CD27 Ligand

CD27 Ligand W. A. M. Loenen* Department of Medical Microbiology, University Hospital Maastricht, PO Box 5800, Maastricht, 6202 AZ, The Netherlands * corresponding author tel: 43 387 6642/6644, fax: 43 387 6643, e-mail: [email protected] DOI: 10.1006/rwcy.2000.05008.

SUMMARY The lymphocyte-specific receptors CD70 and CD27 appear to affect the lymphocyte function of all subsets on which they are expressed in a bidirectional way. The presence of CD70 on activated T and B cells, as well as memory T and activated memory B cells, and that of its ligand CD27 on all naõÈ ve T cells (both resting and activated) as well as memory B cells, potentially allows crosstalk between all subsets involved in antigen-specific immune responses. However, CD70 and CD27 appear to link not only the T helper response with respect to the CTLs and B effector cells. Though data on NK cells are limited, expression of receptor and ligand on resting and activated subsets of these cells would allow additional crosstalk between the two types of killer effector cells (CTLs and NK cells) with respect to T cell help. The latter could contribute to the observed hierarchy of CTL-mediated kill over that of NK cells in combatting virus infections, for example. The mounting evidence for the emerging synergy of the CD70 route with the CD28 and CD40 routes in vitro runs parallel with the first evidence for in vivo efficacy of manipulation of this route in tumor eradication and may herald new strategies for immunotherapeutic interventions for other diseases alone or in conjunction with CD28 and CD40.

BACKGROUND

Discovery CD70 was originally identified by the KI-24 monoclonal antibody as a highly expressed protein on the

surface of Reed-Sternberg cells in Hodgkin's disease. Other mAbs include HNE 51 and HNC 142. CD70 is present on subsets of activated lymphocytes, many T and B cell lymphomas and on cell lines related to activated cells such as virally transformed cells. In 1993 it was identified as a member of the tumor necrosis factor (TNF) gene family, and found to be identical to the ligand for CD27, a lymphocytespecific relative of the TNF receptor (TNFR) gene family, involved in control of T cell-mediated immune responses.

Alternative names CD27 ligand or CD27L (Camerini et al., 1991).

Structure CD70 is a type II transmembrane surface-associated member of the TNF superfamily, with sequence similarity in the C-terminal extracellular region (Goodwin et al., 1993).

Main activities and pathophysiological roles The CD27/CD70 receptor/ligand pair plays an important role in T±T and T±B cell interactions (Lens et al., 1998). It is involved in CD4+ T celldependent cytokine and antibody production, in the generation of memory cells, allospecific CD8+ T cell responses, and there is evidence for involvement in natural killer (NK) cell activity. It promotes the

476 W. A. M. Loenen differentiation of memory B cells into plasma cells (Klein et al., 1998; Nagumo et al., 1998; Tangye et al., 1998). It has been postulated that interactions between CD70 and CD27 coordinate and control the expansion of the various lymphocyte populations upon antigenic triggering by facilitating maturation processes and cell cycle progression without interfering with programmed details of differentiation of individual cells or subsets (Loenen, 1998). Recent evidence suggests direct enhancement of the response between T helper, cytotoxic T, and dendritic cells, which interactions result in increased expression and activity of surface receptors of the CD70/CD27, CD28/B7, and CD40/CD40L pathways, as well as cytokines involved in this response such as IL-2, IFN , and IL-12 (Stuhler et al., 1999). As reported for other relatives, or other costimulatory receptors such as CTLA4 (CD152) and B7 (CD80/CD86), evidence is emerging for potent enhancement of the in vivo antitumor T-cell mediated response via manipulations of the CD70 route (Couderc et al., 1998; Nieland et al., 1998). In diseases characterized by chronic immune activation such as rheumatoid arthritis, levels of CD70+ T helper cells are increased as well as the activation-related soluble form of its ligand CD27. Isolated reports of aberrant expression of CD70 and its ligand CD27 on nonlymphoid cells in patients with atherosclerosis (De Boer et al., 1997) or after induced ischemic renal injury in a rat model (Padanilam et al., 1998) need to be substantiated. The first may prove relevant in the light of similar observations with respect to a potential role for CD40L in vascular disease (Laman et al., 1998; Schonbeck et al., 1999). In contrast to other TNF/TNFR-relatives, CD70/CD27 activities appear to be confined to lymphocytes.

is on chromosome 17 (Tesselaar et al., 1997; Oshima et al., 1998).

Relevant linkages Order mouse: centromere-Tcfeb-14/188-Cd70-0/193Vav-3/188-Fert1-7/170-Lamal. TNF-related 4-1BB ligand (CD137L) maps to this region.

Cells and tissues that express the gene mRNA data on CD70 expression are limited to in vitro studies and summarized in Table 1.

PROTEIN

Accession numbers Human CD70: PIR A40738; SwissProt P32970

Sequence See Figure 1.

Description of protein Data are summarized in Table 2. The CD70 extracellular domain resembles TNF, which consists of a group of sheets arranged in a `jelly-roll', presumably interacting as a trimer with its receptor CD27 (this receptor has a ligand-binding domain

GENE AND GENE REGULATION

Table 1 Human and murine CD70 mRNA expression

Accession numbers

Assay system

Cell type

RT-PCR/Northern blot

Human B cell lines Ramos, MP-1

EMBL/GenBank: Human cDNA: S69339 Mouse cDNA: Y13636 Mouse gene: Y13637 (exon 1,2), Y13638 (exon 3)

Chromosome location Human CD70 is on chromosome 19p13.3 (Goodwin et al., 1993, Gruss and Dower, 1995). Murine CD70

Murine MLV-transformed B cell line 771 Murine A20 B lymphoma Northern blot

a

a

Activated T cells from tonsil, spleen or blood

Negative tissues: resting thymocytes, resting splenocