND THE IMMUNE RESPONSE, Yun-Cai Liu LIGANDS FOR L-SELECTIN: HOMING, INFLAMMATION, AND BEYOND, Steven D. Rosen

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INTEGRINS AND T CELL–MEDIATED IMMUNITY, Jonathan T. Pribila, Angie C. Quale, Kristen L. Mueller, and Yoji Shimizu

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MULTIPLE ROLES OF ANTIMICROBIAL DEFENSINS, CATHELICIDINS, AND EOSINOPHIL-DERIVED NEUROTOXIN IN HOST DEFENSE, De Yang, Arya Biragyn, David M. Hoover, Jacek Lubkowski, and Joost J. Oppenheim

STARTING AT THE BEGINNING: NEW PERSPECTIVES ON THE BIOLOGY OF MUCOSAL T CELLS, Hilde Cheroutre THE BCR-ABL STORY: BENCH TO BEDSIDE AND BACK, Stephane Wong and Owen N. Witte

181 217 247

CD40/CD154 INTERACTIONS AT THE INTERFACE OF TOLERANCE AND IMMUNITY, Sergio A. Quezada, Lamis Z. Jarvinen, Evan F. Lind, and Randolph J. Noelle

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THE THREE ES OF CANCER IMMUNOEDITING, Gavin P. Dunn, Lloyd J. Old, and Robert D. Schreiber

AUTOIMMUNE AND INFLAMMATORY MECHANISMS IN ATHEROSCLEROSIS, Georg Wick, Michael Knoflach, and Qingbo Xu THE DYNAMIC LIFE OF NATURAL KILLER CELLS, Wayne M. Yokoyama, Sungjin Kim, and Anthony R. French

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THE ROLE OF COMPLEMENT IN THE DEVELOPMENT OF SYSTEMIC LUPUS ERYTHEMATOSUS, Anthony P. Manderson, Marina Botto, and Mark J. Walport

DROSOPHILA: THE GENETICS OF INNATE IMMUNE RECOGNITION AND RESPONSE, Catherine A. Brennan and Kathryn V. Anderson RAGS AND REGULATION OF AUTOANTIBODIES, Mila Jankovic,

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Rafael Casellas, Nikos Yannoutsos, Hedda Wardemann, and Michel C. Nussenzweig

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THE ROLE OF SUPPRESSORS OF CYTOKINE SIGNALING (SOCS) PROTEINS IN REGULATION OF THE IMMUNE RESPONSE, Warren S. Alexander and Douglas J. Hilton

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REGULATORY T CELLS FOR IMMUNOLOGIC SELF-TOLERANCE AND NEGATIVE CONTROL OF IMMUNE RESPONSES, Shimon Sakaguchi PHOSPHOINOSITIDE 3-KINASE: DIVERSE ROLES IN IMMUNE CELL ACTIVATION, Jonathan A. Deane and David A. Fruman IMMUNITY TO TUBERCULOSIS, Robert J. North and Yu-Jin Jung MOLECULAR DEFECTS IN HUMAN SEVERE COMBINED IMMUNODEFICIENCY AND APPROACHES TO IMMUNE RECONSTITUTION, Rebecca H. Buckley PHYSIOLOGICAL CONTROL OF IMMUNE RESPONSE AND INFLAMMATORY TISSUE DAMAGE BY HYPOXIA-INDUCIBLE FACTORS AND ADENOSINE A2A RECEPTORS, Michail V. Sitkovsky, Dmitriy Lukashev, Sergey Apasov, Hidefumi Kojima, Masahiro Koshiba, Charles Caldwell, Akio Ohta, and Manfred Thiel

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T LYMPHOCYTE–ENDOTHELIAL CELL INTERACTIONS, Jaehyuk Choi, David R. Enis, Kian Peng Koh, Stephen L. Shiao, and Jordan S. Pober

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IMMUNOLOGICAL MEMORY TO VIRAL INFECTIONS, Raymond M. Welsh, Liisa K. Selin, and Eva Szomolanyi-Tsuda

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CENTRAL MEMORY AND EFFECTOR MEMORY T CELL SUBSETS: FUNCTION, GENERATION, AND MAINTENANCE, Federica Sallusto, Jens Geginat, and Antonio Lanzavecchia CONTROL OF T CELL VIABILITY, Philippa Marrack and John Kappler

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ASTHMA: MECHANISMS OF DISEASE PERSISTENCE AND PROGRESSION, Lauren Cohn, Jack A. Elias, and Geoffrey L. Chupp

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CD1: ANTIGEN PRESENTATION AND T CELL FUNCTION, Manfred Brigl and Michael B. Brenner

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CHEMOKINES IN INNATE AND ADAPTIVE HOST DEFENSE: BASIC CHEMOKINESE GRAMMAR FOR IMMUNE CELLS, Antal Rot and Ulrich H. von Andrian

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INTERLEUKIN-10 AND RELATED CYTOKINES AND RECEPTORS, Sidney Pestka, Christopher D. Krause, Devanand Sarkar, Mark R. Walter, Yufang Shi, and Paul B. Fisher

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INDEXES

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Subject Index Cumulative Index of Contributing Authors, Volumes 12–22 Cumulative Index of Chapter Titles, Volumes 12–22

ERRATA An online log of corrections to Annual Review of Immunology chapters may be found at http://immunol.annualreviews.org/errata.shtml

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Annu. Rev. Immunol. 2004. 22:307–28 doi: 10.1146/annurev.immunol.22.012703.104533 c 2004 by Annual Reviews. All rights reserved Copyright ° First published online as a Review in Advance on October 15, 2003

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CD40/CD154 INTERACTIONS AT THE INTERFACE OF TOLERANCE AND IMMUNITY Sergio A. Quezada,∗ Lamis Z. Jarvinen,∗ Evan F. Lind, and Randolph J. Noelle Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, New Hampshire 03756; email: [email protected]

Key Words immature dendritic cell, transplantation tolerance, suppressor, donor transfusion, cell-mediated immunity ■ Abstract Development of the acquired immune response is dependent on the signaling of CD40 by its ligand, CD154. These molecules govern both the magnitude and quality of humoral- and cell-mediated immunity. A litany of studies have conclusively documented that blockade of this ligand-receptor pair can prevent, and also intervene in, the progression of antibody- and cell-mediated autoimmune diseases, and can instill long-lived allogeneic and xenogeneic graft tolerance. Many effector mechanisms of inflammation are abolished as a result of CD154 blockade, but we are now beginning to understand that CD154 blockade may, in some instances, engender long-lived, antigenspecific tolerance. In the context of transplantation tolerance, we present a hypothesis that αCD154 blockade is most effective at inducing long-lived allospecific tolerance if anergy and regulation can be elicited prior to the onslaught of inflammation that is induced by grafting (preemptive tolerance). This facet of αCD154-induced tolerance appears to co-opt the normal processes of peripheral tolerance induced by immature DCs and can be exploited to induce long-lived antigen-specific tolerance. The underlying science and the prospects for inducing long-lived antigen-specific tolerance in a model of allograft tolerance through CD154 blockade are presented and discussed.

INTRODUCTION The pivotal role played by CD40 in governing humoral and cell-mediated immunity is manifested by the capacity of this ligand-receptor pair to activate B cells and dendritic cells (DCs), respectively. With regard to the former, engagement of CD40 in the presence of cytokines can induce profound clonal expansion and differentiation to Ig secretion, and at the same time enhance the antigen-presenting cell (APC) capacity of the B cell. With regard to the latter, CD40 activation of DCs can, together with signals via toll-like receptors (TLRs), manifest the licensing ∗

These authors contributed equally to this paper.

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of DCs to engender heightened proficiency in antigen presentation, cytokine and chemokine production, and extended survival. The maturational impact on both the B cell and the DC induces the upregulation of a plethora of costimulatory molecules that can reciprocally trigger the cognate T cells to clonally expand and differentiate. Thus, indirectly, engagement of CD40 on B cells and DCs exerts a profound impact on the development of T cell immunity. Likewise, interruption of CD40/CD154 interactions can result in inadequate antigen presentation, a deficiency in the inflammatory environment, partial T cell responses, and in some cases, T cell tolerance. Understanding why CD154 blockade results in T cell tolerance is the focus of this review.

CD40 AND ITS LIGAND CD40 is a 48 kDa transmembrane glycoprotein cell surface receptor that shares sequence homology with the tumor necrosis factor α (TNF-α) receptor family and was initially identified as a B-cell surface molecule that induced B-cell growth upon ligation with monoclonal antibodies. DCs, macrophages, epithelial cells, hematopoietic progenitors (1), and activated T cells (2) have been shown to express CD40. The putative expression and function of CD40 on T cells and its possible function in regulating T cell tolerance and immunity is particularly pertinent and will be discussed below. Its ligand, CD154, is a 34–39 kDa type II integral membrane protein expressed on activated but not resting T cells (3), activated B cells (4), and activated platelets (5, 6). During inflammatory responses, other cell types such as peripheral blood monocytes (7, 8), human vascular endothelial cells, smooth muscle cells, and mononuclear phagocytes (9) have all been shown to express CD154. Engagement of CD40 leads to B cell clonal expansion, germinal center formation, isotype switching, affinity maturation, and generation of longlived plasma cells (10). As is discussed later in this review, within the cytoplasmic tail of CD40, multiple functional domains have been identified that contribute independently or jointly to the vast array of biological responses. An understanding of the contribution of each of these functional domains to the role CD40 plays in immunity is emerging, but not without controversy (11, 12). Blocking of the CD154 ligand, and thus CD40/CD154 ligation, is an effective means by which to abrogate autoimmune diseases (as reviewed in Reference 13) and induce transplantation tolerance (as reviewed in References 14, 15). Innumerable autoimmune models of disease in mice have been shown to be blocked by treatment with αCD154, including experimental autoimmune encephalomyelitis, diabetes, collagen-induced arthritis, uveitis, thyroiditis, lupus, and others, as reviewed in Reference 16. Blocking CD154 in autoimmune disease models such as EAE (13, 17, 18) and lupus (19–21) can be used as both a preventative means by which to block disease and a therapeutic means to treat the progression of disease. Aside from controlling autoimmune diseases, the prevention of transplant rejection by blocking CD40/CD154 interactions has also been repeatedly documented for the induction of long-term tolerance to skin (15, 22–25), islets (26), bone marrow

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(27), and a myriad of other transplanted organs (28, 29). All of these findings on the blockade of CD40/CD154 interaction for the prevention of disease and transplant rejection demonstrate yet once again the importance of understanding the mechanisms of this receptor-ligand pair.

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CD40 SIGNALING PATHWAYS THAT CONTROL APC FUNCTION Stimulation through CD40 results in a complex series of events within an APC. Engagement of CD40 by its ligand, CD154, leads to trimeric clustering of CD40 and the recruitment of adaptor proteins known as TNF receptor–associated factors (TRAFs) to the cytoplasmic tail (30). Binding of the TRAFs results in formation of a signaling complex that includes multiple kinases such as NF-κB inducing kinase (NIK), receptor interacting protein (RIP), members of the mitogen-activated protein kinase (MAPK) family and possibly others. Clustering of these kinases then initiates a downstream cascade of signaling events, resulting in activation of the MAPK and NF-κB pathways and finally transcription of target genes, leading to physiological effects such as production of inflammatory mediators, DC survival (31), and prolonged MHC/antigen complex presentation (32). The first level at which the signal through CD40 is modulated in the APC is through differential effects of binding of the TRAF molecules. Our lab (12) and others (33) have demonstrated that selective mutations to known TRAF binding sites on the cytoplasmic tail of CD40 result in differential signaling and phenotypic outcomes. In B cells, ablation of the TRAF 2,3 binding site results in blockade of p38 and JNK phosphorylation, and a decrease in the phosphorylation of IκBα (34). Despite these signaling defects, mice containing this mutation still have normal early immunoglobulin production. Mutation of the TRAF 6 binding site results in normal phosphorylation of IκBα, p38, and JNK, but deficient affinity maturation (12). Similar studies confirm the requirement of TRAF 2,3 binding in activation of signaling pathways but also implicate TRAF 2,3 binding as playing a role in class switching (11). In DCs, on the other hand, TRAF 6 binding to CD40 is required for activation of p38, JNK, and the production of the proinflammatory cytokine IL-12 p40 (33). The different functions of TRAFs in DCs versus B cells clearly show that CD40 signaling and the downstream effects are cell-type specific and that functional signaling diversity may be controlled at the level of TRAF recruitment in the APC. Activation of the NF-κB pathway via CD40 engagement on DCs has been shown to be critical for their maturation. NF-κB responsive genes include many inflammatory mediators as well as antiapoptotic factors central to DC maturation and longevity (35–38). The survival signal for the DC can be delivered either by CD40 or signaling through the TNF family member TRANCE (39). CD40 signaling has been shown to induce higher levels of the antiapoptotic protein Bcl-XL in mice (39) or Bcl-2 in human DCs (40). This effect has been shown to be NF-κB dependent (41). The NF-κB family consists of five known members

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in mammals, NF-κB1 (p50), NF-κB2 (p52), RelA (p65), c-Rel, and RelB. NF-κB1 and NF-κB2 are expressed as inactive precursor proteins (p105 and p100, respectively), which are held in the cytoplasm by their c-terminal ankyrin repeats (42). The broad NF-κB pathway can be further described as two separate pathways, referred to by Pomerantz and Baltimore as the “canonical” and “noncanonical” pathways (43). The canonical pathway refers to active NF-κB dimers consisting of mainly p50/RelA, and the noncanonical consisting of p52/RelB. The canonical pathway, and c-Rel in particular, has been shown to be responsible for immediate inflammatory responses from DCs such as production of IL-12 (44). Until recently, only one stimuli had been shown to induce processing and activation of NF-κB2—Lymphotoxin Beta signaling (45). Recently, however, several groups have shown that this processing occurs in B cells in response to BAFF binding its receptor (46, 47), as well as after CD40 ligation by CD154. The activation and function of the noncanonical, or NF-κB2, pathway has recently been described in human DCs as functioning to regulate several chemokines (48). Data from our lab indicates that the role of NF-κB2 activation via CD40 is critical for the prolonged survival of DCs after maturation with lipopolysaccharide (LPS) (49). We find that DCs from mice with defective NIK, a kinase critical in the activation of the NF-κB2 pathway, mature and migrate to the periarterial lymphoid sheath (PALS) in response to LPS stimulation, but rapidly undergo apoptotic death and cannot be rescued by stimulation through CD40 (see Figure 1, for a summary of these pathways in DCs). Specifically targeting the NF-κB2 pathway at the level of NIK would then allow one to limit antigen presentation during the duration of an inflammatory response, such as autoimmune disease or transplant engraftment, thus allowing the induction of tolerance after the secession of inflammation. The importance of the NF-κB2 signaling cascade in DC maturation is also underscored by the observation that RelB−/− DCs are incapable of eliciting productive immune responses and in fact are immunosuppressive by virtue of inducing regulatory cells (50). Therefore, understanding the complex biochemical signaling pathways that govern CD40-induced DC licensing will allow us to envision strategies to control immunity versus tolerance.

THE ROLE OF CD40 IN LICENSING DCs TO ELICIT IMMUNITY The two-signal hypothesis of T cell activation is an accepted paradigm that describes the early requirements for T cell activation versus anergy. This paradigm states that the proficient induction of an immune response requires TCR and MHC/peptide interaction (signal one) followed by the interaction between costimulatory molecules, namely CD80/86 and CD28 (signal two). If signal one is generated in absence of signal two, then the outcome is not immunity but tolerance. Providing signal one and signal two becomes the responsibility of the APC, which must efficiently engage and trigger multiple T cell surface molecules. To achieve

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this proficiency, we have learned that APCs must “mature.” This maturation of APCs can be induced by a wide spectrum of factors including TNFα, CD154, cytokines, and a spectrum of TLR agonists. Therefore, decision of tolerance versus immunity is centered, at least in part, on the maturational status of the APC compartment. Appropriate maturation of APCs will license them to trigger productive cell-mediated immunity (CMI). If one plane of control of T cell tolerance versus immunity is at the level of APC maturation, a system of checks and balances must exist to regulate APC licensing. Whereas initially we thought that a single signal can adequately license APCs to trigger CMI responses, we are now beginning to realize that multiple signals are required for APC licensing. Although many studies initially showed that CD40 ligation of DCs alone was optimal to induce maturation (51, 52), far greater adjuvant activities will likely be observed when using coactivators like TLR agonists. A variety of single agents like LPS, TNFα, and CD154 have been shown to be DC activators (37, 53). However, recent in vivo studies have underscored the necessity of multiple signals to impinge on the DC compartment and to achieve true in vivo licensing for triggering CMI. Recent studies, as well as our own unpublished data, show that CD40 engagement alone is insufficient to induce IL-12 p70 production by DCs in vitro and in vivo. By evaluating mRNA for p40 and p35, the authors showed that coengagement via TLR (STAg, an extract from Toxoplasma gondi) and CD40 is critical for enhanced p35 mRNA expression and the production of IL-12 p70 (54). This study was followed by an investigation using human DCs, where it was shown that CpG DNA was a critical costimulus with CD40 signaling for IL-12 p70 production in vitro (55). Therefore, the study of CD40 signaling in DCs warrants considering the synergistic action of TLR triggering. These recent studies on TLR synergy bring into question work done by a large number of investigators, including work from our own lab that concludes that CD40 signaling alone can license DCs. These studies were likely compromised by a number of factors, including the use of supraphysiological levels of CD40 agonists, that the DCs were matured or grown in culture prior to activation with CD154 and/or αCD40, that the isolation procedure “activated” the DCs, or that TLR agonists were present (endotoxin) in the CD40 agonist preparations. Examples of this can be found in seminal papers by Bennet and coworkers (56) and Schoenberger and collaborators (57). With regard to the former, in order to induce CTL priming in absence of CD40 help, mice were immunized with antigen-loaded irradiated spleen cells and treated with high doses of agonistic αCD40 (four doses of 100 µg each). Besides the high levels of αCD40, the use of irradiated APCs probably allowed the release of proinflammatory mediators with the capacity of engaging TLR signaling, therefore licensing DC function and T cell priming (58–60). In fact, some studies have shown that, in isolation, CD40 agonists can impair CMI to tumors (61) and selfantigens (62). This once again argues for the necessity of supplementary signals in addition to CD40 stimulation in order to overcome tolerance and induce immunity. The new emerging paradigm is that combined TLR and CD40 triggering is critical for APC licensing. Pattern-recognition molecules (like TLRs) can recognize

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motifs found in bacterial glycolipids, DNA, and even viral RNA. The detailed mechanism of action and signaling of each one of these receptors has been recently summarized in reviews from the groups of Janeway and Medzhitov at Yale (63–66). Although they have been initially described as part of the innate component of immunity, they clearly are important cosignals in controlling the quality and magnitude of the ensuing acquired immune response. The importance of the synergy between the tumor necrosis factor receptor and TLR systems in licensing DCs to elicit CMI is underscored by a number of published studies (67–72), as well as collaborative studies from the laboratories of Ross Kedl (3M Pharmaceuticals in Minnesota) and our laboratory. These latter studies show that use of agonist αCD40 mAb together with a TLR agonist enhances the frequency of peptide-reactive T cells by more than tenfold. Thus, the administration of αCD40, TLR agonist, and ovalbumin (OVA) results in 10%– 25% of the CD8+ T cells to be antigen-specific in six days. Concordant with an increase in frequency, this synergistic effect was capable of profoundly activating antigen-specific CD8+ CTL responses as assessed by IFN-γ production and CTL activity. What is remarkable is that the magnitude of these responses is reminiscent of those observed to acute viral infections with lymphocytic choriomeningitis virus (LCMV) or vesicular stomatitis virus (VSV) (73, 74). The importance of combined TLR and CD40 signaling becomes self-evident when one histologically evaluates the distinctive impact of CD40 signaling alone versus CD40 and TLR on DC migration and survival. Previous studies by Moser and coworkers demonstrated that TLR agonists (like LPS) induce the rapid migration of the marginal zone DCs into the PALS (75). Once localized to the PALS, the DCs have a short half life unless provided a CD154 signal via antigen-specific helper T cells. Thus, the combined effects of TLR and agonistic αCD40 reposition DCs into the T cell zone for cognate interaction with T cells and provide a CD40dependent survival signal for long-lived presentation of antigen. The importance of this survival signal is underscored by the observation that loss of CD40-induced NIK function in the DC compartment (see CD40 Signaling Pathways That Control APC Function) impairs DC survival in the PALS and limits their capacity to support inflammatory responses. Finally, a number of studies have highlighted the importance of CD40 signaling in the context of DC longevity, as well as longevity of expression of class II MHC–peptide complex on the antigen-presenting DCs (32, 76). Thus, in addition to chemokine and cytokine production, longevity and anatomic location are critical players in the process of DC licensing. Although most studies that have employed CD40 agonists have assumed that they license the APC compartment, there may be alternative explanations to the immunogenic impact of these reagents. Bourgeois and colleagues have been able to demonstrate that the generation of memory CD8+ T cells can occur in the absence of CD40 expression by the APC but requires the help of CD4+ T cells (2). When they utilized APCs from a CD40 knockout mouse, they were able to show that CD4-CD8 T cell collaboration required the engagement of an APC but that activation of the CD8+ T cell was independent of CD40 expression by the APC.

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The function of CD40 expressed on CD8+ T cells in regulating T cell expansion and differentiation in other systems awaits confirmation. Finally, it cannot go unnoticed that T cell function can be substantially influenced through the expression of CD40 on nonhematopoietic cells. For example, it is clear that CD40 plays a critical role in activating endothelial cells leading to the migration of leukocytes (77). CD40 is expressed on vascular endothelium, and its expression is modulated by proinflammatory cytokines (TNF-α), IL-1, IFN-γ , and LPS (78, 79). Ligation of CD40 on endothelial cells leads to the production of proinflammatory cytokines and enhanced expression of CD54 (intracellular adhesion molecule-1), E-selectin, and vascular cell adhesion molecule 1, which results in increased leukocyte binding (79). Therefore, studies that have employed the use of CD40 agonists to manipulate T cells responses have to be cautiously interpreted because the impact of the CD40 agonist could be exerted directly on DCs, T cells, or nonhematopoietic cells.

Denying DC Licensing: Peripheral Self-Tolerance Denying immune responses to self is also the responsibility of the peripheral APC compartment. We know that despite the central deletion of self-reactive T cells and B cells, autoreactive T and B cells manage to escape negative selection, find their way to the periphery, and present a constant threat to the generation of autoimmunity (80). Consequently, mechanisms to prevent the activation of mature, self-reactive lymphocytes are necessary. Among those mechanisms are the following: ignorance, deletion, anergy induction, and active suppression by endogenous CD4+CD25+ suppressor T cells. Ignorance presumes that antigen in the periphery is not available, and unless tissue damage or other type of stress allows its release to the periphery, autoimmunity is not elicited. In contrast, anergy is based on the premise that self-antigen is presented to the T cell compartment, but T cell recognition of self-antigen leads to unresponsiveness. In this case, APCs present self-antigen in absence of signal two (costimulation), leading to a state of hyporesponsiveness by the autoreactive T cell (81, 82). This process has been thought to be more efficient than simple deletion of autoreactive cells in the periphery because anergic autoreactive T cells will compete for the antigen and reduce the chances of na¨ıve autoreactive T cells triggering autoimmunity. In contrast, accumulating evidence suggests that upon presentation of antigen by DCs in absence of costimulation, T cells do indeed proliferate and then disappear (reviewed in Reference 83). In recent years, peripheral suppression has reemerged as a major regulatory phenomenon that controls mature, autoreactive effector T cells. Extensive insights into a specific population of regulatory cells (CD4+CD25+Foxp3+ subset) has been afforded by S. Sakaguchi’s group (84–87) and many others (88–91). These cells represent 5%–10% of the endogenous CD4+ T cells subset and are able to suppress CD4+ and CD8+ T cell responses in vitro and in vivo upon TCR ligation (92, 93). As is extensively reviewed (94), elimination of this subset or shutting down their

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regulatory function using agonistic αGITR mAbs leads to autoimmunity (87, 95, 96), proving that these cells play a critical function in controlling the immune response to self. Another group of regulatory cells recently described (97) are referred to as Type 1 T regulatory cells (Tr1). These cells have poor proliferative capacity and act mainly by secreting IL-10 and transforming growth factor β (TGFβ) (98). Although there is not yet a clear consensus, one difference between Tr1 and CD4+CD25+ suppressor cells is that the latter are a constitutive component of the immune system, whereas Tr1 seem to be induced in response to Ag presentation in presence of IL-10 and IFNα (99). The differences and similarities between these two subsets is clearly presented in a recent review by Bluestone & Abbas (100).

IMMATURE DCS AS MEDIATORS OF PERIPHERAL SELF-TOLERANCE The mechanisms for controlling immune responses to self in the periphery (anergy, regulatory T cell) have converged on the role of the immature DC in managing tolerance. A body of evidence has emerged to show that persistent presentation of self-antigens by immature DCs maintains peripheral self-tolerance (101–104). Supporting this is a recent article by Wilson et al., wherein they elegantly demonstrate that, in a steady state, DCs from most lymphoid organs are phenotypically and functionally immature (105). A body of evidence has also been generated regarding the capacity of immature DCs to sustain peripheral tolerance. In particular, studies show how immature DCs are capable of consuming cell-associated antigens and inducing T cell anergy or deletion as long as they are not induced to mature via CD40 ligation (101, 102, 104, 106). With regard to the capacity of immature DCs to elicit expansion of regulatory subsets, less evidence is available. Tr1 cells have been shown to be generated in vitro when antigen is presented in presence of IL-10 (97, 99). In these cases, the necessity for immature DCs in order to induce Tr1 cells is not clear. Recent experiments have shown that CD40−/− and RelB−/− DCs (which would resemble the immature phenotype) are capable of inducing Tr1 CD4+ T cells in vivo, therefore making a case for the capacity of immature DCs to sustain the generation of regulatory T cells (50). With regard to the endogenous CD4+CD25+ suppressor T cells, it has been recently published that in vivo targeting of antigen to immature DCs via DEC205 leads to the expansion of CD4+CD25+CTLA4+ suppressor T cells (107). Therefore, a link between CD40 signaling of immature DCs and the activities of regulatory T cells can be envisioned. Form and biochemical makeup of the self-antigens may be critical to the outcome of the events programmed by immature DCs. Several groups have shown that the uptake of apoptotic cells by DCs is an effective inducer of T cell tolerance (108–110), whereas the phagocytosis of necrotic cells has been proven to induce maturation of DCs and development of immunity (111). The difference resides in the proinflammatory components released by necrotic cells (like heat shock

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proteins), which result in induction of the innate immune response (60); meanwhile, clearance of apoptotic cells by specific cell-surface receptors is accompanied by secretion of such anti-inflammatory cytokines as TGF-β (112, 113). In addition, new reports underscore the capacity of necrotic or stressed apoptotic cells in the induction of DC maturation as evidence for enhanced expression of CD40 and costimulatory molecules, together with heightened IL-12 secretion (114, 115). Taken together, it is apparent that the boundary line drawn for the induction of peripheral self-tolerance and immunity is a narrow one that is easily crossed by the accumulation of proinflammatory signals like CD40. Recently, studies have shown that CD40 agonist can cause the immune system to cross this line, and as a result, autoreactive responses can evolve (116). The vigilant presentation of self-antigens by immature DCs to maintain selftolerance is likely the reason why fully licensed DCs do not routinely “break” peripheral tolerance. Fully licensed DCs that are presenting peptides derived from pathogens no doubt simultaneously present self-peptides as well. We would contend that the preemptive and continuous induction of anergy to self-peptides in the absence of overt inflammation prohibits the subsequent induction of immune responses to self when licensed DCs are concomitantly presenting foreign and self-antigens.

CD154 AND CD40 IN REGULATING PERIPHERAL TOLERANCE Owing to the profound impact on DC maturation, CD40/CD154 interactions are decisive in the regulation of peripheral self-tolerance. It has been repeatedly demonstrated that induction of anergy by immature DCs can be overridden by the administration of an agonistic αCD40 antibody (117, 118). In most of these studies, it was shown that the delivery of a peptide (sometimes in adjuvant or via peptide-pulsed apoptotic cells) induces CD8+ T cell tolerance. The coadministration of αCD40 resulted in productive CD8+ T cell responses to the administered peptide. In one case, the use of a diabetogenic peptide (119) in conjunction with αCD40 resulted in diabetes. None of these reports have demonstrated the seminal changes in DC biology that are critical for making the transition from tolerance to immunity—no doubt they are many. However, it is of interest that recent studies have shown that DC persistence and antigen persistence is greatly enhanced as a result of CD40 agonists (37). Some insights into the biochemical and biological pathways that govern selftolerance are emerging. Particularly pertinent in this context is the data generated by Martin et al. (50). In their work they showed that RelB KO DCs or CD40 KO DCs loaded ex-vivo with Ag are highly tolerogenic and, most interesting, were able to impede ongoing immune responses. These studies suggest that the NF-κB2 pathway may be particularly important in triggering DC licensing. Similar studies are underway in our laboratory using DCs from mice in which specific CD40

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cytoplasmic functional domains have been mutated by site-directed mutagenesis. In the coming years, we will no doubt be able to deduce the biochemical pathways that are critical for inducing DC licensing.

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WHEN DOES CD154 BLOCKADE INDUCE T CELL TOLERANCE: STUDIES IN ALLOGRAFT TOLERANCE If immature DCs are effective at silencing the self-reactive T cells, exploiting this function to control the response to allopeptides should allow enhanced graft survival. However, as we see from the many reports presented above, crossing the line between tolerance and immunity is, at times, unpredictable. Form of antigen, route of antigen delivery, the inflammatory environment, and the alloreactive pool size all circumvent the rather tenuous boundaries between tolerance and immunity. The discovery of costimulation provided a target to prophylactically intervene on behalf of the host and to instill a state of peripheral allospecific tolerance. Because CD154-CD40 and other costimulatory ligand-receptor pairs were believed critical for DC licensing, numerous studies evaluated the success of costimulation blockade in delaying graft rejection.

Altering the Alloreactive T Cell Response BLOCKING COSTIMULATORY PATHWAYS One of the first pathways to be targeted in an attempt to modify allograft rejection was the CD28/B7 pathway. It was demonstrated that by using a CTLA4-Ig (a soluble form of the high-affinity receptor to B7 molecules), long-term allograft survival of islet cells (120, 121) and cardiac allografts (122) could be achieved. By competitively binding to B7 molecules, CTLA4-Ig blocked CD28 signaling to the T cells, therefore limiting activation of the alloreactive T cell compartment. However, later studies utilizing CTLA4-Ig treatment in nonhuman primates were unable to induce long-lived tolerance with CTLA4-Ig alone and demonstrated that there was a requirement for coadministration of anti-CD154 mAb (123). In an attempt to analyze the immune events associated with tolerance, it was directly shown that a CD28-independent CTLA4 signal delivers a strong negative signal to CD4+ T cells and that by interrupting the CTLA4/B7 interaction, alloreactive T cells were not effectively shut down (124). This finding is supported by earlier results, which demonstrated that CTLA4 signaling was required for inactivating alloreactive T cells (125, 126). Other means by which to disrupt T cell activation have been through the blockade of the CD40/CD154 pathway. Originally, it was thought that αCD154 monotherapy would be effective because it limited APC maturation and downmodulated the B7-CD28 interaction, resulting in the lack of a signal 2 and T cell anergy (127, 128). However, αCD154 as a monotherapy has not been successful in inducing allograft tolerance (129, 130). Studies by Waldmann indicate that failure to induce tolerance using αCD154 therapy is insufficient because of its inability

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to block rejection elicited by CD8+ T cells (131). Our own evidence suggests that αCD154 as a monotherapy is also ineffective at controlling the allogeneic response of CD4+ effector T cells in graft rejection (22). It is clear that blockade of any given pathway is less effective than blocking multiple pathways (i.e., CD40 and CD28 pathways), as has been demonstrated repeatedly (123, 131, 132). Highly immunogenic allografts, such as those of heart and skin, require stronger tolerogenic therapies. Among these, the combination of costimulatory blockade with immunosuppressive drugs (Rapamycin with αCD154 mAb and CTLA4-Ig) has been shown to result in long-term graft acceptance (133). Interestingly, the effect of cyclosporine A impedes the tolerogenic effects of αCD154 mAb and CTLA4-Ig. The explanation for this resides in the requirement of signal 1 to induce tolerance. Cyclosporine A (a calcineurin antagonist) inhibits signal 1 on the T cell, and together with signal 2 blockade results in the failure to induce apoptosis of the alloreactive T cells and thereby ablates tolerance induction (134, 135). The effectiveness of Rapamycin in combination with costimulation blockade to induce tolerance also appears to be dependent on the induction of apoptosis of the alloreactive T cells, as has been shown by Li and collaborators (136). The induction of apoptosis on the alloreactive T cell compartment seems to be an essential component of tolerance, as this contributes mostly to the reduction of the alloreactive clonal size (137). Altogether, enhanced allograft survival can be achieved by targeting independent costimulatory pathways, but greater success is obtained when several pathways are targeted simultaneously, and in some cases, when alloreactive T cells are sufficiently eliminated. Nonetheless, costimulation blockade, in the context of the inflammatory environment resulting from surgery and healing of a highly immunogenic graft is not an ideal context in which to ask immunotherapeutics to induce a state of immunologic tolerance. The immune system is most effective at inducing peripheral tolerance when the environment is quiescent, as we have seen in situations of peripheral self-tolerance. Based on this belief, tolerance may be achieved by exposing the recipient to donor antigens concomitantly with costimulation blockade prior to transplantation, in an effort to facilitate preemptive tolerance induction of the alloreactive T cell compartment. The next section discusses this type of approach, its relevance and effectiveness in experimental systems, and its possible application to clinics. DONOR-SPECIFIC TRANSFUSION We contend that the practice of donor-specific transfusion (DST) exploits the traditional practices of peripheral tolerance to modify the host immune response to alloantigens prior to the immunogenic introduction of an allograft. It is under these conditions that profound, enduring graft tolerance can be established. Historically, the infusion of whole blood from the donor into graft recipients modestly prolonged the longevity of grafts in humans (138) and mice (139). The enhanced graft survival following DST can be substantially lengthened or, in fact, rendered permanent if the DST is combined with blocking of CD154 (140). Recent studies by Xu and colleagues (141) and unpublished data

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from X. Zheng, Y. Li, X. Li, Y. Tian, K. Kawamoto & T. Strom have demonstrated long-term survival of allogeneic skin and islet allografts in monkeys that are treated with αCD154, DST, and Rapamycin. It is evident that we are on the path to bringing long-lived allospecific tolerance to the clinic for the management of allografts. Studies into this phenomenon have provided remarkable insights into the process of allospecific tolerance, peripheral tolerance, and the role of regulatory T cells in the survival of allografts. Long before DCs were recognized to be mediators of peripheral tolerance, Parker and colleagues championed the hypothesis that resting B cells (known for their inadequacies in antigen presentation) could be targeted with antigen to induce antigen-specific tolerance. In their studies (142), they demonstrated that a rabbit Fab αIgD could induce T cell tolerance to rabbit Ig epitopes. Although it was shown that targeting antigens to resting B cells in vivo was tolerogenic, the adoptive transfer of resting B cells carrying antigen or alloantigen was not reproducibly capable of inducing tolerance. At that time, it was reasoned that the transferred resting B cells carrying antigen or alloantigen were ineffective inducers of tolerance because upon entry into the host, they were activated by host CD154-bearing helper T cells. As a result, the transferred B cells were immunogenic, not tolerogenic. This hypothesis was supported by the observation that the adoptive transfer of allogeneic B cells and αCD154 induced profound allospecific unresponsiveness and allograft survival in grafted mice. Based on this observation, we and others hypothesized that the transfused allogeneic B cells were directly presenting alloantigen to the host in a tolerogenic fashion owing to the imposed blockade of CD40 signaling. More recent studies portray a very different picture of how the transfusion of allogeneic cells (DST) and αCD154 induce graft tolerance. Further testing of the proposed hypothesis demanded a critical evaluation of the role of direct or indirect presentation of DST to the host. To address this issue and also many of the remaining issues surrounding the fate of the alloreactive T cell compartment, a CD4+ TCR Tg T cell system was developed (TEa Tg T cells) (24). Briefly, CD4+ TCR Tg T cells that recognize an Eα peptide in the context of IAb were used as a population of alloreactive T cells that could be readily tracked. These cells are adoptively transferred into an H-2b Rag−/− mouse and upon grafting with an F1 graft (H-2bxd), graft rejection was followed over the next few weeks. Infusion of F1 B cells (DST) and αCD154 prolonged graft rejection, as shown in intact non-Tg systems. Among the most relevant findings were that indirect presentation of alloantigen was essential for tolerance induction. That is, the infusion of B cells that were virtually invisible to the TEa Tg T cells via direct recognition (i.e., Balb/c B cells bearing only Eα and not the restricting element, H-2b) induced profound tolerance. Thus, the infused DST was rapidly processed by host APCs and presented via indirect presentation to the TEa in a tolerogenic manner. The tolerogenic impact of DST and αCD154 in this system was to induce a rapid (day 3–4), systemic, abortive expansion of the alloreactive TEa Tg T cells that resulted in profound anergy. One additional unique feature of this system was that we could quantitate the magnitude of the T cell unresponsiveness

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by purifying anergic cells. In these cases, the unresponsiveness was determined to be >95% on a per-cell basis. In striking contrast to the potent tolerogenic impact of alloantigen being delivered via DST, alloantigen present on an F1 skin graft exerted a profoundly immunogenic impact. Analysis of TEa Tg T cell responses to the F1 allograft (in the absence of DST and αCD154) revealed a delayed (6–8 days), regional [mostly draining lymph nodes (LNs)], productive T cell response with extensive expansion and cytokine production (IL-2 and IFN-γ ). Hence, infusion of DST and αCD154 resulted in a preemptive induction of tolerance within the alloreactive T cell compartment, thereby silencing the alloreactive response days prior to the time when the allograft had the opportunity to elicit an immune response. The finding that DST predominantly, if not exclusively, induces tolerance via indirect presentation provided the first clues that DST and αCD154 co-opted the fundamental mechanisms of peripheral tolerance to induce allotolerance. We now envision that the infused DST rapidly undergoes apoptosis and is presented by host APCs. It is of interest to note that αCD154 may facilitate the apoptosis of the DST by depriving it of a CD40 signal. At the same time, αCD154 impairs the maturation of host APCs, committing them to the tolerogenic presentation of DST-derived allopeptides. Delivery of peptides via apoptotic cells appears to be an extremely efficient means to induce peripheral tolerance (Figure 2). In analogous studies, Steinman and coworkers have shown that TAP−/− B cells that are hyperosmotically loaded with OVA can induce abortive expansion and anergy of OVA-specific CTLs in vivo via indirect presentation (143). Similarly, antigens expressed on dying pancreatic cells (144) induce tolerance via indirect presentation. Whether targeted via apoptotic cells, or by vectors that target directly to defined DC surface molecules (like DEC-205), antigens delivered to immature DCs induce profound antigen-specific tolerance, which is amplified in the presence of αCD154. INVOKING REGULATORY T CELLS Although the induction of clonal T cell anergy by peripheral tolerance mechanisms and by DST is near complete, these events are inadequate to achieve long-lived graft acceptance. Studies now suggest that clonal tolerance and graft permanence require the involvement of some regulatory activities (reviewed in Reference 145). Early studies by Waldmann and coworkers were the first to describe an infectious form of tolerance in a variety of allograft tolerance systems (146). Using DST and αCD154, these investigators showed that CD4+ T cells were critical for long-lived survival of the allograft (147). Subsequent studies in allogeneic bone marrow transplantation and other transplant models implicated an important role of CD4+CD25+ suppressor T cells in αCD154-induced graft tolerance (148, 149). Additional evidence substantiating the importance of regulatory T cells in longlived graft tolerance was provided by reconstitution studies from our laboratory. In these studies, we reconstituted RAG−/− mice with defined CD4+ T cell populations,

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treated them with DST and αCD154, and evaluated if graft tolerance could be induced following a skin allograft. Upon reconstitution with only CD4+CD25− T cells, DST and αCD154 significantly delayed the rejection of allogeneic skin, but the graft was ultimately rejected. In this case, the delay is due to extensive clonal abortion of the relevant alloreactive T cells; however, a small frequency remains that eventually rejected the graft. Upon the coadoptive transfer of CD4+CD25+ T cells with the CD25− T cells, permanent graft survival becomes evident. Hence, clonal abortion of the alloreactive CD4+ effectors is incomplete, as there appears to be a CD4+CD25− population that is resistant to tolerance induction. This residual population can be readily silenced by the cotransfer of regulatory T cells. One particularly intriguing observation in these studies was that the loss of CD154 expression on suppressor cells was sufficient to induce long-term skin graft survival with just the administration of DST (22), suggesting an important role of CD154 in regulatory T cell function.

FINAL COMMENTS Although licensed DCs elicit profound immunity to foreign peptides, the responses elicited to copresented self-peptides on the same DCs are silent. One must imagine that the silence to self-peptides afforded to a fully licensed DC is due to the constant presentation of self-peptides by the immature DC compartment and the preemptive silencing of the self-reactive T cell pool. Intervention into ongoing autoimmune responses solely with αCD154 can block many effector mechanisms and ablate the clinical and pathological features of autoimmunity but, in most cases, does not induce a state of tolerance. The delivery of allogeneic peptides via apoptotic cells (DST) to the quiescent immune system, and maintaining that quiescence with CD154 blockade, induces profound clonal abortion and elicits regulatory T cell function. It is under these circumstances that αCD154 instills long-lasting immune tolerance. The Annual Review of Immunology is online at http://immunol.annualreviews.org

LITERATURE CITED 1. van Kooten C, Banchereau J. 1997. Functions of CD40 on B cells, dendritic cells and other cells. Curr. Opin. Immunol. 9:330–37 2. Bourgeois C, Rocha B, Tanchot C. 2002. A role for CD40 expression on CD8+ T cells in the generation of CD8+ T cell memory. Science 297:2060–63 3. Klaus GG, Choi MS, Lam EW, JohnsonLeger C, Cliff J. 1997. CD40: a pivotal

receptor in the determination of life/death decisions in B lymphocytes. Int. Rev. Immunol. 15:5–31 4. Higuchi T, Aiba Y, Nomura T, Matsuda J, Mochida K, et al. 2002. Cutting edge: Ectopic expression of CD40 ligand on B cells induces lupus-like autoimmune disease. J. Immunol. 168:9–12 5. Henn V, Slupsky JR, Grafe M, Anagnostopoulos I, Forster R, et al. 1998. CD40

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QUEZADA ET AL. 1999. CD40 ligand blockade induces CD4+ T cell tolerance and linked suppression. J. Immunol. 163:4805–10 Larsen CP, Elwood ET, Alexander DZ, Ritchie SC, Hendrix R, et al. 1996. Longterm acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways. Nature 381:434–38 Li Y, Zheng XX, Li XC, Zand MS, Strom TB. 1998. Combined costimulation blockade plus rapamycin but not cyclosporine produces permanent engraftment. Transplantation 66:1387–88 Li Y, Li XC, Zheng XX, Wells AD, Turka LA, Strom TB. 1999. Blocking both signal 1 and signal 2 of T-cell activation prevents apoptosis of alloreactive T cells and induction of peripheral allograft tolerance. Nat. Med. 5:1298–302 Li W, Lu L, Wang Z, Wang L, Fung JJ, et al. 2001. Costimulation blockade promotes the apoptotic death of graftinfiltrating T cells and prolongs survival of hepatic allografts from FLT3L-treated donors. Transplantation 72:1423–32 Wells AD, Li XC, Li Y, Walsh MC, Zheng XX, et al. 1999. Requirement for T-cell apoptosis in the induction of peripheral transplantation tolerance. Nat. Med. 5:1303–7 Sho M, Yamada A, Najafian N, Salama AD, Harada H, et al. 2002. Physiological mechanisms of regulating alloimmunity: cytokines, CTLA-4, CD25+ cells, and the alloreactive T cell clone size. J. Immunol. 169:3744–51 Brennan DC, Mohanakumar T, Flye MW. 1995. Donor-specific transfusion and donor bone marrow infusion in renal transplantation tolerance: a review of efficacy and mechanisms. Am. J. Kidney Dis. 26:701–15 Wood ML, Gottschalk R, Monaco AP. 1984. Comparison of immune responsiveness in mice after single or multiple donor-specific transfusions. J. Immunol. 132:651–55

140. Parker DC, Greiner DL, Phillips NE, Appel MC, Steele AW, et al. 1995. Survival of mouse pancreatic islet allografts in recipients treated with allogeneic small lymphocytes and antibody to CD40 ligand. Proc. Natl. Acad. Sci.USA 92:9560–64 141. Xu H, Montgomery SP, Preston EH, Tadaki DK, Hale DA, et al. 2003. Studies investigating pretransplant donor-specific blood transfusion, rapamycin, and the CD154-specific antibody IDEC-131 in a nonhuman primate model of skin allotransplantation. J. Immunol. 170:2776–82 142. Eynon EE, Parker DC. 1992. Small B cells as antigen-presenting cells in the induction of tolerance to soluble protein antigens. J. Exp. Med. 175:131–38 143. Liu K, Iyoda T, Saternus M, Kimura Y, Inaba K, Steinman RM. 2002. Immune tolerance after delivery of dying cells to dendritic cells in situ. J. Exp. Med. 196:1091–7 144. Coulombe M, Yang H, Wolf LA, Gill RG. 1999. Tolerance to antigen-presenting cell-depleted islet allografts is CD4 T cell dependent. J. Immunol. 162:2503–10 145. Wood KJ, Sakaguchi S. 2003. Regulatory T cells in transplantation tolerance. Nat. Rev. Immunol. 3:199–210 146. Qin S, Cobbold SP, Pope H, Elliott J, Kioussis D, et al. 1993. “Infectious” transplantation tolerance. Science 259:974–77 147. Graca L, Honey K, Adams E, Cobbold SP, Waldmann H. 2000. Cutting edge: antiCD154 therapeutic antibodies induce infectious transplantation tolerance. J. Immunol. 165:4783–86 148. Hara M, Kingsley CI, Niimi M, Read S, Turvey SE, et al. 2001. IL-10 is required for regulatory T cells to mediate tolerance to alloantigens in vivo. J. Immunol. 166:3789–96 149. Taylor PA, Noelle RJ, Blazar BR. 2001. CD4(+)CD25(+) immune regulatory cells are required for induction of tolerance to alloantigen via costimulatory blockade. J. Exp. Med. 193:1311–18

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CD40 AND PERIPHERAL TOLERANCE

C-1

Figure 1 DC licensing and CD40 activation of the NF-kB pathways in DCs. (A) DC licensing. DCs reside in the periphery in an immature state. Immature DCs sample their environment and express low levels of MHC molecules. Upon receipt of inflammatory signals such as TLR engagement, they rapidly migrate to the PALS and interact with T cells. Engagement of the TCR by MHC peptide on the T cell results in upregulation of CD154, which further matures the DC and allows costimulation and activation of the T cell. Interfering with the CD40 signal results in tolerance induction via multiple pathways discussed in this review. (B) CD40 activation of NF-kB in DCs. Stimulation of the DC through CD40 results in clustering of CD40 and recruitment of the TRAF molecules. TRAF-receptor complex then recruits multiple kinases such as NIK and MEKK1. Multiple different kinases may result in phosphorylation of IKKb, which in turn results in ubiquitination of the IkB protein and release of NF-kB transcription factor dimers. This pathway leads to rapid inflammatory response and production of IL-12 and IL-8. Phosphorylation of IKKa occurs via NIK and results in phosphorylation of the p100 NF-kB2 precursor protein. This causes p100 to become ubiquitinated and partially digested by the proteosome, thus releasing p52/ RelB dimers. The NF-kB2 pathway results in sustained DC longevity and chemokine production.

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Figure 2 A model for preemptive tolerization of the alloreactive T cell compartment. Upon DST 1 aCD154 injection (1), DST will soon be cleared by host DCs, allowing indirect presentation of donor Ags (2). CD154 blockade also has a proapoptotic effect on the DST, therefore facilitating a noninflammatory environment. Donor antigen indirectly presented to the alloreactive T cells in absence of CD40 signals and DC licensing results in rapid, systemic, and abortive expansion of the T cells (3a). Part of the alloreactive compartment is deleted, and the remaining T cells are hyporesponsive to further stimulation (4). At a similar tempo, CD4+CD25+ suppressor T cells clonally expand to the alloantigen (3b). Some of them migrate to the graft where they suppress expansion of alloreactive T cells recruited to that site (5). When Ag bearing donor DCs finally reach the draining LN from the donor skin (6), the alloreactive T cell compartment is extremely reduced and is nonresponsive to restimulation. Induction of Tr1 might occur and be one of the components of infectious tolerance together with CD4+CD25+ suppressor T cells, but the physiological mechanisms behind this process are still to be resolved.

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CONTENTS FRONTISPIECE—Leonard A. Herzenberg and Leonore A. Herzenberg GENETICS, FACS, IMMUNOLOGY, AND REDOX: A TALE OF TWO LIVES INTERTWINED, Leonard A. Herzenberg and Leonore A. Herzenberg SELF- AND NONSELF-RECOGNITION BY C-TYPE LECTINS ON DENDRITIC CELLS, Teunis B.H. Geijtenbeek, Sandra J. van Vliet, Anneke Engering, Bert A. ’t Hart, and Yvette van Kooyk

x 1

33

TRANSCRIPTIONAL CONTROL OF EARLY B CELL DEVELOPMENT, Meinrad Busslinger

UBIQUITIN LIGASES AND THE IMMUNE RESPONSE, Yun-Cai Liu LIGANDS FOR L-SELECTIN: HOMING, INFLAMMATION, AND BEYOND, Steven D. Rosen

55 81 129

INTEGRINS AND T CELL–MEDIATED IMMUNITY, Jonathan T. Pribila, Angie C. Quale, Kristen L. Mueller, and Yoji Shimizu

157

MULTIPLE ROLES OF ANTIMICROBIAL DEFENSINS, CATHELICIDINS, AND EOSINOPHIL-DERIVED NEUROTOXIN IN HOST DEFENSE, De Yang, Arya Biragyn, David M. Hoover, Jacek Lubkowski, and Joost J. Oppenheim

STARTING AT THE BEGINNING: NEW PERSPECTIVES ON THE BIOLOGY OF MUCOSAL T CELLS, Hilde Cheroutre THE BCR-ABL STORY: BENCH TO BEDSIDE AND BACK, Stephane Wong and Owen N. Witte

181 217 247

CD40/CD154 INTERACTIONS AT THE INTERFACE OF TOLERANCE AND IMMUNITY, Sergio A. Quezada, Lamis Z. Jarvinen, Evan F. Lind, and Randolph J. Noelle

307

THE THREE ES OF CANCER IMMUNOEDITING, Gavin P. Dunn, Lloyd J. Old, and Robert D. Schreiber

AUTOIMMUNE AND INFLAMMATORY MECHANISMS IN ATHEROSCLEROSIS, Georg Wick, Michael Knoflach, and Qingbo Xu THE DYNAMIC LIFE OF NATURAL KILLER CELLS, Wayne M. Yokoyama, Sungjin Kim, and Anthony R. French

329 361 405

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THE ROLE OF COMPLEMENT IN THE DEVELOPMENT OF SYSTEMIC LUPUS ERYTHEMATOSUS, Anthony P. Manderson, Marina Botto, and Mark J. Walport

DROSOPHILA: THE GENETICS OF INNATE IMMUNE RECOGNITION AND RESPONSE, Catherine A. Brennan and Kathryn V. Anderson RAGS AND REGULATION OF AUTOANTIBODIES, Mila Jankovic,

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Rafael Casellas, Nikos Yannoutsos, Hedda Wardemann, and Michel C. Nussenzweig

431 457

485

THE ROLE OF SUPPRESSORS OF CYTOKINE SIGNALING (SOCS) PROTEINS IN REGULATION OF THE IMMUNE RESPONSE, Warren S. Alexander and Douglas J. Hilton

503

NATURALLY ARISING CD4+

REGULATORY T CELLS FOR IMMUNOLOGIC SELF-TOLERANCE AND NEGATIVE CONTROL OF IMMUNE RESPONSES, Shimon Sakaguchi PHOSPHOINOSITIDE 3-KINASE: DIVERSE ROLES IN IMMUNE CELL ACTIVATION, Jonathan A. Deane and David A. Fruman IMMUNITY TO TUBERCULOSIS, Robert J. North and Yu-Jin Jung MOLECULAR DEFECTS IN HUMAN SEVERE COMBINED IMMUNODEFICIENCY AND APPROACHES TO IMMUNE RECONSTITUTION, Rebecca H. Buckley PHYSIOLOGICAL CONTROL OF IMMUNE RESPONSE AND INFLAMMATORY TISSUE DAMAGE BY HYPOXIA-INDUCIBLE FACTORS AND ADENOSINE A2A RECEPTORS, Michail V. Sitkovsky, Dmitriy Lukashev, Sergey Apasov, Hidefumi Kojima, Masahiro Koshiba, Charles Caldwell, Akio Ohta, and Manfred Thiel

531 563 599

625

657

T LYMPHOCYTE–ENDOTHELIAL CELL INTERACTIONS, Jaehyuk Choi, David R. Enis, Kian Peng Koh, Stephen L. Shiao, and Jordan S. Pober

683

IMMUNOLOGICAL MEMORY TO VIRAL INFECTIONS, Raymond M. Welsh, Liisa K. Selin, and Eva Szomolanyi-Tsuda

711

CENTRAL MEMORY AND EFFECTOR MEMORY T CELL SUBSETS: FUNCTION, GENERATION, AND MAINTENANCE, Federica Sallusto, Jens Geginat, and Antonio Lanzavecchia CONTROL OF T CELL VIABILITY, Philippa Marrack and John Kappler

745 765

ASTHMA: MECHANISMS OF DISEASE PERSISTENCE AND PROGRESSION, Lauren Cohn, Jack A. Elias, and Geoffrey L. Chupp

789

CD1: ANTIGEN PRESENTATION AND T CELL FUNCTION, Manfred Brigl and Michael B. Brenner

817

CHEMOKINES IN INNATE AND ADAPTIVE HOST DEFENSE: BASIC CHEMOKINESE GRAMMAR FOR IMMUNE CELLS, Antal Rot and Ulrich H. von Andrian

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INTERLEUKIN-10 AND RELATED CYTOKINES AND RECEPTORS, Sidney Pestka, Christopher D. Krause, Devanand Sarkar, Mark R. Walter, Yufang Shi, and Paul B. Fisher

929

INDEXES

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Subject Index Cumulative Index of Contributing Authors, Volumes 12–22 Cumulative Index of Chapter Titles, Volumes 12–22

ERRATA An online log of corrections to Annual Review of Immunology chapters may be found at http://immunol.annualreviews.org/errata.shtml

981 1011 1018

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Annu. Rev. Immunol. 2004. 22:329–60 doi: 10.1146/annurev.immunol.22.012703.104803 c 2004 by Annual Reviews. All rights reserved Copyright ° First published online as a Review in Advance on October 15, 2003

THE THREE ES OF CANCER IMMUNOEDITING Gavin P. Dunn,1 Lloyd J. Old,2 and Robert D. Schreiber1 Annu. Rev. Immunol. 2004.22:329-360. Downloaded from arjournals.annualreviews.org by HINARI on 09/01/07. For personal use only.

1

Department of Pathology and Immunology, Center for Immunology, Washington University School of Medicine, St. Louis, Missouri 63110; email: [email protected] 2 Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center, New York, NY 10021; email: [email protected]

Key Words immunosurveillance, tumor, lymphocytes, interferon, tumor sculpting ■ Abstract After a century of controversy, the notion that the immune system regulates cancer development is experiencing a new resurgence. An overwhelming amount of data from animal models—together with compelling data from human patients— indicate that a functional cancer immunosurveillance process indeed exists that acts as an extrinsic tumor suppressor. However, it has also become clear that the immune system can facilitate tumor progression, at least in part, by sculpting the immunogenic phenotype of tumors as they develop. The recognition that immunity plays a dual role in the complex interactions between tumors and the host prompted a refinement of the cancer immunosurveillance hypothesis into one termed “cancer immunoediting.” In this review, we summarize the history of the cancer immunosurveillance controversy and discuss its resolution and evolution into the three Es of cancer immunoediting— elimination, equilibrium, and escape.

INTRODUCTION The concept that the immune system can recognize and eliminate primary developing tumors in the absence of external therapeutic intervention has existed for nearly 100 years. However, the validity of this concept has, in the past, been difficult to establish. When first proposed in 1909 (1), the hypothesis could not be experimentally tested because so little was known at the time about the molecular and cellular basis of immunity. Later on, as the field of immunology developed and the concept acquired its name—cancer immunosurveillance (2, 3)—experimental testing became possible but failed to provide evidence for the process, using mice with spontaneous mutations that rendered them immunocompromised but not completely immunodeficient (4). Only recently, with the development of gene targeting and transgenic mouse technologies and the capacity to produce highly specific blocking monoclonal antibodies (mAb) to particular immune components, has the cancer immunosurveillance hypothesis become testable in unequivocal, molecularly defined murine models of immunodeficiency. Over the past ten years, the use of these 0732-0582/04/0423-0329$14.00

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improved in vivo cancer models has provided strong and convincing data that have rekindled interest in the cancer immunosurveillance hypothesis. Most recently, this conundrum has been further clarified by the demonstration that the immune system not only can protect the host against tumor development but also, by selecting for tumors of lower immunogenicity, has the capacity to promote tumor growth. These dual effects of the immune system on developing tumors prompted us to refine the cancer immunosurveillance hypothesis into one we termed cancer immunoediting (5, 6). We envisage that this process is comprised of three phases that are collectively denoted the three Es of cancer immunoediting: elimination, equilibrium, and escape. In this review, we first present data supporting the existence of the elimination phase (i.e., cancer immunosurveillance) as it occurs in mice and humans and propose a model for the molecular and cellular events that underlie this process. Second, we provide evidence for a tumor-sculpting role of immunity and discuss the relationship between this function and the equilibrium and escape phases of cancer immunoediting. Third, we outline the implications of this concept for the understanding and treatment of human cancer.

CANCER IMMUNOSURVEILLANCE IN MICE Historical Perspective The validity of the cancer immunosurveillance hypothesis has emerged only recently from a long history of heated debate (reviewed in 6). The notion that the immune system could protect the host from neoplastic disease was initially proposed by Ehrlich (1) and formally introduced as the cancer immunosurveillance hypothesis nearly 50 years later by Burnet and Thomas (2, 3, 7–9). Based on an emerging understanding of the cellular basis of transplantation and tumor immunity (10–15), Burnet and Thomas predicted that lymphocytes were responsible for eliminating continuously arising, nascent transformed cells. However, when this prediction was put to the experimental test using nude mice, which were the most congenitally immunodeficient mice available at the time (16, 17), no convincing evidence for such a process was obtained. Specifically, CBA/H strain nude mice neither developed increased incidences of carcinogen [methylcholanthrene (MCA)]-induced or spontaneous tumors nor did they show shortened periods of tumor latency compared with wild-type controls (4, 18–22). However, in retrospect, there are several important caveats to these experiments that could not have been appreciated at the time. First, the nude mouse is now recognized to be an imperfect model of immunodeficiency. These mice produce low but detectable numbers of functional populations of αβ T cells (23–25) and therefore can manifest at least some degree of adaptive immunity. Second, the existence of natural killer (NK) cells (which are present and function normally in nude mice) was not well established at the time (26) and thus very little was known about their origins, actions, or roles in promoting innate immunity. In addition, the profound influence of innate immunity on adaptive immunity was

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not recognized (27). Thus, the residual adaptive immune system in the presence of a fully functional innate immune system may provide the nude mouse with at least some cancer immunosurveillance capacity. Third, the CBA/H strain mice used in Stutman’s MCA carcinogenesis experiments express the highly active isoform of the aryl hydroxylase enzyme that is required to metabolize MCA into its carcinogenic form (28, 29). Therefore, it is conceivable that MCA-induced cellular transformation in CBA/H strain mice occurred so efficiently that it masked any protective effect that immunity could provide. Nevertheless, since these caveats can only be appreciated in hindsight, the Stutman experiments were considered to be so convincing that by the end of the 1970s, the death knell had sounded for the cancer immunosurveillance hypothesis.

THE RENAISSANCE OF CANCER IMMUNOSURVEILLANCE IFN-γ , Perforin, and Lymphocytes in Tumor Immunity In the 1990s, two sets of studies incited renewed interest in cancer immunosurveillance. First, endogenously produced interferon-γ (IFN-γ ) was shown to protect the host against the growth of transplanted tumors and the formation of primary chemically induced and spontaneous tumors (30–33). The injection of neutralizing monoclonal antibodies specific for IFN-γ into mice bearing transplanted, established Meth A tumors blocked LPS-induced tumor rejection (30). In addition, transplanted fibrosarcomas grew faster and more efficiently in mice treated with IFN-γ -specific mAb. These observations were then extended to models of primary tumor formation. IFN-γ -insensitive 129/SvEv mice lacking either the IFNGR1 ligand-binding subunit of the IFN-γ receptor or STAT1, the transcription factor responsible for mediating much of IFN-γ ’s biologic effects on cells (34), were found to be 10–20 times more sensitive than wild-type mice to tumor induction by methylcholanthrene (31). Specifically, these mice developed more tumors, more rapidly, and at lower MCA doses than did wild-type controls. These results were subsequently confirmed by independent experiments using C57BL/6 strain mice lacking the gene encoding IFN-γ itself (32). Similarly, in models of genetically driven tumorigenesis, mice lacking the p53 tumor suppressor gene and either IFNGR1 or STAT1 formed a wider spectrum of tumors compared with IFN-γ -sensitive mice lacking only p53 (31). In addition, compared to their IFN-γ sufficient counterparts, IFN-γ −/− C57BL/6 mice showed an increased incidence of disseminated lymphomas, and IFN-γ −/− BALB/c mice displayed an increased incidence of spontaneous lung adenocarcinomas (33). Second, mice lacking perforin (pfp−/−) were found to be more susceptible to MCA-induced and spontaneous tumor formation compared with their wildtype counterparts (32, 33, 35–37). Perforin is a component of the cytolytic granules of cytotoxic T cells and NK cells that plays an important role in mediating lymphocyte-dependent killing (38). Following challenge with MCA, pfp−/− mice developed significantly more tumors compared with wild-type mice treated in the

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same manner (32, 35, 36). Untreated pfp−/− mice also showed a high incidence of spontaneous disseminated lymphomas, which was accelerated on a p53−/− background (37). BALB/c mice lacking perforin also displayed a low incidence of spontaneous lung adenocarcinomas, which was not observed in wild-type mice (33). Taken together, these observations demonstrated that tumor development in mice was controlled by components of the immune system and stimulated a considerable amount of work aimed at better defining this process (Table 1). The definitive work demonstrating the existence of an IFN-γ - and lymphocytedependent cancer immunosurveillance process was based on experiments employing gene-targeted mice that lack the recombinase activating gene (RAG)-2 (5). Mice lacking RAG-2 (or its obligate partner RAG-1) cannot rearrange lymphocyte antigen receptors and thus lack T, B, and NKT cells (39). Since RAG-2 expression is limited to cells of the immune system, the use of RAG-2−/− mice provided an appropriate model to study the effects of host immunodeficiency on tumor development because, unlike other genetic models of immunodeficiency (such as SCID mice), the absence of RAG-2 would not result in impaired DNA repair in nonlymphoid cells undergoing transformation. Following challenge with MCA, 129/SvEv RAG-2−/− mice developed sarcomas more rapidly and with greater frequency than genetically matched wild-type controls (5) (Figure 1A). After 160 days, 30/52 RAG-2−/− mice formed tumors, compared with 11/57 wild-type mice. Similar findings were obtained in MCA tumorigenesis experiments that used RAG-1−/− C57BL/6 mice (40). Moreover, Helicobacter-free RAG-2−/− 129/SvEv mice aged in a specific pathogen-free mouse facility and maintained on broad-spectrum antibiotics formed far more spontaneous epithelial tumors than did wild-type mice housed in the same room (5; A.T. Bruce & R.D. Schreiber, unpublished observations) (Figure 1B). Specifically, 26/26 RAG-2−/− mice ranging in age from 13– 24 months developed spontaneous neoplasia, predominantly of the intestine; 8 of these mice had premalignant intestinal adenomas, 17 had intestinal adenocarcinomas, and 1 had both an intestinal adenoma and a lung adenocarcinoma. In contrast, only 5/20 wild-type mice aged 13–24 months developed spontaneous neoplasia, which was predominantly benign. Three wild-type mice developed adenomas of the Harderian gland, lung, and intestine, respectively; one developed a Harderian gland adenocarcinoma; and one developed an endometrial stromal carcinoma. Thus, lymphocytes protect mice against the formation of both chemically induced and spontaneous tumors. The overlap between the IFN-γ - and lymphocyte-dependent tumor suppressor pathways was explored by comparing tumor formation in 129/SvEv mice lacking either IFN-γ responsiveness (IFNGR1−/− or STAT1−/− mice), lymphocytes (RAG-2−/− mice), or both [RAG-2−/− X STAT1−/− (RkSk) mice] (5). Each of the four lines of gene-targeted mice formed three times more chemically induced tumors than syngeneic wild-type mice when injected with a single 100 µg dose of MCA (Figure 1A). Since no significant differences were detected between any of the gene-targeted mice, the conclusion was reached that the IFN-γ /STAT1 and lymphocyte-dependent extrinsic tumor suppressor mechanisms were heavily

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TABLE 1 Enhanced susceptibility of immunodeficient mice to chemically induced and spontaneous tumors Tumor susceptibility relative to wild type

Technology

Immune status

References

RAG-2−/−

Lacks T, B, NKT cells

↑ MCA-induced sarcomas; ↑ spontaneous intestinal neoplasia

(5)

RAG-2−/− × STAT1−/− (RkSk)

Lacks T, B, NKT cells; IFNγ -, α/β-insensitive

↑ MCA-induced sarcomas; ↑ spontaneous intestinal and mammary neoplasia

(5)

RAG-1−/−

Lacks T, B, NKT cells

↑ MCA-induced sarcomas

(40)

BALB/c SCID

Lacks T, B, NKT cells

↑ MCA-induced sarcomas

(40)

TCRβ −/−

Lacks αβ T cells

↑ MCA-induced sarcomas

(58)

TCRδ −/−

Lacks γ δ T cells

↑ MCA-induced sarcomas; ↑ DMBA/TPA-induced skin tumors

(58)

Jα281−/−

Lacks NKT cell subset

↑ MCA-induced sarcomas

(32, 36, 40)

LMP2−/−

Lacks LMP2 subunit

↑ Spontaneous uterine neoplasms

(169)

Anti-asialo-GM1

Lacks NK cells, mono-cytes/macrophages

↑ MCA-induced sarcomas

(40)

Anti-NK1.1

Lacks NK, NKT cells

↑ MCA-induced sarcomas

(36, 40)

Anti-Thy1

Lacks T cells

↑ MCA-induced sarcomas

(36)

STAT1−/−

IFN-γ -, α/β-insensitive

↑ MCA-induced sarcomas; wider tumor spectrum in STAT1−/− × p53−/−

(5, 31)

IFNGR1−/−

IFN-γ -insensitive

↑ MCA-induced sarcomas; wider tumor spectrum in IFNGR1−/− × p53−/−

(5, 31)

IFN-γ −/−

Lacks IFN-γ

↑ MCA-induced sarcomas; B6: ↑ spontaneous disseminated lymphomas; BALB/c: ↑ spontaneous lung adenocarcinomas

(32, 33)

GM-CSF/IFN-γ −/−

Lacks GM-CSF, IFN-γ

↑ Spontaneous lymphomas; ↑ nonlymphoid solid cancers

(55)

Pfp−/− × IFN-γ −/−

Lacks Perforin, IFN-γ

↑ MCA-induced sarcomas; ↑ spontaneous disseminated lymphomas

(32, 33)

Pfp−/−

Lacks Perforin

↑ MCA-induced sarcomas; ↑ spontaneous disseminated lymphomas

(32, 33, 35–37)

TRAIL−/−

Lacks TRAIL

↑ MCA-induced sarcomas

(61)

Anti-TRAIL

Blockade of TRAIL function

↑ MCA-induced sarcomas; ↑ spontaneous sarcomas, disseminated lymphomas

(60)

IL-12p40−/−

Lacks IL-12

↑ MCA-induced sarcomas

(36)

Wt + IL-12

Exogenous IL-12

↓ MCA-induced sarcomas

(62)

Wt + α-GalCer

Exogenous NKT cell activation

↓ MCA-induced sarcomas

(63)

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Figure 1 Increased incidence of chemically induced and spontaneous tumors in immunodeficient mice. (A) Age- and sex-matched mice were inoculated with 100 µg MCA and monitored for tumor development for 160 days. (B) Mice housed in a specific pathogen-free facility were monitored for spontaneous tumor development between 13–24 months. Adapted from Shankaran et al. (5).

overlapping. However, RkSk mice developed spontaneous breast tumors that were not observed in wild-type or RAG-2−/− mice, therefore demonstrating that the overlap between the two pathways was incomplete (Figure 1B). Similar findings were made in carcinogenesis experiments employing mice that lacked either perforin, IFN-γ , or both, where a small increase was observed in tumor induction in the doubly deficient mice compared with mice lacking only one of the two components (32).

Identification of the Components of the Immmunosurveillance Network TUMOR CELLS AS KEY TARGETS OF IFN-γ The finding that endogenously produced IFN-γ played a critical role in protecting mice against tumor development stimulated a search for the physiologically important cellular targets of this cytokine. Two approaches demonstrated that the tumor cell itself is an important IFN-γ target in tumor rejection. In the first, the effects of ablating IFN-γ sensitivity on the immunogenicity of IFN-γ -sensitive tumor cells was assessed using models of tumor cell transplantation (30). Meth A tumor cells, when

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engineered to be unresponsive to IFN-γ by overexpression of a dominant-negative IFNGR1 mutant (mgR.1IC) (41), grew more aggressively than mock-transfected controls when transplanted into na¨ıve syngeneic wild-type hosts and were resistant to LPS-induced tumor rejection (30, 41). Unlike their IFN-γ -sensitive counterparts, IFN-γ -insensitive Meth A.mgR.1IC cells failed to prime na¨ıve recipients for development of Meth A immunity and were poorly recognized when injected into mice with pre-established immunity to the parental wild-type tumor cell line. Similar results were obtained with a second fibrosarcoma derived from a C57BL/6 mouse (MCA-207). The second approach employed an opposite strategy where the effects on in vivo tumor growth were assessed following restoration of IFN-γ sensitivity to tumor cells generated in IFN-γ -insensitive IFNGR1−/− mice (31). When transplanted into wild-type mice, IFNGR1-deficient RAD.gR.28 tumor cells were highly tumorigenic and formed progressively growing tumors even when injected at very low cell number (10–100 cells/mouse). In contrast, when RAD.gR.28 cells were rendered responsive to IFN-γ by complementation with wild-type IFNGR1, the resulting tumor cell line (RAD.gR.28.mgR) was highly immunogenic and failed to form progressively growing tumors in wild-type recipients even when injected at high cell number (5 × 106 cells/mouse). Demonstration that RAD.gR.28.mgR rejection occurred via an IFN-γ -dependent immunologic mechanism was evidenced by the observations that (a) rejection of RAD.gR.28.mgR cells in wild-type mice was inhibited by administration of IFN-γ mAb (31), (b) rejection was inhibited if wild-type mice were depleted of either CD4+ or CD8+ T cells (A.T. Bruce & R.D. Schreiber, unpublished observations), and (c) RAD.gR.28.mgR cells formed progressively growing tumors when injected into RAG-2−/− mice (31). Thus, the effects of using IFN-γ -insensitive tumor cells are the same as blocking IFN-γ availability in the intact mouse: Immune rejection of the tumor is inhibited. Together, these results formed the basis for the conclusion that the tumor cell is a physiologically relevant target of IFN-γ in the tumor rejection process. Subsequent studies have pointed to several effects of IFN-γ on tumor cells that could promote tumor elimination. IFN-γ ’s capacity to enhance tumor cell immunogenicity by upregulating components of the MHC class I antigen processing and presentation pathway has been shown to be sufficient for tumor rejection. IFN-γ -insensitive RAD.gR.28 tumor cells engineered for enforced expression of either TAP-1 (5) or H-2Db (A.T. Bruce & R.D. Schreiber, unpublished observations) were rejected when transplanted into na¨ıve syngeneic recipients in an immunologic manner that was indistinguishable from that of IFN-γ -responsive RAD.gR.28.mgR cells. In contrast, RAD.gR.28 cells engineered for expression of H-2Kb were not rejected (5). The finding that enforced expression of H-2Db, but not H-2Kb, caused rejection of RAD.gR.28 corresponds to the H-2Db MHC restriction displayed by protective CD8+ T cells that arise naturally in mice immunized with RAD.gR.28.mgR (A.T. Bruce & R.D. Schreiber, unpublished observations). Thus, the capacity of IFN-γ to regulate tumor cell immunogenicity via enhancement of MHC class I pathway function is a physiologically relevant action that promotes tumor rejection.

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Other known IFN-γ -dependent effects on developing tumors may also contribute to the rejection process; however, their physiologic relevance to the process has not yet been established. IFN-γ has profound antiproliferative and/or proapoptotic effects on certain tumor cells. In the former case, IFN-γ can induce expression of cell cycle inhibitors such as p21WAF1/CIP1 or p27KIP1 that bind to and inhibit the cyclin-dependent kinase CDK-2 (42) or CDK-4 (43), respectively. In the latter case, IFN-γ can induce expression of gene products such as caspase-1 (44, 45), Fas, and Fas ligand (46) that, under the proper conditions, can promote tumor cell apoptosis. IFN-γ can also stimulate tumor cells to produce the chemokines CXCL-9 (Mig) and CXCL-10 (IP-10), which, in addition to having potent chemoattractant activity for CXCR3-expressing leukocyte populations, also function as powerful inhibitors of angiogenesis (47–52). Although all the aforementioned processes likely contribute in some way to the antitumor response, the relative importance and interrelationships between the immunologic and nonimmunologic actions of IFN-γ on developing tumors in promoting tumor rejection requires further analysis. HOST CELLS AS POTENTIAL ADDITIONAL TARGETS OF IFN-γ Evidence has also been obtained supporting a role for IFN-γ and/or STAT1 at the level of the host immune system in the tumor rejection process. IFN-γ -unresponsive mice lacking STAT1 failed to reject highly immunogenic P198 tumor cells that were completely eliminated in wild-type mice (53). Similar findings have also been made using the highly immunogenic RAD.gR.28.mgR fibrosarcoma cell line that was rejected in wild-type mice but grew progressively in STAT1−/− mice (V. Shankaran & R.D. Schreiber, unpublished observations). In addition, T cells derived from STAT1−/− mice immunized with poorly immunogenic P1.HTR tumor cells in the presence of IL-12 failed to express cytolytic activity against the tumor. In contrast, T cells derived from similarly immunized wild-type mice developed potent cytocidal capacity. Mice lacking STAT6, which tend to polarize their CD4+ T cell compartment more easily into Th1 cells, spontaneously rejected poorly immunogenic P1.HTR tumor cells that grew progressively in wild-type mice (54). Thus, these studies suggest that IFN-γ ’s well-recognized STAT1-dependent promotion of CD4+ T cell polarization into Th1 cells facilitates development of the appropriate type of cellular immune response needed for tumor rejection. Another study revealed a more indirect immunological action of IFN-γ at the level of the host in preventing tumor development (55). Both GM-CSF/IFN-γ −/− doubly deficient and GM-CSF/IL-3/IFN-γ −/− triply deficient mice were found to be highly susceptible to bacterial infection, displayed acute and chronic inflammation in a variety of different organs, and developed high incidences of spontaneous lymphoma and nonlymphoid solid cancers. The incidences of infection, inflammation, and neoplasia were much reduced in mice lacking GM-CSF alone, IL-3 and GM-CSF only, or IFN-γ alone. Tumor development in the IL-3/GM-CSF/IFN-γ triply gene-targeted mice was prevented or delayed by maintaining the mice on broad-spectrum antibiotics from birth. These results suggest a role for IFN-γ , in combination with GM-CSF, in controlling chronic infections that can lead to

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a chronic inflammatory state that ultimately may result in cancer development. Clearly, the relationship between bacterial/microbial immunosurveillance and cancer immunosurveillance warrants further analysis but must await the development of in vivo models that can unequivocally differentiate between the two processes. Finally, other studies have suggested that host cells of nonimmunologic origin may also be important targets of IFN-γ in the antitumor response (56, 57). These studies report that IFN-γ can induce angiostatic effects in tumors by targeting nontransformed host cells that are in close proximity to the tumor. It is possible that the underlying mechanism of this effect is similar to the one that has already been discussed in the context of the tumor cells themselves—the IFN-γ -dependent induction in host stromal cells of the angiostatic chemokines IP-10 and Mig. THE CELLULAR EFFECTORS OF CANCER IMMUNOSURVEILLANCE Other studies have begun to shed light on the specific lymphocyte subsets that are involved in cancer immunosurveillance. Together, these studies have shown that components of both the adaptive and innate immune systems participate in the process. Girardi et al. (58) examined the relative contributions of different T-cell subsets in blocking primary tumor formation in mice lacking αβ T cells (TCRβ −/−) and/or γ δ T cells (TCRδ −/−). MCA treatment of either type of TCR−/− mouse led to an increased incidence of fibrosarcomas and spindle cell carcinomas compared with wild-type controls, thereby showing that both αβ and γ δ T-cell subsets play critical and nonredundant host-protective roles in this particular model of tumor development. However, in an initiation/promotion model of DMBA- and TPAinduced skin tumorigenesis, TCRδ −/− mice showed an increased susceptibility to tumor formation and a higher incidence of papilloma-to-carcinoma progression than wild-type mice, whereas TCRβ −/− mice did not. This result suggests that immunosurveillance may be a multivariable process requiring the actions of different immune effectors in a manner dependent on the tumor’s cell type of origin, mechanism of transformation, anatomic localization, and mechanism of immunologic recognition. NK and NKT cells represent cellular populations of the innate immune compartment that were shown to protect the host from tumor formation. C57BL/6 mice depleted of both NK and NKT cells using the NK1.1 mAb were two to three times more susceptible to MCA-induced tumor formation than wild-type controls (40). In the same study, C57BL/6 mice depleted of NK cells following anti-asialoGM1 treatment were two to three times more prone to developing MCA-induced tumors than control counterparts. Although anti-asialo-GM1 can also deplete activated macrophages, this study nevertheless supports the involvement of cells of innate immunity in blocking primary tumor development. A role for NKT cells in this process was implicated when Jα281−/− mice, which lack a large population of Vα14Jα281-expressing invariant NKT cells, were found to develop MCA-induced sarcomas at a higher incidence than their wild-type counterparts (36). Additional evidence pointing to cells of innate immunity as critical effectors of cancer immunosurveillance comes from studies of the TNF-related

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apoptosis-inducing ligand (TRAIL). A member of the TNF superfamily that induces apoptosis through engagement of the TRAIL-R2 (DR5) receptor in mice, TRAIL is expressed constitutively on a subset of liver NK cells and is induced by either IFN-γ or IFN-α/β in monocytes, NK cells, and dendritic cells (59). When injected with low doses of MCA, C57BL/6 strain mice treated with neutralizing antibodies to TRAIL (60) or lacking the TRAIL gene (61) developed fibrosarcomas at a higher incidence than wild-type controls. Moreover, C57BL/6 strain p53+/− mice treated with the same neutralizing TRAIL antibody exhibited a higher incidence of spontaneous sarcoma and disseminated lymphoma formation over a two-year span than control IgG-treated mice (60). Further study will be required to identify the specific innate cell subsets that manifest the TRAIL-dependent antitumor effects. Finally, evidence also exists showing that enhancing immune system activity leads to reduced primary tumor formation in models of MCA tumorigenesis. Mice treated with either IL-12 (62) or the prototypic NKT cell activator αgalactosylceramide (α-GalCer) (63) throughout the MCA carcinogenesis process had a reduced incidence of tumors after longer latency periods than control mice. In summary, using a variety of well-characterized gene-targeted mice, specific immune system activators, and blocking monoclonal antibodies highly specific for distinct immunologic components, a large body of work has now accumulated to support the statement that the immune system indeed functions to protect the murine host against development of both chemically induced and spontaneous tumors (Table 1).

CANCER IMMUNOSURVEILLANCE IN HUMANS Given that there is significant evidence supporting the existence of a cancer immunosurveillance process in mice, does a similar process exist in humans? Analysis of individuals with congenital or acquired immunodeficiencies or patients undergoing immunosuppressive therapy has documented a highly elevated incidence of virally induced malignancies such as Kaposi’s sarcoma, non-Hodgkin’s lymphoma, and cancers of the anal and urogenital tracts compared with immunocompetent individuals (64–66). However, the study of the incidence of cancers of nonviral origins that may take many years to develop is confounded by the variety of viral and bacterial infections to which these immunodeficient/immunosuppressed patients are susceptible and by the more rapid appearance of virally induced tumors. Nevertheless, one can draw upon three lines of evidence to suggest that cancer immunosurveillance indeed occurs in humans: (a) immunosuppressed transplant recipients display higher incidences of nonviral cancers than age-matched immunocompetent control populations; (b) cancer patients can develop spontaneous adaptive and innate immune responses to the tumors that they bear, and (c) the presence of lymphocytes within the tumor can be a positive prognostic indicator of patient survival.

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Transplant Recipients Display Increased Incidences of Malignancies Increased relative risk ratios have indeed been observed in immunosuppressed transplant recipients for a broad subset of tumors that have no apparent viral origin. Assessment of 5692 renal transplant patients from 1964–1982 in Finland, Denmark, Norway, and Sweden showed increased standardized cancer incidence ratios for colon, lung, bladder, kidney, ureter, and endocrine tumors compared to the general population (67). For example, the relative risks for colon cancer were 3.2 for men and 3.9 for women. In addition, analysis of 925 patients who received cadaveric renal transplants from 1965 to 1998 in Australia and New Zealand exhibited increased risk ratios for the development of a variety of cancers, including those of the colon, pancreas, lung, and endocrine tumors as well as malignant melanomas (68). When tumor incidence was examined in 608 cardiac transplant patients at the University of Pittsburgh between 1980 and 1993, the prevalence of lung tumors was 25-fold higher than in the general population (69). Furthermore, Penn researchers documented several examples of the increased incidence of tumors of nonviral etiology in immunosuppressed transplant patients through analysis of the Cincinnati Transplant Tumor Registry (CTTR). A review of data accumulated by this database from 1968 to 1995 found a twofold increase in risk in transplant patients for developing melanoma over that of the general population (70). Moreover, whereas only 0.3% to 0.4% of melanomas occur in the general pediatric population, the occurrence in pediatric transplant patients followed in the CTTR was 4% (70). These data complemented other studies that showed approximately fourfold increases in the incidence of de novo malignant melanoma after organ transplantation (71, 72). Finally, analysis of the CTTR showed that transplant patients were three times more likely to develop non-Kaposi’s sarcomas (73). Thus, individuals with normal immune systems who undergo immunosuppression display an increased probability of developing a variety of cancers that have not been linked to a viral etiology. This observation may indicate that immunosuppressive intervention predisposed the transplant patients either to de novo tumor formation or allowed the outgrowth of occult tumors whose growth was contained by a functioning immune system. Either way, these results suggest a protective action of immunity in preventing human tumors.

Spontaneous Tumor Recognition by Adaptive and Innate Immunity ADAPTIVE IMMUNE RESPONSES Substantial amounts of data support the concept that cancer patients can spontaneously develop specific adaptive immune responses to tumor antigens. Because the transplantation techniques used to demonstrate the presence of tumor-specific antigens in the mouse could not be employed in humans, in vitro approaches to identify immune responses to human tumor antigens needed to be developed. A systematic survey of the humoral and cellular immune

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responses of patients to their own tumors was initiated in the 1970s using an approach termed autologous typing (74). Tumor cell lines were established from a large series of patients with melanoma or other tumor types that could be propagated in vitro, and these cells were used as targets for analysis of the humoral or cellular antitumor immune responses of the autologous patient. Fibroblasts and other autologous normal cell types served as control targets to assess the specificity of the antitumor response. Using this system, a small subset of patients was identified who had specific antibody to cell-surface antigens (75, 76) or who had T cells that recognized the autologous tumor (77). The characterization of the molecular targets recognized by autologous typing was made possible by application of the gene cloning and expression systems developed by Boon and colleagues to identify tumor antigens recognized by CD8+ T cells (78, 79) and by Pfreundschuh and colleagues for antibody-defined tumor antigens (80). More recently, it has been possible to identify MHC class II restricted tumor antigens recognized by CD4+ T cells (81). A large array of immunogenic human tumor antigens has now been identified (82–84). These can be segregated into the following four classes: Differentiation Antigens, e.g., melanocyte differentiation antigens, Melan-A/MART-1, tyrosinase, gp-100; Mutational Antigens, e.g., abnormal forms of p53; Overexpressed/Amplified Antigens, e.g., HER-2/neu; Viral Antigens, e.g., EBV and HPV; and Cancer-Testis (CT) Antigens. Using the currently available methodologies, the search for immunogenic human tumor antigens continues. The ultimate objective of this work is to define the human cancer immunome—the complete repertoire of human tumor antigens eliciting an immune response in humans—and a human cancer immunome database containing over 1000 human tumor antigens has been established (https://www2.licr.org/CancerImmunomeDB/). Because of their unique characteristics, CT antigens are of particular interest (85). In adult normal tissues, their expression is limited to germ cells in the testis, whereas in cancer, a variable proportion of a wide range of different tumor types expresses CT antigens. The first members of the CT family of antigens (MAGE, BAGE, GAGE) were cloned by Boon and his colleagues using CD8+ T cells from a patient having strong CD8+ T cell reactivity to autologous melanoma cells (79). The serological expression cloning technique (SEREX) developed by Pfreundschuh and colleagues (80) to detect the humoral response to human cancer has greatly expanded the list of CT antigens as well as other categories of tumor antigens, and there are now more than 20 CT antigens or antigen families recognized in human cancer (85). The analysis of the immune response to NY-ESO-1, a SEREX-defined CT antigen, is one of the best-documented examples of an integrated, naturally occurring spontaneous immune response to a nonviral human cancer. NY-ESO-1 was identified using SEREX analysis of an esophageal squamous cell carcinoma (86). Analysis of NY-ESO-1 at the mRNA and protein levels showed that NYESO-1 expression is limited to testis, fetal ovary, and placenta, but is detected in a variety of tumors including melanoma, bladder cancer, lung cancer, and

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synovial sarcomas (87). Antibody to NY-ESO-1 has been found only in patients with NY-ESO-1-expressing tumors; no antibody has been detected in patients with NY-ESO-1-negative tumors or in normal individuals (88). NY-ESO-1 antibody is rare in patients with early stage cancer, but can be found in up to 50% of patients with advanced NY-ESO-1+ tumors. The presence of antibody appears to be antigen driven, as removal of the tumor by surgery or following chemotherapy is frequently followed by disappearance of antibody (89). CD8+ and CD4+ T cell responses to NY-ESO-1 have been detected in patients with NY-ESO-1+ tumors, and a large number of MHC class I– and II–restricted NY-ESO-1 epitopes have been defined (90–92). These cellular responses are almost invariably associated with a strong NY-ESO-1 humoral immune response, documenting the integrated spontaneous immune response to this tumor antigen. Although there are indications that patients with spontaneous NY-ESO-1 immunity have a more favorable prognosis, proof that such an association exists is difficult to establish because of the variable clinical course of cancer and the influence of chemotherapy and other therapeutic interventions. The development of immunogenic NY-ESO-1 vaccines and randomized clinical trials will undoubtedly be necessary before definitive evidence linking NY-ESO-1 immunity to patient benefit can be substantiated. A second, well-characterized example of spontaneous immune responses to developing tumors in humans comes from the analysis of paraneoplastic neurologic disorders/degenerations (PNDs). PNDs are rare autoimmune neurologic diseases that are thought to be caused by “remote effects of cancer on the nervous system” (93), i.e., they are not caused by either direct primary or metastatic tumor invasion into nervous tissue but rather may be caused by cross reactivity of host antitumor responses with cells of the nervous system. Clinically, PNDs may affect any part of the nervous system and are most commonly associated with tumors of the breast, lung, and ovary (93). In the 1980s, an immunologic link between neuronal degeneration and the presence of cancer was established by the discovery that the serum and cerebrospinal fluid of PND patients harbored high titers of antibodies that reacted with neuronal antigens present in both the affected neuronal population and the associated cancer [antigens are discussed in depth in (94, 95)]. Furthermore, CTLs have been identified in the peripheral blood (96) and cerebrospinal fluid (97) of PND patients that can react with peptides from one of these antigens. However, CTL reactivity and cytotoxicity against intact neuronal cells and antigenexpressing tumor cells has yet to be demonstrated. Data from several clinical studies suggest that the presence of neuronal-reactive autoantibodies is associated with improved prognosis in cancer patients (98–100). Specifically, these studies have noted a positive correlation between the presence of antibody and the extent of disease, response to anticancer therapy, and survival. INNATE IMMUNE RESPONSES Recent studies indicate that the innate arm of the human immune system may also discriminate between tumor cells and normal cells and thus has the potential of participating in cancer immunosurveillance. These studies have centered largely on the human MHC class I chain-related proteins

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A and B (MICA/B) that are differentially expressed on tumor cells and function as ligands for two receptors expressed on cells of the innate immune system: NKG2D and the T cell receptor on Vδ1 γ δ T cells. MICA/B are highly polymorphic nonclassical MHC cell surface glycoproteins that do not associate with β2 microglobulin, nor do they require TAP for expression (101, 102). When a panel of normal tissues was screened by immunohistochemistry for expression of these proteins, MICA expression was found only on gastrointestinal epithelium of the stomach and large and small intestines. However, MICA/B gene expression could be induced in certain nontransformed cell lines by heat shock or viral infection (101, 103). In contrast, constitutive MICA/B expression has been documented in a high percentage of primary carcinomas of the lung, breast, kidney, ovary, prostate and colon (104), melanomas (105), and hepatocellular carcinomas (106). MICA/B are recognized by an activating receptor on NK cells that is also expressed on most human γ δ T cells and CD8+ αβ T cells (107). This receptor is comprised of two subunits: a ligand-binding NKG2D subunit and either a DAP10 or DAP12 signaling subunit (108). This receptor also reacts with other ligands such as those of the ULBP family that were independently identified as cell surface markers present on transformed cells and cells undergoing stress (109, 110). Tumor cells expressing MICA/B are killed by effector cells with functional NKG2D receptors, and lysis can be inhibited by pretreating the effector cell with blocking NKG2D mAb (107). However, recognition of MICA/B has also been ascribed to the direct binding of the γ δ TCR on Vδ1 γ δ T cells, as the lysis of MICAexpressing target cells by Vδ1 γ δ T cells can be inhibited by a Vδ1 γ δ TCR mAb (111), and soluble MICA tetramers can bind specifically to transfected cells expressing various Vδ1 γ δ TCRs but not NKG2D (112). Thus, γ δ T cells possess two mechanisms to recognize the MIC markers on tumors: one involving a direct interaction with the γ δ TCR and the other mediated by a more globally expressed NKG2D activating receptor. Two data sets link MICA/B recognition to immunosurveillance. First, Groh et al. (111) demonstrated that MIC-expressing cells were recognized and killed by the Vδ1 γ δ T-cell subset, and observed a strong in vivo correlation (p < 0.0001) between MICA/B expression on tumors and tumor infiltration by Vδ1 γ δ T cells (104). Second, recent data demonstrated a correlation between downregulation of NKG2D on tumor-infiltrating lymphocytes (TILs) and the expression of MICA/B in the tumor (113). Compared with NKG2D expression in lymphocytes from patients with MIC− tumors, NKG2D expression was reduced on tumor-infiltrating CD8+ αβ T cells, γ δ T cells, and NK cells and also on peripheral blood mononuclear cells (PBMCs) from individuals with MIC+ tumors. Further analysis revealed a correlation between the presence of soluble MIC proteins in the circulation of 7/14 cancer patients and a downregulated expression of NKG2D on lymphocytes. This downregulation could be recapitulated in vitro. Results of a separate study suggested that shedding of MIC proteins from tumor cell surfaces was the result of the actions of an unknown matrix metalloproteinase (114). These observations thus establish a common mechanism of tumor recognition—and potential

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elimination—by both the innate and adaptive immune systems. The finding that soluble MIC proteins may attenuate the expression/function of NKG2D on host immune cells provides one explanation for how a growing tumor could escape cancer immunosurveillance. Recent work has established the generalizable importance of NKG2D-dependent tumor recognition in murine tumor models as well. In these studies, the overexpression of NKG2D ligands H60 and Rae-1 family members in tumors capable of growing progressively led to their rejection in an NK cell-dependent manner (115–117). In summary, a large amount of data has begun to accumulate indicating that human cancer patients indeed develop immune responses to the tumors that they bear. Although these responses may not always be able to prevent cancer development, they may nevertheless function to restrain tumor growth.

The Presence of Tumor-Infiltrating Lymphocytes Correlates with Patient Survival The third line of evidence that a cancer immunosurveillance process exists in humans comes from a growing body of evidence showing that the presence of tumorinfiltrating lymphocytes (TILs) in a cancer patient’s tumor presages an improved clinical outcome for that individual. Some of the groundbreaking studies that established a strong correlation between patient survival and the presence of TILs involved collectively nearly 900 patients with primary or metastatic melanoma (118–120). The paradigm that was established in these studies has been upheld by several recent studies involving patients with other types of cancer. In a recent analysis, Zhang et al. (121) reported a relationship between the presence of CD3+ TILs and favorable clinical outcomes in patients with advanced ovarian adenocarcinoma. In this study, 186 frozen specimens of stage III or IV ovarian cancers from patients undergoing debulking surgery were assessed by immunostaining for the presence of TILs. Of the 174 tumors that could be evaluated, 102 contained TILs, whereas 72 did not. Patients with TIL-containing tumors had five-year overall survival rates of 38% compared with 4.5% for patients whose tumors lacked TILs. In a subset of 74 of these patients who experienced complete responses to surgical debulking and chemotherapy, the five-year overall survival rate was 73.9% for those with TIL-containing tumors versus 11.9% for patients with tumors that lacked TILs. Furthermore, in a multivariate analysis, it was shown that the presence or absence of TILs and the extent of residual tumor were the only independent prognostic factors of progression-free and overall survival in these patients; other variables such as the type of chemotherapy, histologic type of the tumor, tumor grade, or patient age were not predictive of both rates. Other studies examined the prognostic significance of individual T-cell subsets that infiltrate tumors. Naito et al. (122) found that the extent of CD8+ T cell infiltration specifically into cancer cell nests correlated with the survival of patients with colorectal cancer; 56 patients with no infiltration had five-year survival rates of 50%, whereas the 23 patients showing pronounced CD8+ T cell infiltration into

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cancer cell nests had five-year survival rates of 100%. Moreover, multivariate analysis revealed that the presence CD8+ T cells in cancer cell nests was an independent prognostic factor with an impact on patient survival similar to conventional Dukes’ tumor-staging classifications. Analogous findings were made by Schumacher et al. (123) who tracked the clinical course of 70 patients with esophageal squamous cell carcinomas or adenocarcinomas. When histological analysis of the tumor was compared to clinical outcome, the presence of intratumoral lymphocytes correlated with both increased time to disease recurrence and also increased time to death over a five-year period after diagnosis. As in the aforementioned study, a multivariate analysis of the data showed that the presence of intratumoral CD8+ T cells was an independent prognostic factor for survival. Still other studies have shown similar positive correlations between NK cell infiltration and patient survival for gastric carcinoma (124), squamous cell lung carcinoma (125), and colorectal cancer (126). Thus, significant evidence links the presence of TILs to increased survival of cancer patients. Since tumors may attract distinct TIL subsets depending on their tissue of origin (127), it will be important in the future to clarify which particular immune cells are prognostic for each distinct type of cancer. Thus, after a century of controversy, substantial amounts of direct experimental data from mice coupled with correlative data from humans show that innate and adaptive immunity function together to protect the host against neoplastic disease and thereby converge on the original conviction of Burnet and Thomas: immunosurveillance exists.

IMMUNOLOGIC SCULPTING DURING TUMOR DEVELOPMENT Despite strong evidence supporting the existence of a functional cancer immunosurveillance process, immunocompetent individuals still develop cancer. This clinical reality may be explained by the existence of an immune process that facilitates the outgrowth of tumors with reduced immunogenicity that have a better chance of surviving in an immunocompetent host. Recent work from several laboratories now supports this hypothesis. Our laboratory used tumor transplantation approaches to assess the immunogenic characteristics of a large number of primary MCA-induced sarcomas generated in the presence or absence of a functional immune system (5). Tumor cells from either wild-type or RAG-2−/− mice grew progressively with similar kinetics when transplanted into RAG-2−/− recipients, indicating that there were no inherent growth differences between tumors generated in the presence or absence of an intact immune system (Figure 2A,B). Moreover, tumor cells derived from wildtype mice grew progressively when transplanted into na¨ıve immunocompetent 129/SvEv hosts (Figure 2C). In contrast, 8/20 of the tumors originally generated in RAG-2−/− mice were rejected when transplanted into immunocompetent hosts,

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Figure 2 Increased immunogenicity of tumours derived from MCA-treated RAG2−/− mice. Immunodeficient RAG-2−/− hosts were injected with a dose of 105 tumor cells derived from wild-type 129/SvEv mice (A) or RAG-2−/− mice (B). Tumor growth is plotted as mean tumor diameter of 3–5 mice inoculated with each tumor. Groups of 5–8 immunocompetent 129/SvEv × RAG-2−/− F1 mice were injected on day 0 with doses of 106 tumor cells derived from 17 individual 129/SvEv mice (C) or 20 individual RAG-2−/− mice (D) and tumor growth was monitored as above. In (D), the dashed lines denote tumors that grew progressively, whereas solid lines represent tumors that were rejected. Data from Shankaran et al. (5).

even when injected at high cell number (Figure 2D). Thus, tumors formed in the absence of an intact immune system are, as a group, more immunogenic than tumors that arise in immunocompetent hosts. Experiments performed in other laboratories have led to similar conclusions. MCA sarcomas derived from nude (128) or SCID mice (129) were rejected more frequently than similar tumors derived from wild-type mice when transplanted into wild-type hosts. In addition, two MCA-induced sarcomas derived from TCR Jα281−/− mice grew more slowly when transplanted into wild-type hosts than did sarcomas originally isolated from wild-type mice (36). In contrast, these tumors grew in a comparable manner when transplanted into Jα281−/− recipients. It was

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also shown that lymphomas derived from pfp−/− mice grew avidly when transplanted into pfp−/− mice but most were rejected when transplanted into wild-type mice (33). Finally, results from one recent study suggest that immunocompetent mice select tumors that are less sensitive to TRAIL-mediated cytotoxicity (60). MCAinduced fibrosarcomas produced in C57BL/6 strain wild-type or p53+/− mice that were treated with either control IgG, a neutralizing monoclonal TRAIL-specific antibody, or an antibody specific for asialo-GM1 throughout tumor development were tested for susceptibility to TRAIL-mediated killing in vitro. Although only 1/6 tumors derived from control IgG-treated wild-type mice and 1/8 tumors derived from control IgG-treated p53+/− mice were lysed by TRAIL, 5/6 tumors generated in antiasialo-GM1-treated wild-type mice and 5/8 tumors derived from anti-TRAIL-treated p53+/− mice displayed susceptibility to TRAIL killing. Taken together, these results show that tumors are imprinted by the immunologic environment in which they form. By eliminating tumor cells of high intrinsic immunogenicity, this imprinting process may select for tumor cell variants of reduced immunogenicity and therefore favor the generation of tumors that are either poorly recognized by the immune system or that have acquired mechanisms that suppress immune effector functions. In this manner, the immunologic sculpting of developing tumor cells provides them with mechanisms to resist the extrinsic tumor-suppressor actions of the immune system. While the shaping of tumor immunogenicity most likely occurs continuously during tumor development, the major effects of this process probably occur early when the tumor is perhaps histologically—but not clinically—detectable. It follows, then, that the immunogenicity of most clinically apparent tumors has already been attenuated to some degree by the sculpting hand of immunity.

CANCER IMMUNOEDITING: REFINING CANCER IMMUNOSURVEILLANCE Based on the studies summarized in this review, the term “cancer immunosurveillance” no longer suffices to accurately describe the complex interactions that occur between a developing tumor and the immune system of the host. As originally conceived, cancer immunosurveillance was thought to be a host-protective function carried out by the adaptive immune system only at the earliest stages of cellular transformation. In contrast, we now recognize that both the innate and adaptive immune compartments participate in the process and serve not only to protect the host from tumor development but also to sculpt, or edit, the immunogenicity of tumors that may eventually form. Therefore, we have proposed the use of the broader term “cancer immunoediting” to more appropriately emphasize the dual roles of immunity in not only preventing but also shaping neoplastic disease (5, 6). Cancer immunoediting thus represents a refinement of the original cancer immunosurveillance hypothesis but is more comprehensive in its scope. As such,

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we envisage that the cancer immunoediting process is comprised of three phases that we have termed the “three Es of cancer immunoediting:” elimination, equilibrium, and escape. In the following sections, we discuss each of these three phases in more detail (Figure 3). Specifically, we attempt to integrate our enhanced and evolving understanding of immune system-tumor interactions with ongoing work in classical tumor biology. Our intention is not to be dogmatic but rather to present a testable model that will stimulate further work in defining the molecular and cellular basis of each of the three phases of cancer immunoediting.

Elimination The elimination phase represents the original concept of cancer immunosurveillance (Figure 3A; Figure 4). If this phase successfully eradicates the developing tumor, it represents the complete immunoediting process without progression to the subsequent phases. The immune components that participate in the elimination phase are now being identified but their precise roles need to be further clarified. As an extrinsic tumor suppressor, we envisage that the immune system manifests its effects only after transformed cells have circumvented their intrinsic tumorsuppressor mechanisms (130). Immunologic rejection of a developing tumor, as in host defense to microbial pathogens, likely requires an integrated response involving both the innate and adaptive arms of the immune system (27). Initiation of the antitumor immune response (Figure 4A) occurs when cells of the innate immune system become alerted to the presence of a growing tumor, at least in part owing to the local tissue disruption that occurs as a result of the stromal remodeling processes integral to the basic physiology of solid tumor development. This stromal remodeling could result from two of the six “hallmarks of cancer” (131): angiogenesis (132, 133) and tissue-invasive growth (134). The stromal remodeling induced during these processes could produce proinflammatory molecules that, together with chemokines that may be produced by the tumor cells themselves (135), summon cells of the innate immune system to this new source of local “danger” (136, 137). Once recruited to the developing tumor mass, NKT cells, γ δ T cells, NK cells, and/or macrophages may recognize molecules, such as the ligands for NKG2D previously discussed, that have been induced on tumor cells either by the incipient inflammation or the cellular transformation process itself. In addition, γ δ T cells and NKT cells may recognize developing tumors via TCR interaction with either NKG2D ligands or glycolipid-CD1 complexes expressed on tumor cells, respectively (138). Regardless of the precise mechanism of recognition, these events lead to a common outcome that is critical for progression of the antitumor response—the production of IFN-γ . In the second step (Figure 4B), the effects of innate immune recognition of the tumor are amplified. The initial amount of IFN-γ released at the tumor site induces the local production of chemokines that recruit more cells of the innate immune system to the tumor. Products generated during remodeling of the extracellular matrix may induce tumor-infiltrating macrophages to produce low amounts of

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IL-12 (139) that stimulate tumor-infiltrating NK cells to produce low amounts of IFN-γ , which in turn activate macrophages in the tumor to produce more IL-12, leading to increased IFN-γ production by NK cells. In addition to this positive feedback system (140), the binding of NK cell–activating receptors to their cognate ligands on tumor cells stimulates even more NK cell IFN-γ production (115) that can now activate a number of IFN-γ -dependent processes—including antiproliferative (43), proapoptotic (141), and angiostatic (47, 52, 56) effects—that result in the killing of a proportion of the tumor. In addition, macrophages activated by IFN-γ that express tumoricidal products such as reactive oxygen and reactive nitrogen intermediates (142–144) and NK cells activated either by IFN-γ or via engagement of their activating receptors can kill tumor cells via TRAIL- (145, 146) or perforin-dependent (147) mechanisms, respectively. As a result of these processes, a source of tumor antigens from dead tumor cells becomes available and the adaptive immune system is recruited into the process. In the third step (Figure 4C), tumor antigens liberated by the effects of innate immunity on the tumor drive the development of tumor-specific adaptive immune responses. Immature dendritic cells (DCs) that have been recruited to the tumor site become activated either by exposure to the cytokine milieu created during the ongoing attack on the tumor by innate immunity or by interacting with tumor-infiltrating NK cells (148). The activated DCs can acquire tumor antigens directly by ingestion of tumor cell debris or potentially through indirect mechanisms involving transfer of tumor cell–derived heat shock protein/tumor antigen complexes to DCs (149, 150). Activated, antigen-bearing mature DCs then migrate to the draining lymph node (151), where they induce the activation of na¨ıve tumor-specific Th1 CD4+ T cells. Th1 cells facilitate the development of tumor-specific CD8+ CTL induced via cross-presentation of antigenic tumor peptides on DC MHC class I molecules (152–155). In the fourth step (Figure 4D), the development of tumor-specific adaptive immunity provides the host with a capacity to completely eliminate the developing tumor. Tumor-specific CD4+ and CD8+ T cells home to the tumor site, where they participate in the killing of antigen-positive tumor cells. CD4+ T cells produce IL-2 that, together with host cell production of IL-15, helps to maintain the function and viability of the tumor-specific CD8+ T cells. Tumor-specific CD8+ T cells will efficiently recognize their tumor targets [owing to the enhanced immunogenicity of tumor cells that have been exposed to the IFN-γ produced in steps 1 and 2 (5)] and will induce tumor cell death by both direct and indirect mechanisms. It is likely that these CD8+ T cells directly kill many of the tumor cells in vivo. However, these cells will also produce large amounts of IFN-γ following interaction with their tumor targets and thus should also induce tumor cell cytostasis and killing by the IFN-γ -dependent mechanisms of cell cycle inhibition, apoptosis, angiostasis, and induction of macrophage tumoricidal activity. These two scenarios are not mutually exclusive and most likely occur concomitantly; however, their relative contributions may vary among different tumors. Thus, the elimination phase of cancer immunoediting is a continuous process that must be repeated each time antigenically

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distinct neoplastic cells arise. For this reason, it is particularly noteworthy that cancer is more prevalent in aged populations where immune system function, and therefore cancer immunosurveillance, begins to decline.

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Equilibrium In the equilibrium phase (Figure 3B), the host immune system and any tumor cell variant that has survived the elimination phase enter into a dynamic equilibrium, wherein lymphocytes and IFN-γ exert potent and relentless selection pressure on the tumor cells that is enough to contain, but not fully extinguish, a tumor bed containing many genetically unstable and mutating tumor cells. We envision this period to be a crucible of Darwinian selection: Although many of the original tumor cell escape variants are destroyed, new variants arise carrying different mutations that provide them with increased resistance to immune attack. The end result of the equilibrium process is a new population of tumor clones with reduced immunogenicity, hewn from a heterogeneous parental population by the sculpting forces of the immune system. Equilibrium is probably the longest of the three phases and may occur over a period of many years in humans. Indeed, it has been estimated that for many solid human tumors there can be a 20-year interval between initial carcinogen exposure and clinical detection of the tumor (156). During this period, the heterogeneity and genetic instability of cancer cells that survive the elimination phase are possibly the principal forces that enable tumor cells to eventually resist the host’s immunological siege. It has been proposed that the “mutator phenotype” of tumor cells (157) may result from the three types of genetic instability observed in cancer: nucleotide-excision repair instability (NIN), microsatellite instability (MIN), and chromosomal instability (CIN) (158). Of the three, CIN is thought to be the predominant mechanism responsible for destabilizing genomic integrity, and the observation that cancer cell genomes display gains or losses of whole chromosomes (i.e., aneuploidy) associated with an estimated loss of 25%–50% of their alleles reflects the degree of genomic upheaval associated with the CIN phenotype (158). Clearly, genomic instability has the potential to spawn tumor variants of reduced immunogenicity, and some of these will display an enhanced capacity to grow in an unfettered immune selecting environment. A complete mechanistic understanding of the equilibrium phase will require the development of new tumor models to better define the cell-intrinsic mechanisms that generate new tumor phenotypes and to identify the tumor-sculpting immune “editors.” One clinical scenario that may illustrate the equilibrium phase in humans is the transmission of cancer from transplant donors to recipients. In these cases, transplanted organs are grossly normal and cancer-free at the time of harvest. While some donors are subsequently found to harbor disease in other anatomic sites, other transplant donors either have no clinical history of cancer or have been in durable remission from cancer prior to transplantation. Recently, Mackie et al. (159) reported the occurrence of metastatic melanoma 1–2 years post-transplant

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in two allograft recipients who had each received kidneys from the same donor. Upon subsequent analysis, it was found that the donor had been treated for primary melanoma 16 years before her kidneys were donated but was considered tumorfree at the time of her death. Two other case reports described the appearance of donor-derived melanoma in two renal transplant patients and one liver transplant recipient less than one year after these organs were transplanted from a donor with no known history of malignancy (160, 161). These observations, together with others that appear in the clinical literature (70, 162), suggest that the pharmacologic suppression of the immune systems of these transplant recipients facilitated the rapid and progressive outgrowth of occult tumors that had previously been maintained in the equilibrium phase by the donor’s competent immune system.

Escape In the escape phase (Figure 3C), tumor cell variants selected in the equilibrium phase now can grow in an immunologically intact environment. This breach of the host’s immune defenses most likely occurs when genetic and epigenetic changes in the tumor cell confer resistance to immune detection and/or elimination, allowing the tumors to expand and become clinically detectable. Because both the adaptive and innate compartments of the immune system function in the cancer immunosurveillance network, tumors most likely would have to circumvent either one or both arms of immunity in order to achieve progressive growth. Individual tumor cells may employ multiple immunoevasive strategies to elude the powerful integrated innate and adaptive antitumor immune responses to their immunogenic progenitors. Thus, it is likely that several distinct immunologically driven tumor sculpting events must occur before the final immunogenic phenotype of a malignant cell is ultimately established. Much work has recently focused on defining the molecular bases of tumor escape. It is now recognized that tumors can either directly or indirectly impede the development of antitumor immune responses either through the elaboration of immunosuppressive cytokines (such as TGF-β and IL-10) or via mechanisms involving T cells with immunosuppressive activities (i.e., regulatory T cells). Because the mechanisms that target the immune system to achieve tumor escape have been the subject of recent review articles (163, 164), they are not discussed further. Tumor escape can also result from changes that occur directly at the level of the tumor. These can include alterations that affect tumor recognition by immune effector cells [such as loss of antigen expression, loss of MHC components (165), shedding of NKG2D ligands (113), and development of IFN-γ insensitivity (31)] or provide tumors with mechanisms to escape immune destruction [such as defects in death-receptor signaling pathways (60) or expression of antiapoptotic signals such as those induced by constitutively active STAT3 (166)]. Two of these mechanisms, dysregulation of MHC class I processing and presentation and development of IFN-γ insensitivity in tumor cells, would allow tumors to escape from the events discussed in the elimination phase of the cancer immunoediting process and have,

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in fact, been identified in tumor cells. Analysis of large banks of human tumor specimens has shown that between 40%–90% of human tumors display total or selective allelic losses of HLA class I proteins (165, 167). Moreover, other components of this pathway, including TAP1 and the immunoproteasome subunits LMP2 and 7, are also frequently deficient in human tumors (168). The physiologic relevance of LMP2 deficiency in cancer is evidenced by the observation that LMP2−/− mice are more prone to the development of uterine neoplasms than their wild-type counterparts (169). IFN-γ receptor signaling dysfunction represents another potential mechanism of tumor immune escape. In one study, 4/17 (25%) human lung adenocarcinoma cell lines were found to be completely unresponsive to IFN-γ (31). The unresponsive state in these tumors was found to be caused by either the absence or abnormal function of distinct components of the IFN-γ receptor signaling pathway. In addition, unpublished work has shown that 15%–30% of primary MCA-induced fibrosarcomas derived from 129/SvEv mice display IFN-γ insensitivity (G.P. Dunn & R.D. Schreiber, unpublished observations). Clearly, identifying additional escape mechanisms will yield critical insights into how tumor cell immunogenicities are edited by the immune system.

CONCLUSIONS AND IMPLICATIONS In this review, we have summarized some of the salient data supporting the existence and physiologic relevance of a cancer immunoediting process. The recent development of sophisticated tumor models using genetically altered mice and function-blocking monoclonal antibodies has made possible the critical experiments that not only resolved the long-standing controversy surrounding the cancer immunosurveillance hypothesis of Burnet and Thomas but also led to its refinement into the cancer immunoediting hypothesis (5, 6). The continued clarification of the three Es of cancer immunoediting has important implications for cancer immunotherapy in humans. By gaining an improved understanding of the cellular and molecular processes that lead to immunologic tumor rejection in the elimination phase, it will be possible to identify which immune forces need to be augmented to facilitate natural protection against tumors of different tissue origins. By studying the equilibrium phase, it will be possible to understand the genetic processes that lead to development of tumors with reduced immunogenicities and identify the molecular targets of the cancer immunoediting process in order to gain insight into how tumor sculpting can be prevented by stabilizing tumor cell genomes. Finally, by elucidating how tumors escape immune detection and elimination, it will be possible to develop methods to determine the extent to which a tumor has been edited and devise molecular strategies to reverse these cloaking mechanisms and thus unmask tumor immunogenicity. In recent years, there has been a paradigm shift in how cancer is viewed. Rather than emphasizing the differences in the greater than 100 types of cancer, researchers have begun to consider the similarities between these seemingly disparate

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malignancies (170). Hanahan &Weinberg have codified this view by proposing that cancer cells must acquire six enabling characteristics in order to form progressively growing tumors (131). Specifically, they must be able to grow autonomously, develop insensitivity to negative growth regulation, evade intrinsic apoptotic signals, display unlimited replicative potential, develop the capacity for angiogenesis, and develop competence for invasive growth and metastasis. In the current review, we have provided strong evidence that supports the existence of the seventh “hallmark of cancer:” the capacity of a malignant cell to evade the extrinsic tumor suppressor functions of the immune system. Moreover, we have discussed the possibility that this seventh hallmark is a result of a cancer immunoediting process, wherein the malignant cell’s immunogenic phenotype—forged by its interaction with the host immune system—may determine its fitness for continued survival and growth in an immunocompetent environment. We hope a generalized recognition of this new hallmark of cancer will stimulate new efforts to elucidate the pivotal events of cancer immunoediting so that the long history of thinking on the immune system and cancer will have as its d´enouement the enhanced understanding and treatment of neoplastic disease.

ACKNOWLEDGMENTS The authors are grateful to members of their laboratories, past and present, who contributed to the work from our groups that was quoted in this review. We are also particularly grateful to Vijay Shankaran, Hiroaki Ikeda, Allen Bruce, Kathleen Sheehan, Catherine Koebel, Jack Bui, Ravindra Uppaluri, Ruby Chan, and Mark Diamond for their contributions to the development of the cancer immunoediting hypothesis and for their helpful comments during the preparation of this review. The work from the authors was supported by grants from the National Cancer Institute, the Ludwig Institute for Cancer Research, and the Cancer Research Institute. The Annual Review of Immunology is online at http://immunol.annualreviews.org

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Figure 3 The three Es of cancer immunoediting: elimination, equilibrium, and escape. As indicated by the arrows, the immune system may eliminate the tumor in either the elimination or equilibrium phases, returning the tissue to normal.

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Figure 4 A proposed model for the elimination phase of the cancer immunoediting process. The events underlying this process are described in the text. Tumor cells are in blue; nontransformed cells in gray; lymphocytes, dendritic cells (DC), and macrophages (Mac) are marked and colored appropriately. Dead tumor cells are identified as white to gray gradient circles surrounded by a dashed black line, and tumor antigens are in blue squares. Panel (A) represents the initiation of the response, wherein cells of innate immunity recognize the nascent tumor. In panel (B), the initial amount of IFN-g produced starts a cascade of innate immune reactions that result in some tumor cell death by both immunologic and nonimmunologic mechanisms. In panel (C), events of innate immunity charge the adaptive response; tumor cells killed due to the increased cytocidal activities of NK cells and activated macrophages are ingested by DCs, which migrate to the draining lymph node and present antigen to naïve CD4+ and CD8+ T cells. In panel (D), tumor-specific CD4+ and CD8+ T cells home to the tumor along a chemokine gradient where they recognize and destroy tumor cells expressing distinctive tumor antigens.

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CONTENTS FRONTISPIECE—Leonard A. Herzenberg and Leonore A. Herzenberg GENETICS, FACS, IMMUNOLOGY, AND REDOX: A TALE OF TWO LIVES INTERTWINED, Leonard A. Herzenberg and Leonore A. Herzenberg SELF- AND NONSELF-RECOGNITION BY C-TYPE LECTINS ON DENDRITIC CELLS, Teunis B.H. Geijtenbeek, Sandra J. van Vliet, Anneke Engering, Bert A. ’t Hart, and Yvette van Kooyk

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TRANSCRIPTIONAL CONTROL OF EARLY B CELL DEVELOPMENT, Meinrad Busslinger

UBIQUITIN LIGASES AND THE IMMUNE RESPONSE, Yun-Cai Liu LIGANDS FOR L-SELECTIN: HOMING, INFLAMMATION, AND BEYOND, Steven D. Rosen

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INTEGRINS AND T CELL–MEDIATED IMMUNITY, Jonathan T. Pribila, Angie C. Quale, Kristen L. Mueller, and Yoji Shimizu

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MULTIPLE ROLES OF ANTIMICROBIAL DEFENSINS, CATHELICIDINS, AND EOSINOPHIL-DERIVED NEUROTOXIN IN HOST DEFENSE, De Yang, Arya Biragyn, David M. Hoover, Jacek Lubkowski, and Joost J. Oppenheim

STARTING AT THE BEGINNING: NEW PERSPECTIVES ON THE BIOLOGY OF MUCOSAL T CELLS, Hilde Cheroutre THE BCR-ABL STORY: BENCH TO BEDSIDE AND BACK, Stephane Wong and Owen N. Witte

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CD40/CD154 INTERACTIONS AT THE INTERFACE OF TOLERANCE AND IMMUNITY, Sergio A. Quezada, Lamis Z. Jarvinen, Evan F. Lind, and Randolph J. Noelle

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THE THREE ES OF CANCER IMMUNOEDITING, Gavin P. Dunn, Lloyd J. Old, and Robert D. Schreiber

AUTOIMMUNE AND INFLAMMATORY MECHANISMS IN ATHEROSCLEROSIS, Georg Wick, Michael Knoflach, and Qingbo Xu THE DYNAMIC LIFE OF NATURAL KILLER CELLS, Wayne M. Yokoyama, Sungjin Kim, and Anthony R. French

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THE ROLE OF COMPLEMENT IN THE DEVELOPMENT OF SYSTEMIC LUPUS ERYTHEMATOSUS, Anthony P. Manderson, Marina Botto, and Mark J. Walport

DROSOPHILA: THE GENETICS OF INNATE IMMUNE RECOGNITION AND RESPONSE, Catherine A. Brennan and Kathryn V. Anderson RAGS AND REGULATION OF AUTOANTIBODIES, Mila Jankovic,

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Rafael Casellas, Nikos Yannoutsos, Hedda Wardemann, and Michel C. Nussenzweig

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THE ROLE OF SUPPRESSORS OF CYTOKINE SIGNALING (SOCS) PROTEINS IN REGULATION OF THE IMMUNE RESPONSE, Warren S. Alexander and Douglas J. Hilton

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REGULATORY T CELLS FOR IMMUNOLOGIC SELF-TOLERANCE AND NEGATIVE CONTROL OF IMMUNE RESPONSES, Shimon Sakaguchi PHOSPHOINOSITIDE 3-KINASE: DIVERSE ROLES IN IMMUNE CELL ACTIVATION, Jonathan A. Deane and David A. Fruman IMMUNITY TO TUBERCULOSIS, Robert J. North and Yu-Jin Jung MOLECULAR DEFECTS IN HUMAN SEVERE COMBINED IMMUNODEFICIENCY AND APPROACHES TO IMMUNE RECONSTITUTION, Rebecca H. Buckley PHYSIOLOGICAL CONTROL OF IMMUNE RESPONSE AND INFLAMMATORY TISSUE DAMAGE BY HYPOXIA-INDUCIBLE FACTORS AND ADENOSINE A2A RECEPTORS, Michail V. Sitkovsky, Dmitriy Lukashev, Sergey Apasov, Hidefumi Kojima, Masahiro Koshiba, Charles Caldwell, Akio Ohta, and Manfred Thiel

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T LYMPHOCYTE–ENDOTHELIAL CELL INTERACTIONS, Jaehyuk Choi, David R. Enis, Kian Peng Koh, Stephen L. Shiao, and Jordan S. Pober

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IMMUNOLOGICAL MEMORY TO VIRAL INFECTIONS, Raymond M. Welsh, Liisa K. Selin, and Eva Szomolanyi-Tsuda

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CENTRAL MEMORY AND EFFECTOR MEMORY T CELL SUBSETS: FUNCTION, GENERATION, AND MAINTENANCE, Federica Sallusto, Jens Geginat, and Antonio Lanzavecchia CONTROL OF T CELL VIABILITY, Philippa Marrack and John Kappler

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ASTHMA: MECHANISMS OF DISEASE PERSISTENCE AND PROGRESSION, Lauren Cohn, Jack A. Elias, and Geoffrey L. Chupp

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CD1: ANTIGEN PRESENTATION AND T CELL FUNCTION, Manfred Brigl and Michael B. Brenner

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CHEMOKINES IN INNATE AND ADAPTIVE HOST DEFENSE: BASIC CHEMOKINESE GRAMMAR FOR IMMUNE CELLS, Antal Rot and Ulrich H. von Andrian

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INTERLEUKIN-10 AND RELATED CYTOKINES AND RECEPTORS, Sidney Pestka, Christopher D. Krause, Devanand Sarkar, Mark R. Walter, Yufang Shi, and Paul B. Fisher

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INDEXES

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Subject Index Cumulative Index of Contributing Authors, Volumes 12–22 Cumulative Index of Chapter Titles, Volumes 12–22

ERRATA An online log of corrections to Annual Review of Immunology chapters may be found at http://immunol.annualreviews.org/errata.shtml

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Annu. Rev. Immunol. 2004. 22:361–403 doi: 10.1146/annurev.immunol.22.012703.104644 c 2004 by Annual Reviews. All rights reserved Copyright ° First published online as a Review in Advance on November 3, 2003

*View Erratum at http://arjournals.annualreviews.org/errata/immunol

AUTOIMMUNE AND INFLAMMATORY MECHANISMS IN ATHEROSCLEROSIS Georg Wick,1 Michael Knoflach,1 and Qingbo Xu2 Annu. Rev. Immunol. 2004.22:361-403. Downloaded from arjournals.annualreviews.org by HINARI on 09/01/07. For personal use only.

1

Institute for Pathophysiology, University of Innsbruck, Medical School, Fritz-Pregl-Str. 3/IV, A-6020 Innsbruck, Austria; email: [email protected] 2 Department of Cardiovascular Medicine, St. George’s Hospital Medical School, Cranmer Terrace, London SW 17 0RE, United Kingdom; email: [email protected]

Key Words aging, inflammation, heat shock proteins, infections, signal transduction ■ Abstract The present review focuses on the concept that cellular and humoral immunity to the phylogenetically highly conserved antigen heat shock protein 60 (HSP60) is the initiating mechanism in the earliest stages of atherosclerosis. Subjecting arterial endothelial cells to classical atherosclerosis risk factors leads to the expression of HSP60 that then may serve as a target for pre-existent cross-reactive antimicrobial HSP60 immunity or bona fide autoimmune reactions induced by biochemically altered autologous HSP60. Endothelial cells can also bind microbial or autologous HSP60 via Toll-like receptors, providing another possibility for targetting adaptive or innate immunological effector mechanisms.

INTRODUCTION AND DEFINITIONS The arterial wall consists of four main layers: the innermost monolayer of endothelial cells, which is separated by a basement membrane from the intima consisting of connective tissue and some SMCs, the middle layer, the so-called media, consisting of SMCs, and finally an outer connective tissue layer, the adventititia, which embeds the vessel in its surroundings. Atherosclerotic lesions emerge in the intima, and for many years general dogma considered the so-called fatty streaks, cushion-like lipid-rich elevations protruding into the lumen, as the earliest stages of the disease that later transform into advanced lesions, so-called atherosclerotic plaques (1) (Figure 1). From the viewpoint of a pathologist, arteriosclerosis can be distinguished from atherosclerosis (2), where the former condition is characterized by the thickening and hardening (sclerosis) of the arterial wall associated with a loss of elasticity due to infiltration of the intima with mononuclear cells, SMCs, and increased ECM depositions. Atherosclerosis designates a special form of arteriosclerosis that is additionally characterized by the occurrence of so-called foam cells, i.e., lipid-laden macrophages and SMCs that may rupture and release 0732-0582/04/0423-0361$14.00

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their contents into the lesional areas, so that even cholesterol crystals can form. Whereas all nucleated cells of the body express surface receptors for the cholesterol transport particles, i.e., native LDLs, macrophages and SMCs additionally carry scavenger receptors that bind biochemically altered, e.g. oxidized, LDL (oxLDL). In contrast to the classical LDL receptor, the scavenger receptor is not saturable, i.e., not downregulated by an excess of oxLDL, thus leading to an overload of cells with biochemically altered LDL (3). More recently, it has been shown that DC can also transform into foam cells, affording indirect evidence that they are capable of expressing the scavenger receptor (4). The atherosclerotic plaque is a complicated end-stage lesion that may exulcerate and even calcify. These severe lesions have a tendency to rupture at the edges, the so-called shoulder regions, provoke thrombus formation, and thus lead to the dreaded final complications such as myocardial infarction or stroke. Although arteriosclerosis is the umbrella term for these various forms of the disease, including atherosclerosis, the latter designation is now becoming the generally accepted term and is used throughout this review. It is only during the past 15–20 years that attention has also been given to the fact that inflammatory processes occur in the course of atherogenesis. This belated insight is astonishing in view of many earlier reports, some dating back more than a century, that had clearly described inflammatory processes in the walls of afflicted arteries (5). Historically, a controversy that arose in the middle of the nineteenth century relating to this issue is worth mentioning here. During this period, the two most prominent European pathologists, Karl von Rokitansky in Vienna, Austria, and Rudolf von Virchow in Berlin, Germany, had both recognized that inflammation takes place in the atherosclerotic vessel wall. Whereas von Rokitansky considered these changes to be of secondary nature, von Virchow emphasized that he assigned a primary role to them. Interestingly, our laboratory recently had the opportunity to study paraffin sections of early and late atherosclerotic lesions derived from autopsies that had been performed by von Rokitansky himself approximately 160 years ago. In the earliest of these lesions we found abundant CD3+ T cells, thus supporting the concept of von Virchow rather than that of von Rokitansky (6). Most studies during the last decade on inflammatory-immunologic aspects of atherosclerosis concentrated exclusively on advanced lesions, i.e., they did not relate to incipient stages of the disease. Furthermore, some of the classical papers as well as textbooks only relied on conventional histological procedures and did not harness immunofluorescence and immunohistological techniques.

CLASSICAL CONCEPTS OF ATHEROGENESIS Atherosclerosis is a multifactorial disease for which numerous pathogenetic concepts have been proposed. The main hypotheses are the following: Based upon a large body of earlier data, Ross formulated the response to injury hypothesis, stating that hyperlipidemia, hormone dysfunction, and the increased

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shear stress in hypertension injure the endothelium and alter the nature of the endothelial barrier to the passage of blood constituents (7, 8). Until now, a long causative list of possible injuries consisting of classical risk factors for atherosclerosis, like high levels of LDL-cholesterol or oxLDL, free radicals caused by cigarette smoking, hyperglycemia as well as infectious agents (e.g., Chlamydia pneumoniae or herpes viruses) has been assembled (9). Also, genetic susceptibility to enthothelial damage (familial and male predisposition) has been proposed (10). Owing to this endothelial dysfunction, the permeability for lipoproteins and other plasma constituents—including growth factors— increases, leading to the deposition of lipids within the vessel wall and the activation and proliferation of macrophages and SMCs. In addition, differences in expression patterns of endothelial surface molecules alter the adhesion and migration properties of T lymphocytes and monocytes. The altered-lipoprotein hypothesis postulates an initiating role of chemically altered lipoproteins, most notably oxLDL, in forming foam cells and acting as chemoattractants for SMCs and mononuclear cells into the intima (11, 12). Advocates of the monoclonal hypothesis pretend that atherosclerosis is derived from a mono- or oligoclonal proliferation of SMCs, but data supporting this concept have become sparse in recent years (13). During the past 15 years, our group has developed a new immunological hypothesis of atherogenesis (14, 15), the roots of which were immunohistological data from very early arterial changes that do not yet lead to clinical symptoms. In essence, we have shown that the first cell types found in the arterial intima at sites known to be predisposed for the later development of atherosclerotic lesions are not foam cells, but rather lymphoid cells followed by macrophages and SMCs (16). Within the T cell population in these early lesions, CD4+ clearly prevail over CD8+ cells. This observation differs from findings by van der Wal et al. (17), who described a tendency of an increased CD8/CD4 ratio in both early and late lesions. Furthermore, in our specimens the CD4+ cells were mostly activated, i.e., positive for HLA-DR and CD25. The majority of the intima infiltrating T cells carry the T cell receptor αβ (TCRαβ), but an unexpectedly high proportion of these T cells (10%–15%) are TCRγ δ +, a frequency that far exceeds that of TCRγ δ + cells in the peripheral blood (1%–2%). Further characterization of TCRγ δ +-cells revealed that TCRγ 9δ2+, a configuration that is characteristic for human peripheral blood, made up only a small proportion (1%–2%, like in peripheral blood) of this subpopulation, whereas the majority expressed the TCR Vδ1 chain that is typical for the human MALT (18). A constitutive expression of HLA-DR by endothelial cells could not be detected in our sections of unafflicted arteries or in early lesions. As a matter of fact, HLADR+ endothelial cells were only found in those instances where activated IFN-γ producing T cells were present in the underlying intima (16). However, a recent report by Buono et al. (19) showed MHC class II antigen expression on endothelial cells overlying atherosclerotic lesions in LDL-R/ IFN-γ double knockout mice.

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Granulocytes are usually not present in early atherosclerotic lesions (16, 20). B cells and NK cells are rare, but mast cells do occur in considerable numbers (21). This latter finding may not only be relevant with respect to the vascular permeability promoting effects of vasoactive peptides but also because of their profibrotic properties. In an extension of our first immunohistochemical studies, we then had the opportunity to analyze arterial specimens from a multicenter cooperative study that was begun in 1985 in the United States, the PDAY study (22). In the PDAY study, more than 3000 arterial fragments were collected from young (15–34-yearold) Americans who died from noncardiovascular causes, mostly accidents and suicides. Surprisingly, earlier histological studies of this valuable autopsy material did not address the question of an intimal inflammatory process in general, and the participation of T cells in particular. Our previous phenotypical observations summarized above could again be corroborated in the PDAY material with the following additional features: This time we also looked for CD1a DC and, in agreement with the previous results of Bobryshev et al. (23), found them to be present in the intima of all subjects. Because DC obviously form a link between the innate and the adaptive immune systems, it is of interest that Aicher et al. (24) have recently described a strong DC-activating potential of nicotine. This is reflected by the expression of costimulatory molecules (CD86, CD40) and MHC class II and adhesion molecules (LFA-1, CD54), and a sevenfold increase in secretion of the proinflammatory Th-1-activating cytokine IL-12. This observation is, of course, especially relevant in view of the known atherosclerosis-promoting effect of cigarette smoking. In contrast to our earlier investigations, PDAY specimens contained considerable numbers of CD19+ B cells, again depending on and increasing with severity of lesions. Although the present review concentrates on conventional atherosclerosis, i.e., atherosclerosis that can afflict everybody when applicable, albeit avoidable, risk factors are present, there are also other variants of this disease that emerge under very special conditions. On one hand, accelerated atherosclerosis occurs in allotransplant recipients; on the other hand, atherosclerosis develops on a clear-cut genetic basis, i.e., in experimental animals or humans lacking lipoprotein E (ApoE) or the LDL-R. While transplant atherosclerosis is mainly mediated by T cells, excessive hypercholesterolemia in the latter genetically compromised groups seems to entail a form of disease that is nearly exclusively based on foam cell formation and cholesterol deposition.

THE ROLE OF THE INNATE IMMUNE SYSTEM The repertoire of the highly conserved PRRs by cells of the innate defense system is based on a natural selection of germline-encoded genes and includes TLRs and collectins (mannan-binding lectin, surfactant). Probably fewer than 100 different

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types of receptors exist, with each recognizing restricted patterns of entire classes of pathogen ligands, called PAMPs. PAMPs are present not only on the surface of pathogens, but also in solution, e.g., as bacterial endotoxins (LPS), denatured proteins (e.g., malondialdehyde derivatized or oxidized lipoproteins), bacterial and denatured eukaryontic DNAs, mannans, teichoic acids, and a variety of other compounds (25). The binding of ligands leads to internalization of the ligandreceptor complex, activation of the cell, and the mounting of an inflammatory defensive response via activation of various transcription factors, most notably NFκB. As will be detailed below in the section dealing with the vascular-associated lymphoid tissue, cellular components of the innate immune system are already assembled in the intima of arteries in children at certain branching points, known to be predilection sites for the possible later development of atherosclerotic lesions. It should be emphasized here that these sites could be considered to be part of the surface exposed areas of the body, albeit in this instance an inner surface exposed to PAMPs and exogenous as well as autoantigens contained in the blood stream. When the rolling, adhesion, and transendothelial migration of leucocytes is prevented, either by lack of expression of adhesion molecules or chemotactic molecules, respectively, atherosclerotic lesions are greatly reduced or do not develop. Thus, atherosclerosis develops only to a minor extent in hypercholesterolemic mice deficient in VCAM-1 (26). The same is true for P-selectin (27) and ICAM-1 (28), although these latter adhesion molecules seem to play a less prominent role. MCP-1 is essential for the recruitment of monocytes into the intima. MCP-1/Apo-E or LDL-R double knockout mice do not develop atherosclerosis (29). Also, crosses of Apo-E−/− or LDL-R−/− mice with mice deficient in the CCR-2 (the receptor for MCP-1) exhibit significantly impaired development of atherosclerotic lesions (30). It has to be remphasized that oxLDL deposited in the intima acts as a monocyte chemoattractant too, and oxLDL phospholipid constituents stimulate MCP-1 expression by endothelial cells manifested, by, the induction of VCAM-1 for example (31). VCAM-1 is an adhesion molecule for both monocytes and T cells that both express the respective ligand on their surface, i.e., the integrin VLA-4. It is not yet clear how cells of the innate system are recruited toward these sites. However, it is of interest that the arterial intima of wild-type mice contain only very few, if any, DC as compared to the elaborate network of such cells in human arteries (32). This may be one of the reasons why wild-type mice are relatively resistant to the induction of atherosclerosis, be it being fed a cholesterol-rich diet or by other means. The presence of monocytes seems to be absolutely necessary for the development of atherosclerosis because hypercholesterolemic MCP-1−/− or CCR-2−/− mice develop only minor, if any, atherosclerotic lesions. Arterial intimal macrophages derived from blood-borne monocytes exert both phagocytic functions via their scavenger receptors and innate defense functions via other PRRs. The main representatives of scavenger receptors are CD36, SR-P1, and SR-A. These receptors bind oxLDL and, due to the fact that they are not saturable, entail the formation of foam cells as mentioned above. Phagocytosis in general and

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activation of macrophages via TLRs in particular lead to the generation of reactive oxygen species—the major microbial killer mechanisms—and thus transduction of inflammatory signals. An additional role for TLRs as target presenting structures that has so far not yet been clarified in detail may be due to the fact that CD14, the nontransmembrane receptor for LPS involved in the induction of nonspecific inflammation, interacts with different TLRs and that TLR-2 and TLR-4 have both been shown to bind HSPs, i.e., highly conserved molecules that act both as PAMPs and as potent antigens for adaptive immunity (33). Finally, humoral components of the innate immune system also have to be considered in this context. These include natural antibodies, complement components, acute-phase proteins, such as CRP, and MMPs and their antagonists, TIMPs. Deposits of complement components as a result of activation—via the classical, the alternative, or the mannose-dependent pathways—have been known for a long time within atherosclerotic lesions and seem to represent a transitional mechanism between innate and adaptive immunity in atherogenesis (34). It is of interest here that complement receptor-3 (CR-3)-deficient LDR−/− mice are more susceptible to atherosclerosis when compared to wild-type animals, showing a protective effect of complement activation, at least under certain circumstances (35). The association of inflammatory processes reflected by increased levels of CRP with an increased risk for atherosclerosis has now been supported by many groups, including ourselves (36, 37, 38). CRP is a useful parameter for the infectious load of a given individual. This issue is dealt with in more detail later in this review. Recently, the group of Witztum has described protection from atherosclerosis by natural antibodies with a certain idiotype (D15) directed against oxLDL (39). Natural antibodies are generated without known antigenic stimulation and belong to the IgM type produced by a special subset of innate B lymphocytes, the B1 cells. They are characterized by the expression of restricted germline-encoded B cell receptors conveying specificity for natural or self-antigens. Natural antibodies have been shown to bind oxidized phopholipids, such as POVPC, and serve to remove oxLDL, thus preventing its uptake by macrophages. Interestingly, these antibodies recognize similar oxidation-specific epitopes on apoptotic cells and are structurally and functionally identical to classical anti-PC antibodies with the D15 idiotype of B1 cell origin that is reported to provide optimal protection against pneumococcal infection (40). The authors suggest that a natural selection process for B1 cells secreting oxidation-specific D15 antibodies has been operative, both for their role in natural immune defense and for housekeeping purposes against oxidation-dependent epitopes under healthy and pathologic conditions. In a recent paper, Binder et al. (41) showed that mice immunized with pneumococci do develop D15 antibodies that protect from atherosclerosis. In conclusion, cellular and humoral components of the innate immune system certainly play a major role in atherogenesis. It is, however, not yet clear if this role is of a primary or secondary nature within the complicated network of factors contributing to the various stages of this disease.

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THE ROLE OF ADAPTIVE IMMUNITY

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Humoral Antibodies Complement activation via the classical pathway could be the result of the deposition of immune complexes in the arterial intima, or it may reflect the binding of specific antibodies to autologous or exogenous antigens localized in the arterial wall. As detailed below, the former include oxLDL and HSP60, whereas the latter comprise various types of microorganisms such as EBV, CMV, or bacteria, such a Chlamydiae. A further possibility is the activation of complement via the alternative pathway. Here again, cholesterol crystals and other lipid components have been shown to activate this pathway in vitro (42). Interestingly, complement activation also occurs in the arterial intima of rabbits shortly after beginning a cholesterol-rich diet (34, 43, 44). That intralesional complement is activated by the classical pathway is supported by the codistribution with IgG, although the specificity of such locally deposited antibodies has not yet been demonstrated. Infection has an aggravating effect on atherogenesis, most probably due to the endothelial damaging effect of circulating immune complexes (45). The candidates for antigens against which such antibodies are directed are discussed below.

Cellular Immunity In human atherosclerosis, functional studies on intima-infiltrating T cells have so far been restricted to those harvested from advanced lesions. Obviously, these are easier to obtain in the form of surgically removed tissue fragments as compared to the more interesting (at least for us) early, clinically silent incipient stages. This is also the reason why most papers advocate an intralesional preponderance of macrophages over T cells in human atherosclerosis, as well as atherosclerosis in cholesterol-fed rabbits and ApoE knockout mice. Applying RT-PCR technology, Stemme et al. (46) showed more than a decade ago that T cells in human atherosclerotic plaques are of polyclonal origin, suggesting that they are either recruited to the plaque in an activated stage or activated locally by mechanisms that do not lead to clonal proliferation. However, the possibility that these populations contain pathogenic clones with locally relevant antigenic specificity cannot be ruled out. Nevertheless, oligoclonal T cell proliferation has been demonstrated in atherosclerotic lesions of ApoE−/− mice (47). In order to probe this idea, in vitro screenings of all populations of T cells reacting with predefined, potentially atherogenic antigens should be performed. Most importantly, this type of analysis has not yet been done on cells derived from early lesions. There is no question that knockout mouse models for cholesterol-induced atherosclerosis have contributed considerably to our understanding of atherogenesis. It has to be emphasized, however, that these models do not reflect those situations in common human atherosclerosis that are induced by a variety of

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risk factors and hit nearly everybody in the Western world. The murine knockout models, such as LDL-R and ApoE knockout mice, in essence have their counterparts in genetically determined familial hypocholesterolemia in human patients. In common atherosclerotic lesions, Th1 cells expressing the cytokines IFN-γ and IL-2 prevail over IL-4-, IL-5-, and IL-10-producing Th2 cells (48, 49). This fact is also reflected by significantly elevated serum levels of neopterin, an IFNγ induced macrophage product (50, 51). IFN-γ has a proinflammatory and thus proatherogenic effect. This Th1 cell product locally activates macrophages and inhibits the proliferation of SMC and collagen synthesis. This then leads to a higher risk of plaque instability, i.e., plaque rupture. The proinflammatory effect of IFN-γ is augmented by the macrophage-derived cytokines IL-1 and TNF-α, and reflected by the induction of expression of acute-phase proteins such as IL-6 and CRP in the liver (52). In contrast, the anti-inflammatory cytokine TGF-β produced by macrophages, SMC, and Th3 cells, has a profibrotic effect, and thus promotes plaque stability. Blocking TGF-β signaling by appropriate monoclonal antibodies entails the development of larger and unstable lesions (53). Results obtained in ApoE−/− mice crossed with immunodeficient RAG1/2−/− mice originally seemed to support the idea that atherosclerosis can also develop without T cells (54, 55). However, careful recalculation of these data clearly shows a significant increase in the extent of lesion formation in these immunocompro- *Erratum mised combinations as compared to pure immunocompetent hypercholesterolemic strains (56). We have treated rabbits with high doses of monoclonal anti-CD43 antibodies, leading to nearly complete depletion of peripheral blood T cells and found that this regimen prevented the development of atherosclerosis (57). However, it must be emphasized that data published after the original production and commercial availability of this antibody have shown that CD43 is also expressed, albeit to a minor extent, by macrophages and endothelial cells, and its atherosclerosis-inhibiting effect can therefore perhaps not only be assigned to T cell depletion (57, 58). Finally, it has recently been shown that splenectomy, both of hypercholesterolemic ApoE−/− mice and human patients, leads to significantly more severe atherosclerosis (59, 60, 61). In mice, this effect could be compensated by the transfer of purified T or B cells from atherosclerotic ApoE−/− donors. Although an explanation of this interesting phenomenon is still lacking, it probably reflects the susceptibility to infections with an increased odds ratio to develop atherosclerosis.

Antigens Multifactorial diseases such as atherosclerosis are complicated by definition, but even complicated diseases have to begin by a single event, albeit not necessarily the same one in all instances. Later in this review, we show that we are of the opinion that conventional atherosclerosis is initiated by specific cellular and humoral immune reactions. Based on data from our laboratories and others, we hypothesize

*Erratum (24 Mar. 2004): See online log at http://arjournals.annualreviews.org/errata/immunol

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that atherosclerosis is started by T cells that immigrate from the blood stream into the intima via the endothelial layer and that this process is accelerated by humoral antibodies (62). What are the antigens that are recognized by these antibodies and T cells, respectively? Over the years, a great number of antigens have been incriminated as playing a role in atherosclerosis-associated immune reactions. Originally, these included undefined “endothelial surface antigens,” sperm components, herpes viruses, biochemically altered lipoproteins, oxidized lipids, cardiolipin, structural vessel wall antigens, milk proteins, and others. In recent years, the list of candidate antigens has been narrowed down to a few major groups, both exogenous and autologous. The former comprise various viral and bacterial components, and the latter β-2 GP-1 (63), as well as biochemically modified arterial wall proteins and modified LDL, such as oxLDL. Our own group has introduced the concept that a family of phylogenetically highly conserved proteins, the stress or HSPs, play a major role in the induction of the earliest atherogenic immune responses. They also represent the missing link between exogenous and endogenous disease-promoting antigens, as is discussed in detail below. Another extensively studied candidate antigen is biochemically modified LDL, i.e., oxLDL or artificially derivatized LDL such as MDA-LDL or Cu SO4 oxLDL (Cu oxLDL) (64, 65). These modifications of LDL lead to the formation of several oxidation-specific epitopes, with the oxidized PCcontaining phospholipid forming an immunodominant epitope (66). As detailed in subsequent sections of this review, the notion now has emerged that immune reactions against HSP are proatherogenic, whereas—in contrast to assumptions in earlier reports—immune reactivity against oxLDL is protective.

Heat Shock Protein 60 HSPs are expressed in prokaryotic and eukaryontic cells under physiological conditions and in response to various forms of stress (Figure 2). These were first detected in Drosophila as a response to heat (hence the name), but it later turned out that many other forms of stress exert the same effect. They are classified into various families depending on their molecular weight, ranging from the 100 kDa over the 70 kDa, 60 kDa down to low-molecular-weight families (67). HSPs fulfill a wide variety of physiological functions during the process of intracellular protein transport, protein folding, cellular signaling, and protein degradation. Under stress conditions, some HSPs associate with denaturing cellular proteins and protect them from aggregation (chaperone function) (68). With regard to atherogenesis, the 60 kDa HSP family is of special importance because the members of this family were identified by us to represent the culprit antigens in the earliest stages of atherosclerosis (14, 69). The HSP60 family comprises, among others mammalian HSP60, the mycobacterial homologue mHSP65, cHSP60, and the Escherichia coli homologue GroEL (70). The members of the HSP60 family are phylogenetically highly conserved in mammalian and bacterial

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Figure 2 Inducers of cellular stress. Various forms of stress induce transcription of HSPs via heat-shock factors (HSFs).

species. This fact forms the basis for extensive immunological cross-reactions between pathogens and autologous HSP60 (71). Other authors have provided evidence that other HSPs might also be involved in the development of atherosclerosis, for example HSP47 (72) or HSP70 (73). However, in contrast to the situation with HSP60, evidence has not been provided that immunization of experimental animals with these HSPs leads to the induction of atherosclerosis. More than 95% sequence homology exists on both the DNA and protein levels between HSP60 from various bacteria, e.g., mHSP65, cHSP60, and GroEL. Even between bacterial and hHSP60 an approximately 50%–55% sequence homology exists, and in highly conserved regions it reaches more than 70% (71). HSP60 can also be found in parasites, and even in the envelope layers of viruses such as HIV, the latter acquiring this molecule when budding off the surface of infected host cells (74). HSP60 is not only qualitatively a major microbial component, but also quantitatively constitutes an important and very immunogenic antigen. Practically all humans and animals develop humoral and cellular immunity against this antigen as a consequence of infection or vaccination, respectively. However, protective immunity may have to be “paid for” by the risk of cross-reactivity with autologous HSP60 that can, e.g., be expressed by stressed or otherwise maltreated vascular endothelial cells, as discussed below (75). Furthermore, copious amounts of HSP60 are released from the surface of stressed or damaged cells, and thus can be demonstrated in the supernatant of cell cultures or in the serum under in vivo conditions, respectively (76). We have previously shown that this latter sHSP60 can also be biochemically modified (77) and thus may lead to bona fide autoimmunity.

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In eukaryontic cells, e.g., human endothelial cells, HSP60 expression can be induced by many different types of stressors, such as mechanical stress, temperature, oxygen radicals, infections, toxins, heavy metals, proinflammatory cytokines (e.g., TNF-α), etc. (69). Importantly, the same stressors lead to the simultaneous expression of HSP60 and adhesion molecules ICAM-1, ELAM-1, and VCAM-1 (78), thus providing the prerequisites not only for an interaction of potentially bacterial/human HSP60 cross-reactive antibodies, but also of T cells with endothelial targets. At later stages of atherogenesis, intralesional macrophages and SMC also express HSP60 (18), and the anti-HSP60 cellular immune reaction could, therefore, be perpetuated in situ. HSP60 is a mitochondrial protein that can be translocated into the cytoplasm under stress conditions (Figure 3), and it is even transported to the cell surface where it seems to provide a danger signal (79, 80). In vivo treatment of rats with LPS leads to the simultaneous expression of HSP60 and ICAM-1 by endothelial cells (81). It was further shown that leukocytes attached at exactly those sites, where EC had already been subject to major haemodynamic stress, e.g., the branching points of intracostal arteries from the aorta (81). More recently, an additional possible mechanism of cell surface presentation has been described for sHSP60, i.e., passive binding to surface receptors on endothelial cells (82). On the one hand, this provides another possibility for specific T cells and antibodies to interact with their target antigen; on the other hand, receptor-bound HSP60 may trigger signal transduction via the proinflammatory MAPK pathway. HSP60 might also be a ligand for TLR-4 and TLR-6, the former in conjunction with CD14 (83, 84). Interestingly, recent data obtained in a large number of volunteers from a well-controlled prospective atherosclerosis prevention study, the Bruneck Study (85, 86), provided evidence for a significant role of TLR-4 polymorphism in the susceptibility to atherosclerosis (87). However, functional data on possible alterations of HSP60 binding to and signal transduction via certain TLR isotypes are still missing.

EXPERIMENTAL MODELS FOR IMMUNOLOGICALLY INDUCED ATHEROSCLEROSIS Rabbits The first step of our own investigations into the possible role of (auto)immune mechanisms in atherogenesis consisted of the immunization of normocholesterolemic rabbits with appropriate antigens plus CFA (88). For this purpose, groups of normocholesterolemic New Zealand white rabbits were immunized either with delipidated proteins isolated from human atherosclerotic plaques or with similarly prepared plaque proteins from Watanabe rabbits (which lack the LDL-R and develop a hereditary form of atherosclerosis), emulsified with CFA. A control group of rabbits was immunized with OVA plus CFA. We reasoned that the first two groups would develop atherosclerotic lesions if appropriate autoantigens

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were present in the plaque extracts, and the controls should remain negative. Surprisingly, all three groups exhibited macroscopically visible lesions at the known predilection sites. Upon microscopic scrutiny it was found that these lesions consisted of infiltrations of the intima by mononuclear cells and SMC, however without foam cell formation. Because CFA was the only common denominator in these experiments, normocholesterolemic rabbits were then immunized with CFA alone, and atherosclerosis again emerged in these animals. Immunization with adjuvants that—in contrast to CFA—did not contain mycobacteria, and thus were devoid of mycobacterial HSP65, such as IFA, Ribi or lipopeptide, were without effect. HSP60 is known to be a major component of mycobacteria (mHSP65) and has been discussed as a culprit bacterial-mammalian cross-reactive antigen in a variety of diseases such as RA (89, 90). We therefore repeated our experiments by immunizing normocholesterolemic rabbits with recombinant mHSP65 alone, and the same results were again observed, i.e., mononuclear cell infiltrations of the intima at those arterial sites that are known to be subjected to major turbulent haemodynamic stress (88). In rabbits, a cholesterol rich diet has been the classical way to induce experimental atherosclerosis. Therefore, we subsequently combined immunization with mHSP65 by supplementation with a cholesterol-rich diet (2% cholesterol), and observed significantly more severe atherosclerotic lesions in these animals as compared to those that were either fed a cholesterol rich diet alone or were only immunized with mHSP65 (91). Using this model, we have shown that the earliest inflammatory stage of atherosclerosis induced by immunization with mHSP65 is still reversible, whereas the severe atherosclerotic changes induced by combining immunization and feeding a cholesterol-rich diet are not. As expected, the peripheral blood of rabbits immunized with mHSP65 contained antibodies and T cells reacting with this antigen (92). Analysis of mHSP65specific T cell lines derived from the peripheral blood, or atherosclerotic lesions of immunized rabbits showed an intralesional accumulation of such cells. It was, however, surprising that we also found abundant T cells in the atherosclerotic lesions (fatty streaks and plaques) of rabbits from the control group that was only fed a cholesterol-rich diet, without concomitant immunization. When T cell lines were produced from these cholesterol-rich lesions of a given rabbit, and compared to those derived from the peripheral blood of the same animal, a significant enrichment of HSP65-reactive T cells was observed in the lesions in comparison with cells derived from the peripheral blood (92). In conclusion, HSP60 has been found to be an optimal candidate for an antigen that plays a proatherogenic role in the very early inflammatory stages of the disease in the rabbit model. These changes may progress into more severe lesions when high serum concentrations of LDL are present, entailing the formation of foam cells and extracellular lipid deposition.

Mice Wild-type mice are notoriously resistant against the induction of atherosclerosis using the previously mentioned conventional dietary cholesterol supplementation.

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Out of all the strains, C57BL6J is perhaps the most susceptible to developing some atherosclerosis upon being fed a high cholesterol diet, although still to a much lesser extent than that observed in rabbits. More recently, several knockout models have become available concerning genes and thus proteins that are crucial in lipid metabolism. These models have opened new possibilities for experimental atherosclerosis research. For example, ApoE−/− (93) and LDL-R−/− mice (94) accumulate excessive amounts of serum cholesterol and consequently develop severe atherosclerosis even when only given mildly cholesterol-enriched food, the so called Western diet. We have, therefore, also used these models in combination with various immunization procedures to study the role of immune reactions in atherogenesis. Our main interest was focused on the, at that time still-controversial, issue of whether biochemically altered LDL, i.e., oxLDL or MDA-LDL, is a possible antigenic candidate for a proatherogenic immune reaction. On the other hand, we were also interested to know if immunity to HSP60 may also lead to atherosclerosis in mice. The results of our experiments can be summarized as follows: The immunization of wild-type C57BL6J mice and ApoE−/− mice with mHSP65 or MDA-LDL, respectively, showed that the former led to an aggravation of the disease (95), whereas immunity against the latter was protective (96). Furthermore, the fact that—in contrast to the situation in rabbits—inbred mouse strains are available allowed for the demonstration of passive transfer of atherosclerosis from immunized donors to these hypercholesterolemic recipients (97). It is obvious that this new concept of atherogenesis provoked the idea that tolerization against atherogenic HSP60 epitopes may be a possible approach to prevent or even treat atherosclerosis. This principle has, in the meantime, been successfully applied in murine hypercholesterolemic ApoE−/− and LDL-R−/− models by treating these either intranasally or orally with whole mHSP65 preparations (98, 99). In contrast to the well-defined proarthritogenic and arthritis-preventing HSP60 epitopes that had been identified in the model of adjuvant arthritis in rats (100, 101), and human RA (102), atherogenic T cell epitopes have so far not yet been identified. This would, however, be of prime importance before embarking on such a preventive or therapeutic approach. The high frequency of HSP60 reactive T cells within the MALT and the occurrence of low titers of anti-HSP60 antibodies in most humans suggests that immunity against this phylogenetically highly conserved antigen has an important protective task, the complete circumvention of which may lead to higher susceptibility to a variety of different infectious diseases.

AUTOIMMUNE REACTIONS IN ATHEROSCLEROSIS HSP Expression in Atherosclerosis HSP60 expression in atherosclerotic lesions was shown by Kleindienst et al. (18). These authors reported that HSP60 was detected in endothelial cells, SMC, and

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mononuclear cells of carotid and aortic specimens showing atherosclerotic lesions. In contrast, disease-free control vessels showed no expression of HSP60 (18). Increased expression of HSP70 has been shown in human (103) and rabbit arteries, and also in DCs in the arterial wall (104). Interestingly, expression of HSP60 and HSP70 was also found to correlate with the development of atherosclerotic lesions in the aortic tree of ApoE−/− mice (105). HSP47, acting as a chaperone for procollagen, has also been found to be involved in atherosclerosis (72). These findings identified HSPs as novel constituents of human coronary atheroma and suggested that selective upregulation of HSPs by stress may play a role in atherogenesis. However, only immunization with HSP60 seems to be capable of inducing atherosclerotic lesions in experimental animals. In vitro studies have demonstrated that the heat shock response is primarily regulated at the level of transcription. It is mediated by one or more members of a family of HSFs that interact with a specific regulatory element, the heat shock element (HSE), which is present in the promoters of the HSP genes (106, 107). In scrutinizing the molecular mechanisms of HSP expression involving HSF activation in atherosclerotic lesions, we recently demonstrated that HSF1—mainly present in the nuclei—was highly expressed in the cap and valve regions of atherosclerotic lesions in oneyear-old ApoE−/− mice (108). Immunohistochemical double labeling of vascular sections indicated that a proportion of SMC in the lesions were HSF1 positive. The level and activity of HSF1 in protein extracts from atherosclerotic lesions of hypercholesterolemic rabbits were significantly higher than those of normal vessels, as identified by Western blot and gel mobility shift assays. Furthermore, TRLP, oxidized-TRLP, LDL, and oxLDL did not activate HSF1 in cultured SMC, whereas HSF1 was highly activated in cells treated with TNF-α. Interestingly, mechanical stretching of SMC resulted in HSF1 hyperphosphorylation, translocation from cytoplasm to the nucleus, followed by increased HSP70 expression (108). Thus, our findings provide the first evidence that HSF1 is activated and highly expressed in atherosclerotic lesions, and that cytokine stimulation and excessive mechanical stress to the vessel wall may be responsible for such activation (Figure 4). So far, the kinases of other enzymes responsible for HSF hyperphosphorylation are unknown. However, there is evidence indicating that HSF1 activity can be inhibited through phosphorylation of HSF1 serine residues by ERKs (109). In fact, three families of MAPKs (ERKs, JNK/SAPK, and p38MAPK) are activated in vascular cells stimulated by heat shock (110), free radicals (111), LDL and oxLDL (112), arachidonic acid (113), hyperlipidemia (114, 115), and mechanical stress (116). This indicates a possible relationship between MAPK activation and HSP expression in cells of atherosclerotic vessels. Furthermore, different stimuli seem to activate different signal pathways leading to HSF activation. In SMC for instance, mechanical stress stimulation of the integrin-rac pathway results in HSP induction, whereas H2O2 activates the JAK2-STAT pathway leading to HSP expression (117). However, further studies will be needed to clarify the molecular mechanism of HSP expression in vivo and in vitro.

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Figure 4 Signal pathways of HSP expression in vascular cells induced by various forms of stress. STRAIN indicates mechanical stress. ERK, extracellular regulatedprotein kinase; MEK, mitogen-activated protein kinase/ERK kinase; HSF, heat-shock transcription factor.

Surface Expression and Release of HSPs Although it is assumed that HSPs must be located in the cytoplasmic compartment in order to exert their function, Xu et al. (80) found that aortic endothelial cells express HSP60 on their surface after cytokine stimulation. Surface staining of endothelial cells was possible with the monoclonal antibody II-13, which recognizes amino acid residues 288–366 of HSP60, but not by ML-30, which binds to residues 315–318 or LK1, LK2-recognizing residues 383–447. Several groups (79, 118, 119, 120) have confirmed the surface expression of HSP60 in different cell types. Furthermore, Schett and coworkers (121) demonstrated that rat heart ischemia/reperfusion resulted in HSP60 release. These data suggest that HSPs are not only expressed within cells, but also on the cell surface, and can be released into the cultured medium or intercellular space in certain circumstances.

Autoimmune Reactivity Against HSP In Vivo in the Human System HUMORAL AUTOANTIBODIES Based on the experimental evidence reviewed above, the autoimmune hypothesis of atherogenesis featuring HSP60 as a major potential

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autoantigen was formulated. In 1993, our group could demonstrate a correlation of the prevalence of sonographically demonstrable carotid atherosclerosis with antibody titers against mHSP65 in a large population-based study (122). In follow-up examinations, it became apparent that high antibody titers against mHSP65 are not only associated with atherosclerosis morbidity, but also with mortality due to cardiovascular disease (CVD) (123). In addition, anti-HSP60/65 antibodies were found to be significantly increased in the saliva of patients with periodontal disease that is also possibly associated with atherosclerosis (124). Since then, many groups have assessed the impact of antibodies against different HSPs in different clinical studies. Although the laboratory method measuring anti-HSP60 antibodies remained consistent between different publications, e.g., a classical sandwich ELISA, the clinical definition of atherosclerosis is a matter of constant change. In order to evaluate the role of immunoreactivity to HSP60, either large prospective studies focusing on clinical endpoints, like stroke and myocardial infarction, or good surrogate markers for atherosclerosis, like the sonographically determined IMT, are needed. Taking into account that acute cardiovascular events can alter anti-HSP60 antibody titers (125), interpretation of results from studies relying only on blood samples obtained directly after myocardial infarction or coronary angiography close to cardiovascular events has to be made very carefully. Anti-HSP60 antibody titers drop under these circumstances due to immune complex formation with sHSP60 released from disintegrated cells. Interestingly, probands who lacked a drop of anti-HSP65 antibody titers after coronary dilatation restenosed more frequently (126). Apart from differences in the clinical definition of atherosclerosis, different authors recruited probands in different age groups. Taking all these factors into account, the literature on antibodies to HSP is difficult to compare. Some of these data are summarized in Table 1. In conclusion, antibodies against mHSP65 (as a paradigmatic bacterial HSP60) have become a well established risk factor for prevalence, incidence, and mortality owing to cardiovascular events. According to the autoimmune hypothesis of atherogenesis, these antibodies are potentially cross-reactive to human HSP60. However, not all studies could demonstrate a positive correlation with antibodies against human HSP60. This might be due to the fact that only antibody subtypes reacting against certain epitopes shared by human and mycobacterial HSP 60/65 (127, 128), or complement activating antibodies, are the key players in atherogenesis. Positive correlation or lack of correlation in the studies summarized in Table 1 might thus reflect a higher or lower percentage of a certain subtype of anti-HSP60 antibodies. The effect of antibodies against HSP70 in atherosclerosis is still a matter of debate (129, 130). T-CELL REACTION AGAINST HSP60 IN ANIMAL EXPERIMENTS AND THE HUMAN SYSTEM The pathogenetic role and specificity of intralesional T-lymphocytes is

still the subject of intensive research. A central role of T cells specific against HSP60s has been established in animal experiments. Our results in mHSP65

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TABLE 1 Clinical studies with measurement of antibodies against different HSP60s, with method of assessment of atherosclerosis, the number of cases, and their age Antibodies against

Assessment of atherosclerosis

Cases/controls

Significant correlation

Agec

References

hHSP60

CA

276/129

Yes

58

(204)

hHSP60a

Familial predisposition

32/63

Yes

12

(205)

hHSP65

IMT

750

Yes

40

(122, 123)

mHSP65

Clinical + IMT + CA

203/76

Yes

60+

(125, 206)

mHSP65

CA pos./neg.

28/12

Yes

35+

(126)

mHSP65

CA pos./neg.

b

Yes

b

(207)

mHSP65

CA pos./neg.

357/67

No

58

hHSP60 mHSP65

Yes CVE

386/386

hHSP60 hHSP60

Yes

66

No Cerebral ischaemia

180/64

Yes

(209) (209)

69

mHSP65 hHSP 60

(208) (208)

(210) (210)

CVE in follow up

239/239

Chlamydial HSP60

Yes

48

No

Chlamydial HSP60

After CVE

179/100

HSP70

CA

99/99

HSP60, 65

(211) (211)

Yes

33+

(212)

No

52

(129)

Yes

(129)

HSP60, 65

CA pos. versus healthy

357/321

Yes

HSP60, 65, 70

IMT in hypertensive probands

b

No

50

(213)

HSP60, 70

Cerebral ischaemia (clinical)

292/485

No

72

(214)

HSP70

Peripheral atherosclerosis

61/21

Yes

60

(130)

HSP70

CA pos./neg.

421

No

57

(215)

a

Complement-activating antibodies.

b c

(129)

Data not available.

Mean age or age of youngest participant.

CA, coronary angiography; IMT, intima-media thickness; CVE, cardiovascular event.

immunized rabbits as well as in rabbits that—in addition to immunization— received a cholesterol-rich diet, have been summarized above. Also, immunization of LDL-R−/− mice with HSP65 induced specific T cell reactivity against mHSP65 as well as mammalian HSP60. Transfer of lymphocytes or

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Figure 5 Bars reflect the impact (odds ratio per standard deviation unit) of the different vascular risk factors in the ARMY Study population (17- or 18-year-old clinically healthy males). Results from a stepwise logistic regression analysis of high IMT: Already in this young population, smoking is the most important risk factor. A high T cell reactivity against human HSP60 (hHSP60) equals the risk of an approximately 18 mm Hg rise in diastolic blood-pressure. Also, the humoral immune reaction against mycobacterial HSP65 (humoral reactivity) is an important risk factor. As shown in adults previously, HDL-cholesterol levels and alcohol consumption are protective factors, as is good pulmonary function measured by the maximum expiratory flow (MEF). ∗∗ P < 0.01; ∗ P < 0.05; (∗ ) P = 0.05 (130a).

isolated IgG of immunized mice into nonimmunized litter-mates enhanced lesion size (97). As mentioned, induction of tolerance against HSP65 by mucosal administration lowers the number of CD4+ T cells in plaques of cholesterol-fed LDL-R−/− mice, and can also lower the mitogenic in vitro response of lymph node T cells against HSP65 (98). In the course of the Bruneck Study (85, 86), we measured peripheral blood lymphocyte reaction against various HSPs60 in 50 males with, and 50 without, atherosclerosis, aged 50 years and above. Yet, no correlation could be found in this group with late stage atherosclerosis (B. Mayrl, unpublished results). On the other hand, specific T cell reactivity against HSP60 could be demonstrated as an independent major risk factor for early intima-media thickening in clinically healthy male 17- or 18-year-olds (ARMY Study). Antibodies against mHSP65 afforded less pronounced correlation with sonographically determinable surrogate of early atherosclerosis in this young population. The results of this study are illustrated in Figure 5 (130a). In summary, it has become increasingly clear that circulating HSP60-specific T cells are important in early atherogenesis, as their reactivity correlates with

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TABLE 2 The role of T cells and HSP60 in early and late atherosclerosis Early atherosclerosis

Late atherosclerosis

T cells in plaques are

Oligoclonal in mouse (47)

Polyclonal in human (216, 217)

T cells reactive against HSP60 in plaque

Demonstrated in rabbits (92)

Demonstrated in humans (160)

Peripheral blood T cells specific for HSP60

Positive correlation (130a)

No correlationa

Anti-HSP60 antibodies

Yes (130a)

Yes (122, 123)

a

B. Mayerl, S. Kiechl, A. Mayr, B. Grubeck-Loebenstein, G. Wick, unpublished results (Bruneck Study).

sonographically demonstrable arterial wall thickening in the young males of the ARMY Study, but not in the adult and old males of the Bruneck Study. Deducing from information obtained in other autoimmune disorders—like human autoimmune thyroiditis—lymphocytes specific against an autoantigen can mainly be detected in peripheral blood during the early phase of an autoimmune disease. As the inflammatory process continues, specific T cells can be found inside the target structure, i.e., the afflicted arteries, rather than in peripheral blood (131, 132). However, such similar information from early human lesions is still missing (Table 2).

IMMUNE REACTIONS TO oxLDL oxLDL Induces Innate Immune Response How does oxLDL trigger the events leading to the generation and/or enhancement of atherosclerotic lesions? Recently, there has been considerable progress in identifying the components of oxLDL that make it a ligand for macrophage receptors, including CD36, SR-B1, and CD14/ TLR4. For instance, the monoclonal antibody EO6 binds to intact oxLDL, blocks its binding and uptake by macrophages in a dose-dependent manner, and specifically prevents the binding of oxLDL to the scavenger receptors CD36 and SR-B1 (39, 133). Also, Miller et al. (134) demonstrated that minimally modified LDL binds to CD14, induces macrophage spreading via TLR4/MD2, and inhibits phagocytosis of apoptotic cells. Following TLR4/MD activation, NF-kB can be activated, and proinflammatory cytokines are released. These data strongly indicate a common innate immune response to apoptotic cells and oxLDL via competitive binding to macrophage scavenger receptor (135, 136). Therefore, oxLDL promotes foam cell formation participating in early lesion development in the intima mediated by innate immune reactions, which may progress to advanced lesions in the presence of other proatherogenic factors (137). One of the earliest responses induced by oxLDL is an increase in the expression of VCAM-1 on the arterial endothelial surface (26), a key adhesion molecule

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for monocytes and T cells. oxLDL is itself directly chemotactic for monocytes and T cells (3, 138). Among other biological effects, oxLDL is cytotoxic for endothelial cells (139), mitogenic for macrophages and smooth muscle cells, and it stimulates the release of MCP-1 and MCSF from endothelial cells (31). The oxidative modification hypothesis has been mentioned above and was extensively reviewed by Steinberg (137).

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Adaptive Immune Response to oxLDL As described above, circulating IgG and IgM antibodies against oxLDL, MDA– LDL and CuOx–LDL, are present in the plasma of animals and humans, and form immune complexes with oxLDL in atherosclerotic lesions (140, 141). The presence and titer of these antibodies closely correlate with atherosclerosis progression and regression, respectively, in murine models and also with the degree of lipid peroxidation (142). Several studies have shown that plasma titers of antibodies against oxLDL epitopes, particular of the IgG class, correlate with the presence of risk factors in patients with coronary heart disease (143). Because many variables affect such titers in humans, the clinical utility of such measurements remains to be determined. T cells isolated from human atherosclerotic plaques were shown to be specifically reactive to oxLDL (144). One fourth of all CD4+ T cells cloned from human plaques recognized oxLDL in an HLA-DR-restricted fashion. oxLDL-specific T cells are present in lymph nodes of ApoE−/− mice (145), which afford strong humoral, as well as cellular, immune responses to such modified lipoproteins (47). In humans, oxLDL induces activation of a subset of peripheral T cells. The immune response to oxLDL seems to play a pathogenetic role in atherosclerosis because lesion progression can be inhibited by immunization or induction of neonatal tolerance with oxLDL (59). It seems paradoxical that both tolerization and hyperimmunization can reduce the extent of disease; this may be due to the different effector pathways activated by these two kinds of treatment.

INFECTIONS, IMMUNITY, AND ATHEROSCLEROSIS It is well established that smoking, diabetes mellitus, hypertension, and high blood cholesterol levels are classical risk factors for atherosclerosis. On the other hand, growing evidence indicates that microorganisms play a role in the pathogenesis of the disease and may be a primary risk factor in people who do not suffer from other established risk factors (146). It was found that infectious organisms reside in the wall of atherosclerotic vessels, including CMV and C. pneumoniae. Seroepidemiological studies demonstrate an association between pathogen-specific IgG antibodies and atherosclerosis (147, 148). However, the data are inconsistent with other studies showing no increased risk for atherosclerosis (149). One possible explanation for this disparity is that infections contributing to atherosclerosis risk may depend, at least in part, on the host response to the pathogen, i.e., innate

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and adaptive immune reactions. Trials by Zhu et al. (150), together with a clinical investigation by Espinola-Klein et al. (151), support the notion that a significant association exists between the number of infectious organisms a person has been exposed to and the extent of atherosclerosis. Epstein postulates the “pathogen burden” to be of significance, whereby multiple pathogens are involved in atherogenesis. The increased “pathogen load” augments the risk for CAD (152), implying that the coexistence of several organisms in the vessel wall has a synergistic effect in the induction of vessel injury. In vitro experiments have shown that C. pneumoniae infects macrophages, the vascular endothelium, and vascular SMC (153). This organism is capable of replicating within aortic endothelial cells. C. pneumoniae may also have a tropism for macrophages, which in turn accumulate in atherosclerotic plaques. This is supported by studies of postmortem specimens of vascular tissue, which found a high correlation between the distribution of atherosclerosis and C. pneumoniae as well as other microorganisms. In normal, nonatherosclerotic vessels these pathogens were absent (154). C. pneumoniae contributes to atherogenesis in a variety of ways. One mechanism is activating innate immune reactions by its ability to promote macrophages into becoming lipid-filled foam cells (155). This is due to an effect of LPS in the cell wall of the microorganism which, in one study, has been shown to be an independent factor in the accumulation of LDL by macrophages (156). It has also been reported that cHSP60 protein, a constituent of the bacteria, is involved in stimulating macrophages to secrete TNF-α and to synthesize MMPs (157). Thus, bacterial infections could also enhance lesion development via activation of innate immune responses. Bacterial infections can exacerbate a pre-existing plaque via activation of T lymphocytes and nonspecific inflammatory processes, which can lead to destabilization of the fibrous cap of the lesions (158). C. pneumoniae produces large amounts of HSP60 during infection, which is thought to play a role in atherogenesis (159). In fact, T cell lines established from human atherosclerotic plaques have been demonstrated to specifically react with bacterial products of C. pneumoniae, including membrane proteins and cHSP60 (160). These HSP reactive T cells and antibodies can in turn evoke autoimmune responses in humans owing to antigenic cross-reactivity.

THE VASCULAR-ASSOCIATED LYMPHOID TISSUE In the course of our immunohistological studies of early arteriosclerotic lesions, we originally also included, as a negative control, the carotid branching area from a single one-year-old baby who had died from an accident. Surprisingly, we observed accumulations of considerable numbers of mononuclear cells at those areas that are known to become predilection sites for atherosclerotic lesions later in life (16). We then embarked on a series of more detailed studies of this phenomenon, including carotid and other arterial specimens from many clinically healthy babies, children, and young adults aged 8 months to 16 years. These studies revealed that

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mononuclear cell infiltration at these special sites started with T cells, followed by macrophages, SMC, and a few scattered mast cells. In very young children (8 months to 8 years), macrophages did not show the characteristics of foam cells, and extracellular lipid deposits were not yet detectable in the intima (161). This observation argues in favor of the pre-existence of mononuclear cell infiltrations that are not triggered by subendothelial lipid influx. Only older children showed the beginning of lipid accumulation paralleling that of healthy adults. In the CD3+ population, CD4+ cells generally predominate over CD8+ cells. Most T cells carry the TCR α/β, but TCR γ /δ + cells were again present in a proportion that significantly exceeds that in the peripheral blood of the same individual (161). In analogy to the MALT, we designated these mononuclear cell infiltrations as the VALT. Similar to the MALT, we tentatively assigned a similar function to the VALT, i.e., as a local immune-monitoring site for exogenous or autologous potentially harmful antigens passing by in the circulation. The mononuclear cells that make up the VALT are, of course, less abundant than those in accumulations of the MALT, e.g., the GALT, especially with respect to the lack of B cells (15, 162). Interestingly, however, the VALT has proven to be very rich in DC. We have recently made the unexpected discovery that the intima of arteries—but not of veins—contains a so-far-unreported network of DC that is especially dense in the VALT area, where it resembles that formed by Langerhans cells in the skin (32). Bobryshev and colleagues (23) earlier pointed out the existence of DC within advanced atherosclerotic lesions, whereas our studies were performed exclusively on arterial sections of children not yet affected by the disease. Comparing the DC phenotypes in atherosclerotic lesions and in healthy intima revealed a similar pattern of phenotypic characteristics, i.e., CD1a+ S100+ MHC II+ lag+, but a difference with respect to activation markers because DC in healthy arterial intima lack CD86 and CD83 (32). Because these latter two molecules, among others, are characteristic for mature DC that are able to stimulate naive T cells, it appears that immature DC found in the healthy intima transform into mature cells during atherogenesis. So far, we cannot present any functional data that would define the stimulators or timepoint of vascular-associated DC maturation because fresh arteries from children are fortunately only very rarely available. Finally, it has recently been shown that the vascular-associated DC may represent as a reservoir for HIV in AIDS patients (163) and pathogenic PrPsc in Creuzfeld-Jacob disease, respectively (164). In the latter case, this finding may be of relevance for the clarification of the question of how PrPsc from BSE-contaminated meat is transported from the gut to the central nervous system. Although we do not yet have any definitive data on the route of immigration of mononuclear cells to the VALT area, or the specificity of the involved T cells, indirect evidence based on the distribution of certain adhesion molecules on endothelial cells as well as the composition of ECM molecules may provide certain clues in this respect (165). A constitutive basic expression of ICAM-1 and P-selectin by endothelial cells in the VALT area of normal carotid arteries has been found, thus

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confirming the work of other authors. ELAM-1 was not found on endothelial cells in any of the specimens investigated, explaining the lack of neutrophils that are known to preferentially adhere via this adhesion molecule. VCAM-1 expressed by both endothelial cells and by macrophages within the VALT may be instrumental in recruiting further mononuclear cells and the subsequent development of arteriosclerotic lesions. It should be re-emphasized here that different stress factors, notably the classical atherosclerosis risk factors, can simultaneously induce the expression of HSP60 as well as an upregulation of adhesion molecules ICAM-1, VCAM-1, and ELAM-1 (78). The ECM molecules, together with other factors, such as cytokines and growth factors, are known to crucially contribute to the microenvironment of any tissue, including arteries. The cells of the immune system are known to interact with ECM in many ways, resulting in the promotion or inhibition of their migration and function. They support cellular migration, e.g., collagen triple helices acting as conveyer belts for the movement of DC, whereas T cells show a similar pattern of migration depending on the three-dimensional structure of the ECM environment, e.g., via collagen-binding sites of VLA-1 and VLA-2. The ligand binding to these receptors induces T cell stimulation, resulting in the synthesis of cytokines and increased migration (166).

INFLAMMATION AND ATHEROGENESIS Inflammatory Mediators Although an association of infections with the development of atherosclerosis has been discussed for a long time, and was well supported by anecdotal evidence, strictly controlled epidemiological studies including the exact determination of mediators of inflammation have only been performed in recent years. In our own work within the framework of the Bruneck Study, chronic infection has been found to be significantly associated with the presence and extent of atherosclerotic lesions (38, 166a). Significant differences between study participants with and without chronic infections emerged with respect to the following serum markers of inflammation: white blood cell count, neutrophil count, CRP, α1-antitrypsin, ceruloplasmin, sICAM-1, sVCAM-1, sE-selectin, endotoxin, and sHSP60. When odds ratios (95% CIs) for new carotic plaques were calculated for chronic infection status according to subject subgroups and adjusted for age, sex and baseline atherosclerosis, only CRP, sVCAM-1, sE-selectin, endotoxin, and sHSP60 showed a significant association. In previous studies, CRP has been found to be elevated in patients with myocardial infarction and was also found to be an independent indicator for future coronary events (167). In our cohort, we did not determine IL-6 levels because it is considered to be a much less stabile marker of systemic inflammation than CRP. The role of inflammatory mediators in atherogenesis has been discussed both with respect to its inhibitory potential and its ability to promote (168, 169).

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Proatherogenic mediators include IFN-γ , IL-8 (CXCL8), IL-12, IL-1β, IL-18, CD40–CD154, MCP-1, CCL-2, leukotriene P4 (LTP4), and 12/15 lipoxygenase products, whereas antiatherogenic properties have been assigned to IL-4, IL-10, PPR-γ , TGF- β, and PDGF-β. IFN-γ −/− × ApoE−/− double KO-mice develop less-pronounced atherosclerotic lesions than ApoE−/− only controls, and these are characterized by low abundance of macrophages and less-pronounced ECM deposition (170). IL-18, a Th-1 IFN-γ -inducing cytokine, promotes the development of atherosclerotic lesions in ApoE−/− mice, which are characterized by an excessively high number of activated (MHC II+) intralesional T cells (171). In contrast, the macrophagedeactivating cytokine IL-10 protects hypercholesterolemic LDL-R−/− mice from atherosclerosis (172). Considering what has been said so far about the cellular makeup of atherosclerotic lesions, it is not surprising that chemokines have been found to be of relevance in the development of the disease. Specifically, MCP-1 (CCL-2) and the expression of its receptor CCR-2 exert a proatherogenic effect (30). Activation and chemotaxis of monocytes by various chemokines, notably those of a CXC group, has been proven in vitro and in vivo, speaking for a role early in the disease process. Other members of the chemokine family, such as IFN-inducible protein-10 (CXCL-10), fractalkine (CX3 CR13), eotaxin (CCL-11) thymus- and activation-regulated chemokine (CCL-17), and macrophage-derived CCL-22 can be demonstrated in advanced lesions, although their potential role early in the disease process remains to be elucidated (168). These latter chemokines may also affect plaque stability and plaque remodeling, respectively. The possible contribution of fractalkine to atherogenesis has been deduced from the observation that certain polymorphisms in the CX3CR1 (human fractalkine receptor) gene are associated with an increased incidence of CAD (173). Involvement of LTP4, a potent leukocyte-attracting chemokine, has been suggested based on the antiatherogenic effect of an LTP4 receptor antagonist in LDL-R−/− mice. Furthermore, disruption of the 12/15-lipoxygenase gene diminished atherosclerosis in ApoE−/− mice (174). Finally, considerable attention has been paid in recent years to the CD40CD40 ligand (CD154) interaction as a mediator of inflammation in general, and during atherogenesis in particular. When CD40+ endothelial cells, macrophages, and SMC are treated with CD40-L, proatherogenic factors are induced in these cells, such as proinflammatory cytokines, chemokines, growth factors, and MMPs. When the CD40-CD154 interaction is blocked in LDL-R−/− mice with specific neutralizing monoclonal antibodies, the development of atherosclerosis is significantly reduced (175, 176). The role of CD40-CD40L interaction in atherosclerotic plaque rupture is discussed below.

Soluble HSP 60 In the Bruneck Study involving 826 patients, Xu et al. (77) demonstrated that sHSP60 levels were significantly elevated in subjects with prevalent/incident

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Figure 6 Risk of carotid atherosclerosis according to baseline serum concentrations of sHSP60, chronic infection, and the logistic regression analysis of incident carotid atherosclerosis on sHSP60 categories and chronic infection (77).

carotid atherosclerosis and correlated with arterial IMT (Figure 6). Interestingly, sHSP60 was also correlated with anti-LPS, anti-Chlamydia, and anti-HSP60 antibodies, inflammation markers, and a history of chronic infections. The concentration of sHSP60 in some patients was >1 µg/ml, which is enough to produce extracellular-based signaling. Concomitantly, Pockley et al. (177) found that sHSP60 was increased in patients with borderline hypertension, and associated with an increased IMT and early atherosclerosis. Lewthwaite et al. (178) studied 229 civil servants and provided evidence that sHSP60 is associated with physiological and psychosocial stress. Previously, Sethna et al. (179) had reported that M. tuberculosis HSP60 could be detected in the sera of patients with tuberculosis. The source of the soluble HSP is currently not known, and the mechanisms of their release has not been identified. There are a number of theoretical possibilities. First, the presence of the infectious organism within the host cells could lead to increased synthesis of HSP as an immune defense mechanism by the host cell to protect itself from the effects of the bacteria. The effects these extracellular proteins exert on the body may include a cytokine-like activity (157). A second possibility could be that infectious agents such as C. pneumoniae, which eventually lyse the infected cell as part of their replication cycle, cause the release of these typically intracellular proteins (180). An argument in favor of this hypothesis is that sHSP60 levels are significantly correlated with antichlamydial antibodies (77), and both chlamydial and human HSP60s exist at high levels in human atherosclerotic lesions (159). Third, the elevation of soluble HSP could reflect the general inflammatory processes that are occurring within the vascular wall during CAD. Fourth, sHSP60 may be released from necrotic cells in the plaque, as studies have shown the presence of cell death within atherosclerotic lesions (181, 182). Lastly, cell-surface HSPs may be released into the circulation from apoptotic cells via the formation of microparticles (183–186), which have been detected in the circulation of patients suffering from acute coronary syndromes and in nonischemic patients.

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INFLAMMATION AND ATHEROSCLEROTIC PLAQUE RUPTURE

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C-Reactive Protein CRP is an acute-phase protein that is involved in inflammatory processes. Levels of CRP were associated with the presence of carotid atherosclerosis in a large community-based cohort. Elevated CRP levels may increase the atherosclerotic burden, explaining part of the increased risk of cardiovascular events in individuals, particularly women (187). Liuzzo et al. (188) demonstrated early on that elevated CRP correlates with an adverse short-term prognosis in selected patients with coronary atherosclerosis. Half of all patients with coronary heart disease have persistently elevated CRP after discharge, a finding associated with recurrent episodes of plaque instability and infarction (37). CRP may not only be a marker of inflammation and atherosclerosis, it may also be an active component participating in atherogenesis (167, 189, 190, 191). It binds to lipoproteins and activates the complement system via the classical pathway. CRP deposits in the arterial wall early during lesion formation and is colocalized with the terminal complement complex. This suggests that CRP may promote atherosclerotic lesion formation by activating the complement system and is involved in foam cell formation, which may be caused in part by the uptake of CRP-opsonized LDL (191).

CD40/CD40L The CD40 receptor has been shown to be present on the surface of endothelial cells, smooth muscle cells, macrophages, T lymphocytes, and platelets within human atheroma (192, 193). The proatherogenic functions of CD40 ligation include augmented expression of matrix metalloproteinases, procoagulant tissue factor, chemokines, and cytokines (194–196). Indeed, interruption of CD40 signaling not only reduced the initiation and progression of atherosclerotic lesions in hypercholesterolemic mice in vivo (176, 197), but also modulated plaque architecture in ways that might lower the risk for causing thrombosis (175). Although in vitro and in vivo studies established that CD40 signaling participates in atherosclerosis, the initial trigger for CD40/CD40L expression within atheroma may be regulated by oxidized LDL. In addition to the 39 kDa cell membrane–associated form, CD40L also exists as a soluble protein, termed sCD40L (198). Although lacking the cytoplasmic, the transmembrane region, and parts of the extracellular domains, this, the soluble form of CD40L, is considered to possess biological activity. It was recently demonstrated that elevated plasma concentrations of sCD40L predict risk for future cardiovascular events (199). Of note, patients with unstable angina express higher sCD40L plasma levels than healthy individuals or patients with stable angina (200). Thus, CD40/CD40L may be a mediator in the inflammatory responses during the development of atherosclerosis.

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DIAGNOSTIC, PROGNOSTIC, AND THERAPEUTIC CONSEQUENCES It has been emphasized throughout this review that our own scientific interest in atherogenesis is highly focused on the earliest stages of the disease. Although it is common knowledge that numerous factors contribute to the pathohistological and clinical features of late and finally life-threatening complicated lesions, atherosclerosis—like any other disease—must start by a single pathogenic event, probably not necessarily the same in each patient. The elucidation of these earliest effector mechanisms stands at the center of our own scientific endeavors. We consider this issue not only to be of scientific interest, but also of utmost clinical importance. If this earliest stage can be appropriately diagnosed, most desirably, by a simple blood test, preventive and therapeutic measures could be taken to curtail further progression into more advanced, clinically relevant stages. Except for the genetically determined cases of hypercholesterolemia, we are convinced that the earliest events in atherogenesis are of an immunologic inflammatory nature with the reactivity of the adaptive and perhaps also innate immune system against HSP60 playing a primary role. Animal experiments as well as human studies performed by us and in other laboratories point to an initiation of the disease by HSP60-reactive T cells and an acceleration of the inflammatory intimal lesion development by humoral anti-HSP60 antibodies. A combination of HSP60-specific humoral and cellular immune reaction, therefore, had emerged as a new diagnostic parameter reflecting the risk to develop atherosclerosis independent of other classical risk factors. So far, the relative weight of microbial-human anti-HSP60 cross-reactivity and bona fide anti-HSP60 autoimmunity, respectively, has not been determined. Also, the identification of atherogenic B and T cell HSP60 epitopes is not yet concluded. Achieving these latter goals will allow for the design of more specific diagnostic tests. Furthermore, the induction of tolerance against such atherogenic peptides may minimize the risk for increased susceptibility to infections that may emerge when tolerance is induced against the whole HSP60 molecule. Finally, HSP60-specific anti-inflammatory and/or immunosuppressive measures may be indicated when early atherosclerosis is diagnosed. The significant association of serum levels of acute phase proteins as well as parameters reflecting an individual’s infectious load with sonographically demonstrable atherosclerotic lesions have prompted clinical trials aimed at assessing the effect of anti-inflammatory and antibiotic therapeutic strategies. In depth discussion of this is beyond the scope of the present review. It should be mentioned, however, that we have shown that aspirin leads to a downregulation of the expression of adhesion molecules but not HSP60 by endothelial cells in vitro (201). Furthermore, it is noteworthy that the immunosuppressive drug cyclosporin A has been identified as a potent inducer of HSP60 expression by endothelial cells (201), an observation that may explain the increased development of atherosclerosis in patients treated with this drug (202). The lipid-lowering drugs of the statin family have long been known to

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also have anti-inflammatory and immunosuppressive effects, the molecular basis of which may be a change in plasma membrane viscosity, and thus alteration of cell surface receptor function (203, 203a). Finally, it is conceivable that interference with HSP60 expression by endothelial cells may prevent atherosclerosis, and we are in the process of addressing this issue.

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CONCLUSIONS In this review, we put our new autoimmune hypothesis for atherogenesis in the context of other data that speak for an important role of inflammatory-immunologic processes. Our particular focus of attention is on the very earliest stages of atherosclerosis, where HSP60 expression by arterial endothelial cells subjected to classical atherosclerosis risk factors, such as high blood pressure, smoking, increased blood cholesterol levels, diabetes, infections, etc., induce HSP60 expression at the known predilection sites for the development of atherosclerotic lesions. These HSP60 positive endothelial cells then become the target of pre-existent innate and adaptive cellular and humoral immunity against cross-reactive microbial HSP60 epitopes or bona fide autoimmunity to altered self-HSP60 (Figure 7). The first cells invading the intima have been identified as HSP60-reactive T cells followed by macrophages and SMC. Our concept is that HSP60-reactive T cells initiate the disease while anti-HSP60 antibodies play an accelerating role that still awaits confirmation in the human system. ACKNOWLEDGMENTS The work of the authors was supported by the Austrian Science Fund (FWF), the Merkur Insurance Company, and the Austrian Ministry of Defense. We would also like to acknowledge the contribution of those authors of our group over the years, the work of which is cited in the review. We thank Ms. Christina Mayerl and Dr. Gerald Pfister for providing Figures 1 and 3, respectively, Ms. Barbara Gschirr, Ms. Ilona Atzinger for the expert secretarial and artwork help, and Dr. Blair Henderson for the careful assessment of the manuscript for the proper use of the English language.

APPENDIX Abbreviatons ARMY Study—Atherosclerosis Risk-Factors in Male Youngsters Study BSE—bovine spongiform encephalopathy CAD—coronary artery disease CCR-2—chemokine receptor-2 CD—cluster of differentiation

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CD40L—CD40 ligand CFA—complete Freund’s adjuvant cHSP60—chlamydial 60 kDa HSP CMV—cytomegalovirus

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CRP—C-reactive protein DC—dentiritic cells DNA—deoxyribonucleic acid EBV—Epstein Barr Virus ECM—extracellular matrix ELAM-1—endothelial leukocyte adhesion molecule 1 ERKs—extracellular signal-regulated kinases GALT—gut-associated lymphoid tissue GroEL—HSP60 of E. coli hHSP60—human 60 kDa HSP HLA—human leukocyte antigen HSF—heat-shock transcription factor HSP—heat-shock protein ICAM-1—intercellular adhesion molecule-1 IFA—incomplete Freund’s adjuvant IFN-γ —interferon gamma IgG—immunoglobulin G IL-2—interleukin-2 IMT—intima-media thickness JAK2-STAT-pathway—Janus kinase2 signal transducers and activators of transcription-pathway JNK/SAPK—c-Jun NH2-terminal kinase/stress-activated protein kinase LDL—low-density lipoproteins LFA-1—lymphocyte function–associated antigen-1 LPS—lipopolysaccharide MALT—mucosa-associated lymphoid tissue MAPK—mitogen-activated protein kinase MCP-1—macrophage chemoattractant protein-1 MCSF—monocyte colony-stimulating factor MDA-LDL—malondialdehyde LDL MD-LDL—malondialdehyde-modified LDL mHSP65—mycobacterial HSP65 MMP—matrix-metalloproteinase

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NF-κB—nuclear factor κB NK cells—natural killer cells OVA—ovalbumin oxLDL—oxidized LDL PAMPs—pathogen-associated molecular patterns PC—phosphatidylcholine

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PDAY study—Pathobiological Determinants of Atherosclerosis in Youth study PDGF-β—platelet-derived growth-factor beta POVPC—1-palmytoyl–2 (5-oxo-valeroyl)–sn glycerol-3 phosphorylcholine PPR—peroxisome proliferators–activated receptor γ PrPsc—prion protein PRR—pattern-recognition receptor RA—rheumatoid arthritis RT-PCR—reverse trascriptase polymerase chain reaction sHSP60—soluble form of HSP60 SMC—smooth muscle cell SR-B1—scavenger receptor B1 TCR—T cell receptor TGF-β—Transforming growth-factor beta Th1—T helper cell 1 TIMPs—tissue inhibitors of metalloproteinases TLR—Toll-like receptor TRLP—triglyceride-rich lipoprotein VALT—vascular associated lymphoid tissue VCAM-1—vascular cell adhesion molecule-1 VLA-1—very-late-activation antigen-1 β-2 GP-1—beta-2 glycoprotein-1 The Annual Review of Immunology is online at http://immunol.annualreviews.org

LITERATURE CITED 1. Stary HC, Chandler AB, Dinsmore RE, Fuster V, Glagov S, et al. 1995. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the

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JL, Rader DJ, et al. 2001. Absence of 12/15-lipoxygenase expression decreases lipid peroxidation and atherogenesis in apolipoprotein e-deficient mice. Circulation 103:2277–82 Palinski W, Witztum JL. 2000. Immune responses to oxidative neoepitopes on LDL and phospholipids modulate the development of atherosclerosis. J. Intern. Med. 247:371–80 Stemme S, Faber B, Holm J, Wiklund O, Witztum JL, Hansson GK. 1995. T lymphocytes from human atherosclerotic plaques recognize oxidized low density lipoprotein. Proc. Natl. Acad. Sci. USA 92:3893–97 Zhou X, Stemme S, Hansson GK. 1996. Evidence for a local immune response in atherosclerosis. CD4+ T cells infiltrate lesions of apolipoprotein-Edeficient mice. Am. J. Pathol. 149:359– 66 Epstein SE, Zhou YF, Zhu J. 1999. Infection and atherosclerosis: emerging mechanistic paradigms. Circulation 100:E20–28 Folsom AR, Nieto FJ, Sorlie P, Chambless LE, Graham DY. 1998. Helicobacter pylori seropositivity and coronary heart disease incidence. Atherosclerosis Risk In Communities (ARIC) Study Investigators. Circulation 98:845–50 Danesh J, Collins R, Peto R. 1997. Chronic infections and coronary heart disease: is there a link? Lancet 350:430– 36 Danesh J, Peto R. 1998. Risk factors for coronary heart disease and infection with Helicobacter pylori: meta-analysis of 18 studies. BMJ 316:1130–32 Zhu J, Nieto FJ, Horne BD, Anderson JL, Muhlestein JB, Epstein SE. 2001. Prospective study of pathogen burden and risk of myocardial infarction or death. Circulation 103:45–51 Espinola-Klein C, Rupprecht HJ, Blankenberg S, Bickel C, Kopp H, et al. 2002. Impact of infectious burden

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on extent and long-term prognosis of atherosclerosis. Circulation 105:15– 21 Epstein SE, Zhu J, Burnett MS, Zhou YF, Vercellotti G, Hajjar D. 2000. Infection and atherosclerosis: potential roles of pathogen burden and molecular mimicry. Arterioscler. Thromb. Vasc. Biol. 20:1417–20 Gaydos CA, Summersgill JT, Sahney NN, Ramirez JA, Quinn TC. 1996. Replication of Chlamydia pneumoniae in vitro in human macrophages, endothelial cells, and aortic artery smooth muscle cells. Infect. Immun. 64:1614–20 Shor A. 2001. Mechanism of arterial infection by Chlamydia pneumoniae. Circulation 104:E75 Davidson M, Kuo CC, Middaugh JP, Campbell LA, Wang SP, et al. 1998. Confirmed previous infection with Chlamydia pneumoniae (TWAR) and its presence in early coronary atherosclerosis. Circulation 98:628–33 Hu H, Pierce GN, Zhong G. 1999. The atherogenic effects of chlamydia are dependent on serum cholesterol and specific to Chlamydia pneumoniae. J. Clin. Invest. 103:747–53 Kol A, Bourcier T, Lichtman AH, Libby P. 1999. Chlamydial and human heat shock protein 60s activate human vascular endothelium, smooth muscle cells, and macrophages. J. Clin. Invest. 103:571–77 Gura T. 1998. Infections: a cause of artery-clogging plaques? Science 281:35–37 Kol A, Sukhova GK, Lichtman AH, Libby P. 1998. Chlamydial heat shock protein 60 localizes in human atheroma and regulates macrophage tumor necrosis factor-alpha and matrix metalloproteinase expression. Circulation 98:300– 7 Curry AJ, Portig I, Goodall JC, Kirkpatrick PJ, Gaston JS. 2000. T lymphocyte lines isolated from atheromatous

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plaque contain cells capable of responding to Chlamydia antigens. Clin. Exp. Immunol. 121:261–69 Millonig G, Malcom GT, Wick G. 2002. Early inflammatory-immunological lesions in juvenile atherosclerosis from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY)-study. Atherosclerosis 160:441–48 Waltner-Romen M, Falkensammer G, Rabl W, Wick G. 1998. A previously unrecognized site of local accumulation of mononuclear cells. The vascular-associated lymphoid tissue. J. Histochem. Cytochem. 46:1347–50 Bobryshev YV. 2000. Identification of HIV-1 in the aortic wall of AIDS patients. Atherosclerosis 152:529–30 Koperek O, Kovacs GG, Ritchie D, Ironside JW, Budka H, Wick G. 2002. Disease-associated prion protein in vessel walls. Am. J. Pathol. 161:1979–84 Millonig G, Schwentner C, Mueller P, Mayerl C, Wick G. 2001. The vascularassociated lymphoid tissue: a new site of local immunity. Curr. Opin. Lipidol. 12:547–53 Savino W, Villa-Verde DM, LannesVieira J. 1993. Extracellular matrix proteins in intrathymic T-cell migration and differentiation? Immunol. Today 14:158–61 Mayr M, Kiechl S, Willeit J, Wick G, Xu Q. 2000. Infections, immunity, and atherosclerosis: associations of antibodies to Chlamydia pneumoniae, Helicobacter pylori, and cytomegalovirus with immune reactions to heat-shock protein 60 and carotid or femoral atherosclerosis. Circulation 102(8):833–39 Torzewski J, Torzewski M, Bowyer DE, Frohlich M, Koenig W, et al. 1998. Creactive protein frequently colocalizes with the terminal complement complex in the intima of early atherosclerotic lesions of human coronary arteries. Arterioscler. Thromb. Vasc. Biol. 18:1386–92 Greaves DR, Channon KM. 2002.

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INFLAMMATION IN ATHEROSCLEROSIS 178. Lewthwaite J, Owen N, Coates A, Henderson B, Steptoe A. 2002. Circulating human heat shock protein 60 in the plasma of British civil servants: relationship to physiological and psychosocial stress. Circulation 106:196–201 179. Sethna KB, Mistry NF, Dholakia Y, Antia NH, Harboe M. 1998. Longitudinal trends in serum levels of mycobacterial secretory (30 kD) and cytoplasmic (65 kD) antigens during chemotherapy of pulmonary tuberculosis patients. Scand. J. Infect. Dis. 30:363–69 180. Beatty WL, Morrison RP, Byrne GI. 1994. Persistent chlamydiae: from cell culture to a paradigm for chlamydial pathogenesis. Microbiol. Rev. 58:686–99 181. Bennett MR, Boyle JJ. 1998. Apoptosis of vascular smooth muscle cells in atherosclerosis. Atherosclerosis 138:3–9 182. Mayr M, Xu Q. 2001. Smooth muscle cell apoptosis in arteriosclerosis. Exp. Gerontol. 36:969–87 183. Boulanger CM, Scoazec A, Ebrahimian T, Henry P, Mathieu E, et al. 2001. Circulating microparticles from patients with myocardial infarction cause endothelial dysfunction. Circulation 104:2649– 52 184. Mallat Z, Hugel B, Ohan J, Leseche G, Freyssinet JM, Tedgui A. 1999. Shed membrane microparticles with procoagulant potential in human atherosclerotic plaques: a role for apoptosis in plaque thrombogenicity. Circulation 99:348–53 185. Mallat Z, Tedgui A. 2001. Current perspective on the role of apoptosis in atherothrombotic disease. Circ. Res. 88:998–1003 186. Mesri M, Altieri DC. 1999. Leukocyte microparticles stimulate endothelial cell cytokine release and tissue factor induction in a JNK1 signaling pathway. J. Biol. Chem. 274:23111–18 187. Wang TJ, Nam BH, Wilson PW, Wolf PA, Levy D, et al. 2002. Association of C-reactive protein with carotid atherosclerosis in men and women: the

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196. Schonbeck U, Libby P. 2001. The CD40/CD154 receptor/ligand dyad. Cell Mol. Life Sci. 58:4–43 197. Lutgens E, Gorelik L, Daemen MJ, de Muinck ED, Grewal IS, et al. 1999. Requirement for CD154 in the progression of atherosclerosis. Nat. Med. 5:1313–16 198. Ludewig B, Henn V, Schroder JM, Graf D, Kroczek RA. 1996. Induction, regulation, and function of soluble TRAP (CD40 ligand) during interaction of primary CD4+ CD45RA+ T cells with dendritic cells. Eur. J. Immunol. 26:3137–43 199. Schonbeck U, Libby P. 2001. CD40 signaling and plaque instability. Circ. Res. 89:1092–103 200. Aukrust P, Muller F, Ueland T, Berget T, Aaser E, et al. 1999. Enhanced levels of soluble and membrane-bound CD40 ligand in patients with unstable angina. Possible reflection of T lymphocyte and platelet involvement in the pathogenesis of acute coronary syndromes. Circulation 100:614–20 201. Amberger A, Hala M, Saurwein-Teissl M, Metzler B, Grubeck-Loebenstein B, et al. 1999. Suppressive effects of antiinflammatory agents on human endothelial cell activation and induction of heat shock proteins. Mol. Med. 5:117–28 202. Miller LW. 2002. Cardiovascular toxicities of immunosuppressive agents. Am. J. Transplant. 2:807–18 203. Dichtl W, Dulak J, Frick M, Alber HF, Schwarzacher SP, et al. 2003. HMGCoA reductase inhibitors regulate inflammatory transcription factors in human endothelial and vascular smooth muscle cells. Arterioscler. Thromb. Vasc. Biol. 23:58–63 203a. Jurgens G, Xu QB, Huber LA, Bock G, Howanietz H, et al. 1989. Promotion of lymphocyte growth by high density lipoproteins (HDL). Physiological significance of the HDL binding site. J. Biol. Chem. 264(15):8549–56 204. Zhu J, Quyyumi AA, Rott D, Csako G,

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Wu H, et al. 2001. Antibodies to human heat-shock protein 60 are associated with the presence and severity of coronary artery disease: evidence for an autoimmune component of atherogenesis. Circulation 103:1071–75 Veres A, Szamosi T, Ablonczy M, Szamosi T Jr, Singh M, et al. 2002. Complement activating antibodies against the human 60 kDa heat shock protein as a new independent family risk factor of coronary heart disease. Eur. J. Clin. Invest. 32:405–10 Hoppichler F, Koch T, Dzien A, Gschwandtner G, Lechleitner M. 2000. Prognostic value of antibody titre to heat-shock protein 65 on cardiovascular events. Cardiology 94:220–23 Birnie DH, Holme ER, McKay IC, Hood S, McColl KE, Hillis WS. 1998. Association between antibodies to heat shock protein 65 and coronary atherosclerosis. Possible mechanism of action of Helicobacter pylori and other bacterial infections in increasing cardiovascular risk. Eur. Heart J. 19:387–94 Prohaszka Z, Duba J, Horvath L, Csaszar A, Karadi I, et al. 2001. Comparative study on antibodies to human and bacterial 60 kDa heat shock proteins in a large cohort of patients with coronary heart disease and healthy subjects. Eur. J. Clin. Invest. 31:285–92 Veres A, Fust G, Smieja M, McQueen M, Horvath A, et al. 2002. Relationship of anti-60 kDa heat shock protein and anticholesterol antibodies to cardiovascular events. Gromadzka G, Zielinska J, Ryglewicz D, Fiszer U, Czlonkowska A. 2001. Elevated levels of anti-heat shock protein antibodies in patients with cerebral ischemia. Cerebrovasc. Dis. 12:235– 39 Huittinen T, Leinonen M, Tenkanen L, Manttari M, Virkkunen H, et al. 2002. Autoimmunity to human heat shock protein 60, Chlamydia pneumoniae

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INFLAMMATION IN ATHEROSCLEROSIS infection, and inflammation in predicting coronary risk. Arterioscler. Thromb. Vasc. Biol. 22:431–37 212. Ciervo A, Visca P, Petrucca A, Biasucci LM, Maseri A, Cassone A. 2002. Antibodies to 60-kilodalton heat shock protein and outer membrane protein 2 of Chlamydia pneumoniae in patients with coronary heart disease. Clin. Diagn. Lab. Immunol. 9:66–74 213. Pockley AG, de Faire U, Kiessling R, Lemne C, Thulin T, Frostegard J. 2002. Circulating heat shock protein and heat shock protein antibody levels in established hyp. J. Hypertens. 20(9): 1815–20 214. Kramer J, Harcos P, Prohaszka Z, Horvath L, Karadi I, et al. 2000. Frequencies of certain complement protein alleles and

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serum levels of anti-heat-shock protein antibodies in cerebrovascular diseases. Stroke 31:2648–52 215. Zhu J, Quyyumi AA, Wu H, Csako G, Rott D, et al. 2003. Increased serum levels of heat shock protein 70 are associated with low risk of coronary artery disease. Arterioscler. Thromb. Vasc. Biol. 23(6):1055–59 216. Swanson SJ, Rosenzweig A, Seidman JG, Libby P. 1994. Diversity of T-cell antigen receptor V beta gene utilization in advanced human atheroma. Arterioscler. Thromb. Vasc. Biol. 14:1210–14 217. Oksenberg JR, Stavri GT, Jeong MC, Garovoy N, Salisbury JR, Erusalimsky JD. 1997. Analysis of the T-cell receptor repertoire in human atherosclerosis. Cardiovasc. Res. 36:256–67

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Figure 1 Macroscopic appearance of the inner surface of a human artery. I, normal intima; F, fatty streak; P, raised plaque; E, exulcerated plaque. The insert in the lower right corner shows immunohistochemical staining of CD3+ T-lymphocytes in the shoulder-region of an early atherosclerotic lesion.

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Figure 3 Immunofluorescence staining for HSP60 (green) on cultured human umbilical vein endothelial cells (HUVEC) before (a, c) or after 30 min 42°C heat stress (b, d) on unfixed (a, b) or permeabilized, fixed (c, d) cells. HSP60 is expressed after stress on the cell surface (b) as well as in the cytosol (d). Nuclei are stained in red.

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Figure 7 Atherosclerosis: the price we pay for immunity to heat-shock protein 60 (HSP60). Protection against microbial infection is mediated by humoral and cellular adaptive immunity directed against microbial HSP60 among other microbial antigens. In addition, the innate immunity is activated by HSP60 bound to Toll-like receptors. (a) Under physiological conditions, human vascular endothelial cells (EC) do not express HSP60, so no disease results. (b) The stress-induced expression of HSP60 on target ECs can result in cross-reactivity of the immune response between human and microbial HSP60 entailing immune destruction of ECs. This might also result from bona fide autoimmune reactions induced by altered self-HSP60. (c) In some cases, autoimmunity might not develop, despite the presence of human HSP60 on ECs, because the MHC class I and II grooves of these individuals do not accommodate the atherogenic HSP60 epitopes.

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CONTENTS FRONTISPIECE—Leonard A. Herzenberg and Leonore A. Herzenberg GENETICS, FACS, IMMUNOLOGY, AND REDOX: A TALE OF TWO LIVES INTERTWINED, Leonard A. Herzenberg and Leonore A. Herzenberg SELF- AND NONSELF-RECOGNITION BY C-TYPE LECTINS ON DENDRITIC CELLS, Teunis B.H. Geijtenbeek, Sandra J. van Vliet, Anneke Engering, Bert A. ’t Hart, and Yvette van Kooyk

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TRANSCRIPTIONAL CONTROL OF EARLY B CELL DEVELOPMENT, Meinrad Busslinger

UBIQUITIN LIGASES AND THE IMMUNE RESPONSE, Yun-Cai Liu LIGANDS FOR L-SELECTIN: HOMING, INFLAMMATION, AND BEYOND, Steven D. Rosen

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INTEGRINS AND T CELL–MEDIATED IMMUNITY, Jonathan T. Pribila, Angie C. Quale, Kristen L. Mueller, and Yoji Shimizu

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MULTIPLE ROLES OF ANTIMICROBIAL DEFENSINS, CATHELICIDINS, AND EOSINOPHIL-DERIVED NEUROTOXIN IN HOST DEFENSE, De Yang, Arya Biragyn, David M. Hoover, Jacek Lubkowski, and Joost J. Oppenheim

STARTING AT THE BEGINNING: NEW PERSPECTIVES ON THE BIOLOGY OF MUCOSAL T CELLS, Hilde Cheroutre THE BCR-ABL STORY: BENCH TO BEDSIDE AND BACK, Stephane Wong and Owen N. Witte

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CD40/CD154 INTERACTIONS AT THE INTERFACE OF TOLERANCE AND IMMUNITY, Sergio A. Quezada, Lamis Z. Jarvinen, Evan F. Lind, and Randolph J. Noelle

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THE THREE ES OF CANCER IMMUNOEDITING, Gavin P. Dunn, Lloyd J. Old, and Robert D. Schreiber

AUTOIMMUNE AND INFLAMMATORY MECHANISMS IN ATHEROSCLEROSIS, Georg Wick, Michael Knoflach, and Qingbo Xu THE DYNAMIC LIFE OF NATURAL KILLER CELLS, Wayne M. Yokoyama, Sungjin Kim, and Anthony R. French

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THE ROLE OF COMPLEMENT IN THE DEVELOPMENT OF SYSTEMIC LUPUS ERYTHEMATOSUS, Anthony P. Manderson, Marina Botto, and Mark J. Walport

DROSOPHILA: THE GENETICS OF INNATE IMMUNE RECOGNITION AND RESPONSE, Catherine A. Brennan and Kathryn V. Anderson RAGS AND REGULATION OF AUTOANTIBODIES, Mila Jankovic,

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Rafael Casellas, Nikos Yannoutsos, Hedda Wardemann, and Michel C. Nussenzweig

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THE ROLE OF SUPPRESSORS OF CYTOKINE SIGNALING (SOCS) PROTEINS IN REGULATION OF THE IMMUNE RESPONSE, Warren S. Alexander and Douglas J. Hilton

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REGULATORY T CELLS FOR IMMUNOLOGIC SELF-TOLERANCE AND NEGATIVE CONTROL OF IMMUNE RESPONSES, Shimon Sakaguchi PHOSPHOINOSITIDE 3-KINASE: DIVERSE ROLES IN IMMUNE CELL ACTIVATION, Jonathan A. Deane and David A. Fruman IMMUNITY TO TUBERCULOSIS, Robert J. North and Yu-Jin Jung MOLECULAR DEFECTS IN HUMAN SEVERE COMBINED IMMUNODEFICIENCY AND APPROACHES TO IMMUNE RECONSTITUTION, Rebecca H. Buckley PHYSIOLOGICAL CONTROL OF IMMUNE RESPONSE AND INFLAMMATORY TISSUE DAMAGE BY HYPOXIA-INDUCIBLE FACTORS AND ADENOSINE A2A RECEPTORS, Michail V. Sitkovsky, Dmitriy Lukashev, Sergey Apasov, Hidefumi Kojima, Masahiro Koshiba, Charles Caldwell, Akio Ohta, and Manfred Thiel

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T LYMPHOCYTE–ENDOTHELIAL CELL INTERACTIONS, Jaehyuk Choi, David R. Enis, Kian Peng Koh, Stephen L. Shiao, and Jordan S. Pober

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IMMUNOLOGICAL MEMORY TO VIRAL INFECTIONS, Raymond M. Welsh, Liisa K. Selin, and Eva Szomolanyi-Tsuda

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CENTRAL MEMORY AND EFFECTOR MEMORY T CELL SUBSETS: FUNCTION, GENERATION, AND MAINTENANCE, Federica Sallusto, Jens Geginat, and Antonio Lanzavecchia CONTROL OF T CELL VIABILITY, Philippa Marrack and John Kappler

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ASTHMA: MECHANISMS OF DISEASE PERSISTENCE AND PROGRESSION, Lauren Cohn, Jack A. Elias, and Geoffrey L. Chupp

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CD1: ANTIGEN PRESENTATION AND T CELL FUNCTION, Manfred Brigl and Michael B. Brenner

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CHEMOKINES IN INNATE AND ADAPTIVE HOST DEFENSE: BASIC CHEMOKINESE GRAMMAR FOR IMMUNE CELLS, Antal Rot and Ulrich H. von Andrian

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INTERLEUKIN-10 AND RELATED CYTOKINES AND RECEPTORS, Sidney Pestka, Christopher D. Krause, Devanand Sarkar, Mark R. Walter, Yufang Shi, and Paul B. Fisher

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INDEXES

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Subject Index Cumulative Index of Contributing Authors, Volumes 12–22 Cumulative Index of Chapter Titles, Volumes 12–22

ERRATA An online log of corrections to Annual Review of Immunology chapters may be found at http://immunol.annualreviews.org/errata.shtml

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Annu. Rev. Immunol. 2004. 22:405–29 doi: 10.1146/annurev.immunol.22.012703.104711 c 2004 by Annual Reviews. All rights reserved Copyright ° First published online as a Review in Advance on November 3, 2003

THE DYNAMIC LIFE OF NATURAL KILLER CELLS Wayne M. Yokoyama,1 Sungjin Kim,1 and Anthony R. French1,2 Annu. Rev. Immunol. 2004.22:405-429. Downloaded from arjournals.annualreviews.org by HINARI on 09/01/07. For personal use only.

1

Howard Hughes Medical Institute, Rheumatology Division, Department of Medicine, Department of Pathology and Immunology, and 2Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110; email: [email protected], [email protected], French [email protected]

Key Words NK cells, development, proliferation, virus, innate immunity ■ Abstract Natural killer (NK) cells play important roles in immunological processes, including early defense against viral infections. This review provides an overview of the dynamic in vivo life of NK cells from their development in the bone marrow to their mature peripheral responses and their ultimate demise, with particular emphasis on mouse NK cells and viral infections.

INTRODUCTION Natural killer (NK) cells are bone marrow–derived lymphocytes, distinct from T and B cells, that are capable of lysing certain tumor cells without prior sensitization (1, 2). Because of this capacity, termed natural killing, NK cells were initially thought to serve primarily in defense against tumor cells. Over the years, however, NK cells have been shown to have other functions. They produce cytokines that regulate the development of acquired, specific immunity, and they can reject bone marrow (BM) transplants (3, 4). In view of their accumulation at the maternal-fetal interface, NK cells are also thought to play essential roles during pregnancy (5). They are also implicated in other pathological processes, including autoimmunity and tissue inflammation (6–8). A primary physiological role of NK cells is to provide early defense against pathogenic organisms during the initial response period while the adaptive immune system is being activated (reviewed in 9). Although NK cells respond to a variety of microorganisms, including bacteria and protozoa, they are particularly important in viral infections (10). This is well illustrated in the case report of an adolescent with a selective NK cell defect who had recurrent infections with particular difficulty in controlling herpes viruses (11). Other human patients with selective NK cell deficiencies have similar clinical courses (12). In mice, depletion of NK cells enhances susceptibility to several viral infections, including murine cytomegalovirus (MCMV) (13). Thus, NK cells are critical in host defense against infectious agents. 0732-0582/04/0423-0405$14.00

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NK cells have two major triggering mechanisms: (a) target recognition and (b) cytokine stimulation. Both are intertwined with their effector responses: target killing and cytokine production. These processes play important roles in NK cell effects especially during viral infections, as indicated by numerous viral strategies that limit NK cell responses that in turn emphasize the significance of NK cells in antiviral defense (reviewed in 14). Significant progress has been made in understanding NK cell target recognition that is guided by two general types of NK cell receptors, i.e., inhibitory and activation receptors (15–18). NK cells express inhibitory receptors specific for MHC class I molecules on target cells. As a result of direct ligand interaction, these inhibitory receptors prevent NK cell activation and killing, providing the molecular basis for the “missing-self” hypothesis (19). In the mouse, the inhibitory receptors are encoded in the NK gene complex (NKC) and include the Ly49 family of receptors, including Ly49A, and CD94/NKG2A (20, 21). NK cells also express activation receptors that recognize target cell ligands and can trigger perforindependent natural killing. Many of these receptors, such as Ly49D and Ly49H, are structurally related to the inhibitory receptors (22, 23) but their signaling activities are limited by the inhibitory receptors. Stimulation of NK cells through the activation receptors can lead to production of cytokines such as interferon-γ (IFN-γ ), tumor necrosis factor-α (TNF-α), and granulocyte-macrophage colony stimulating factor (GM-CSF) (24–30). Additionally, infected or activated dendritic cells (DCs) and macrophages produce cytokines and chemokines such as IFNα/β, IL-12, IL-15, and IL-18 that stimulate NK cells to rapidly produce other cytokines (including IFNγ , TNFα, and GM-CSF) and chemokines (such as ATAC/lymphotactin, Mig, and MIP-1α) (31–37; B. Dorner & W.M. Yokoyama, manuscript submitted). The cytokine effects on NK cells are intricately related. For example, during the course of viral infections, IFNα/β enhances NK cell cytotoxicity through STAT1 (signal transducer and activator of transcription 1) signaling, whereas IL-12 stimulates STAT4-dependent IFNγ production through STAT4 that is inhibited by STAT1 (38–41). Thus, sophisticated regulatory pathways control NK cell cytokine production. Considering the importance of NK cells in immune processes, this review provides an overview of the dynamic in vivo life of NK cells from their development in the BM to their mature cellular responses in the periphery and their ultimate demise (Figure 1), with particular emphasis on mouse NK cells and viral infections.

NK CELL DEVELOPMENT Natural killer (NK) cells comprise the third major lymphocyte population (2, 42) and can be distinguished from other lymphocytes by the absence of B- and T-cell antigen receptors, i.e., sIg and T-cell receptor (TCR), respectively. A unique feature of NK cells is that, unlike other lymphocytes, their development does not require events that are necessary for antigen receptor gene rearrangement. Indeed, they are

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Figure 1 Dynamic life of NK cells. A simplified scheme shows the development of NK cells in the bone marrow from hematopoietic stem cells (HSC) to the common lymphoid progenitor (CLP) to bipotential T/NK progenitor (T/NKP) to the NK progenitor (NKP) and mature NK cells. Immature NK cells proliferate during development. In the periphery, NK cells are generally quiescent until stimulated to kill, produce cytokines, and proliferate.

present in scid and RAG-1- or -2-deficient mice (43–46). Despite close resemblance between T and NK cell effector functions, NK cells also develop normally in athymic nude mice that lack T cells (47, 48). The features distinguishing NK cells from other lymphocytes and apparent normal development in mice lacking B and T cells suggest that NK cells possess a unique developmental pathway.

In Vitro and In Vivo Models of NK Cell Development Available evidence indicates that the complete phenotypic and functional maturation of NK cells requires an intact BM microenvironment. Early studies of mice treated with estrogen (17-beta-estradiol) or bone-seeking isotopes (89Sr) demonstrated that BM ablation leads to the functional impairment of NK cells (49, 50). Moreover, NK cells derived from congenitally osteopetrotic (mi/mi) mice display impaired natural killing (51, 52). Interestingly, these mice possess substantial numbers of cells that express NK cell markers (50, 52, 53), suggesting a critical role of BM microenvironment in the full functional maturation of NK cells. Other studies support a role for direct interaction between stromal cells and the developing NK cell. Lymphotoxin-α (LTα)-deficient mice lack NK and NKT cells (54). Reciprocal BM transfer experiments suggest that close interactions between membrane LTα-expressing NK cell precursors and LTα-responsive stromal cells are necessary for normal NK and NKT cell development (54, 55). The LTαdeficient mouse also manifests a defect in lymph node development that resembles the phenotype of mice deficient in the helix-loop-helix inhibitor Id2 (56), suggesting that the NK cell defect in Id2-deficient mice may also involve similar NK cell interactions with stromal cells.

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Certain aspects of NK cell development are regulated by direct interactions between developing NK cells and stromal elements. In vitro models of NK cell differentiation have shown that cytolytic NK cells can be generated from early hematopoietic cells (57–61). Mouse NK cells can develop in vitro from BM precursor populations in a cytokine cocktail consisting of stem cell factor (c-kit ligand), IL-7, flt-3 ligand (FL), and IL-15 (62, 63). However, the presence of these cytokines alone is insufficient to generate phenotypically mature NK cells that express Ly49 receptors. Importantly, direct contact with stromal cells is required for acquisition of Ly49 receptors by developing NK cells. The in vitro studies led to identification of soluble factors capable of supporting the generation of NK cells and also demonstrated the importance of direct contact between precursors of NK cells and stromal cells. NK cell defects in mice with targeted mutations in cytokines and transcription factors have been instructive (Figure 2) (54–56, 64–77; reviewed in 78, 79). Analysis of gene-manipulated mice and reconstitution studies using alymphoid RAG-2−/− × IL-2R (common) γ (γ c)−/− mice (72, 80, 81) have also proven useful both in defining the steps of NK cell developmental process and in elucidating molecular mechanisms governing this process. Several other mouse models of NK cell deficiency have also been described. While the beige (bg) mouse has defective natural killing and has been used for many years as an “NK cell-deficient” model, the bg mutation does not dramatically affect NK cell number. It involves a molecule that affects the granules of many cells, not just CD3– NK cells (82), rather than affecting NK cell development per se. On the other hand, a mouse transgenic (tg) for the human CD3ε gene (tgε26) has an NK

Figure 2 In vivo models of NK cell development. Informative gene knockout and transgenic mice have helped establish major NK cell developmental steps from HSC to CLP to bipotential T/NK progenitor (T/NKP) to NK progenitor (NKP) to mature NK cells. Based on phenotypic analysis, the NK cell developmental block in these mice can be placed as indicated by knockout and transgenic (tg) mice. Partial defects (P) are also noted.

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cell deficiency and also a significant defect in T cell development, indicating a block in development at an early stage of T and NK cell development (83, 84), but this has not been characterized further. A similar phenotype is observed in FcεRIγ tg mice (85). Another mouse, transgenic for a granzyme A-Ly49a construct, also has an NK cell deficiency that appears to be more selective, suggesting that this mouse may be manifesting a block in a terminal differentiation step in NK cell development (86).

Generation of NK Cell Progenitors from Hematopoietic Stem Cells Based on the data currently available, a model has been proposed for the developmental process of NK cells in the BM that is divided into several major steps (Figures 1 and 2). The earliest step involves the commitment of hematopoietic stem cells (HSC) to the lymphoid cell lineage. Recent studies have identified common lymphoid progenitors (CLP) in the BM of adult mice and human (87, 88). In vivo reconstitution assays indicated that CLP give rise to NK, T, and B cells but not to myeloid cell lineages (87). Mice that are deficient in the zinc-finger transcription factor Ikaros or express a dominant-negative form display severe defects in the development of all lymphoid cell lineages including NK cells, whereas myeloid and erythroid lineages are less affected (Figure 2) (64, 89). A member of the Ets family, PU.1, has also been implicated as a critical transcription factor regulating early hematopoiesis and lymphopoiesis (90, 91). Compared to wild type, PU.1−/− fetal liver HSC differentiated less efficiently into NK cells (or B and T cells) when transferred into alymphoid RAG-2−/− × γ c−/− mice (72). Near-complete, partial, or minor defects in NK cell development were observed in FL-, c-Kit-, or IL-7-deficient mice, respectively, in addition to defects in the development of other cell lineages (73, 81, 92). The early impairment of hematopoiesis in Ikaros-deficient and PU.1-deficient mice may be explained by the observations that the Ikaros-deficient HSC express lower levels of the c-Kit and Flk2/flt3 (93), whereas the PU.1-deficiency leads to reduced expression of various cytokine receptors, including IL-7Rα (72, 91, 94). Ikaros and PU.1 may therefore influence NK cell development by promoting early hematopoiesis through up-regulation of receptors for early acting factors. Thus, the earliest step of NK cell development appears to share a common pathway with other lymphocytes involving differentiation of HSC to CLP. Another major step of NK cell development involves the differentiation of the CLP to a bipotential T/NK progenitor (T/NKP) (Figure 2). Consistent with the close resemblance between T and NK cell effector functions, T/NKP have been identified in various fetal organs including blood, thymus, spleen, and liver (95–99). Depending on culture conditions, T/NKP can give rise to T and/or NK cells but not to other lineages. Unexpectedly, T/NKP present in fetal thymus and blood express NK1.1 (96, 97), the most specific serological marker for NK cells (in C57BL/6 mice) at later stages of differentiation, whereas T/NKP present in

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fetal liver do not express this marker (99). T/NKP have not yet been identified in adult tissues, suggesting that adult NK cell development may differ from fetal development. However, unipotent NK cell progenitors (NKP) destined to become mature NK cells are likely to be generated via T/NKP even in adults because CD3ε and FcεRIγ tg mice exhibit selective defects in NK and T cell development (83, 85), and because IL-15 and IL-15Rα-deficiencies affect both NK and NKT cell development. The acquisition of IL-2/15Rβ subunit (CD122) is likely to mark the transition from T/NKP to NKP in both fetus and adult (98, 100) (Figure 2). This acquisition, in part, renders NKP responsive to IL-15, a critical cytokine for NK cell development, which mediates its effects through the IL-15R complex, consisting of IL-15Rα, IL-2/IL-15Rβ, and the IL-2R (common) γ (γ c) chains (101). IL-15or IL-15Rα−targeted mutations produce a relatively selective NK cell deficiency that also affects NK/T, intestinal epithelial lymphocytes (IEL), and memory CD8+ T cells (67, 68). This requirement for IL-15 in NK cell development explains why deficiencies in IL-2 or IL-2Rα do not affect NK cell development, whereas deficiency in IL-2Rβ, which forms part of the IL-15R complex, does affect NK cell development (66). On the other hand, γ c is required for response to many cytokines, including IL-2, -4, -7, -9, and -15, so it is not surprising that γ c deficiency produces a profound block in lymphocyte development, apparently affecting the CLP (65, 102). Interestingly, recent reports indicate that IL-15 can mediate its effects when presented in trans by IL-15Rα to responsive cells expressing IL-15Rβγ alone (103). Although the physiological relevance of this finding is still under investigation, the effect can be observed in vivo (104, 105). When IL-15Rα–specific antibodies become widely available, it may be possible to determine if IL-15Rα expression regulates either the CLP to T/NKP and/or T/NKP to NKP step. The transition from CLP and/or T/NKP to NKP is regulated by transcriptional activity of specific factors (Figure 2). Consistent with the essential role of IL-15 and its receptor in NK cell development, mice deficient in components of the IL-15R signaling pathway, such as Jak3 and STAT5a/b, exhibit defects in NK cell development (74, 77, 106). The ability of FL to enhance the expression of IL-2/15Rβ subunit on hematopoietic progenitor cells may account for the positive effect of FL on the generation of NKP (60–62, 98, 100). IRF-1 (interferon regulatory factor 1)-deficient mice lack NK cells, and this defect can be overcome by the addition of IL-15, suggesting that stromal cells produce IL-15 in an IRF-1-dependent manner (70). Thus, IL-15 and its receptor play significant roles in NK cell development, although detailed studies of the arrested NKPs in deficient mice have not been published. Other studies implicate Ets1 transcription factor and Id2 DNA-binding protein in NK cell development (Figure 2). In Ets1- or Id2-deficient mice, NK cells fail to develop, although T and B cells normally develop (56, 71). The Id proteins do not directly activate a target gene and instead appear to promote the generation of NKP by negatively regulating the activity of the basic helix-loop-helix family of transcription factors that affect B or T cell development (107–109). Thus, the

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commitment of CLP (and/or T/NKP) to NKP may be initiated by expression of specific transcription factors and/or by modulating interactions among already present transcription factors that affect the IL-15R signaling pathway and its downstream consequences.

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NK Cell Developmental Stages from NKP to Mature NK Cells The next major step of NK cell development involves the differentiation of NKPs into phenotypically and functionally mature NK cells (Figure 3). During this step, NKPs undergo a series of phenotypic changes, including acquisition of receptors (CD94/NKG2 and Ly49 in mice) specific for MHC class I molecules that guide target cell–specificity of mature NK cells. In addition, NK cell development during

Figure 3 Developmental stages of committed NK cells. During development in BM, informative surface markers characterize distinct stages from the NK cell progenitor to mature NK cells. After acquisition of NK cell receptors (NKG2 and Ly49), significant proliferation occurs while the cells are still immature.

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this step is characterized by significant proliferation before the cells become phenotypically and functionally mature. The changes during this step can be divided into several putative developmental intermediate stages, as described below, all of which occur in the BM (100, 110). Although NKP were previously identified from in vitro culture and from fetal thymus (60, 98), an equivalent cell was recently identified from adult BM (100). The BM-derived NKP expresses CD122 but neither NK1.1 nor DX5 (pan-NK cell markers), and gives rise exclusively to functional NK cells in vitro. This population is denoted as intermediate Stage I (Figure 3) (110). Thereafter, NK1.1 (also known as Nkrp1c) (111) is expressed (Stages II to V), comparable to studies of in vitro differentiation of human NK cells where NKR-P1A molecule is one of the earliest markers expressed (112). Among the mouse CD3– CD122+ NK1.1+ population, there is an integrin αv+ c-Kit– population (Stage II) that can express CD94/NKG2 receptors without concomitant expression of Ly49 receptors (110). They also express NKG2D (S.K. & W.M.Y., unpublished observations). NK cells at this stage appear to be equivalent to fetal or neonatal mouse NK cells that express CD94/NKG2 receptors without expressing Ly49 receptors (113, 114). Subsequently, Ly49 receptors are expressed on NK1.1+ cells that express both αv and c-Kit (Stage III). However, CD94/NKG2 expression is not a prerequisite for Ly49 expression because there are cells expressing Ly49 molecules without expressing CD94/NKG2. The initial expression of Ly49 receptors appears to be controlled by a stochastic process (reviewed in 115). This process may involve specific transcription factors. A deficiency in the transcription factor TCF-1 selectively affects Ly49a expression with minimal effects on other Ly49 genes (116, 117), although less is known about regulation of CD94 expression (118, 119). Additional studies are under way to explore the promoters and developmental regulation of Ly49 molecules (120– 124). Nevertheless, the acquisition of CD94/NKG2 and Ly49 receptor expression in the adult BM at Stage II and III recapitulates expression of these receptors on fetal and neonatal NK cells in which CD94/NKG2 receptors are first expressed, then the cells acquire Ly49 expression in an ordered manner (113, 114, 125). At Stage IV, the expression of integrin α2 (DX5) is increased and developing NK cells undergo a substantial expansion in the BM with vigorous proliferation. Thereafter, as NK cells finally acquire high-level expression of Mac-1 (αMβ1) and CD43 (Stage V), further NK cell proliferation is markedly reduced unless challenged by pathogens such as viruses that can stimulate mature NK cell proliferation (see below) (110, 126). Importantly, NK cells at Stage V become fully capable of functional activities associated with mature peripheral NK cells. Developing NK cells undergo significant proliferation at a defined, developmentally immature stage in the BM, as evidenced by acute in vivo BrdU (bromodeoxyuridine, a nucleotide analogue) incorporation by Mac-1lo DX5hi NK1.1+ cells (110). Regardless of the mechanism by which these receptors are initially expressed on the developing NK cell, the proliferation of immature NK cells in the BM occurs after they express CD94/NKG2 and Ly49 receptors because

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most BrdU+ cells among CD122+ cells express NK1.1 and at least one of the CD94/NKG2 or Ly49 receptors. Expression of MHC class I–specific inhibitory receptors at this point may have consequences on the ultimate size and distribution of mature NK cell populations expressing the “missing-self” receptors as well as on functional maturation. The receptors themselves may be predicted to directly encounter MHC class I, although it is not currently known if the receptors themselves trigger proliferation and further development or whether the proliferation phase more simply affects the receptor repertoire of mature NK cells. Detailed examination of the receptor repertoire on mature NK cells in mice with different MHC class I haplotypes has indicated that there is a modest reduction of NK cells coexpressing receptors for self-MHC class I molecules (115). Consistent with this phenomenon, in vitro studies have shown that engagement of a Ly49 receptor with MHC class I on stromal cells affects further acquisition of other Ly49 receptors recognizing the same MHC class I molecule (63). There is also an MHC class I effect on the level of receptors expressed such that, in the presence of the self-MHC class I molecule, there is down-regulation of the corresponding Ly49 receptor (127). Studies of BM chimeric mice suggest that this is due to an extracellular interaction between Ly49 on the NK cell and host MHC class I (128). Indeed, recent studies show the presence of Ly49 receptors on the NK cell surface bound with its MHC class I ligand that was acquired from surrounding cells (129, 130). In addition, cis effects between Ly49 receptors and their ligands on the same NK cell have been noted (128, 131), but the significance of ligand capture and cis effects requires further investigation. Nevertheless, taken together, these studies indicate that there are direct in vivo interactions between Ly49 receptors and their cognate ligands. Thus, it will be important to investigate the possible influence of CD94 and Ly49 receptor engagement on proliferation and functional maturation of NK cells during development in the BM. Interestingly, phenotypically immature NK cells are present in the adult liver (110). Although these cells express CD122 and NK1.1, they do not express other markers such as DX5. Perhaps the most striking feature of the liver Mac-1lo DX5− NK cells is the rare expression of Ly49 receptors while they express CD94/NKG2 receptors at a high frequency. The relatively poor capacity of liver Mac-1lo DX5− NK cells to produce IFN-γ supports the idea that these cells are immature NK cells. The more frequent expression of CD94/NKG2 receptors on these cells is also consistent because these receptors are expressed earlier than Ly49 receptors during NK cell ontogeny. These Mac-1lo DX5− NK cells are phenotypically equivalent to NK cells at Stage II in the BM and are reminiscent of the previously termed “nonlytic NK1.1+ cells” found in osteopetrotic mice that display poor expression of Mac-1 and Ly49 receptors (53, 132). Thus, the liver contains NK cells with an immature phenotype, raising the interesting possibility that peripheral tissues serve as reservoirs for less differentiated NK progenitors, which may expand in the periphery under certain conditions. Our current model of NK cell development in the BM is based on the apparent sequential acquisition of certain informative molecules with concomitant

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down-regulation of other markers. Whether these molecules represent functionally important, rate-limiting steps needs to be determined. Nevertheless, the current model provides guidance for future investigation. Most importantly, the model highlights the points that developing NK cells expand at a phenotypically distinct stage and that NK cell development is characterized by a dynamic process involving up- and down-regulation of surface receptors for cytokines, extracellular matrix, and self- and target-recognition, rather than the cumulative, progressive acquisition of such receptors.

Human NK Cell Development NK cell development is likely to be similar in mice and humans. In the BM, acquisition of functional maturity of mouse NK cells, i.e., the capacity to kill targets and produce cytokines, is accompanied by changes in phenotypic markers (110). Similarly, immature human NK cells display regulated in vitro development of the capacity to secrete different cytokines and kill targets using different cytotoxic pathways (112, 133–135). On the other hand, there are some differences between mouse and human NK cell development. For example, IL-12 has been shown to be important in human NK cell development studied in vitro (136). However, studies on NK cell function in IL-12 or IL-12 receptor-deficient mice indicate that peripheral splenocytes have essentially normal natural killing and IL-2-activated NK cell activity against YAC-1 cells (137–139). Furthermore, IL-12 receptor-deficient mice backcrossed onto the C57BL/6 background have normal numbers of NK cells (140). Finally, human NK cell development appears to be dependent on IFN-γ or IL-18. However, there is no deficiency in NK cell number in mice with deficiencies of IFN-γ or IL-18 (140, 141). Therefore, there may be either in vitro versus in vivo or species effects to explain the similarities and differences in studies of mouse and human NK cell development.

MATURE NK CELLS IN THE PERIPHERY Mature NK cells in the periphery (outside the BM) are well suited to respond rapidly to infected or transformed cells and to play an important role in innate defense. NK cells, however, constitute only a small population of cells (about 2.5% of splenic leukocytes). How can this small population quickly respond with enough of a critical mass to effect significant innate defense? One mechanism involves the expression of multiple activation receptors by individual NK cells (23). By contrast to clonally distributed TCRs that endow the individual T cell with the ability to respond only to one antigen, an individual NK cell appears capable of responding to multiple activation receptor ligands. Furthermore, the na¨ıve T cell population contains only rare cells with a TCR for the relevant antigen, whereas large percentages of the NK cell population express any given activation receptor in an overlapping fashion. This multiple activation

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receptor expression on sizeable subpopulations would allow a substantial number of NK cells to quickly respond to a given specific insult. Another mechanism allowing a significant NK cell response is related to their constitutive expression of cytokine receptors that permit many NK cells to be stimulated by proinflammatory cytokines produced early in the course of an immune response. Thus, large numbers of NK cells can rapidly respond to a particular stimulus through their activation or cytokine receptors.

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Peripheral NK Cells Mature peripheral NK cells that have exited the BM are found primarily in the blood, spleen, and liver as well as in the uterus. The homing of NK cells to these locations is not well characterized but NK cells appear to have developmentally regulated expression of a number of integrins that may play a role in their localization as well as effector functions (110, 142). In addition, several chemokines, including CXCL12 and MIP1α, have been implicated in NK cell localization (143–148). Interestingly, immunohistochemical in situ staining has shown that NK cells are localized to the red pulp of the spleen and the sinusoidal regions of the liver (149, 150). Few NK cells are present in other solid organs, and surprisingly, there are relatively few NK cells in lymph nodes (149, 151). In experimental in vivo tumor models, NK cells are more frequently found when the targets are also sensitive to NK cell killing in vitro (152). In viral infections, NK cells infiltrate the liver parenchyma in the vicinity of infected foci (146, 149). However, NK cells may be less effective in killing when they migrate into parenchymal tissues (153). Thus, from the vantage point of the peripheral blood, spleen, and blood pool of the liver and lung, NK cells may be particularly suited for surveying the blood for pathogens and infected or transformed cells. Supporting a role for NK cells in controlling targets (tumors or infections) in the blood, early studies indicated that NK cells control experimental metastases (1). In more recent studies, NK cells have been shown to readily eradicate radiolabeled tumor cells injected intravenously. In as little as 4 h after injection, few NKsensitive targets can be found in the lungs, whereas when NK cells are absent or depleted, large numbers of injected cells migrate to the lungs via the blood circulation (86, 154). In viral infections, an absence of human NK cells is also associated with viremia due to viruses that are usually mucosal pathogens, such as herpes simplex (11). Thus, peripheral NK cells appear to be efficient in controlling dissemination of tumors and infections. How this peripheral pool is maintained is a topic of recent interest.

Peripheral NK Cell Homeostasis and Survival The half-life of mature NK cells in the periphery appears to be about seven to ten days based on the survival of adoptively transferred NK cells (104, 105, 155). Mature peripheral NK cells are relatively quiescent, undergoing low levels of

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proliferation (126). Acute short-term in vivo BrdU incorporation assays have demonstrated that only 1%–3% of splenic NK cells in na¨ıve mice are dividing (126), whereas longer-term BrdU incorporation studies indicate that peripheral NK cells have a relatively high turnover rate (156; S. Kim & W.M. Yokoyama, unpublished data). Mature NK cells can undergo homeostatic proliferation. When splenic CFSElabeled NK cells were adoptively transferred into RAG−/− × γ −/− mice that lack T, B, and NK cells, the transferred cells proliferated and accumulated in a manner analogous to that of transferred T cells in a lymphopenic host (105, 155). In contrast, mature NK cells did not proliferate or accumulate when transferred into wild-type or RAG−/− mice that have endogenous NK cells, suggesting that some factor, perhaps a cytokine or “space,” is limiting when there are endogenous NK cells present (155, 157). Comparative reconstitution studies using alymphoid or cytokine-deficient mice support the conclusion that the limiting factor is IL-15, with a smaller, partially redundant contribution from IL-7 (105, 155). This conclusion is bolstered by observations that the injection of exogenous IL-15 or transgenic overexpression of IL-15 results in higher in vivo NK cell numbers (41, 67, 158, 159), demonstrating that space was not the limiting factor in homeostatic proliferation. IL-15 is also involved in the homeostasis of CD8+ memory T cells and Vα14+ NKT cells, suggesting that all three cell types may compete for available IL-15 (160–166). Therefore, IL-15 appears to play a primary role in peripheral NK cell homeostasis in addition to its crucial role in NK cell development. IL-15 is also necessary for survival of peripheral NK cells (105, 155, 157). Splenic NK cells could be successively adoptively transferred into wild-type but not IL-15−/− mice. In addition, blockade of IL-15R signaling by treatment of mice with Fab fragments of anti-IL-2/IL-15Rβ resulted in the loss of 90% of splenic NK cells (157). The survival effect of IL-15 has been linked to its ability to maintain high levels of the antiapoptotic factor Bcl-2 in NK cells in vivo (155, 157). Thus, IL-15 promotes survival of peripheral NK cells apparently by maintaining antiapoptotic factors. In spite of their dependence on IL-15, NK cells themselves do not need to express IL-15Rα to survive (104). The adoptive transfer of mature NK cells into IL-15Rα −/− recipients resulted in rapid loss of the NK cells. However, IL-15Rαdeficient NK cells could develop when IL-15Rα-deficient BM is transplanted to IL-15Rα-sufficient hosts. Furthermore, the IL-15Rα-deficient NK cells from chimeric mice survive when adoptively transferred into wild-type hosts but not into IL-15Rα −/− recipients, demonstrating a role for IL-15Rα expression on nonNK cells in supporting the survival of peripheral NK cells. IL-15Rα on non-NK cells has been shown to bind IL-15 with high affinity, recycle through the endosomal compartment while complexed with IL-15, and present IL-15 in trans to NK cells, resulting in tight localization of IL-15 signaling as well as prolonged stimulation (103). Though this trans effect can act on na¨ıve NK cell development and homeostasis, it is not yet known if this effect will be observed in other NK cell in vivo responses, such as during viral infections when IL-15Rα on NK cells is upregulated on mature NK cells (A.R. French & W.M. Yokoyama, unpublished data).

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NK Cell–Proliferative Responses to Viral Infections Mature peripheral NK cells rapidly proliferate during viral infections (126). Biron and colleagues have long noted indirect evidence of NK cell proliferation as measured by increased cell size (“blastogenesis”) during murine cytomegalovirus (MCMV) infection that correlated with increased NK cell numbers in the spleen and liver (34, 167, 168). Recent in vivo studies using intracellular BrdU staining as a direct measure of NK cell proliferation have demonstrated nonspecific NK cell proliferation early during the course of MCMV infection, regardless of NK cell expression of the MCMV-specific Ly49h receptor (126) (Figure 4, Phase I). This initial nonspecific proliferative phase resembles the cytokine-driven “bystander proliferation” observed in T cells in response to viral infections or stimulation with type I interferons (169), suggesting that this early phase of viral-induced NK cell proliferation represents a nonspecific response to proliferative cytokines such as IL-15. Although IL-15 levels are difficult to measure in vivo, accumulating evidence suggests that IFN α/β induction of IL-15 is involved in viral-induced NK cell proliferation (34, 41). Viral infections as well as polyinosinic:polycytidylic acid (pI:C) injections elicit strong IFN α/β responses that up-regulate IL-15 mRNA in dendritic cells and macrophages (41, 170, 171). The up-regulation of IL-15

Figure 4 Stages of NK cell responses in vivo. Following MCMV infection, NK cells undergo three phases of responses, as illustrated by their proliferation. During the first phase, proliferation is enhanced but nonspecific with respect to the Ly49h receptor specific for MCMV-infected cells. In this phase (I), there is no difference in proliferation of Ly49h+ (solid line) and Ly49h− (dashed line) NK cells. A second specific phase (II) then follows whereby significant proliferation of Ly49h+ NK cells occurs. In the third phase (III), specific proliferation wanes.

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mRNA during MCMV infection or pI:C injection was abrogated in the absence of IFNα/βR or STAT1 (41, 171). Correlated with this abrogation, the percentage of proliferating NK cells early during MCMV infection in IFNα/βR−/− or STAT1−/− mice was significantly lower than in wild-type littermates (41). However, direct confirmation of the role of IL-15 in mediating viral-induced NK cell proliferation has proven difficult due to a paucity of relevant reagents and because effective blockade of IL-15 signaling in the periphery results in NK cell death (157). In spite of this, strong circumstantial evidence suggests that IL-15 is involved in mediating viral-induced NK cell proliferation. After the early nonspecific phase of NK cell proliferation during MCMV infection, there is a later phase (Figure 4, Phase II) of selective proliferation of NK cells expressing the specific activation receptor (Ly49h) that is responsible for genetic NK cell-mediated resistance to MCMV by recognizing MCMV-infected cells, specifically m157 encoded by the virus (30, 126, 172–175). This period of preferential proliferation of Ly49h+ NK cells peaked at days 4 to 6 post-MCMV infection and resulted in an expansion of the pool of Ly49h+ NK cells. NK cells expressing other NK activation receptors such as Ly49d underwent proliferation during the initial nonspecific phase but did not undergo preferential expansion during the later specific phase. The specific proliferation of Ly49h+ NK cells was abrogated with F(ab0 )2 fragments of anti-Ly49h but not anti-Ly49d monoclonal antibodies supporting the hypothesis that Ly49h recognition of MCMV infected cells stimulates selective proliferation of Ly49h+ NK cells. In addition, the selective proliferation of Ly49h+ NK cells was shown to be MCMV-specific. Mice infected with vaccinia virus underwent a similar initial phase of nonspecific NK cell proliferation but did not undergo specific proliferation of Ly49h+ NK cells at later time points. However, vaccinia infection did result in the selective proliferation of a Ly49h-negative NK cell population, suggesting that the responding NK cells may express a different vaccinia-specific activation receptor. Interestingly, specific stimulation of Ly49h+ NK cells was not detectable at the earlier stage even though these cells should have been specifically triggered through Ly49h to control MCMV by day 2. It is therefore likely that the “nonspecific” stimulation of NK cells masks the detection of specific NK cell stimulation until later in the infection when it becomes manifest (Figure 4, Phase II). Following the selective expansion phase during MCMV infection, NK cells undergo a significant contraction of both Ly49h+ and Ly49h− NK cells (Figure 4, Phase III), which coincides with the onset of the adaptive immune response (126). This contraction that occurs around day 6 of MCMV infection is not well characterized but may be driven by antiproliferative cytokines derived from other cells such as activated T cells or simply the down-regulation of cytokines or cytokine receptors involved in stimulating proliferation. A recent report suggested that IL21 from activated CD4+ T cells might be involved in limiting NK cell responses and facilitating the transition to the adaptive immune response (176). However, the signals responsible for resolution of the NK cell response during MCMV infection remain to be identified.

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Therefore, mature NK cells in the periphery remain primarily quiescent until they respond to a stimulus such as a viral infection. They then rapidly proliferate in an initial nonspecific mode resembling the “bystander proliferation” seen in T cells early during a viral infection or following stimulation with IFN α/β (169). This is followed by a specific phase of proliferation of NK cells expressing the activation receptor that recognizes virus-infected cells in a manner somewhat analogous to T-cell clonal expansion. This phase is followed by a resolution phase during which the number of NK cell is significantly contracted and rapidly returns back to its steady-state levels in a manner similar to the resolution of an adaptive immune response with a significant apoptosis of T cells.

SUMMARY NK cells undergo dynamic processes during development and immune responses. In the BM, developing NK cells up- and down-regulate surface receptors for cytokines and extracellular matrix that help define developmental stages. At an immature stage where they have already expressed receptors important in “missing-self,” proliferation that may modulate the receptor repertoire of mature NK cells occurs. In the periphery, mature NK cells are relatively quiescent. Upon viral challenge, they undergo both nonspecific and specific proliferative phases, the latter related to NK cell-activation receptors for infected cells, then return to a quiescent state. Numerous viral strategies to thwart NK cell responses have been discovered although not detailed here. Taken together, these data indicate that the life of NK cells is dynamic with respect to expression of receptors for cytokines, extracellular matrix, self- and target-recognition, and proliferation, and they signify the importance of NK cells in antiviral innate immunity.

ACKNOWLEDGMENTS The authors thank past and present members of the Yokoyama laboratory for their contributions to the understanding of NK cell biology, and R. Rodrigues for evaluation of the manuscript. Work in the Yokoyama laboratory is supported by the Howard Hughes Medical Institute, the Barnes-Jewish Hospital Foundation, and grants from the National Institute of Allergy and Infectious Diseases. The Annual Review of Immunology is online at http://immunol.annualreviews.org

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killer (NK) cell inflammation and protection through macrophage inflammatory protein 1-alpha (MIP-1-alpha)-dependent pathways. J. Exp. Med. 187:1–14 Salazar-Mather TP, Hamilton TA, Biron CA. 2000. A chemokine-to-cytokine-tochemokine cascade critical in antiviral defense. J. Clin. Invest. 105:985–93 Salazar-Mather TP, Lewis CA, Biron CA. 2002. Type I interferons regulate inflammatory cell trafficking and macrophage inflammatory protein 1alpha delivery to the liver. J. Clin. Invest. 110:321–30 Hanna J, Wald O, Goldman-Wohl D, Prus D, Markel G, et al. 2003. CXCL12 expression by invasive trophoblasts induces the specific migration of CD16 negative human natural killer cells. Blood. 102:1569– 77 Beider K, Nagler A, Wald O, Franitza S, Dagan-Berger M, et al. 2003. Involvement of CXCR4 and IL-2 in the homing and retention of human NK and NK T cells to the bone marrow and spleen of NOD/SCID mice. Blood. 102:1951–58 Dokun AO, Chu DT, Yang L, Bendelac AS, Yokoyama WM. 2001. Analysis of in situ NK cell responses during viral infection. J. Immunol. 167:5286–93 Andrews DM, Farrell HE, Densley EH, Scalzo AA, Shellam GR, Degli-Esposti MA. 2001. NK1.1+ cells and murine cytomegalovirus infection: What happens in situ? J. Immunol. 166:1796–802 Fehniger TA, Cooper MA, Nuovo GJ, Cella M, Facchetti F, et al. 2003. CD56bright natural killer cells are present in human lymph nodes and are activated by T cell-derived IL-2: a potential new link between adaptive and innate immunity. Blood 101:3052–57 Glas R, Franksson L, Une C, Eloranta ML, Ohlen C, et al. 2000. Recruitment and activation of natural killer (NK) cells in vivo determined by the target cell phenotype. An adaptive component of NK cell-mediated responses. J. Exp. Med. 191:129–38

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153. Tay CH, Welsh RM. 1997. Distinct organdependent mechanisms for the control of murine cytomegalovirus infection by natural killer cells. J. Virol. 71:267–75 154. Hackett J, Jr., Bennett M, Kumar V. 1985. Origin and differentiation of natural killer cells. I. Characteristics of a transplantable NK cell precursor. J. Immunol. 134:3731– 38 155. Ranson T, Vosshenrich CA, Corcuff E, Richard O, Muller W, Di Santo JP. 2003. IL-15 is an essential mediator of peripheral NK cell homeostasis. Blood 101:4887–93 156. Wang JW, Howson JM, Ghansah T, Desponts C, Ninos JM, et al. 2002. Influence of SHIP on the NK repertoire and allogeneic bone marrow transplantation. Science 295:2094–97 157. Cooper MA, Bush JE, Fehniger TA, VanDeusen JB, Waite RE, et al. 2002. In vivo evidence for a dependence on interleukin 15 for survival of natural killer cells. Blood 100:3633–38 158. Marks-Konczalik J, Dubois S, Losi JM, Sabzevari H, Yamada N, et al. 2000. IL2-induced activation-induced cell death is inhibited in IL-15 transgenic mice. Proc. Natl. Acad. Sci. USA 97:11445–50 159. Fehniger TA, Suzuki K, Ponnappan A, VanDeusen JB, Cooper MA, et al. 2001. Fatal leukemia in interleukin 15 transgenic mice follows early expansions in natural killer and memory phenotype CD8+ T cells. J. Exp. Med. 193:219–31 160. Goldrath AW, Sivakumar PV, Glaccum M, Kennedy MK, Bevan MJ, et al. 2002. Cytokine requirements for acute and basal homeostatic proliferation of naive and memory CD8+ T cells. J. Exp. Med. 195:1515–22 161. Tan JT, Ernst B, Kieper WC, LeRoy E, Sprent J, Surh CD. 2002. Interleukin (IL)-15 and IL-7 jointly regulate homeostatic proliferation of memory phenotype CD8+ cells but are not required for memory phenotype CD4+ cells. J. Exp. Med. 195:1523–32

162. Prlic M, Lefrancois L, Jameson SC. 2002. Multiple choices: regulation of memory CD8 T cell generation and homeostasis by interleukin (IL)-7 and IL-15. J. Exp. Med. 195:F49–52 163. Becker TC, Wherry EJ, Boone D, MuraliKrishna K, Antia R, et al. 2002. Interleukin 15 is required for proliferative renewal of virus-specific memory CD8 T cells. J. Exp. Med. 195:1541–48 164. Judge AD, Zhang X, Fujii H, Surh CD, Sprent J. 2002. Interleukin 15 controls both proliferation and survival of a subset of memory-phenotype CD8+ T cells. J. Exp. Med. 196:935–46 165. Matsuda JL, Gapin L, Sidobre S, Kieper WC, Tan JT, et al. 2002. Homeostasis of V alpha 14i NKT cells. Nat. Immunol. 3:966–74 166. Ranson T, Vosshenrich CA, Corcuff E, Richard O, Laloux V, et al. 2003. IL-15 availability conditions homeostasis of peripheral natural killer T cells. Proc. Natl. Acad. Sci. USA 100:2663–68 167. Biron CA, Turgiss LR, Welsh RM. 1983. Increase in NK cell number and turnover rate during acute viral infection. J. Immunol. 131:1539–45 168. Biron CA, Sonnenfeld G, Welsh RM. 1984. Interferon induces natural killer cell blastogenesis in vivo. J. Leukoc. Biol. 35: 31–37 169. Tough DF, Borrow P, Sprent J. 1996. Induction of bystander T cell proliferation by viruses and type I interferon in vivo. Science 272:1947–50 170. Zhang X, Sun S, Hwang I, Tough DF, Sprent J. 1998. Potent and selective stimulation of memory-phenotype CD8+ T cells in vivo by IL-15. Immunity 8:591– 99 171. Mattei F, Schiavoni G, Belardelli F, Tough DF. 2001. IL-15 is expressed by dendritic cells in response to type I IFN, doublestranded RNA, or lipopolysaccharide and promotes dendritic cell activation. J. Immunol. 167:1179–87 172. Brown MG, Dokun AO, Heusel JW, Smith

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DYNAMIC LIFE OF NK CELLS HR, Beckman DL, et al. 2001. Vital involvement of a natural killer cell activation receptor in resistance to viral infection. Science 292:934–37 173. Lee SH, Girard S, Macina D, Busa M, Zafer A, et al. 2001. Susceptibility to mouse cytomegalovirus is associated with deletion of an activating natural killer cell receptor of the C-type lectin superfamily. Nat. Genet. 28:42–45 174. Lee SH, Zafer A, de Repentigny Y, Kothary R, Tremblay ML, et al. 2003. Transgenic expression of the activating natural killer receptor Ly49H confers re-

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sistance to cytomegalovirus in genetically susceptible mice. J. Exp. Med. 197:515– 26 175. Arase H, Mocarski ES, Campbell AE, Hill AB, Lanier LL. 2002. Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors. Science 296:1323–26 176. Kasaian MT, Whitters MJ, Carter LL, Lowe LD, Jussif JM, et al. 2002. IL-21 limits NK cell responses and promotes antigen-specific T cell activation: a mediator of the transition from innate to adaptive immunity. Immunity 16:559–69

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CONTENTS FRONTISPIECE—Leonard A. Herzenberg and Leonore A. Herzenberg GENETICS, FACS, IMMUNOLOGY, AND REDOX: A TALE OF TWO LIVES INTERTWINED, Leonard A. Herzenberg and Leonore A. Herzenberg SELF- AND NONSELF-RECOGNITION BY C-TYPE LECTINS ON DENDRITIC CELLS, Teunis B.H. Geijtenbeek, Sandra J. van Vliet, Anneke Engering, Bert A. ’t Hart, and Yvette van Kooyk

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TRANSCRIPTIONAL CONTROL OF EARLY B CELL DEVELOPMENT, Meinrad Busslinger

UBIQUITIN LIGASES AND THE IMMUNE RESPONSE, Yun-Cai Liu LIGANDS FOR L-SELECTIN: HOMING, INFLAMMATION, AND BEYOND, Steven D. Rosen

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INTEGRINS AND T CELL–MEDIATED IMMUNITY, Jonathan T. Pribila, Angie C. Quale, Kristen L. Mueller, and Yoji Shimizu

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MULTIPLE ROLES OF ANTIMICROBIAL DEFENSINS, CATHELICIDINS, AND EOSINOPHIL-DERIVED NEUROTOXIN IN HOST DEFENSE, De Yang, Arya Biragyn, David M. Hoover, Jacek Lubkowski, and Joost J. Oppenheim

STARTING AT THE BEGINNING: NEW PERSPECTIVES ON THE BIOLOGY OF MUCOSAL T CELLS, Hilde Cheroutre THE BCR-ABL STORY: BENCH TO BEDSIDE AND BACK, Stephane Wong and Owen N. Witte

181 217 247

CD40/CD154 INTERACTIONS AT THE INTERFACE OF TOLERANCE AND IMMUNITY, Sergio A. Quezada, Lamis Z. Jarvinen, Evan F. Lind, and Randolph J. Noelle

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THE THREE ES OF CANCER IMMUNOEDITING, Gavin P. Dunn, Lloyd J. Old, and Robert D. Schreiber

AUTOIMMUNE AND INFLAMMATORY MECHANISMS IN ATHEROSCLEROSIS, Georg Wick, Michael Knoflach, and Qingbo Xu THE DYNAMIC LIFE OF NATURAL KILLER CELLS, Wayne M. Yokoyama, Sungjin Kim, and Anthony R. French

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THE ROLE OF COMPLEMENT IN THE DEVELOPMENT OF SYSTEMIC LUPUS ERYTHEMATOSUS, Anthony P. Manderson, Marina Botto, and Mark J. Walport

DROSOPHILA: THE GENETICS OF INNATE IMMUNE RECOGNITION AND RESPONSE, Catherine A. Brennan and Kathryn V. Anderson RAGS AND REGULATION OF AUTOANTIBODIES, Mila Jankovic,

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Rafael Casellas, Nikos Yannoutsos, Hedda Wardemann, and Michel C. Nussenzweig

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THE ROLE OF SUPPRESSORS OF CYTOKINE SIGNALING (SOCS) PROTEINS IN REGULATION OF THE IMMUNE RESPONSE, Warren S. Alexander and Douglas J. Hilton

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NATURALLY ARISING CD4+

REGULATORY T CELLS FOR IMMUNOLOGIC SELF-TOLERANCE AND NEGATIVE CONTROL OF IMMUNE RESPONSES, Shimon Sakaguchi PHOSPHOINOSITIDE 3-KINASE: DIVERSE ROLES IN IMMUNE CELL ACTIVATION, Jonathan A. Deane and David A. Fruman IMMUNITY TO TUBERCULOSIS, Robert J. North and Yu-Jin Jung MOLECULAR DEFECTS IN HUMAN SEVERE COMBINED IMMUNODEFICIENCY AND APPROACHES TO IMMUNE RECONSTITUTION, Rebecca H. Buckley PHYSIOLOGICAL CONTROL OF IMMUNE RESPONSE AND INFLAMMATORY TISSUE DAMAGE BY HYPOXIA-INDUCIBLE FACTORS AND ADENOSINE A2A RECEPTORS, Michail V. Sitkovsky, Dmitriy Lukashev, Sergey Apasov, Hidefumi Kojima, Masahiro Koshiba, Charles Caldwell, Akio Ohta, and Manfred Thiel

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T LYMPHOCYTE–ENDOTHELIAL CELL INTERACTIONS, Jaehyuk Choi, David R. Enis, Kian Peng Koh, Stephen L. Shiao, and Jordan S. Pober

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IMMUNOLOGICAL MEMORY TO VIRAL INFECTIONS, Raymond M. Welsh, Liisa K. Selin, and Eva Szomolanyi-Tsuda

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CENTRAL MEMORY AND EFFECTOR MEMORY T CELL SUBSETS: FUNCTION, GENERATION, AND MAINTENANCE, Federica Sallusto, Jens Geginat, and Antonio Lanzavecchia CONTROL OF T CELL VIABILITY, Philippa Marrack and John Kappler

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ASTHMA: MECHANISMS OF DISEASE PERSISTENCE AND PROGRESSION, Lauren Cohn, Jack A. Elias, and Geoffrey L. Chupp

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CD1: ANTIGEN PRESENTATION AND T CELL FUNCTION, Manfred Brigl and Michael B. Brenner

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CHEMOKINES IN INNATE AND ADAPTIVE HOST DEFENSE: BASIC CHEMOKINESE GRAMMAR FOR IMMUNE CELLS, Antal Rot and Ulrich H. von Andrian

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INTERLEUKIN-10 AND RELATED CYTOKINES AND RECEPTORS, Sidney Pestka, Christopher D. Krause, Devanand Sarkar, Mark R. Walter, Yufang Shi, and Paul B. Fisher

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INDEXES

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Subject Index Cumulative Index of Contributing Authors, Volumes 12–22 Cumulative Index of Chapter Titles, Volumes 12–22

ERRATA An online log of corrections to Annual Review of Immunology chapters may be found at http://immunol.annualreviews.org/errata.shtml

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Annu. Rev. Immunol. 2004. 22:431–56 doi: 10.1146/annurev.immunol.22.012703.104549 c 2004 by Annual Reviews. All rights reserved Copyright ° First published online as a Review in Advance on November 10, 2003

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THE ROLE OF COMPLEMENT IN THE DEVELOPMENT OF SYSTEMIC LUPUS ERYTHEMATOSUS Anthony P. Manderson,1 Marina Botto,1 and Mark J. Walport1,2 1

Rheumatology Section, Division of Medicine, Faculty of Medicine, Imperial College, Hammersmith Campus, London W12 0NN, United Kingdom; email: [email protected], [email protected] 2 The Wellcome Trust, London NW1 2BE, United Kingdom; email: [email protected]

Key Words autoimmunity, tolerance, apoptosis ■ Abstract Complement has both beneficial and deleterious roles in the pathogenesis of systemic lupus erythematosus (SLE). On the one hand, patients with SLE present with decreased complement levels and with complement deposition in inflammed tissues, suggestive of a harmful role of complement in the effector phase of disease. On the other hand, homozygous deficiency of any of the classical pathway proteins is strongly associated with the development of SLE. There are two main hypotheses to explain these observations. The first invokes an important role for complement in the physiological waste-disposal mechanisms of dying cells and immune complexes. The second hypothesis is based around the role of complement in determining the activation thresholds of B and T lymphocytes, with the proposal that complement deficiency causes incomplete maintenance of peripheral tolerance. These two hypotheses are not mutually exclusive. In addition, there is evidence for a contribution from other genetic factors in determining the phenotype of disease in the absence of complement.

INTRODUCTION Links between the complement system and systemic lupus erythematosus (SLE) were first identified when it was discovered that complement levels were decreased in patients with SLE. In addition, it was noted that autoantibodies and complement were deposited in inflammatory lesions in the glomeruli of patients with renal involvement. The original model proposed to explain these observations was that immune complexes containing autoantigens and autoantibodies activate complement, and deposition of these complexes within tissues causes inflammatory injury. This model implies that deficiency in complement would protect patients from the development of tissue injury in SLE. 0732-0582/04/0423-0431$14.00

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However, the reverse appears to be the case. It was discovered that hereditary homozygous deficiency of the early proteins of the classical pathway of complement is strongly associated with the development of SLE. This suggests a protective role for complement against the development of SLE. In this review, we first discuss these clinical associations between the complement system and SLE. We review findings from animals with complement deficiency that have confirmed the link between deficiency of classical pathway proteins and predisposition to the development of SLE. Second, we review the hypotheses that have been advanced to explain these associations.

CLINICAL ASSOCIATIONS OF COMPLEMENT DEFICIENCIES AND SLE Inherited Complement Deficiencies in Humans HOMOZYGOUS COMPLEMENT DEFICIENCY In recent years, compelling evidence has emerged that homozygous deficiency of any of the early components of the classical pathway of complement activation (C1q, C1r, C1s, C4, and C2) predisposes to the development of SLE. In fact, these deficiencies are the strongest susceptibility factors for the development of SLE identified up to now in humans. It has also become apparent that the disease association is rather precise, with subtle but important variations according to the position of the missing protein in the triggered cascade. Overall, there appears to be a hierarchy of association of both disease prevalence and severity within the classical pathway, with patients deficient in one of C1-complex proteins (1–3) or C4 (1, 4) exhibiting the strongest prevalence (>80%) and the most severe disease, whereas the strength of the association decreases significantly in C2-deficient patients (1, 5). In this context, as most individuals with homozygous deficiency of C2 appear to remain asymptomatic, it is difficult to ascertain the correct strength of the association of C2 deficiency with SLE. One report estimated that SLE occurs in approximately one third of C2deficient patients (5); however, population studies have shown that the prevalence of homozygous C2-deficient individuals is of the order of 1/20,000 in western Europe (1). In light of this, the true strength of the association between SLE and C2 deficiency is likely to be that no more than 10% of C2-deficient subjects develop SLE. Furthermore, C2 deficiency is associated with a female-to-male ratio of 7:1, respectively, which is similar to the ratio observed among patients with SLE in the absence of complement deficiencies. This is in direct contrast to the ratio of females to males seen in patients with SLE who are deficient in C1 or C4, which is approximately 1:1, illustrating the very powerful effect of these deficiencies that overcomes the normal female preponderance seen in SLE. Finally, C3 deficiency, described only in 23 subjects, has only been associated with lupus-like disease in three patients in two families (1, 6–8). A small number of SLE patients have also been shown to carry deficiencies in components of the membrane attack complex (C5, C6, C7, C8, and C9). However, these represent only very rare or even unique

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associations, and therefore it is likely that there is no causal association between deficiency in these proteins and increased susceptibility to SLE. In these cases, the association between membrane attack complex protein deficiencies and SLE may be an example of an ascertainment artifact. A detailed description of the clinical cases falls outside the scope of this review, and the interested reader is referred to a recent review by Pickering et al. (1). Although homozygous complement deficiencies are extremely rare, they tell us a great deal about the normal physiological activities of the complement system in humans and may provide important insights for understanding the underlying mechanisms leading to the development of an autoimmune response. Collectively, the clinical observations suggest that a physiological activity of the early part of the classical pathway of complement, independent of C3 activation, provides a protective role against the development of SLE. In support of this hypothesis, there are three additional sets of observations in humans. First, two large population surveys in Switzerland and in Japan failed to identify healthy individuals with homozygous deficiency of any classical pathway protein or of C3 (9, 10). Second, studies of the inbred Turkish populations among which C1q-deficient patients had been identified revealed no asymptomatic C1q-deficient individuals (11). Third, there is a very high concordance of SLE among siblings with C1q, C1r/C1s, and C4 deficiency (90%, 67%, and 80%, respectively) (1). These concordance data are strikingly higher when compared to those observed in twin studies, which showed concordance of SLE of 2% among dizygotic twin and 24% among monozygotic twins (12). PARTIAL INHERITED COMPLEMENT DEFICIENCIES, NULL ALLELES, AND POLYMORPHISMS Although there is strong circumstantial evidence that homozygous de-

ficiency of one of the early components of the classical complement pathway increases susceptibility to SLE, the results are less conclusive with respect to partial complement deficiencies. This is in part due to the difficulty of identifying heterozygous individuals using phenotypic analyses. The serum levels of complement proteins are highly variable in normal individuals, and there is overlap between the protein concentrations observed in normal homozygous individuals and heterozygous subjects. In addition, active SLE is commonly associated with activation and consumption of classical pathway complement proteins. These difficulties can be overcome only if the molecular basis of common null alleles of complement proteins and polymorphisms affecting complement levels is known. Subsequent genotypic analysis of patient cohorts can then be performed to determine possible disease associations. So far this has been possible for only a few complement components. C1q-deficient patients have a very high incidence of SLE; however, no clinical manifestations have been observed among any heterozygous C1q-deficient siblings of the homozygous-deficient patients. Interestingly, a recent report demonstrated a single nucleotide polymorphism (SNP) in the C1qA gene, resulting in decreased serum levels of C1q and an increased incidence of this SNP in patients with

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subacute cutaneous lupus erythematosus (13). The incidence of this SNP in patients with systemic disease has not been reported. In human serum C4 exists in two isoforms encoded by separate genes that have arisen by gene duplication, C4A and C4B, with the genes located in tandem within the MHC class III region. Both genes are highly polymorphic, and the relatively high frequency of null alleles in the C4A and C4B genes in the normal population highlighted the potential for association between partial deficiency of C4 and SLE. Several independent studies investigating different ethnic groups have shown a strong association between null alleles in C4A and SLE (1, 14). However, not all studies have confirmed this association. In contrast to the associations between C4A deficiency and SLE, most studies have found no increase of C4B null alleles in patients with SLE. The reason for this discrepancy between the associations of C4A and C4B deficiencies and SLE is most likely related to the effector functions of the individual proteins. Although C4A and C4B probably arose by gene duplication, the proteins encoded by these genes have slightly different activities, especially in respect to their acceptor sites (15). C4A binds preferentially to amine groups and C4B to hydroxyl groups. It is estimated that approximately 1 in 170 western European Caucasians are carriers for the C2 null allele. However, with the exception of one study, no significant association has been found linking C2 heterozygosity in any population to increased susceptibility to the development of SLE (1, 16). The mannose-binding lectin (MBL) pathway is homologous to the classical complement pathway, with MBL replacing C1q as the recognition component. MBL is a pattern-recognition molecule that binds to arrays of mannose found on many bacteria. A number of polymorphisms have been identified within both structural and promoter regions of the gene, and these polymorphisms result in wide variation in the level of circulating MBL (17). In most studies, polymorphisms associated with low levels of MBL activity were found at higher frequencies in patients with SLE, and conversely, polymorphisms that result in high-level MBL expression were underrepresented in SLE patients (18–21). Two studies have also demonstrated that individuals carrying null alleles for C4B, in combination with a dysfunctional MBL allele, had a higher likelihood of developing SLE (20, 21). Taken together, the current data suggest that MBL may play a similar role to C1q in conferring protection against the development of SLE, although with a much weaker effect, possibly reflecting the lower levels of MBL in circulation compared to those of C1q.

Acquired Complement Deficiencies in Humans In addition to hereditary defects of the classical complement pathway components, there is supporting evidence from other disease conditions that acquired low levels of complement components predispose individuals to the development of SLE. There is an increased prevalence of lupus disease among patients with hereditary angioedema who, because of an autosomal dominant functional deficiency of

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C1-inhibitor, fail to regulate classical pathway complement activation, resulting in chronically low levels of C4 and C2. Among these patients, there is a female predominance and a high incidence of antinuclear antibodies, skin lesions, and photosensitivity, all common characteristics in SLE (1, 22). Patients with C3 nephritic factors, autoantibodies that bind and stabilize the alternative pathway C3 convertase, leading to uncontrolled complement activation, have chronic hypocomplementemia. These patients can initially present with a range of clinical symptoms; however, a number of them have been reported to subsequently develop features of SLE, in each case many years after the initial development of nephritic factor (23, 24).

Complement Activation in SLE Complement is strongly activated in patients with SLE. Deposits of C3, C4, and associated complement proteins can be easily detected in biopsies from inflamed tissues from patients with SLE. Complement activity and classical pathway protein levels are generally reduced in relation to disease activity and increase following treatment. The initial cause of complement activation in SLE is thought to be the formation of high levels of immune complexes (IC) that, in turn, activate complement via the classical pathway. However, following the initial disease onset, there are a number of factors that may influence the degree of reduction of serum levels of complement components. These include disease activity per se, the rate of production versus catabolism, and importantly, the presence of autoantibodies directed against complement proteins, such as anti-C1q antibodies. Consistent with this, studies on cohorts of SLE patients have demonstrated that complement levels in the circulation provide only a rough guide to disease activity (25, 26). The associations between complement and SLE seem paradoxical. Active SLE is accompanied by activation of the complement pathway, and there is circumstantial evidence that complement participates in causing inflammatory damage to tissues in SLE. This proinflammatory role of complement in SLE is difficult to reconcile with the clinical observations, described above, that inherited deficiency of classical pathway complement proteins plays a causal role in the induction of SLE. Thus, it is now generally thought that complement is a double-edged sword in SLE. On the one hand, it provides important protective roles against the development of SLE. On the other hand, a direct pathogenic role for complement may still influence disease expression. The initial observations showing a link between complement deficiency and autoimmunity have all come from studies in humans. Thus, in recent years it became necessary to generate animal models of complement deficiency in order to perform the experiments that may provide an explanation for this association. A number of mouse strains have now been generated with classical pathway complement deficiencies, and their analysis has already provided important insights into the pathogenesis of SLE. We first review the relevant data that have emerged

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from the studies of these mice and then discuss some of the current hypotheses on the role of complement in the pathogenesis of SLE.

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Animal Models Linking Complement Deficiency and SLE The genes for C1q, C4, C3, and CD35/CD21 (CR1/2) have been successfully targeted in mice, and these mouse strains showed a hierarchy of disease susceptibility similar to that observed in humans. C1q- and C4-deficient mice on the hybrid (129 × C57BL/6) genetic background were shown to develop higher levels of autoantibodies compared to strain-matched controls and to have histological evidence of glomerulonephritis by 8–10 months of age (27–30). In contrast, no disease manifestations were detected in C3- or CR1/2-deficient mice on this genetic background (27), indicating that, like in humans, the lack of C3 was not critical for the development of SLE. Interestingly, in mice the effects of complement deficiency on disease expression is dependent on the background genes (Table 1). In initial studies of C1qdeficient mice, it was observed that C1q deficiency is associated with antinuclear antibody production and glomerulonephritis in hybrid 129 × C57BL/6 mice but not in either parental strain (28, 30), suggesting that additional susceptibility genes were required for disease expression. Similarly, C4-deficient mice backcrossed onto C57BL/6 had no histological evidence of glomerulonephritis, although increased levels of anti-double-strand DNA antibodies were still detected (29). Further evidence that background genes provide essential contributions to the development of SLE in the absence of complement was given by studies introducing complement deficiency onto lupus-prone genetic backgrounds. Backcrossing C1q-deficient mice onto the autoimmune MRL/Mp background accelerated both the onset and severity of the autoimmune disease (28), and the introduction of the lpr mutation to C4-deficient mice (C57BL/6 × 129) (32) and CR1/2-deficient mice (C57BL/6 × 129 or C57BL/6) (32, 34) had the same effect. However, it is of note that the introduction of the lpr mutation to C1q-deficient mice

TABLE 1 Effect of genetic background on the level of autoimmune disease in complement-deficient mice 129 × C57BL/6

C57BL/6

MRL/Mp

C57BL/6 × lpr/lpr

MRL × lpr/lpr

Control

+

−

++

++

+++

C1qa−/−

++

−

+++

++

+++

(28, 30)

C4−/−

++

+

ND

+++b

ND

(29, 31, 32)

C3−/−

+

ND

ND

++

Cr2−/−

+

ND

ND

+++

a

a

ND = not determined.

b

On hybrid 129 × C57BL/6 background.

b

References

++

(27, 31–33)

ND

(32b, 34)

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backcrossed onto C57BL/6 or MRL did not have any effect on disease progression compared to strain-matched lpr/lpr mice (28). Several environmental and genetic factors may contribute to these differences, including the chromosome location of each complement gene. For example, the C4 gene resides within the MHC region, and it is possible that 129-specific polymorphisms tightly linked to the C4 gene may explain the preserved autoreactivity observed in the C4-deficient mice after backcrossing onto C57BL/6. In this context, it has been suggested that the influence of background genes on the development of SLE appears to be greater in complement-deficient mice than in humans. However, although more than 90% of humans with C1q deficiency develop at least one manifestation of SLE, only a proportion of them (approximately one third) develop glomerulonephritis (1). This variation in prevalence of lupus glomerulonephritis in humans with C1q deficiency may be analogous to the genetic effects that have been observed in different strains of C1q-deficient mice. In summary, both the clinical observations and animal models have clearly established that the classical complement pathway proteins play a protective role against the development of SLE. So what are the complement-dependent mechanisms that could mediate this protection from disease, resulting in predisposition to the development of autoimmunity in their absence?

CURRENT WORKING HYPOTHESES FOR LINKING COMPLEMENT DEFICIENCY AND SLE There are two main hypotheses to explain the causal link between complement deficiency and the development of SLE, neither of which are mutually exclusive (Figure 1). The first involves the role of complement in physiological wastedisposal mechanisms, in particular the clearance of dying cells and immune complexes. It has been proposed that deficiency of complement impairs a normal mechanism of waste disposal and that dying cells and tissue injury provide a source of autoantigens and inflammatory cues that drive the production of autoantibodies and further tissue inflammation. The second hypothesis proposes that complement plays a role in determining the thresholds of activation of B and T lymphocytes and that complement deficiency causes autoantibody production and SLE by impairing the normal mechanisms of tolerance induction and maintenance. We discuss each of these hypotheses in turn.

Clearance of Dying Cells AUTOANTIGENS DERIVED FROM APOPTOTIC CELLS DRIVE SLE Despite the clinical heterogeneity of SLE, different murine lupus models and SLE patients are unified by the presence of autoantibodies specific for ubiquitous self-antigens. Indeed, the repertoire of these target autoantigens is surprisingly limited, and among these, antibodies directed against nuclear components feature prominently. This implies

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Figure 1 Model describing the association of SLE and complement deficiency.

that a general immune dysregulation cannot account for the restricted autoantibody repertoire observed in lupus, and understanding how these specific autoantigens come to drive the pathogenic autoimmune response is paramount to deciphering the etiology of disease. A breakthrough in determining the likely source of the autoantigenic drive in SLE was provided by Rosen and colleagues, who established that a number of autoantigens targeted in SLE are localized in high concentrations within and on the surface of apoptotic cell blebs (35, 36). This led to the hypothesis that dying cells provide the source of autoantigens responsible for driving autoantibody production in SLE. Defects in the clearance mechanisms for dying cells could enhance the chance of developing SLE. There is a now a large amount of direct and indirect evidence describing defects in the uptake of apoptotic cells being associated with autoimmunity. In humans, monocyte-derived macrophage isolated from SLE patients have significantly reduced ability to phagocytose apoptotic cells when incubated in the presence of autologous serum in vitro (37). In some patients with SLE, nucleosomal deposits can be observed within the skin and in renal lesions (38, 39). In another group of

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SLE patients, apoptotic cells were observed within lymph node germinal centers, and the numbers of tingible body macrophage, which usually remove apoptotic nuclei, were significantly reduced in these patients (40). In addition, free nucleosomes were found in the blood of SLE patients, with the highest levels observed in patients with the most active disease (41, 42). Similar observations have been made in murine models of lupus. High levels of circulating nucleosomes, including histones and DNA, were detected in the serum from NZB/W F1 mice and MRL/lpr mice (43, 44). In addition, injection of apoptotic cells into nonautoimmune mouse strains induced the formation of autoantibodies characteristic of SLE (45). These results directly imply that the material from apoptotic cells can induce specific autoimmunity characteristic of SLE. Additional insight linking the ineffective clearance of apoptotic cell material and the development of SLE is provided by mice carrying genetic deficiencies that also develop a progressive SLE-like disease. These include genes that are thought to protect the immune system from potentially pathogenic chromatin by masking its presence (serum amyloid P component) (46) or directly digesting it (DNase I) (47, 48). Finally, mice deficient in membrane tyrosine kinase c-mer carry a defect that is thought to cause a loss of phosphatidylserine recognition by phagocytic cells, resulting in decreased ability to bind to and ingest apoptotic cells. Mice lacking membrane tyrosine kinase c-mer develop a progressive autoimmunity characterized by the presence of high levels of antinuclear antibodies (49, 50). So what evidence is there that complement is involved in the clearance of apoptotic cells, which could promote the development of SLE in its absence? Activation of complement by necrotic cells is well established; however, the importance of complement in the process of scavenging apoptotic cells is a recent discovery. Complement was first implicated in this process by the observation that C1q could bind directly and specifically to surface blebs on apoptotic keratinocytes, with deposition increasing as the blebs mature (51). Subsequently, the binding of C1q to apoptotic blebs was shown to occur via the globular heads of C1q, and it was also shown to induce the activation of the classical pathway (52, 53). These observations led to the hypothesis that deficiency of complement, especially C1q, may predispose to autoimmunity as a consequence of impaired clearance of apoptotic cells. In vitro studies in humans have implicated both the classical and alternative complement pathways in enhancing the uptake of apoptotic cells by peripheral blood-derived macrophage (54). The presence of activated C3 fragments on the surface of the apoptotic cells, and direct blocking experiments, have suggested that binding and ingestion is mediated through CR3 and/or CR4 on the surface of phagocytes (54). In addition, in a small number of patients carrying hereditary deficiencies in C1q, monocyte-derived macrophages showed defective uptake of apoptotic cells in the presence of autologous serum, a defect completely reversible by the addition of exogenous C1q (55). Interestingly, a similar defect is observed in the uptake of apoptotic cells by monocyte-derived macrophage from SLE patients (37).

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The strongest evidence that complement may play an essential role in the clearance of apoptotic cells came from studies in complement-deficient mice. In addition to in vitro data demonstrating enhanced uptake of apoptotic cells by serum complement (54), in vivo studies showed the existence of a hierarchy for classical complement proteins in mediating the internalization of apoptotic cells by peritoneal macrophage, with deficiency in C1q displaying the most severe phenotype (55). In addition, C1q-deficient mice developed a proliferative glomerulonephritis characterized by the presence of multiple apoptotic cell bodies, suggesting impaired ability to clear cellular debris (30). Importantly, these findings parallel the hierarchy of disease susceptibility and severity observed in patients and in murine models of complement deficiency. Collectively these data strongly support the proposed hypothesis that deficiency in complement predisposes to the development of SLE through inefficient removal of potentially pathogenic apoptotic cell debris. The process that mediates the ingestion of apoptotic cells is remarkably complex, pointing to possible roles for many phagocytic receptors, various bridging molecules, and several specific molecules on the dying cells that mark them for uptake (56). With respect to complement, in vitro studies have demonstrated that collectins such as C1q, as well as MBL, can drive the ingestion of apoptotic cells through interaction with calreticulin and CD91 on the phagocyte (57, 58). In addition, in humans, CR3 and CR4 have also been implicated in the recognition of iC3b bound to the surface of apoptotic cells (54). To date, the identification of additional receptors mediating the complement-dependent uptake of opsonized apoptotic material by phagocytes has remained elusive. In addition to the direct binding of C1q to apoptotic cells, a number of other molecules that can bind C1q and activate the classical complement pathway have been shown to recognize the modified cell membranes that form during the process of apoptosis (59). Among them, human c-reactive protein (CRP) (60) and natural IgM, but not IgG (61), have been shown to bind to apoptotic cells and activate the classical pathway of complement. In this context it is of note that mice lacking soluble IgM develop a lupus-like disease (62, 63). The molecules on the surface of apoptotic cells recognized by CRP and IgM have been determined, and independent studies have suggested almost identical recognition patterns, binding to lysophospholipids containing phosphorylcholine (60, 61). In addition, the binding of CRP to apoptotic cells was shown to protect the cells from assembling the membrane attack complex, and to mediate the noninflammatory uptake of apoptotic cells, a mechanism dependent on the presence of C1q (60). These accessory proteins may, in part, account for some of the complement deposition on dying cells, leading to their safe clearance by complement-dependent mechanisms. Further investigations are required to clarify and further define their importance for the complement-dependent clearance of apoptotic cells. It is interesting to note that the binding of complement components, as well as IgM and pentraxins, to apoptotic cells appears to occur only during a late phase of the process of apoptosis, and to cells that have undergone secondary necrosis (64). This could suggest that a hierarchy exists in the clearance mechanisms of

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apoptotic cells, with uptake by local macrophage representing a very early event, and complement-mediated processes a rather late event. Recently, it was reported that cells undergoing apoptosis only release low levels of nucleosomes, one of the major autoantigens in SLE, during the first 24 hours postinduction of apoptosis (65). Under normal situations, this should provide ample opportunity for efficient clearance by macrophage phagocytosis; however, in situations with high local rates of apoptosis and low or impaired phagocytic capacity, the additional opsonic activity of complement could become essential to ensure the safe clearance of the nuclear material. Therefore, a selective defect in the complement-dependent mechanisms could result in an increased release of apoptotic material into the circulation, driving an autoimmune response. This hypothesis may also explain why approximately one third of SLE patients, who are not C1q-deficient, develop autoantibodies to C1q. If C1q bound to apoptotic cells normally promotes their physiological clearance, in SLE patients poor clearance may lead to C1q-containing complexes on the surface of dying cells becoming antigenic and triggering an autoantibody response against C1q. So how might an increased peripheral load of autoantigens from dying cells lead to the development of SLE? IMMUNITY VERSUS TOLERANCE The process of apoptosis and the clearance of apoptotic cells by phagocytic cells usually occurs in the absence of tissue injury or inflammation. Breakdown in the physiological process of clearance can lead to the release of material with powerful proinflammatory properties as well as releasing potentially immunogenic self-antigens into the circulation. The release of selfantigens in a proinflammatory environment is proposed to result in their uptake by professional antigen presenting cells and the inappropriate presentation of selfantigens to T cells, leading to autoimmunity. What evidence exists to support this model for the development of autoimmune disease? The processes involved in the uptake and processing of apoptotic and necrotic material and how abnormalities in these pathways could lead to the development of SLE are currently an extremely active area of research. Immature dendritic cells (iDCs) avidly take up both apoptotic and necrotic cells, and the level of maturation regulates the consequential immune response, with maturation being the main difference between the induction of tolerance and immune activation (56). Therefore, a great potential for autoimmunity exists, and deciphering the mechanisms responsible for dendritic cell (DC) maturation is crucial to understanding the etiology of SLE. A number of specific signals that lead to the maturation of DCs have been identified and include viral and bacterial proteins, proinflammatory cytokines, high antigen load (66), and potentially uptake of necrotic cells (67, 68). The process of phagocytosis of apoptotic cells by macrophage and iDCs actively suppresses inflammation and promotes peripheral tolerance through the increased production of anti-inflammatory mediators such as transforming growth factor-β (TGF-β) and IL-10, and inhibition of proinflammatory cytokines such as tumor necrosis factor-α (TNF-α) (69–72). Even strong proinflammatory signals, such as LPS-driven maturation of DCs, can be suppressed by the engulfment of apoptotic

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cells by iDCs, also reducing the capacity of the DCs to directly stimulate T cells. In addition, cells that are actively undergoing apoptosis can also directly secrete cytokines with immunosuppressive properties (73, 74). So how can autoimmune proinflammatory responses to apoptotic tissue be generated when abundant data demonstrate that the clearance of apoptotic cells in vivo is normally a tolerogenic event? In contrast to the uptake of apoptotic cells, a number of studies have demonstrated that uptake of necrotic cells by iDCs can induce their maturation. This is an important consideration to the development of SLE, as it has been proposed that as a result of an impaired clearance the apoptotic cells may undergo secondary necrosis, releasing proinflammatory signals that could affect the maturation state of the ingesting DC and inducing a break in peripheral tolerance. A number of studies using tumor cell lines have shown the ability of necrotic cells to induce DC maturation in vitro (75–77). Another study also confirmed these observations in tumor cell lines; however, it did not observe DC maturation following uptake of necrotic cells induced from primary cell cultures (67). Furthermore, a recent study casts doubt on the interpretations of these findings. The investigators examined the ability of a number of apoptotic and necrotic cells to induce DC maturation and found that necrotic cells induced DC maturation only from cell lines that were contaminated by mycoplasma (68). Clearly, further investigations will be required to resolve whether cells that have undergone secondary necrosis play a role in inducing autoimmunity. There is also now a large body of evidence suggesting that in SLE the maturation of DCs could be mediated by the cytokine interferon-α (IFN-α) (78, 79). This cytokine is usually produced in response to infections and, in addition to mediating the maturation of DCs, may also promote the development of autoimmunity through its direct ability to regulate the activation thresholds of T and B cells (80). An increased proportion of functionally active monocyte-derived DCs has been observed in the blood of SLE patients. In addition, monocytes, normally quiescent cells, when isolated from the blood of SLE patients, are able to induce a strong mixed lymphocyte reaction, a property usually used to define mature DCs (81). Both of these observations suggest that DC maturation is abnormal in SLE. It was also shown that incubating normal monocytes with serum of some SLE patients induced the differentiation of normal monocytes to DCs, with the factor in SLE serum responsible for this spontaneous maturation of DCs shown to be IFN-α (81). Although high levels of IFN-α are not present in serum from all SLE patients, it has been recently demonstrated, using microarray technology, that peripheral blood mononuclear cells from all SLE patients with active disease have a dysregulated expression of genes induced through the IFN pathway (82–84). This discrepancy may reflect the production of IFN-α at local sites by DCs not measurable in the circulation. In addition, it has become apparent that prolonged IFN treatment in patients with virus infections or malignant diseases can induce symptoms much like those found among patients with active lupus (78). In agreement with the observations in humans, IFN-α has also been implicated in disease exacerbation

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in murine models of lupus. Direct administration of IFN-α accelerated disease in NZB/W mice (85), and introduction of a deficiency in the type I IFN receptor reduced lupus-like disease in NZB mice, characterized by decreases in autoantibodies, kidney disease, and mortality (86). So, what cells are responsible for producing the IFN-α, and what causes its production? Plasmacytoid DCs (pDCs) are capable of producing unusually large amounts of IFN-α in response to inducers such as viral or bacterial infections, and surprisingly also when exposed to sera of patients with lupus (78, 87). This is consistent with the observation that very high numbers of pDCs are found in lymphoid tissues in patients with active SLE (88). An inducer of IFN-α in the sera was shown to comprise small immune complexes containing DNA and IgG anti-DNA autoantibodies as essential components (89, 90). Apoptotic cells were shown to provide the antigen for these complexes, and expression of FcgRII and toll-like receptor 9 (TLR9) on DCs were required for recognition of these complexes and IFN-α production (91). Importantly, DNA-IgG immune complexes (ICs) have recently also been implicated in the aberrant activation of autoreactive B cells, mediated through synergistic B cell receptor/TLR9 signaling (92). How mammalian DNA, usually poorly immunogenic, can form activatory ICs is still poorly understood; however, it is becoming evident that even methylated CpG motifs, present within mammalian DNA, do have the potential to induce B cell activation (93, 94). It is also interesting to note that in addition to anti-DNA ICs, other events that can trigger secretion of excessive amounts of IFN-α, such as infection and UV skin injury, are both known activators of lupus. In conclusion, there is strong circumstantial evidence suggesting that chronic stimulation of DCs can lead to a break in peripheral tolerance and the development of SLE. In the absence of complement, elevated levels of apoptotic cell debris lead to uptake and inappropriate presentation of these autoantigens to T cells, leading to the development of autoimmunity. What still remains to be confirmed is the role of complement in regulating the maturation of DCs. Is the presence of increased circulating autoantigens sufficient, or does complement regulate additional mechanisms that lead to the break of tolerance toward self-antigens? What stimulates the production of IFN-α?

Clearance of Immune Complexes The formation of ICs is an important process of the adaptive immune response, promoting the removal of foreign antigens. Complement plays two main roles in the process: maintaining solubility of the complexes and, via complement receptors, promoting their recognition and clearance by phagocytic cells in conjunction with Fcγ receptors. IC precipitation is prevented primarily by the binding of the C1 complex and the subsequent covalent deposition of C4 and C3 binding to both antigen and the heavy chain of IgG (95, 96). The deposition of the complement components within the IC is thought to prevent the formation of large insoluble ICs by reducing the effective

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valency of antigen and antibody, as well as interfering with Fc-Fc interactions (97, 98). Complement is also able to induce the solubilization of insoluble ICs, a process mediated by the alternative complement pathway. However, this process is relatively inefficient, requiring consumption of large amounts of complement (99). In addition to maintaining the solubility and minimizing the size of IC, complement fragments bound within the ICs provide ligands for the clearance of these complexes by phagocytic cells. In primates, CR1 on erythrocytes is predominantly responsible for the transporting of IC to tissue macrophage present in the liver and spleen (100). Although CR1 is not expressed by rodent erythrocytes, soluble IC are also predominantly removed through the liver and spleen (101). There are numerous studies demonstrating that IC processing is abnormal in SLE patients (102, 103). The in vivo studies have been performed using both particulate and soluble ICs with similar observations made in both models (104, 105). In patients with SLE or complement deficiency, the initial clearance of immune complexes was impaired in the spleen; however, the uptake by the liver was more rapid. Most strikingly, the ICs were poorly retained within the liver with a proportion released back to the circulation. These ICs have the potential to deposit in tissues throughout the body, inducing inflammation. Owing to the similarities in the observations in complement-deficient and SLE patients with acquired reduction in complement levels, the cause of this phenomenon is presumably due to reduced complement binding to ICs, as well as the decreased levels of erythrocyte CR1 that have been characterized in SLE patients (106). In addition, an accelerated hepatic and decreased splenic uptake of IC was demonstrated in C1q-deficient mice, analogous to the observations in humans (101). Collectively, these observations led to the hypothesis that in the absence of complement, or in the presence of acquired hypocomplementaemia, the impaired clearance and decreased solubility of IC could lead to their deposition within tissues, inducing inflammatory injury that may cause the release of autoantigens, augmenting an autoimmune response. This theory is complementary to the hypothesis proposed in the previous section, suggesting that defective clearance of dying cells in the absence of complement leads to the development of SLE.

Complement and Lymphocyte Responses PHYSIOLOGICAL REGULATION OF B CELL RESPONSES BY COMPLEMENT B cells are responsible for the production of pathogenic autoantibodies characteristic of SLE. Therefore, dissection of the mechanisms by which complement regulates these cells is crucial for understanding disease etiology. B cells of the B-1 subtype are known to produce “natural” IgM with specificities for autoantigens, even in healthy individuals, with higher titers observed in the sera of SLE patients. In patients with SLE, B cells of the B-2 subtype produce a large array of pathogenic IgG autoantibodies. The autoreactive B-2 B cells have been shown to undergo antigendriven hypermutation, isotype switching, and selection to produce antibodies with

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a very high affinity for specific autoantigens. These observations suggest that autoantibody generation is a T cell–dependent process. There is evidence linking complement to regulation of B cell development, activation, and tolerance. In the absence of C1q, C4, or C3, humoral immune responses to T-dependent antigens are severely impaired with poor IgM responses and an inability of the B cells to switch antibody isotypes (107). Two mechanisms were proposed to explain enhanced humoral responses in the presence of complement. Initially, it was proposed that retention of ICs on follicular dendritic cells (FDCs) was essential for the development of normal T-dependent antibody responses. In mice depleted of C3 or inherently deficient in complement components (C3, C4, and C1q) or CR1/2, loss of antigen retention (as IC) on FDCs was noted (108–112). More recently, however, extensive biochemical and in vivo studies (113, 114), using anti-CR1/2 blocking antibodies (115–118) and CR1/2 knockout mice (119, 120), have revealed that an important complement effect is mediated directly on B cells via the complement receptors CD21/CD35. Coligation of the B cell receptor with CD21 (CR2) on the surface of B cells provides the necessary costimulation for enhanced B cell activation to T-dependent antigens (113). Direct evidence for this was provided by Dempsey and colleagues, who found that coupling multiple oligomers of C3d to an antigen, hen egg lysozyme (HEL), lowered the amount of the antigen required for the induction of HEL-specific IgG responses (121). How this coupling of C3d to antigen occurs in vivo is poorly understood, although it is believed to involve IC formation, possibly involving natural IgM (122). Evidence for the involvement of natural IgM comes from findings that deficiency in secreted IgM leads to impaired B cell responses to low doses of T-dependent antigens that are similar to those seen in the absence of complement (123). Importantly, although expression of CR1/2 on B cells is sufficient for the development of short-term antibody responses, the retention of ICs bound to CR1/2 on FDCs is important for the long-term maintenance of the memory B cell response (124). Do these findings help to decipher the mechanisms responsible for linking complement deficiency to the development of SLE? On the contrary, they show that one of the normal activities of complement is to lower the threshold for B cell activation by T-dependent antigens. Therefore, as the autoantibodies commonly found in SLE are thought to form via T-dependent B cell responses, individuals devoid of complement should be protected from developing disease, rather than deficiency promoting the development of SLE. This apparent paradox can be explained by the fact that the necessity for complement and complement receptors in humoral immune responses can be overcome by the presence of large doses of antigen (110, 125, 126). In the context of SLE it has been demonstrated, both in patients (41, 42) and animal models (44, 127), that high levels of circulating autoantigen are present, as previously discussed. Therefore, the effect of complement deficiency on B cell activation, through providing costimulation via the complement receptors on the B cell, is probably minimal or even negated by other effects of complement, such as the increase of antigen available to the B cells.

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However, there is some evidence demonstrating that an absence of complement can cause a breakdown in B cell tolerance, resulting in the escape of autoreactive B cells and predisposition to autoimmunity in the absence of complement. The reports published to date testing this hypothesis are somewhat contradictory and are reviewed below (31, 32, 128). COMPLEMENT DEFICIENCY, B CELLS, AND TOLERANCE An alternative hypothesis to the waste disposal hypothesis to explain the association between complement deficiencies and SLE is that a breakdown in B cell tolerance results in the escape from deletion/anergy of self-reactive B cells that are subsequently activated on encountering autoantigen within the periphery (32, 125, 129–131). A transgenic model comprising soluble HEL (sHEL) as autoantigen and an antiHEL as the autoantibody has been extensively studied in the presence and absence of complement proteins. Prodeus and colleagues found that self-tolerance to sHEL was dependent on the presence of C4 and CR1/2, but not C3. They hypothesized that the attachment of C4b to self-antigens and localization of these complexes to CD35 on stromal cells within the bone marrow may regulate the selection of potentially autoreactive B cells (32). However, in complete contrast to these results, the interbreeding of C1q-deficient mice with the same transgenic model (sHEL/antiHEL) demonstrated no alterations in B cell tolerance to sHEL expressed as a self-antigen in the absence of C1q (128). The different genetic background of the mice used could account for the opposing observations made in these two studies. As disease in SLE is known to be influenced by multiple genetic factors (28, 132), when employing mice of mixed genetic background, as in the study of C4- and CR1/2-deficient mice, a number of different genetic loci could affect the break in tolerance observed. In addition, the transgenic expression of sHEL is not the best model for studying the maintenance of tolerance in SLE. Soluble secreted HEL is not a natural autoantigen, and the majority of the autoantigens targeted by autoantibodies in SLE are cell-associated (1). Experimental studies are currently underway exploring the role of complement deficiency in tolerance induction in experimental animals expressing transgenic lupus autoantibodies and transgenic cell-associated autoantigens. These mice will provide a better tool for investigating the extent to which complement contributes to the regulation of autoreactive B cells. COMPLEMENT AND T LYMPHOCYTE ACTIVATION Extensive experimental evidence clearly underlines the critical role of CD4+ T cells in the pathogenesis of SLE (133–137). It is thought that the effector T cells induce their pathogenic effects in two ways, indirectly, through the provision of T cell help to autoreactive B cells (138–140), resulting in the production of high-affinity autoantibodies, and directly, inducing tissue damage (141). Until recently, any effect of complement in mediating activation of autoreactive T cells was thought to be largely indirect, with altered APC function resulting in inappropriate signaling to helper T cells. However, there is now growing evidence that complement may directly influence T cell activation/regulation mechanisms.

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Subpopulations of human T cells have been shown to express receptors for C1q (142–144), and proliferation of the T cells was significantly inhibited when soluble C1q was present in mitogen-induced T cell cultures (144) and in a number of T cell lines (142). The physiological significance of these observations is not known. Some insight to these earlier observations may be provided by a recent report showing that C1q-containing ICs, but not nonopsonised ICs, can activate human T cells, inducing the secretion of both TNF-α and IFN-γ (145). Crosslinking of C1q on the surface of the T cells had the same effect. To date no direct T cell abnormalities have been observed in the complementdeficient animals. However, in C1q-deficient mice, cytokine production by antigenspecific T cells was altered in response to immunization with a T-dependent antigen, with diminished levels of IFN-γ (112). The mechanism responsible is not known. The primary function of complement regulatory proteins is to prevent complement deposition on the surface on which they reside. However, new data suggest an additional costimulatory role for these proteins in T cell activation. In humans, ligation of CD3 with membrane-bound complement regulatory proteins, either CD46 [also known as membrane cofactor protein (MCP)] or CD55 [decay accelerating factor (DAF)], induced a synergistic activation of human T cells, promoting T cell proliferation and altered cytokine production (146–150). Similarly, in mice the coligation of CD3 and Crry, which possesses both MCP and DAF activity, led to increased CD4 T cell proliferation and decreased IFN-γ production (151). In addition, the coligation of CD3 and CD46 on human CD4+ T cells induced development of a T-regulatory phenotype, when cultured in the presence of IL-2 (148). What could be the physiological significance of these observations, and do they have any relevance to the pathogenesis of SLE associated with complement deficiencies? Complement fragments bound within immune complexes could ligate a number of receptors expressed on the membrane of T cells and alter their activation threshold. In addition, as regulatory T cells have been shown to prevent and/or regulate systemic autoimmunity and have been directly implicated in a number of autoimmune diseases (152, 153), a link to SLE is an attractive hypothesis.

SUMMARY The evidence is overwhelming from both the clinical observations and animal models that the classical complement pathway proteins play a protective role against the development of SLE. A flow diagram linking the current hypotheses that may account for the development of autoimmunity in the absence of complement is presented in Figure 1. First, the absence of complement-dependent clearance of dying cells and/or immune complexes could lead to elevated levels of potentially immunogenic self-antigens. The uptake and inappropriate presentation of these antigens could drive the production of autoantibodies. In addition, the formation of DNA/anti-DNA immune complexes could directly induce tissue inflammation, as well as mediating the inappropriate maturation of dendritic cells with

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potentially pathogenic consequences. Second, the absence of regulatory signals to B and T lymphocytes, usually provided by activated complement fragments, could lead to a breakdown in the maintenance of peripheral tolerance to self-antigens. Thus, the presence of elevated levels of autoantigens and inappropriate presentation of these antigens by dendritic cells may explain the loss of self-tolerance associated with complement deficiency.

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The Annual Review of Immunology is online at http://immunol.annualreviews.org

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112. Cutler AJ, Botto M, van Essen D, Rivi R, Davies KA, et al. 1998. T cell-dependent immune response in C1q-deficient mice: defective interferon gamma production by antigen-specific T cells. J. Exp. Med. 187:1789–97 113. Fearon DT, Carroll MC. 2000. Regulation of B lymphocyte responses to foreign and self-antigens by the CD19/CD21 complex. Annu. Rev. Immunol. 18:393– 422 114. Fearon DT, Carter RH. 1995. The CD19/CR2/TAPA-1 complex of B lymphocytes: linking natural to acquired immunity. Annu. Rev. Immunol. 13:127–49 115. Thyphronitis G, Kinoshita T, Inoue K, Schweinle JE, Tsokos GC, et al. 1991. Modulation of mouse complement receptors 1 and 2 suppresses antibody responses in vivo. J. Immunol. 147:224–30 116. Gustavsson S, Kinoshita T, Heyman B. 1995. Antibodies to murine complement receptor 1 and 2 can inhibit the antibody response in vivo without inhibiting T helper cell induction. J. Immunol. 154:6524–28 117. Heyman B, Wiersma EJ, Kinoshita T. 1990. In vivo inhibition of the antibody response by a complement receptorspecific monoclonal antibody. J. Exp. Med. 172:665–68 118. Hebell T, Ahearn JM, Fearon DT. 1991. Suppression of the immune response by a soluble complement receptor of B lymphocytes. Science 254:102–5 119. Ahearn JM, Fischer MB, Croix D, Goerg S, Ma M, et al. 1996. Disruption of the Cr2 locus results in a reduction in B-1a cells and in an impaired B cell response to T-dependent antigen. Immunity 4:251– 62 120. Molina H, Holers VM, Li B, Fung Y, Mariathasan S, et al. 1996. Markedly impaired humoral immune response in mice deficient in complement receptors 1 and 2. Proc. Natl. Acad. Sci. USA 93:3357–61 121. Dempsey PW, Allison ME, Akkaraju S, Goodnow CC, Fearon DT. 1996. C3d

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Kakkanaiah VN, Cohen PL, Kotzin BL. 1993. Selection of the T cell receptor repertoire in Lpr mice. J. Immunol. 151:3450–59 Kotzin BL, Kappler JW, Marrack PC, Herron LR. 1989. T cell tolerance to self antigens in New Zealand hybrid mice with lupus-like disease. J. Immunol. 143:89– 94 Mihara M, Ohsugi Y, Saito K, Miyai T, Togashi M, et al. 1988. Immunologic abnormality in NZB/NZW F1 mice. Thymus-independent occurrence of B cell abnormality and requirement for T cells in the development of autoimmune disease, as evidenced by an analysis of the athymic nude individuals. J. Immunol. 141:85– 90 Steinberg AD, Roths JB, Murphy ED, Steinberg RT, Raveche ES. 1980. Effects of thymectomy or androgen administration upon the autoimmune disease of MRL/Mp-lpr/lpr mice. J. Immunol. 125:871–73 Wofsy D, Seaman WE. 1985. Successful treatment of autoimmunity in NZB/NZW F1 mice with monoclonal antibody to L3T4. J. Exp. Med. 161:378–91 Ando DG, Sercarz EE, Hahn BH. 1987. Mechanisms of T and B cell collaboration in the in vitro production of anti-DNA antibodies in the NZB/NZW F1 murine SLE model. J. Immunol. 138:3185–90 Datta SK, Patel H, Berry D. 1987. Induction of a cationic shift in IgG anti-DNA autoantibodies. Role of T helper cells with classical and novel phenotypes in three murine models of lupus nephritis. J. Exp. Med. 165:1252–68 Shivakumar S, Tsokos GC, Datta SK. 1989. T cell receptor alpha/beta expressing double-negative (CD4−/CD8−) and CD4+ T helper cells in humans augment the production of pathogenic antiDNA autoantibodies associated with lupus nephritis. J. Immunol. 143:103–12 Shlomchik MJ, Craft JE, Mamula MJ. 2001. From T to B and back again:

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positive feedback in systemic autoimmune disease. Nat. Rev. Immunol. 1:147– 53 Ghebrehiwet B, Habicht GS, Beck G. 1990. Interaction of C1q with its receptor on cultured cell lines induces an antiproliferative response. Clin. Immunol. Immunopathol. 54:148–60 Ghebrehiwet B, Lu PD, Zhang W, Keilbaugh SA, Leigh LE, et al. 1997. Evidence that the two C1q binding membrane proteins, gC1q-R and cC1q-R, associate to form a complex. J. Immunol. 159:1429– 36 Chen A, Gaddipati S, Hong Y, Volkman DJ, Peerschke EI, Ghebrehiwet B. 1994. Human T cells express specific binding sites for C1q. Role in T cell activation and proliferation. J. Immunol. 153:1430–40 Jiang K, Chen Y, Xu CS, Jarvis JN. 2003. T cell activation by soluble C1q-bearing immune complexes: implications for the pathogenesis of rheumatoid arthritis. Clin. Exp. Immunol. 131:61–67 Zaffran Y, Destaing O, Roux A, Ory S, Nheu T, et al. 2001. CD46/CD3 costimulation induces morphological changes of human T cells and activation of Vav, Rac, and extracellular signal-regulated kinase mitogen-activated protein kinase. J. Immunol. 167:6780–85

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CONTENTS FRONTISPIECE—Leonard A. Herzenberg and Leonore A. Herzenberg GENETICS, FACS, IMMUNOLOGY, AND REDOX: A TALE OF TWO LIVES INTERTWINED, Leonard A. Herzenberg and Leonore A. Herzenberg SELF- AND NONSELF-RECOGNITION BY C-TYPE LECTINS ON DENDRITIC CELLS, Teunis B.H. Geijtenbeek, Sandra J. van Vliet, Anneke Engering, Bert A. ’t Hart, and Yvette van Kooyk

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TRANSCRIPTIONAL CONTROL OF EARLY B CELL DEVELOPMENT, Meinrad Busslinger

UBIQUITIN LIGASES AND THE IMMUNE RESPONSE, Yun-Cai Liu LIGANDS FOR L-SELECTIN: HOMING, INFLAMMATION, AND BEYOND, Steven D. Rosen

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INTEGRINS AND T CELL–MEDIATED IMMUNITY, Jonathan T. Pribila, Angie C. Quale, Kristen L. Mueller, and Yoji Shimizu

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MULTIPLE ROLES OF ANTIMICROBIAL DEFENSINS, CATHELICIDINS, AND EOSINOPHIL-DERIVED NEUROTOXIN IN HOST DEFENSE, De Yang, Arya Biragyn, David M. Hoover, Jacek Lubkowski, and Joost J. Oppenheim

STARTING AT THE BEGINNING: NEW PERSPECTIVES ON THE BIOLOGY OF MUCOSAL T CELLS, Hilde Cheroutre THE BCR-ABL STORY: BENCH TO BEDSIDE AND BACK, Stephane Wong and Owen N. Witte

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CD40/CD154 INTERACTIONS AT THE INTERFACE OF TOLERANCE AND IMMUNITY, Sergio A. Quezada, Lamis Z. Jarvinen, Evan F. Lind, and Randolph J. Noelle

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THE THREE ES OF CANCER IMMUNOEDITING, Gavin P. Dunn, Lloyd J. Old, and Robert D. Schreiber

AUTOIMMUNE AND INFLAMMATORY MECHANISMS IN ATHEROSCLEROSIS, Georg Wick, Michael Knoflach, and Qingbo Xu THE DYNAMIC LIFE OF NATURAL KILLER CELLS, Wayne M. Yokoyama, Sungjin Kim, and Anthony R. French

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THE ROLE OF COMPLEMENT IN THE DEVELOPMENT OF SYSTEMIC LUPUS ERYTHEMATOSUS, Anthony P. Manderson, Marina Botto, and Mark J. Walport

DROSOPHILA: THE GENETICS OF INNATE IMMUNE RECOGNITION AND RESPONSE, Catherine A. Brennan and Kathryn V. Anderson RAGS AND REGULATION OF AUTOANTIBODIES, Mila Jankovic,

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Rafael Casellas, Nikos Yannoutsos, Hedda Wardemann, and Michel C. Nussenzweig

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THE ROLE OF SUPPRESSORS OF CYTOKINE SIGNALING (SOCS) PROTEINS IN REGULATION OF THE IMMUNE RESPONSE, Warren S. Alexander and Douglas J. Hilton

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REGULATORY T CELLS FOR IMMUNOLOGIC SELF-TOLERANCE AND NEGATIVE CONTROL OF IMMUNE RESPONSES, Shimon Sakaguchi PHOSPHOINOSITIDE 3-KINASE: DIVERSE ROLES IN IMMUNE CELL ACTIVATION, Jonathan A. Deane and David A. Fruman IMMUNITY TO TUBERCULOSIS, Robert J. North and Yu-Jin Jung MOLECULAR DEFECTS IN HUMAN SEVERE COMBINED IMMUNODEFICIENCY AND APPROACHES TO IMMUNE RECONSTITUTION, Rebecca H. Buckley PHYSIOLOGICAL CONTROL OF IMMUNE RESPONSE AND INFLAMMATORY TISSUE DAMAGE BY HYPOXIA-INDUCIBLE FACTORS AND ADENOSINE A2A RECEPTORS, Michail V. Sitkovsky, Dmitriy Lukashev, Sergey Apasov, Hidefumi Kojima, Masahiro Koshiba, Charles Caldwell, Akio Ohta, and Manfred Thiel

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T LYMPHOCYTE–ENDOTHELIAL CELL INTERACTIONS, Jaehyuk Choi, David R. Enis, Kian Peng Koh, Stephen L. Shiao, and Jordan S. Pober

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IMMUNOLOGICAL MEMORY TO VIRAL INFECTIONS, Raymond M. Welsh, Liisa K. Selin, and Eva Szomolanyi-Tsuda

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CENTRAL MEMORY AND EFFECTOR MEMORY T CELL SUBSETS: FUNCTION, GENERATION, AND MAINTENANCE, Federica Sallusto, Jens Geginat, and Antonio Lanzavecchia CONTROL OF T CELL VIABILITY, Philippa Marrack and John Kappler

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ASTHMA: MECHANISMS OF DISEASE PERSISTENCE AND PROGRESSION, Lauren Cohn, Jack A. Elias, and Geoffrey L. Chupp

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CD1: ANTIGEN PRESENTATION AND T CELL FUNCTION, Manfred Brigl and Michael B. Brenner

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CHEMOKINES IN INNATE AND ADAPTIVE HOST DEFENSE: BASIC CHEMOKINESE GRAMMAR FOR IMMUNE CELLS, Antal Rot and Ulrich H. von Andrian

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INTERLEUKIN-10 AND RELATED CYTOKINES AND RECEPTORS, Sidney Pestka, Christopher D. Krause, Devanand Sarkar, Mark R. Walter, Yufang Shi, and Paul B. Fisher

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INDEXES

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Subject Index Cumulative Index of Contributing Authors, Volumes 12–22 Cumulative Index of Chapter Titles, Volumes 12–22

ERRATA An online log of corrections to Annual Review of Immunology chapters may be found at http://immunol.annualreviews.org/errata.shtml

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Annu. Rev. Immunol. 2004. 22:457–83 doi: 10.1146/annurev.immunol.22.012703.104626 c 2004 by Annual Reviews. All rights reserved Copyright ° First published online as a Review in Advance on November 10, 2003

DROSOPHILA: The Genetics of Innate Immune Recognition and Response

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Catherine A. Brennan and Kathryn V. Anderson Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer, New York, New York 10021; email: [email protected], [email protected]

Key Words Toll, Imd, PGRP, autoimmunity, pathogenesis ■ Abstract Because of the evolutionary conservation of innate mechanisms of host defense, Drosophila has emerged as an ideal animal in which to study the genetic control of immune recognition and responses. The discovery that the Toll pathway is required for defense against fungal infection in Drosophila was pivotal in studies of both mammalian and Drosophila immunity. Subsequent genetic screens in Drosophila to isolate additional mutants unable to induce humoral responses to infection have identified and ordered the function of components of two signaling cascades, the Toll and Imd pathways, that activate responses to infection. Drosophila blood cells also contribute to host defense through phagocytosis and signaling, and may carry out a form of self-nonself recognition that is independent of microbial pattern recognition. Recent work suggests that Drosophila will be a useful model for dissecting virulence mechanisms of several medically important pathogens.

INTRODUCTION In 1989, Janeway proposed that innate immune mechanisms, those that rely on detection of microbes by germline encoded receptors, are ancient and essential for earliest detection of and defense against infection in mammals (1). In 1996, Lemaitre and coworkers demonstrated that the Toll receptor, previously known for its essential role during Drosophila embryonic development, is required for antifungal defense in Drosophila (2). This finding stimulated the identification of the mammalian Toll-like receptors (TLRs) and the demonstration of their importance in mammalian innate immunity. We now know that mice that lack TLRs are susceptible to infection and are impaired in the ability to activate adaptive immune mechanisms, supporting Janeway’s predictions (3–5). Well before the power of Drosophila genetics was harnessed to study regulation of immune responses, insects were already known to have sophisticated immune systems, involving phagocytic blood cells, serine proteolytic cascades, and inducible humoral responses, thanks to decades of biochemical work with larger insects. In particular, insects induce a number of antimicrobial peptides 0732-0582/04/0423-0457$14.00

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upon immune challenge that are effective against Gram-negative or Gram-positive bacteria or fungi. Following the discovery of the immune function of Drosophila Toll, genetic screens were designed to isolate Drosophila mutants that could not induce particular antimicrobial peptides in response to infection. Genetic methods have identified about two dozen genes required for induction of the antimicrobial peptides. Many of these genes encode proteins in two signaling pathways that control the activation of NF-κB-like factors in response to infection, the Toll and Imd pathways, both named for the first gene to be discovered in the pathway. Immune signaling through Toll leads to the activation of two NF-κB factors, Dif and Dorsal. Activation of the Imd signaling pathway culminates in the activation and nuclear translocation of the third Drosophila NF-κB-like factor, Relish. The early finding that Toll mutants are impaired in survival to fungal infection and imd mutants impaired in antibacterial responses suggested that distinct pathways are used to detect and induce responses against bacteria and fungi. However, we now know that survival to Gram-positive bacterial infection also requires the Toll pathway. In addition to its importance in activation of antifungal responses, Toll is a central regulator of multiple aspects of Drosophila immunity, including resistance to bacterial infection, blood cell activation, and regulation of a melanization cascade. Genetic screens have also identified two peptidoglycan recognition proteins (PGRPs) that bind bacterial components directly. One recognizes Gram-negative bacteria and activates the Imd pathway, and the other detects Gram-positive bacteria and triggers Toll signaling. These findings fulfil Janeway’s prediction that in innate immunity, pattern recognition receptors (PRRs) would recognize conserved molecular features of microbes, or pathogen-associated molecular patterns (PAMPs). What was not foreseen in 1989, and what Drosophila has revealed, is that innate immune systems can discriminate among PAMPs that are characteristic of different microbial classes and activate the most appropriate defenses. Still under intense scrutiny in Drosophila are the mechanisms linking detection of microbes to signaling through the Imd and Toll pathways. Other aspects of the Drosophila immune response are not as well understood as the signaling pathways that lead to the humoral responses, but are ripe for genetic dissection. Blood cells are activated in response to infection, but our understanding of the mechanisms and consequences of blood cell activation are fragmentary. Serine protease cascades, which also activate several aspects of the mammalian immune response (6, 7), are required for activation of Toll signaling and the melanization response in Drosophila. Drosophila can also activate immune responses in the absence of microbial PAMPs—both in response to infestation with parasites, and under autoimmune conditions generated by a variety of mutations. Although the mechanisms of immune activation under these circumstances are not known, insect blood cells are able to discriminate between self and nonself, and both aberrant basement membrane patterns and endogenous DNA may be immunostimulatory.

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Drosophila has recently emerged as a suitable model organism to investigate virulence mechanisms of a wide range of medically important pathogens, including Pseudomonas, Serratia, Mycobacteria, and malaria parasites. Many of the bacterial virulence mechanisms that are essential to establish infection in mammals also contribute to pathogenesis in flies, including type three secretion systems (TTSS) and ability to proliferate inside macrophages. Major questions in innate immunity concern how germline encoded receptors distinguish self from nonself and discriminate among various types of foreign invaders in order to activate the most effective response. The striking commonalities between Drosophila and mammalian innate immunity, including Toll-NF-κB signaling, phagocytosis, serine protease cascades, PGRPs, and autoimmune defects suggest that in the years to come studies in Drosophila will continue to shed light on immune mechanisms that are also important in humans.

OVERVIEW OF THE DROSOPHILA IMMUNE RESPONSE A Diversity of Infectious Threats Because Drosophila is not an agricultural pest, there is not a long history of entomological study of their pathogens. Much of our knowledge of Drosophila immunity thus concerns the responses to microbes that are not normally pathogenic and do not infect wild-type Drosophila unless directly injected. Studying immune responses to these opportunistic infections may be particularly relevant to mammalian immunity, as generalized immune defenses tend to be more evolutionarily conserved than ones specific to individual virulent pathogens. Nevertheless, some microorganisms and parasites are known that can naturally infect Drosophila, permitting finer analysis of immune mechanisms without the complications that a wound can introduce (8–10). This review primarily addresses Drosophila immunity to extracellular bacteria and fungi, as well as recognition of parasites, but a brief survey of a wider range of pathogens is presented. Drosophila are very adept at eliminating invading bacteria: Larvae injected with 5000 E. coli CFU clear the infection within 6 h (11). Two Gram-negative bacteria are known that can naturally infect larvae through the gut (9, 12). Otherwise, Drosophila antibacterial responses are assessed in the lab by directly injecting Gram-negative and Gram-positive bacteria. Neither of two intracellular bacterial types studied in Drosophila, Mycobacteria, or the obligate intracellular rickettsial symbiont Wolbachia, elicits a humoral antibacterial response (13, 14). Specific immune defenses against intracellular pathogens are not known in Drosophila. BACTERIA

Several fungal species, including Beauveria bassiana, can penetrate the cuticle of Drosophila and establish a lethal infection. Other fungi can be injected, and are lethal only in immunocompromised mutants (2, 8).

FUNGI

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PARASITES Parasitoid wasps that lay their eggs in fly larvae represent a significant threat to wild Drosophila. In a successful infestation, the wasp egg hatches, the larva eats the fly pupa from inside, and an adult wasp eventually emerges (10, 15). The host protective response includes the encapsulation of the wasp egg by specialized lamellocyte blood cells (see below). Specific genetic loci in Drosophila correlate with ability to resist wasp infestation, although the genes have not yet been identified (16). A flagellate protozoan can induce systemic antimicrobial expression from the fly gut, and kills Drosophila when injected (17).

VIRUSES Several viruses that can infect Drosophila have been characterized, including rhabdoviruses, picornaviruses, baculoviruses, retroviruses, and birnaviruses (18–23). General insect antiviral strategies are not understood, although one Drosophila gene required for resistance to a rhabdovirus encodes a protein that may interfere with virus replication (24).

Overview of Innate Immune Responses There is no evidence in Drosophila or other insects for an adaptive immune system like that of mammals: specific antisera are not produced, and no sign of somatic gene rearrangement or a system resembling MHC antigen presentation has been found (25). Drosophila and most other invertebrates are thought to rely exclusively on innate immune mechanisms. Drosophila has an open circulatory system that disseminates the mediators and effectors of immune responses, most notably the blood cells and the antimicrobial peptides. The blood, also called the hemolymph, circulates in the extracellular space, or hemocoel, which is lined with a basement membrane (26). The fat body, an analog of the mammalian liver, is an extensive monolayer sheet of cells and is the source of most of the antimicrobial peptides produced in response to systemic infection (27, 28). ANTIMICROBIAL PEPTIDES Within hours of infection, transcription of a battery of antimicrobial peptides is induced in the fat body and the peptides are secreted into the blood. Insect antimicrobial peptides were originally isolated from larger insects based on their activities against different types of microbes and are active against fungi (Drosomycin, Metchnikowin, Cecropin), Gram-negative bacteria (Attacin, Cecropin, Diptericin, Drosocin), or Gram-positive bacteria (Defensin, Metchnikowin). Many of the peptides work by disrupting bacterial membranes (29, 30). Mutants impaired in the Imd and Toll signaling pathways that induce the antimicrobial peptide genes are severely immunocompromised (2). The ability of these mutants to resist infection can be rescued by transgenic expression of the appropriate peptides, attesting to the importance of the antimicrobial peptides in fighting infection (31).

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Drosophila also relies on blood cells to protect against infection. Plasmatocytes, phagocytic macrophage-like cells, comprise about 90% of the blood cell population (26, 32). Crystal cells are a source of enzymes for the melanization reaction (see below) (33). Lamellocytes are extremely flattened cells that differentiate in response to certain immune challenges, and encapsulate large invaders such as parasite eggs (26, 32). The plasmatocytes may have functionally distinct subgroups. Some are sessile while others circulate, and some are more highly phagocytic than others (32). Several genes are differentially expressed among plasmatocytes, and efforts are under way to generate monoclonal antibodies that can discriminate among Drosophila blood cells (34, 35). Phagocytosis is a vital contribution of blood cells to immunity; most bacteria injected into a fly are taken up by the blood cells within minutes (26, 36). Blood cells are required for signaling to the fat body under some infection conditions (9, 37). They also accumulate at wound sites and help form clots (33, 38). The importance of blood cells in fighting infection is shown by sensitization to infection seen when phagocytosis is blocked or in mutants that lack blood cells (36, 39). Although it is beyond the scope of this review, there is significant homology between Drosophila and mammalian hematopoieisis. Both require the function of genes in the GATA, NF-κB, Notch, Runt/AML1, JAK-STAT, Ras, and VEGF families and pathways (40–48).

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CELLULAR RESPONSES

MELANIZATION The deposition of melanin is a rapid, highly localized defense triggered by wounding and the presence of foreign invaders. Melanization contributes to wound clotting and encapsulation of wasp eggs, and produces toxic intermediates including reactive oxygen species. Phenoloxidase, which catalyzes melanin production, is maintained as an inactive zymogen and is activated by a serine protease cascade (49). A mutant lacking hemolymph phenoloxidase is sensitized to infection and is vulnerable to death from wounds (38, 39). BARRIER EPITHELIA All the surface epithelia of Drosophila that contact the environment, including the exterior, the gut, and the tracheae, induce antimicrobial gene expression upon contact with microbes (50–52). The Imd pathway regulates the induction of all peptides in the epithelia, including antifungal peptides (50– 52). In mammals, antimicrobial peptides also play key roles in epithelial defenses against infection (53, 54).

The Question of Specificity Can innate immune systems tailor responses to the type of immune challenge? Some aspects of the Drosophila humoral response are highly specific. For example, fungal infection specifically induces Metchnikowin and Drosomycin, the two antifungal peptides (8). Infection with Gram-negative bacteria, on the other hand, induces many antimicrobial peptides, even the antifungal Drosomycin (9, 37). However, some specificity is apparent because Drosomycin is induced only transiently by Gram-negative bacterial infection, whereas the expression of antibacterial

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peptides is sustained (8, 55). Selective activation by different microbes of either the Imd or the Toll pathway has been proposed to account for the specificity of immune response in Drosophila. However, there is evidence that the system is more complex than this, which is discussed below. Although there is no evidence in insects for a system of adaptive immunity like that in mammals, the possibility of specific immunological memory has not been excluded. Indeed, the recent finding that some arthropods are able to transfer specific immunity to their offspring suggests that a system of inducible immunological memory could also exist in insects (55a). Recognition and memory of evolved pathogens likely involves molecules that remain to be characterized.

THE IMD AND TOLL PATHWAYS CONTROL THE HUMORAL RESPONSES Signaling through the Imd and Toll pathways results in the translocation of distinct NF-κB factors to the fat body nucleus and accounts for most of the transcriptional induction of genes in response to fungal and bacterial infection (2, 56–59) (Figure 1).

Toll Pathway Adult Drosophila mutants lacking the function of Toll pathway elements are unable to induce Drosomycin in response to fungi and are susceptible to fungal infection, −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−→ Figure 1 Imd and Toll signaling pathways activate humoral antimicrobial defenses in the Drosophila fat body. Toll signaling is activated by fungal and Gram-positive invaders by different mechanisms. By an unknown mechanism, fungi trigger a cascade involving the serine protease Persephone, which results in the proteolytic activation of Sp¨atzle, a ligand for Toll. Gram-positive invaders are recognized by an independent process that requires a circulating peptidoglycan recognition protein. Toll signaling culminates in the translocation of the NF-κB factor Dif to the nucleus where it activates transcription of the antifungal Drosomycin and other genes. Gram-negative bacteria are recognized by a transmembrane peptidoglycan receptor, PGRP-LC. In at least some cases (see text), blood cells are required for induction of defenses against Gram-negative bacteria, suggesting that the blood cells may signal to the fat body. Nitric oxide (NO) is implicated in blood cell activation of antibacterial defenses in the fat body, although its specific role is unknown. PGRP is upstream of the Imd pathway that culminates in the phosphorylation and cleavage of the Relish NF-κB factor, which enters the nucleus and activates many genes including the antibacterial Diptericin. Overexpression of Imd and several other constituents of the Imd pathway causes constitutive Diptericin expression. Genetic epistasis between overexpressing transgenes and mutations in other genes has tentatively ordered the pathway as shown. The dotted line indicates relationships suggested by overexpression experiments or physical associations.

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yet they are able to induce Diptericin normally and resist most Gram-negative bacterial infections (2, 59–62). Toll signaling was thus originally considered an antifungal pathway. Interestingly, however, mutants lacking Toll pathway elements are also susceptible to Gram-positive infection (59, 63) (see Figure 1). Toll, first discovered in Drosophila, is a transmembrane protein with extracellular leucine-rich repeats and an intracellular signaling domain similar to that of the Interleukin-1 receptor (64). The ligand for Drosophila Toll is a circulating endogenous protein, Sp¨atzle, which is proteolytically activated by a serine protease cascade in response to infection (65, 66). Ligand binding to Toll activates a cytoplasmic cascade involving dMyD88, the IRAK-like kinase Pelle, and the adaptor

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protein Tube. This results in the degradation of the IκB-like Cactus, permitting the nuclear translocation of the NF-κB-like proteins Dif and Dorsal (2, 56, 57, 62, 67– 69). Most of the Toll pathway mutants were originally isolated for their maternal effect embryonic patterning defects; the mutants are viable, but females produce abnormally patterned embryos (70). Dif and dMyD88 mutants were isolated by reverse genetic approaches (56, 60–62). Although Drosophila has 9 Toll receptors, they are not believed to provide specificity by recognizing different PAMPs as they are in mammals. Toll does not directly bind microbial components. None of the other Drosophila Tolls have been identified in genetic screens for immunodeficient mutants or are upregulated by immune challenge (71). An early report that 18Wheeler (the second Drosophila Toll) had specific antibacterial defects has not been confirmed (72, 73). Several of the other Drosophila Tolls have morphogenetic and neural functions (74, 75). Sequence comparisons suggest that the last common ancestor of mammals and invertebrates may have had only one or a few Toll receptors that subsequently duplicated and diverged under different selection pressures in the two lineages (76). Some of the other Drosophila Tolls may have immune functions, but assessment of their contributions awaits loss-of-function analysis (Table 1).

Imd Pathway The Imd signaling pathway mediates the induction of Diptericin and other antibacterial peptide genes in the fat body in response to Gram-negative bacterial infection, and bears some resemblance to the mammalian TNF-α pathway (Figure 1) (77–79). Although Imd itself was discovered serendipitously, most Imd pathway components were identified in genetic screens for mutants unable to induce reporters of Diptericin expression in response to bacterial challenge, or to survive infection (36, 80–83). The Imd signaling pathway culminates in the activation of the NF-κB-family member Relish. Relish, like mammalian p100 and p105, is a compound protein with an N-terminal Rel domain and C-terminal ankyrin repeat domain and is proteolytically processed in response to upstream signals to generate an N-terminal Rel protein that enters the nucleus and activates transcription of target genes including Diptericin (58, 84). Proteolytic activation of Relish differs from that of p100 and p105 in that it is proteasome-independent and mediated directly by the caspase Dredd (58, 85). Relish activation also requires phosphorylation by an IκB kinase (IKK) complex (11, 83, 86). The genes encoding dTAK (a MAPKKK) and the adaptor protein dFADD are also required for induction of antibacterial peptide genes (87–90). All the Imd pathway mutants are unable to induce Diptericin and are susceptible to bacterial infection (2, 36, 82–84, 88, 89, 91, 92), whereas in vivo overexpression of Imd and other pathway elements causes constitutive Diptericin expression (87, 88, 91). Imd pathway mutants are often able to resist Gram-positive infection almost as well as wild-type (59, 63, 92). Negative regulators in the Imd pathway cannot be recovered in screens for immunodeficient mutants, but a screen for mutants that overexpress Diptericin

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TABLE 1 Proteins that may activate immune responses in response to microbial invasion. The roles of these proteins have not been confirmed by mutant analysis Gene(s)

Type of protein encoded

Evidence

References

PGRP-LE

PRR

In vivo overexpression induces constitutive Diptericin and melanization

(117)

dSR-C1

Scavenger receptor

RNAi in S2 blood cell line impairs ability to bind and phagocytose bacteria

(118)

GNBPs

Secreted; similar to bacterial β-1,3 glucanases and CD14 (3 in Drosophila)

Binds LPS, β-1,3 glucan; overexpression in S2 cells increases ability to induce antimicrobial peptides

(116, 119)

TEPs

Thiolester-containing; complement factor C3-like; opsonin?

Upregulated upon infection; RNAi of mosquito homolog impairs Gram-negative phagocytosis

(99, 120)

Masquerade

“Inactive” serine protease (null mutations lethal)

Upregulated upon Gram-positive, fungal infection; crayfish homolog is an opsonin

(55, 121)

dToll5

Toll-like receptor

Chimeric constitutively active protein with dToll5 cytoplasmic domain activates Drosomycin in S2 cells; coreceptor with Toll?

(122, 123)

dToll9

Toll-like receptor

Wild-type protein constitutively activates Drosomycin in S2 cells in absence of infection; through canonical Toll pathway

(124)

identified a ubiquitin ligase complex which targets Relish for destruction in the absence of infection (93).

Other Signaling Pathways The JAK-STAT and JNK pathways are important in the mammalian immune response (94, 95) and also signal during the Drosophila immune response. LPS stimulation of Drosophila blood cells activates JNK within minutes (96). Microarray analysis of RNAi-treated blood cells exposed to LPS indicates that the JNK pathway controls the rapid upregulation of cytoskeletal genes in response to infection (90). Although null JNK pathway mutants die as embryos due to a requirement for this pathway for early developmental events including epithelial fusion (97), a hypomorphic allele of DFos, a transcriptional effector of JNK signaling, impairs wound healing (38).

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JAK-STAT signaling in Drosophila is required for the induction in the fat body of a number of genes in response to infection, including the stress-induced gene totA, as well as Tep1, which encodes a thiolester-containing protein that may be an opsonin (see Table 1) (90, 98, 99). Upd3 is a cytokine-like protein produced by the blood cells upon infection, and it activates transcription of totA in the fat body by signalling through the receptor Domeless and the JAK-STAT pathway (98). In general, dependence on JAK-STAT signaling correlates with delayed, transient induction following immune challenge (90). In addition, constitutive JAK signaling hyperactivates the blood cells (see below).

PATTERN RECOGNITION AND ACTIVATION OF IMD AND TOLL SIGNALING The Imd and Toll pathways can be activated through binding by specific PGRPs of Gram-negative or Gram-positive bacterial molecules, respectively. It is not yet clear how fungal recognition activates Toll signaling, nor have the functions of other candidate PRRs been defined.

Recognition of Microbes PGRPs were first identified in moths as infection-induced proteins that bind peptidoglycan, triggering the proteolytic melanization cascade (100, 101). The Drosophila genome encodes at least 13 PGRPs, some with multiple splice-forms, and the human genome encodes 4 that also have splice variants (102–104). PGRPs share a 160 amino acid peptidoglycan recognition domain, and both mammals and Drosophila have genes that encode secreted (S) and transmembrane (L) forms (101). In Drosophila, a secreted PGRP is required for survival to Gram-positive bacteria, whereas mutants lacking the function of a transmembrane PGRP are susceptible to Gram-negative bacterial infection (92, 105–107). In addition, at least one of the Drosophila secreted PGRPs scavenges and degrades peptidoglycan (108). A hydrophobic groove shared by both secreted and transmembrane PGRPs may function to bring downstream effectors into proximity, promoting signaling (109), while the cytoplasmic tails of transmembrane PGRPs may also contribute to downstream signaling. PGRP-LC AND GRAM-NEGATIVE DETECTION Mutants in PGRP-LC fail to induce the antibacterial peptides and are susceptible to Gram-negative but not Grampositive infection (92, 106, 107). The transmembrane PGRP-LC has two major splice variants that share common transmembrane and cytoplasmic domains but have very different extracellular peptidoglycan recognition domains (103, 106). PGRP-LC acts upstream of the Imd pathway: Mutants are unable to proteolytically activate Relish during infection, and constitutive expression of Diptericin caused by PGRP-LC overexpression requires wild-type Imd function (92, 106).

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It was surprising to find a PGRP implicated in the recognition of Gram-negative bacteria because Gram-negative peptidoglycan (PG) is in the inner cell wall layer, which is covered by the outer membrane. In contrast, the PG of Gram-positive bacteria is much more accessible on the cell wall surface. Lipopolysaccharide (LPS), on the other hand, is an abundant constituent of the Gram-negative outer membrane, and is an extremely immunogenic molecule in mammals (110). Because LPS is not found in Gram-positive bacteria, it was expected to be the key to the discrimination between Gram-negative and Gram-positive bacteria by Drosophila. However, Drosophila is able to discriminate between Gram-negative and Grampositive PG, which differ in a single amino acid, whereas LPS is not a potent inducer of the humoral response in vivo (111, 112). The PGRPs play an essential role in the recognition of and disrimination between Gram-negative and Gram-positive bacteria. Gram-negative PG, but not Gram-positive PG, is a potent inducer of Diptericin in flies and cultured blood cells, and requires PGRP-LC function (103, 112, 113). PGRP-LC was also identified in a blood cell RNAi screen as a protein involved in Gram-negative, but not Gram-positive, binding and phagocytosis (107). PGRP-SA AND GRAM-POSITIVE DETECTION A mutant lacking the function of PGRP-SA was identified in a screen for mutants unable to induce Drosomycin following a mixed bacterial infection (105). Although Drosomycin is an antifungal peptide, it is induced through the Toll pathway by both fungi and Gram-positive bacteria. PGRP-SA mutants are specifically susceptible to Gram-positive infection; resistance to fungi and Gram-negative bacteria is normal (105). Consistent with this, PGRP-SA mutants cannot induce Drosomycin in response to Gram-positive infection or Gram-positive PG, although they induce Drosomycin normally in response to fungal infection. Diptericin is induced normally in response to Gramnegative PG or whole bacteria (105, 112). PGRP-SA is a secreted PGRP consisting mainly in a single peptidoglycan recognition domain, and binds Gram-positive PG with high affinity (102, 105). The inability of the mutants to induce Drosomycin suggests that PGRP-SA may activate the Toll pathway, although this has not been tested genetically. Some aspects of secreted PGRP function may be evolutionarily conserved. A mouse mutant lacking the function of a secreted PGRP is also vulnerable to Gram-positive infection (114). OTHER POSSIBLE PATTERN RECOGNITION PROTEINS Other Drosophila proteins may have roles in recognizing microbial invaders, but because no mutants have yet been isolated, their requirements in immune function have not been directly tested. Some of these are listed in Table 1. Currently, there are no genetic data concerning host molecules involved in detection of fungi, although fungal β-1,3D-glucans induce antimicrobial gene expression in a Drosophila blood cell line, and a β-1,3-glucan-binding protein contributes to this response (115, 116).

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From Recognition to Fat Body Signaling

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A major focus of current research is how pattern recognition events involving PGRPs or other host receptors leads to activation of the fat body NF-κB signaling pathways that induce the antimicrobial peptides. The importance of a circulating PGRP for Gram-positive detection and a transmembrane PGRP for Gram-negative detection suggests that the fly immune system detects these two classes of bacteria rather differently. Gram-positive detection has more in common with fungal pathways in the dependence on the Toll pathway, and possibly also on serine proteolytic cascades. ACTIVATION OF THE IMD PATHWAY The fat body is the source of the majority of the antimicrobial peptides produced in a systemic immune response. Relish translocation can be visualized here, and Imd signaling presumably takes place in fat body cells. However, the site of microbial detection by PGRP-LC may be elsewhere. Whereas constitutive fat body Diptericin expression can be induced by overexpressing PGRP-LC in the adult fat body, endogenous larval PGRP-LC expression is higher in the blood cells than the fat body (92, 102, 106). Consistent with this, in larvae, blood cells are required for the induction of Diptericin in the fat body in response to a Gram-negative gut infection (9, 37). These data suggest that blood cells might detect Gram-negative microbes and signal this information to the fat body. Blood cells are not required for induction of fat body Diptericin when Gram-negative bacteria are introduced through a wound (39), which may be the result of a signal generated at the site of injury. NO is implicated in the blood cell–dependent induction of fat body Diptericin. Exogenous NO induces Diptericin, and a pharmacological inhibitor of nitric oxide synthase (NOS) prevents Diptericin induction in response to a Gram-negative infection (37, 125). The response to NO requires Imd, suggesting that NO acts upstream of the Imd pathway. However, NO is unlikely to be the signal from blood cells to the fat body, as exogenous NO does not stimulate Diptericin induction in a mutant that lacks blood cells (37). NO appears to be important in some step in blood cells downstream of microbial recognition and upstream of a signal that is relayed to the fat body, possibly in blood cell activation. ACTIVATION OF THE TOLL PATHWAY In the Drosophila embryo, the Toll pathway is triggered by a cascade of four serine proteases that proteolytically activate the endogenous ligand Sp¨atzle (126). Although Sp¨atzle is also required for immune responses, the embryonic proteases are not (2). Necrotic is a serine protease inhibitor (serpin) that prevents constitutive activation of Toll-dependent immune responses in the absence of immune challenge, suggesting that a distinct serine proteolytic cascade activates Sp¨atzle in immune responses (65). Persephone, an immune response serine protease, was identified in a screen for mutations that suppressed the ability of necrotic mutants to constitutively activate Toll signaling. persephone mutants are susceptible to fungal infection and unable

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to activate the Toll pathway in response to fungi (127). It is unclear how fungal infection leads to Persephone activation, but the possession of a prodomain suggests that Persephone may be activated by another serine protease (127). Necrotic may directly inhibit Persephone; fungal infection is likely to shift the balance between protease and serpin activities (127, 128). It is also not known whether Persephone directly activates Sp¨atzle, or whether there are additional intervening proteases. Activation of the Toll pathway by Gram-positive bacteria does not require Persephone, suggesting that fungi and Gram-positive bacteria activate Toll signaling by distinct mechanisms (127). Because Sp¨atzle is required for responses to some Gram-positive bacteria, PGRP-SA can likely activate a distinct serine protease cascade that leads to Sp¨atzle cleavage (59, 63, 105).

Do Imd and Toll Really Provide Specificity of Response? The model that selective activation of the Imd or Toll pathways confers specificity of response against Gram-negative bacteria or against Gram-positive bacteria and fungi, respectively, is an oversimplification. For example, Imd Toll pathway double mutants are more susceptible than single Imd pathway mutants to E. coli infection, and Toll pathway mutants are susceptible to Pseudomonas infection, arguing that Toll is important for resistance to Gram-negative infection (59, 129). On the other hand, Imd signaling is important for resistance to some Gram-positive bacteria such as Micrococcus luteus (59, 82). Another difficulty with the model that the Imd and Toll pathways confer specificity of response is the sharing of the Toll pathway by fungi and Gram-positive bacteria. Despite the use of distinct mechanisms for detecting fungi and Grampositive bacteria, the signals apparently converge at Sp¨atzle and Toll. In fact, some responses to Gram-positive bacteria and fungi are remarkably similar: Both types of infection trigger the massive induction of Masquerade, a serine protease-like protein, whereas Gram-negative infection does not (55). Another similarity between fungal and Gram-positive immune induction is the apparent reliance on circulating, rather than cell-associated detection mechanisms. Why would an immune system have one pathway dedicated to Gram-negative defense and another for responses to microorganisms as disparate as fungi and Gram-positive bacteria? It could be that the Toll pathway is the ancestral immune induction pathway in insects (Figure 2), and that a blood cell-mediated system to recognize Gramnegative bacteria evolved later, triggering a distinct pathway. The Imd pathway may also have an apoptotic role, suggesting that its immune function may have been co-opted secondarily (91). There may be features of Gram-negative bacteria that selected for an additional immune detection and induction mechanism, such as a higher growth rate or concealment of PG beneath the outer membrane. Indeed, a genome-wide microarray analysis of the kinetics of induction of immuneresponsive genes in wild-type and mutant conditions found a correlation between Imd regulation of early activated genes and Toll regulation of genes with a more delayed response (90). Specialization of Imd signaling for rapid responses would be

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Figure 2 Toll is a central regulator of the Drosophila immune response. In agreement with the idea that Toll may represent the ancestral immune signaling pathway in insects, Toll regulates many aspects of the immune response. In addition to activating antifungal defenses, Toll is also required for survival to many Gram-positive and some Gram-negative bacterial infections, for regulation of the melanization cascade and for regulation of blood cell proliferation, and is implicated in blood cell differentiation and activation. Toll may fulfill these roles in several tissues, such as the fat body and the blood cells. Sp¨atzle is the only known ligand for Toll in Drosophila; however, Toll mutants are more impaired in the induction of antimicrobial peptides than are null sp¨atzle mutants (2), suggesting that there may be additional Toll ligands.

consistent with the independence of Imd of both Drosomycin induction, which has slow kinetics, and survival to fungi, which are slower-growing microorganisms.

ACTIVATION OF MELANIZATION AND BLOOD CELL RESPONSES In addition to the well-characterized antimicrobial peptide induction, infection also triggers blood cell activation and melanization, events that are less well understood in Drosophila.

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Activation of the Prophenoloxidase Pathway Biochemical experiments in the silkworm and crayfish revealed that a serine protease cascade regulates the activation of prophenoloxidase (PPO), which catalyzes melanin production (49, 130–132). An important regulator of the melanization response is Serpin27A (Spn27A), which specifically inhibits the PPO-activating enzyme (PPAE) (133, 134). Spn27A mutants exhibit sporadic melanization in the absence of immune challenge, and the entire animal becomes melanized after septic injury (133, 134). The inhibitory effect of Spn27A on melanization appears to be overcome in two ways under conditions of immune challenge. The melanization cascade can be rapidly triggered by microbial products, by mechanisms that involve PGRPs (100, 117, 131) and that likely activate an upstream protease that leads to hyperproduction of PPAE, depleting Spn27A. An additional uncharacterized inhibitor of Spn27A may be transcriptionally induced by Sp¨atzle-Toll signaling (134). It appears that rapid activation of a protease cascade, triggered by pattern recognition, initiates an immediate melanization response, and that sustained activation is ensured by local Toll-mediated depletion of Spn27A.

Activation of Blood Cells PHAGOCYTOSIS Phagocytic uptake of invaders by blood cells is a vital defense strategy in both flies and mammals (36, 135). Drosophila and mammalian phagocytosis are homologous actin-mediated processes (118). Critical unanswered questions in both mammalian and Drosophila phagocytosis include how ingested particles are trafficked and the role of phagocytosis in stimulating other immune responses (135). The ability of a blood cell to phagocytose a particular particle is influenced by the affinity of host receptors for surface molecules on the particle. For example, a Drosophila scavenger receptor-like protein, dSR-C1, confers the ability to phagocytose bacteria but not yeast on a heterologous cell line (118). However, Drosophila blood cells are able to phagocytose abiotic particles such as polystyrene beads, so pattern recognition of microbial PAMPs is not an absolute requirement (36). Few Drosophila mutants are detectably impaired in phagocytosis, possibly reflecting redundancy of mechanisms promoting particle uptake and requirements for cytoskeletal proteins for viability. An RNAi screen in cultured blood cells tested the requirements for 1000 randomly selected genes in phagocytosis of different microbes, and defined roles for proteins involved in cytoskeletal function and vesicle formation and transport (107). In addition, the removal of PGRP-LC function impaired the binding and phagocytosis of Gram-negative bacteria by approximately 30% (107). Null PGRP-LC mutants are not detectably impaired in phagocytosis, suggesting either that a 30% reduction in phagocytic ability is not detectable in vivo or that additional mechanisms compensate in vivo for the loss of this receptor (106). Several Drosophila proteins have been proposed to bind microbes and promote their uptake by blood cells (Table 1).

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OTHER ASPECTS OF BLOOD CELL ACTIVATION Wasp parasitization triggers blood cell proliferation, the differentiation of the lamellocyte blood cell type, and an encapsulation response (see below) (32, 35, 136). Although the regulation of these dramatic events is not understood, they are mimicked in mutants with hyperactivated Toll and JAK-STAT signaling (42, 137, 138) (Figure 3). Toll also regulates steady-state hemocyte numbers: There are fewer blood cells in loss-of-function mutants (42). In addition, blood cells accumulate at wound sites (38); because blood cells with overactivated Toll signaling also aggregate, Toll could also be involved in this type of activation (42). In short, Toll signaling is implicated in several aspects of blood cell activation in Drosophila, but the regulation of blood cell activation in response to actual immune challenge is not understood.

IMMUNE RESPONSES IN THE ABSENCE OF MICROBIAL PATHOGENS PAMPs are most clearly defined for bacteria and fungi, microorganisms from entirely different kingdoms than animals. However, like mammals, Drosophila is able to mount immune responses in the absence of PAMPs, for example during parasite infestation and under autoimmune conditions. Deviations from the normal basement membrane pattern as well as presence of endogenous DNA in the blood are both associated with immune activation.

Basement Membrane PARASITES A parasitic wasp egg in a Drosophila larva triggers an encapsulation immune response designed to seal off and kill the wasp embryo before it can hatch and kill the larva. Circulating plasmatocytes appear to recognize the wasp as foreign, and attach to it. Lamellocytes then adhere in layers, and the entire capsule is melanized (32, 139). This protective response has some similarities to granuloma formation by mammalian macrophages and T cells (140). Because wasps are also insects, they are not expected to have obligate molecular signatures, or PAMPs, that allow them to be recognized as invaders. How, then, are wasp eggs recognized as foreign? Transplantation experiments suggest that Drosophila blood cells may recognize the absence of endogenous or presence of foreign basement membrane on invaders as nonself. Drosophila does not encapsulate fat bodies of within-species transplants, but fat bodies transplanted from other species are encapsulated (141).

In some mutants, Drosophila blood cells aberrantly encapsulate the fly’s own tissue, representing a kind of autoimmune defect (Figure 3). The resulting melanotic capsules resemble encapsulated parasitoid eggs, with layers of melanized lamellocytes. Although melanotic capsules can appear in mutants with constitutively activated blood cells (Figure 3), they also occur in mutants in which damaged or aberrant tissues trigger an immune response (142).

MELANOTIC CAPSULES

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Several melanotic capsule mutants show disruption of the basement membrane surrounding various tissues and the subsequent encapsulation of the exposed tissues. For example, in Tu-Sz[ts] mutants, disruption of the basement membrane over part of the fat body precedes the adhesion of lamellocytes and formation of melanotic capsules there (26). Transplanted Drosophila fat bodies whose basement membranes have been damaged are encapsulated, whereas intact fat bodies are not, supporting the notion that disruptions to the endogenous basement membrane can trigger immune responses (141). BLOOD CELLS AND BASEMENT MEMBRANE The blood cells are implicated in the recognition of basement membrane abnormalities in parasite infestation and autoimmune activation. The notion of blood cells constantly surveying the basement membrane lining the hemocoel is consistent with their roles in basement membrane secretion, repair, and degradation (26, 33, 143). Blood cells seem to be able to distinguish the basement membrane of healthy self from that of damaged self, as well as absence of basement membrane on abiotic material, and possibly presence of foreign basement membrane on parasites. The basement membrane is a proteoglycan-rich matrix, and experiments in other insects, in which beads coated with different materials were transplanted, suggest that the self characteristics may be related to carbohydrate composition (33, 144).

Endogenous DNA In addition to those with basement membrane defects, some other mutants with melanotic capsules have defects in apoptosis. Mutants lacking the function of the fly proapoptotic homologs of Ced-3 caspase and Ced-4/Apaf-1 develop melanotic capsules (145, 146). Drosophila blood cells do normally recognize and phagocytose apoptotic cells through a CD36-like receptor called Croquemort (147). It is possible that cells failing to undergo proper apoptosis are recognized as abnormal, triggering encapsulation. Alternatively, cells undergoing aberrant apoptosis might release immunostimulatory molecules. Ced-3 protein is able to fragment DNA; perhaps DNA in the blood of Ced-3 caspase mutants triggers an immune response resulting in encapsulation of self tissue (145). Fly mutants lacking the function of two other DNAses required for the degradation of apoptotic cell DNA show constitutive expression of Diptericin (148). This further suggests that endogenous DNA may stimulate the innate immune system of Drosophila as it does in mammals (149).

STUDYING MEDICALLY IMPORTANT PATHOGENS IN DROSOPHILA Drosophila has recently emerged as a very promising system in which to study the virulence of a variety of medically important pathogens. Several microbes have been shown to infect flies with similar mechanisms to those known from mammals.

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Because Drosophila is a genetically tractable animal with a sophisticated, bloodcell-dependent innate immune system, the possibilities for increasing our understanding of pathogenesis are tremendous. Pseudomonas aeroginosa is a ubiquitous Gram-negative bacterium that is responsible for opportunistic infections in wounds and in immunocompromised patients. Remarkably, some of the mechanisms used by this bacterium to infect and kill the host are common to mammals, insects, nematodes, and plants (150). All 11 virulence factors required for maximal pathogenicity in mammals are also required for maximum virulence in flies (129). The TTSS, which contributes to virulence in both mammals and insects, is activated upon entry into Drosophila (151). This is one of the first reports of activation of the TTSS of any bacterial species in a whole animal, suggesting that Drosophila may be a suitable in vivo alternative to simulating combinations of signals in vitro. A screen for P. aeroginosa mutants impaired in Drosophila killing led to the identification of a gene cluster that regulates motility factors important for virulence in flies and mammals (152). Serratia marcescens is a Gram-negative insect pathogen responsible for opportunistic infections in humans. Several S. marcescens mutants impaired in Drosophila killing are also attenuated in mammalian infection models (153). Like Mycobacterium tuberculosis, M. marinum can proliferate inside vertebrate macrophages in which phagosome acidification has been blocked. M. marinum can also infect Drosophila blood cells by a similar mechanism, killing the fly. M. marinum upregulates some of the same genes in vertebrate and insect phagosomes, and at least one bacterial virulence factor contributes to pathogenesis in both systems (13). A Gram-negative plant pathogen, Erwinia carotovora, that may be spread by Drosophila, has also provided tools for the study of mammalian disease. A novel virulence factor was identified from a genetic screen for E. carotovora mutants unable to infect Drosophila larvae. This gene is sufficient to confer ability to infect Drosophila not only on noninfectious E. carotovora strains, but also on other Enterobacteria such as E. coli and Salmonella typhimurium (154). These new strains of medically important bacteria that are infectious in Drosophila may prove to be powerful tools to investigate virulence mechanisms. In addition to serving as lab models for medically important bacterial diseases, insects are also the natural vectors for many pathogens that infect mammals. Although malaria-causing Plasmodia are transmitted by mosquitoes, Plasmodia are able to infect Drosophila in the lab and progress through several steps of their complex life cycle (155). In addition, knowledge of insect immunity that Drosophila studies have yielded is being applied to studies of mosquito-Plasmodium infections with the goal of developing antimalaria strategies (156).

FUTURE DIRECTIONS In the eight years since Toll and imd mutants were found to be differentially susceptible to fungal and bacterial infection (2), and the six years since the first genetic screen for immune defects was reported (57), genetic analysis has revealed many of

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the essential aspects of these two signaling pathways. Continued forward genetic screens, as well as reverse genetic analysis of genes regulated by infection, will identify more components required for diverse aspects of the immune response. We can anticipate that future research in Drosophila immunity is likely to identify more novel pattern recognition mechanisms, define mechanisms of blood cell activation, illuminate interactions between NF-κB and other signaling pathways, define mechanisms that allow recognition of intracellular bacterial and viral infections, provide perspectives on autoimmunity, and define specific responses to pathogenic organisms. ACKNOWLEDGMENTS The authors wish to thank Derek Sant’Angelo for comments on the manuscript. CAB is the Keyser Family Fellow supported by the Damon Runyon Cancer Research Foundation (DRG-3582). KVA is supported by National Institutes of Health grant # AI45149. The Annual Review of Immunology is online at http://immunol.annualreviews.org

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activation of Toll-mediated antifungal defense in serpin-deficient Drosophila. Science 285:1917–19 Weber AN, Tauszig-Delamasure S, Hoffmann JA, Leli`evre E, Gascan H, et al. 2003. Binding of the Drosophila cytokine Sp¨atzle to Toll is direct and establishes signaling. Nat. Immunol. 4:794–800 Belvin MP, Anderson KV. 1996. A conserved signaling pathway: the Drosophila Toll-Dorsal pathway. Annu. Rev. Cell Dev. Biol. 12:393–416 Nicolas E, Reichhart J-M, Hoffmann JA, Lemaitre B. 1998. In vivo regulation of the IκB homologue cactus during the immune response of Drosophila. J. Biol. Chem. 273:10463–69 Imler JL, Hoffmann J. 2002. Toll receptors in Drosophila: a family of molecules regulating development and immunity. Curr. Top Microbiol. Immunol. 270:63–79 Morisato D, Anderson KV. 1995. Signaling pathways that establish the dorsalventral pattern of the Drosophila embryo. Annu. Rev. Genet. 29:371–99 De Gregorio E, Spellman PT, Rubin GM, Lemaitre B. 2001. Genome-wide analysis of the Drosophila immune response by using oligonucleotide microarrays. Proc. Natl. Acad. Sci. USA 98:12590–95 Williams MJ, Rodriguez A, Kimbrell DA, Eldon ED. 1997. The 18-wheeler mutation reveals complex antibacterial gene regulation in Drosophila host defense. EMBO J. 16:6120–30 Ligoxygakis P, Bulet P, Reichhart J-M. 2002. Critical evaluation of the role of the Toll-like receptor 18-Wheeler in the host defense of Drosophila. EMBO Rep. 3:666–73 Seppo A, Matani P, Sharrow M, Tiemeyer M. 2003. Induction of neuronspecific glycosylation by Tollo/Toll-8, a Drosophila Toll-like receptor expressed in non-neural cells. Development 130: 1439–48 Eldon E, Kooyer S, D’Evelyn D, Duman M, Lawinger P, et al. 1994. The

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142. Watson KL, Johnson TK, Denell RE. 1991. Lethal(1) aberrant immune response mutations leading to melanotic tumor formation in Drosophila melanogaster. Dev. Genet. 12:173–87 143. Murray MA, Fessler LI, Palka J. 1995. Changing distributions of extracellular matrix components during early wing morphogenesis in Drosophila. Dev. Biol. 168:150–65 144. Lavine MD, Strand MR. 2001. Surface characteristics of foreign targets that elicit an encapsulation response by the moth Pseudoplusia includens. J. Insect Physiol. 47:965–74 145. Song ZW, McCall K, Steller H. 1997. DCP-1, a Drosophila cell death protease essential for development. Science 275:536–40 146. Rodriguez A, Oliver H, Zou H, Chen P, Wang XD, Abrams JM. 1999. Dark is a Drosophila homologue of Apaf-1/CED4 and functions in an evolutionarily conserved death pathway. Nat. Cell Biol. 1:272–79 147. Franc NC, Heitzler P, Ezekowitz RA, White K. 1999. Requirement for Croquemort in phagocytosis of apoptotic cells in Drosophila. Science 284:1991–94 148. Mukae N, Yokoyama H, Yokokura T, Sakoyama Y, Nagata S. 2002. Activation of the innate immunity in Drosophila by endogenous chromosomal DNA that escaped apoptotic degradation. Genes Dev. 16:2662–71 149. Napirei M, Karsunky H, Zevnik B, Stephan H, Mannherz HG, Moroy T. 2000. Features of systemic lupus erythematosus in Dnase1-deficient mice. Nat. Genet. 25:177–81 150. Rahme LG, Ausubel FM, Cao H, Drenkard E, Goumnerov BC, et al. 2000. Plants and animals share functionally common bacterial virulence factors. Proc. Natl. Acad. Sci. USA 97:8815–21 151. Fauvarque MO, Bergeret E, Chabert J, Dacheux D, Satre M, Attree I. 2002. Role and activation of type III secretion

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F. 2003. A single gene that promotes interaction of a phytopathogenic bacterium with its insect vector, Drosophila melanogaster. EMBO Rep. 4:205–9 155. Schneider D, Shahabuddin M. 2000. Malaria parasite development in a Drosophila model. Science 288:2376– 79 156. Dimopoulos G, Muller HM, Levashina EA, Kafatos F. 2001. Innate immune defense against malaria infection in the mosquito. Curr. Opin. Immunol. 13:79– 88

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Figure 3 Drosophila blood cells in normal and autoimmune conditions. (A) Two plasmatocytes stained with phalloidin, showing filamentous actin. (B) Phase contrast images of two blood cells from a larva with a gain-of-function allele of Toll, Toll10b. Constitutive Toll signaling causes the differentiation of lamellocytes, the large flat cells. The arrow indicates a plasmatocyte. (C) The blood cells of a Toll10b larva carrying an enhancer trap that expresses lacZ in lamellocytes. Here the lamellocytes are beginning to encapsulate self-tissue, but melanization has not yet begun. Scale bars in (A), (B), and (C) are all 10 µm. Melanotic capsules (arrows) are visible through the cuticle of Toll10b larvae (D), and adults (E) and (F).

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CONTENTS FRONTISPIECE—Leonard A. Herzenberg and Leonore A. Herzenberg GENETICS, FACS, IMMUNOLOGY, AND REDOX: A TALE OF TWO LIVES INTERTWINED, Leonard A. Herzenberg and Leonore A. Herzenberg SELF- AND NONSELF-RECOGNITION BY C-TYPE LECTINS ON DENDRITIC CELLS, Teunis B.H. Geijtenbeek, Sandra J. van Vliet, Anneke Engering, Bert A. ’t Hart, and Yvette van Kooyk

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TRANSCRIPTIONAL CONTROL OF EARLY B CELL DEVELOPMENT, Meinrad Busslinger

UBIQUITIN LIGASES AND THE IMMUNE RESPONSE, Yun-Cai Liu LIGANDS FOR L-SELECTIN: HOMING, INFLAMMATION, AND BEYOND, Steven D. Rosen

55 81 129

INTEGRINS AND T CELL–MEDIATED IMMUNITY, Jonathan T. Pribila, Angie C. Quale, Kristen L. Mueller, and Yoji Shimizu

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MULTIPLE ROLES OF ANTIMICROBIAL DEFENSINS, CATHELICIDINS, AND EOSINOPHIL-DERIVED NEUROTOXIN IN HOST DEFENSE, De Yang, Arya Biragyn, David M. Hoover, Jacek Lubkowski, and Joost J. Oppenheim

STARTING AT THE BEGINNING: NEW PERSPECTIVES ON THE BIOLOGY OF MUCOSAL T CELLS, Hilde Cheroutre THE BCR-ABL STORY: BENCH TO BEDSIDE AND BACK, Stephane Wong and Owen N. Witte

181 217 247

CD40/CD154 INTERACTIONS AT THE INTERFACE OF TOLERANCE AND IMMUNITY, Sergio A. Quezada, Lamis Z. Jarvinen, Evan F. Lind, and Randolph J. Noelle

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THE THREE ES OF CANCER IMMUNOEDITING, Gavin P. Dunn, Lloyd J. Old, and Robert D. Schreiber

AUTOIMMUNE AND INFLAMMATORY MECHANISMS IN ATHEROSCLEROSIS, Georg Wick, Michael Knoflach, and Qingbo Xu THE DYNAMIC LIFE OF NATURAL KILLER CELLS, Wayne M. Yokoyama, Sungjin Kim, and Anthony R. French

329 361 405

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THE ROLE OF COMPLEMENT IN THE DEVELOPMENT OF SYSTEMIC LUPUS ERYTHEMATOSUS, Anthony P. Manderson, Marina Botto, and Mark J. Walport

DROSOPHILA: THE GENETICS OF INNATE IMMUNE RECOGNITION AND RESPONSE, Catherine A. Brennan and Kathryn V. Anderson RAGS AND REGULATION OF AUTOANTIBODIES, Mila Jankovic,

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Rafael Casellas, Nikos Yannoutsos, Hedda Wardemann, and Michel C. Nussenzweig

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THE ROLE OF SUPPRESSORS OF CYTOKINE SIGNALING (SOCS) PROTEINS IN REGULATION OF THE IMMUNE RESPONSE, Warren S. Alexander and Douglas J. Hilton

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NATURALLY ARISING CD4+

REGULATORY T CELLS FOR IMMUNOLOGIC SELF-TOLERANCE AND NEGATIVE CONTROL OF IMMUNE RESPONSES, Shimon Sakaguchi PHOSPHOINOSITIDE 3-KINASE: DIVERSE ROLES IN IMMUNE CELL ACTIVATION, Jonathan A. Deane and David A. Fruman IMMUNITY TO TUBERCULOSIS, Robert J. North and Yu-Jin Jung MOLECULAR DEFECTS IN HUMAN SEVERE COMBINED IMMUNODEFICIENCY AND APPROACHES TO IMMUNE RECONSTITUTION, Rebecca H. Buckley PHYSIOLOGICAL CONTROL OF IMMUNE RESPONSE AND INFLAMMATORY TISSUE DAMAGE BY HYPOXIA-INDUCIBLE FACTORS AND ADENOSINE A2A RECEPTORS, Michail V. Sitkovsky, Dmitriy Lukashev, Sergey Apasov, Hidefumi Kojima, Masahiro Koshiba, Charles Caldwell, Akio Ohta, and Manfred Thiel

531 563 599

625

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T LYMPHOCYTE–ENDOTHELIAL CELL INTERACTIONS, Jaehyuk Choi, David R. Enis, Kian Peng Koh, Stephen L. Shiao, and Jordan S. Pober

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IMMUNOLOGICAL MEMORY TO VIRAL INFECTIONS, Raymond M. Welsh, Liisa K. Selin, and Eva Szomolanyi-Tsuda

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CENTRAL MEMORY AND EFFECTOR MEMORY T CELL SUBSETS: FUNCTION, GENERATION, AND MAINTENANCE, Federica Sallusto, Jens Geginat, and Antonio Lanzavecchia CONTROL OF T CELL VIABILITY, Philippa Marrack and John Kappler

745 765

ASTHMA: MECHANISMS OF DISEASE PERSISTENCE AND PROGRESSION, Lauren Cohn, Jack A. Elias, and Geoffrey L. Chupp

789

CD1: ANTIGEN PRESENTATION AND T CELL FUNCTION, Manfred Brigl and Michael B. Brenner

817

CHEMOKINES IN INNATE AND ADAPTIVE HOST DEFENSE: BASIC CHEMOKINESE GRAMMAR FOR IMMUNE CELLS, Antal Rot and Ulrich H. von Andrian

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INTERLEUKIN-10 AND RELATED CYTOKINES AND RECEPTORS, Sidney Pestka, Christopher D. Krause, Devanand Sarkar, Mark R. Walter, Yufang Shi, and Paul B. Fisher

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INDEXES

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Subject Index Cumulative Index of Contributing Authors, Volumes 12–22 Cumulative Index of Chapter Titles, Volumes 12–22

ERRATA An online log of corrections to Annual Review of Immunology chapters may be found at http://immunol.annualreviews.org/errata.shtml

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Annu. Rev. Immunol. 2004. 22:485–501 doi: 10.1146/annurev.immunol.22.012703.104707 c 2004 by Annual Reviews. All rights reserved Copyright ° First published online as a Review in Advance on November 10, 2003

RAGs AND REGULATION OF AUTOANTIBODIES Mila Jankovic,1 Rafael Casellas,2 Nikos Yannoutsos,1 Hedda Wardemann,1 and Michel C. Nussenzweig1,3 Annu. Rev. Immunol. 2004.22:485-501. Downloaded from arjournals.annualreviews.org by HINARI on 09/01/07. For personal use only.

1

Laboratory of Molecular Immunology, 3Howard Hughes Medical Institute, The Rockefeller University, New York, New York 10021; email: [email protected]; [email protected]; [email protected]; [email protected] 2 Division of Biology, California Institute of Technology, Pasadena, California 91125; email: [email protected]

Key Words B cell development, tolerance, receptor editing, RAG1 and RAG2 expression, antiself antibodies ■ Abstract Autoreactive antibodies are etiologic agents in a number of autoimmune diseases. Like all other antibodies these antibodies are produced in developing B cells by V(D)J recombination in the bone marrow. Three mechanisms regulate autoreactive B cells: deletion, receptor editing, and anergy. Here we review the prevalence of autoantibodies in the initial antibody repertoire, their regulation by receptor editing, and the role of the recombinase proteins (RAG1 and RAG2) in this process.

INTRODUCTION Antigen receptor diversity is generated by random rearrangements between variable (V) diversity (D) and joining (J) gene segments in developing B cells and T cells (1). This receptor diversity ensures efficient immune responses to a universe of rapidly evolving potential pathogens. However, random gene reassortment can also produce self-reactive antibodies that could cause “horror autotoxicus,” as pointed out by Ehrlich (2). Burnett, Talmage, and Lederberg provided a framework for understanding how self-reactive lymphocytes might be removed from the nascent repertoire as part of the clonal selection theory (3–5): They proposed that any self-reactive antibody producing lymphocytes would be deleted during development. In the past 20 years transgenic experiments in mice have shown that at least three mechanisms account for silencing of self-reactive antibodies during B cell development in the bone marrow: receptor editing, deletion, and anergy (6–9). One of these mechanisms, receptor editing, relies on V(D)J recombination to obviate autoantibody production in vivo. Here we review recent work on aspects of V(D)J recombination relevant to production and regulation of autoreactive antibodies in vivo. 0732-0582/04/0423-0485$14.00

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MOST NASCENT B CELLS PRODUCE AUTOANTIBODIES How B cells produce a diverse antibody repertoire while maintaining self-tolerance has been an important question since the time of Ehrlich (2). Landsteiner’s finding that the antibody repertoire is almost infinitely diverse further stressed the potential importance of avoiding self-reactivity and raised the problem of prevalence of autoantibodies in the initial repertoire (10). A number of investigators found that the majority of nascent immature B cells are deleted before they reach the mature B cell compartment, suggesting that autoreactive B cells might be a large part of the initial repertoire (11–15). Only 10%–20% of the bone marrow immature cells reach the periphery, and as few as 3% contribute to the mature B cell pool (14, 16–18). Furthermore, deletion was not random because there was a specific shift in the representation of antibodies in the repertoire between the immature and mature B cell stages (19–21). The number of self-reactive antibodies was determined for human B cells by single cell analysis of the bone marrow and blood (22) (Figure 1). Two types of autoreactive antibodies were measured by ELISA, antinuclear antibodies (ANAs) and antibodies to defined antigens such as DNA, insulin and LPS. Antibodies that bound to more than one of these defined antigens were considered polyreactive. The ANAs were assayed by ELISA on HEp-2 cell lysates and verified by indirect immunofluorescence. Fifty-five percent to 75% of all antibodies in the early immature B cell compartment (B cells with the surface phenotype of pre-B cells that contained in-frame Igκ or Igλ chains) produced self-reactive antibodies (22). The self-reactive antibodies were lost from the B cell repertoire at two discrete checkpoints in development. The first checkpoint was between the early immature B cell stage and the immature B cell stage. Nearly all antibodies (poly)reactive with defined antigens were lost in this early transition in the bone marrow. ANA antibodies were lost from the repertoire in the immature B cell compartment and also in the periphery at the transition between the immature and mature B cell pool. Therefore, the majority of nascent human B cells is self-reactive. Future experimentation should focus on understanding changes in the efficiency of autoantibody removal that might lead to increased susceptibility to autoimmunity.

RAG EXPRESSION AND ANTIBODY ASSEMBLY IN DEVELOPING B CELLS RAG1 and RAG2 proteins catalyze V(D)J recombination and antibody gene assembly (23, 24). RAGs bind to and cleave DNA at conserved recombination signal sequences (RS) that flank immunoglobulin (Ig) and T cell receptor (TCR) gene segments (25). These proteins are essential for the recombination reaction, and loss of either one in mice or humans results in complete block of lymphocyte development (26–28). RAG1 and RAG2 are only coexpressed in developing lymphocytes, and the level of expression is regulated in a developmental stage–specific manner (29, 30)

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(see Figure 1). The first B cells to express RAG1 and RAG2 are early lymphoid committed progenitors found in fraction A1 (31, 32). These cells are Lin−CD27+ckitHiScaHi and express low levels of RAGs and exhibit low levels of recombinase activity as measured by recombination of antibody D and J gene segments (33). RAGs are further induced in pro-B cells where Ig heavy chain gene assembly begins (31, 32, 34). Successful heavy chain gene recombination leads to expression of membrane Ig heavy chains (µ), which in turn induce clonal expansion, RAG downregulation, heavy chain allelic exclusion, and progression to the pre-B cell stage (35–40). It is essential for heavy chain allelic exclusion to be established at this stage of B cell development because persistent recombination might inactivate the productively rearranged heavy chain or produce a cell with two heavy chains and multiple antibody specificities. RAG1 and RAG2 downregulation is likely an important initial aspect of establishing allelic exclusion at the heavy chain locus. However, exclusion is maintained in later B cell stages by RAG-independent changes in heavy chain accessibility that appear to be induced through IL-7 (41, 42). RAG1 and RAG2 expression is downregulated in cycling pre-B cells but it is not known whether this downregulation is mediated at the transcriptional level or at the level of mRNA stability (43). Decreased transcription is suggested by decreased GFP expression in mice that carry YFP and GFP inserted into the RAG1 or RAG2 genes, respectively (32, 44). RAG protein levels are also regulated by phophorylation of the RAG protein, which decreases the half-life of the protein (45). A second wave of RAG expression is induced when pre-B cells stop dividing, and it is associated with onset of high levels of Ig light chain gene recombination (35, 46). Upon successful expression of an Ig light chain gene and assembly of a functional BCR, pre-B cells become immature B cells. Immature B cells are the first B cells to express surface IgM, and it is in this compartment that antibodies are initially tested for self-reactivity and that central B cell tolerance is established by receptor editing or deletion (6, 7). Immature B cells display two features that facilitate induction of central tolerance: persistent RAG expression that allows for receptor editing, and apoptosis in response to high levels of BCR cross-linking that promotes deletion (32, 44, 47, 48).

PERSISTENT RAG EXPRESSION AND RECEPTOR EDITING Receptor editing involves replacement of self-reactive antibody V region (7, 49) genes by V(D)J recombination (6). Gene replacement by persistent V(D)J recombination was first described in B cell lines in vitro (50–52). In mice, it was noted that Igκ transgenes did not induce high levels of allelic exclusion and that there was frequent persistent V(D)J recombination with some antibody transgenes (53, 54). However, the potential physiologic significance of secondary recombination of Ig genes in maintaining tolerance was only appreciated from studies of transgenic mice carrying anti–double stranded DNA or anti-MHC antibodies (6, 7). In these mice, immature B cells are exposed to multivalent self-antigens at early stages

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of development (8, 55). Most of these B cells are deleted, but a small cohort of B cells escapes deletion and migrates to the spleen and lymph nodes where they accumulate with age (6). It was shown that while the transgenic heavy chain was present in the B cells that escape deletion, they expressed an endogenous, nontransgenic κ or λ gene, and the resulting chimera was no longer self-reactive (6, 7, 49). Thus, the nontransgenic κ or λ gene was said to “edit” the original transgenic self-reactivity. Further insight into light chain editing came from the analysis of the transgenic mice that carry only the 3H9 heavy chain of an anti-DNA antibody (49, 56). 3H9 produces anti-DNA when combined with most light chains but a small group of light chains with low isoelectric points such as Vκ12A block anti-DNA reactivity. Despite the high level of reactivity of 3H9 with DNA, splenic B cells from these mice did not produce anti-DNA antibodies. 3H9 peripheral B cells showed highly skewed Vκ and Jκ usage with a large number of cells expressing Vκ12A, and the majority of the Vκ genes were joined to Jκ5, indicating that multiple recombination events had occurred on the same chromosome (49). Efficient light chain “editors” differed from other κ light chains in that their CDRs are very acidic and have the capacity to prevent DNA binding by neutralizing the arginines in the CDR3 of 3H9 (57). Enhanced editing was associated with high levels of RAG expression, suggesting that editing induced or prolonged RAG expression (7). The efficiency of editing was assessed using mice produced by gene targeting to express anti-MHC (H-2Kk-b) or anti-DNA heavy and light chains (58, 59). In contrast to the severely reduced numbers of mature B cells reported in conventional anti-MHC transgenic mice, the bone marrow and peripheral B cell compartments of these knock-in mice were nearly normal, suggesting that editing was highly efficient (58, 59). IgVH genes can also be replaced by secondary V(D)J recombination through the use of cryptic recombination signal sequences embedded in the VH gene (52, 60–62). Studies in mice and humans have shown evidence for VH replacement in autoantibody-producing B cells (63–65). However, edited heavy chains frequently show N nucleotide addition, suggesting that this process can occur in progenitor B cells before light chain assembly (63, 66, 67). Such replacements would not be a response to self-antigen binding. Nevertheless, it has been estimated that 5%–12% of the human antibody repertoire is produced by VH replacement (68).

SITE OF EDITING RAG expression was believed to be upregulated for a third time in immature B cells that carry self-reactive receptors. In vitro experiments with both transgenic and wild-type B cells showed increased RAG mRNA levels in cultures of developing B cells following BCR cross-linking (69, 70). In addition bone marrow cells from mice that carry anti-MHC (H-2Kk-b) antibody transgenes show higher levels of RAG expression in the self-reactive background (71). Whether this increase in RAG

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expression is due to increased transcription or selection for cells that express high levels of RAG remains to be determined. Immature B cells are not a homogeneous population with respect to the level of RAG or BCR expression (Figure 1). Analysis of the RAG2-GFP indicator mice showed that RAG levels were inversely correlated with the density of the surface B cell receptor and B cell maturation (44, 72). More mature B cells with higher levels of cell surface BCR expression showed lower levels of RAG expression, suggesting that RAG expression is gradually turned off as B cells mature (44, 72). Immature B cells that express high levels of surface IgM are also more susceptible to negative selection (47, 48). Thus, the apparent upregulation of RAG mRNA by BCR cross-linking in vitro could also be a consequence of the selective survival of the cells that expressed higher levels of RAGs and lower levels of BCR to begin with. Similarly, increased RAG expression in transgenic B cells altered B cell maturation and enrichment for less mature B cells that have lower levels of surface BCR and higher RAG expression. To visualize the editing compartment in vivo, an Igκ allelic polymorphism was created by targeted replacement of the mouse constant region gene (mCκ) by its human homologue (hCκ) (73). In mice heterozygous for both a prerecombined light chain (at the mCκ locus) and the hCκ allele, edited B cells were distinguished as those cells that lost expression of the prerecombined mCκ allele (73). Kinetic studies showed that B lymphocytes undergoing editing were arrested for at least two hours at the pre-BII cell stage when compared to unedited counterparts. The delayed and edited B cell population showed higher levels of RAG expression than unedited cells (73). Similar kinetic data have been obtained using mice that carry a prerecombined Vλ gene instead of hCκ (74). These observations are consistent with a model where self-recognition activates secondary gene recombination by inducing a developmental arrest at a stage where RAG1 and RAG2 are expressed. In this model, cross-linking of the cell surface receptor by self-antigen does not reinduce but sustains RAG1 and RAG2 expression and allows for secondary V(D)J recombination. The model further clarifies how light chain allelic exclusion is maintained in the presence of high levels of editing: B cells expressing innocuous receptors transit rapidly from this stage to a compartment where RAG expression and V(D)J recombination are turned off. Thus, B cells with a nonself-reactive receptor are not exposed to prolonged V(D)J recombination, and the self-reactive cells that are trapped in the editing compartment remain so only until they produce a nonself-reactive receptor. In this regulated model for allelic exclusion, both Igκ alleles could be accessible to the V(D)J recombinase simultaneously without interfering with allelic exclusion.

EXTENT OF EDITING Several lines of evidence suggest that secondary gene rearrangements are a common occurrence. For example, analysis of hybridomas generated from Vκ4Jκ4 and Vκ8Jκ5 knock-in mice shows that both prerearranged light chains are replaced by

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editing in a large number of B lymphocytes (75). Likewise, the Vκ3-83Jκ2 light chain is edited by secondary recombination occurring at the targeted allele and this is accompanied by V(D)J recombination at the wild-type allele (58). Editing has also been examined in Igλ expressing nontransgenic B cells in mice and man (76, 77). Forty-seven percent of all mouse Igλ expressing B cells that have had their Igκ genes inactivated by RS rearrangements show in-frame and potentially functional Igκ genes (77). In man, almost all λ expressing B cells also carry a rearranged κ locus, whereas only 2% of κ expressing B cells carry rearrangement Ig λ genes (76). Furthermore, inactivated in-frame κ joints are found in 30% of human λ expressing cells (76). However, it was not determined why the in-frame Igκ alleles were replaced in mouse or man. A direct measurement of the extent of receptor editing was made using the hCκ and Vλ knock-in alleles (73, 74). These studies revealed that on average 25% of the repertoire is the result of secondary gene replacements, indicating that editing makes an important contribution to the normal antibody repertoire.

TRANSCRIPTION AND SECONDARY V(D)J RECOMBINATION Ig gene expression has been proposed to be essential for primary V(D)J recombination based on the direct correlation between the onset of germline transcription and antibody gene recombination (78–80). In support of this model, targeted deletion of transcription regulatory elements and some transcription factors impairs both expression and recombination of TCR and Ig genes in vivo (81–85). In addition, V(D)J recombination can only be induced in nonlymphoid cells when Ig genes are transcribed (86). However, experiments with cell lines, transgenic recombination substrates, and Pax5−/− B cells show that transcription does not always correlate with recombinational accessibility (87–91). Furthermore, the question of whether there is a role of transcription per se as opposed to indirect enhancement of locus accessibility has not been resolved. The role of transcription in secondary recombination was investigated in mice mutant for the transcriptional coactivator OcaB. OcaB (also known as Bob-1 and OBF-1) (92–94) forms a ternary complex with the transcription factor Oct-1 (or Oct-2) (95) on octamer motifs present in some Ig gene promoters. This octamer/ Oct-1(2)/OcaB ternary complex is thought to activate Ig gene transcription by specific interactions with the TATA-box-associated basal transcription machinery (96, 97). A direct correlation was found between light chain promoter transcription and receptor editing (98). In the absence of OcaB, the Igκ chromatin domain is accessible as measured by DNA demethylation, histone acetylation, promoter loading of Oct-1, and low level transcription (98). However, open chromatin and low level transcription were not sufficient for gene replacement by V(D)J recombination. Only strongly transcribed promoters were replaced (98). Thus, a specific threshold of Vκ gene transcription is required for secondary gene recombination.

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TERMINATION OF RAG EXPRESSION RAG expression was initially thought to be confined to pro-B, pre-B, and immature B cells in the bone marrow. However, several reports showed RAG mRNA and protein expression in germinal centers and in vitro activated B cells (99, 100). RAG1 and RAG2 mRNAs were detected in IgD+ B cells cultured in the presence of CD40 (or lipopolysaccharide) and IL4, whereas splenic, Peyer’s patches, or lymph node germinal center B cells showed abundant RAG1 protein expression as determined by immunostaining (99, 100). Unlike most peripheral B cells, RAG+ lymphocytes (in both mice and humans) expressed several cell surface markers characteristic of pro-B or pre-B cells such as λ5, VpreB, TdT, GL7, low levels of B220, and IL7R (99, 101–105). Ongoing recombination in these peripheral cells was implied by the presence of DNA double-stranded break V(D)J intermediates (106–108) and de novo formation of Vλ1-Jλ1 signal joints. However, the similarities between bone marrow and peripheral RAG+ B cells raised the possibility that these cells might in fact represent B cell precursors. Experiments with transgenic and GFP knock-in mice supported this hypothesis (44, 72). In both cases, GFP expression in developing B and T cells mimics endogenous RAGs with the caveat that the GFP expression level in the transgenic mice was one order of magnitude higher than in the knock-in mice. Despite this, the results obtained with both models were similar in that they showed that RAG-GFP expression in spleens was restricted to immature new immigrant B cells (44, 72). Furthermore, adoptive transfer experiments showed that mature B cells could not be induced to re-express RAGs during an immune response in vivo or by culturing them in the presence of LPS and IL4 (44, 72). Interestingly, the RAG+ immature B cell compartment in the spleen was increased in animals immunized with antigen, infectious agents, or adjuvant only at late stages of the immune response (44, 72, 109, 110). Increase in production and export of immature B cells from the bone marrow (109, 110) accounted for accumulation of these RAG+ immigrants with kinetics similar to germinal center formation (99, 100). The levels of RAG expression in developing B cells decreased as they acquired higher levels of surface IgM expression (see above). New immigrant B cells in the periphery express substantially lower levels of RAG than immature B cells in the bone marrow (44, 72). Nevertheless, alterations in the kinetics of immature B cell migration to the periphery under conditions of immunization might explain reports on RAG expression in peripheral B cells even in the absence of reinduction.

FROM EDITING TO DELETION Termination of RAG expression prevents further V(D)J recombination and receptor editing. To maintain tolerance, B cells that cannot edit self-reactive receptors must be deleted or rendered anergic. The idea that self-reactive clones are deleted during development was put forward by Joshua Lederberg as a refinement of the clonal selection theory (5). This

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concept was confirmed by experiments in which mice were treated with anti-Igs from birth and were found to be B cell depleted (111). The assumption linking this result to tolerance was that anti-IgM antibodies must mimic autoantigens by cross-linking the cell surface receptor. Likewise, bone marrow B cells challenged in vitro with anti-IgM antibodies downregulate surface Ig and undergo apoptosis (11, 13, 15, 19). In transgenic mice, expression of certain self-specificities also induced clonal B cell deletion (8, 55, 112–114). In anti-MHC expressing B cells exposure to antigen induced a developmental block that was concurrent with secondary VL gene recombination and replacement of cell surface receptors (48, 69, 70). Cells that failed to undergo successful editing were destined for death by apoptosis. This idea was confirmed in experiments with RAG-deficient mice that carried anti-DNA or self-MHC antibodies (115, 116). In the absence of secondary recombination all autoreactive B cells were deleted and there were no peripheral B cells (115, 116). Thus, antigen-induced apoptosis is a relatively late event in bone marrow B cell development that is preceded by an editing permissive stage that appears to be dependent on the bone marrow microenvironment (21, 48, 117).

CIS REGULATION OF RAG EXPRESSION Highly regulated RAG expression is required for successful assembly of Ig and TCR genes and normal lymphocyte development. On the other hand, silencing RAGs in mature lymphoid cells is necessary in order to ensure genomic stability. The RAG locus is peculiar in that RAG1 and RAG2 are adjacent but convergently transcribed genes that entered the vertebrate genome at the time of emergence of jawed fish (23–25, 118, 119). This unusual evolutionarily conserved genomic organization and the finding that RAG proteins can mediate transposition in vitro lead to the hypothesis that these genes originate from a mobile element that entered the vertebrate genome at the time of emergence of jawed fish (120, 121). Regulation of RAG expression has been studied by transfection in cell lines in vitro and in vivo using bacterial artificial chromosome (BAC) transgenic mice, using green or yellow fluorescent protein (GFP or YFP) as reporters in reconstitution experiments with transfected ES cells, and by gene targeting. The disadvantage of the transfection systems is that the transfected cells represent static stages in B or T cell development and therefore the dynamic aspects of RAG regulation in developing lymphocytes cannot be explored. Nevertheless, much has been learned about the chromatin structure and transcription factors that bind the murine and human RAG1 and RAG2 TATA-less promoters in vitro (122–126). The RAG1 promoter is not active or tissue specific in transient transfections in the absence of a heterologous enhancer such as the Ig Eµ (125). In contrast, the murine RAG2 promoter is active in transient transfection experiments in B and T cell lines, and the activity is dependent on PAX5 and GATA3 (127, 128). However, stable transfectants showed little activity for either RAG1 or RAG2 promoters in the absence of exogenous enhancers (129). A second method used to evaluate RAG regulation was RAG2−/− blastocyst reconstitution by transfected RAG2 transgenes (130). These experiments suggested

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that all of the information required for RAG2 regulation was found in an 18 kb genomic fragment extending from 9 kb upstream of the RAG2 promoter to 2.4 kb 30 of the untranslated region because it rescued thymocyte development (130). Similar rescue of RAG2−/− mice was also obtained with a yeast artificial chromosome (RYAC) that contained both functional RAG genes and 12 kb of DNA 50 of RAG2 (131). The double positive (DP) compartment was fully reconstituted, and mature CD4+CD8− and CD4−CD8+ thymocytes were present at one third of normal levels in the RYAC/RAG2−/− mice (131). However, this reconstitution of the DP and single positive (SP) stage differed significantly from the normal wild-type T cell development in that the mature cells were reduced by up to 70% and that the TCRα rearrangements were restricted to only the initial recombination at the 50 end of the Jα locus (131). Reconstitution was nonphysiological because RYAC failed to induce detectable RAG1 or RAG2 transcription in DP T cells. Thus, neither the 18 kb genomic fragment (130) nor the RYAC contained sequences required for RAG expression in DP T cells (131), and the RAG2−/− blastocyst reconstitution is not a sensitive assay to study RAG regulation in vivo. Transgenic mouse and gene targeting experiments have confirmed the requirement for distal enhancers in regulating RAG expression in vivo. Two elements with RAG promoter-enhancing activity have been identified: One element is active in B cells and the second in DP T cells (32, 129, 131). Both of these elements are on the RAG2 side of the locus, and both elements have effects on RAG1 and on RAG2 promoters, suggesting a mechanism for achieving coordinate regulation of the two genes by one set of genetic elements (32). The B cell specific element is found in a 2.3 kb area located approximately 22 kb 50 of RAG2. In cell lines this element enhances transcription over background levels in a highly variegated manner (36% of the transfected cells show no expression at all and only 10% of the clones show high levels of expression) (129). Nevertheless, enhancement is found only in pro-B cells and is absent from T, adult B, or nonlymphoid cell lines. Targeted deletion of this element from the mouse genome leads to a B cell specific tenfold and a twofold decrease in RAG1 and RAG2 mRNA levels, respectively, with no effect on RAG expression in DN or DP cells (129). Although the targeted deletion shows that this element is required for complete regulation, no ectopic or developmentally aberrant expression is reported in its absence. It remains to be determined whether this element is sufficient to drive tissue-specific and developmentally regulated expression of RAG, as is the case for other enhancers such as the Igµ enhancer. The T cell specific element was identified in transgenic experiments with bacterial artificial chromosomes (BACs) that carry fluorescent protein indicator genes in place of the RAG genes (32). These experiments showed that the transcription of both RAG1 and RAG2 in DP thymocytes is coordinated by one or more cis element(s) located between 32 and 87 kb 50 of RAG2. In addition to regulating expression in DP thymocytes, this region was also required to prevent position effect variegation in developing T cells and B cells. Therefore, an element (or elements) in this region is a required part of a traditional locus control region (132, 133).

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Like developing B cells, thymocytes express RAGs in two waves. V(D)J recombination is initiated with the first wave of RAG expression at the TCRβ locus in CD4−CD8− (DN) T cells. The TCRβ locus is analogous to the Ig heavy chain locus, and DN T cells are analogous to pro-B cells (134). Once a TCRβ chain is expressed, it combines with pre-Tα and CD3 components to produce the pre-TCR (135, 136). Similar to the pre-BCR, the pre-TCR downregulates RAG expression and induces T cells to mature to the CD4+CD8+ double positive (DP) stage. Upon entering the DP stage there is a second wave of RAG expression and progressive V(D)J recombination along the Jα locus (29, 131, 137–139). V(D)J recombination is only turned off in DP cells when they express a TCR that recognizes self-MHC with an affinity that allows for positive selection (140, 141). Thus, TCR cross-linking in DP T cells is the signal that extinguishes RAG expression. This is different from pre-B cells where receptor cross-linking delays extinction of RAG expression and prolongs recombination leading to receptor editing (73). We speculate that the separate B cell and DP T cell specific elements for RAG regulation may provide a molecular explanation for why T cells turn off RAG expression upon TCR cross-linking, whereas immature B cells prolong RAG expression and induce receptor editing upon BCR cross-linking. The Annual Review of Immunology is online at http://immunol.annualreviews.org

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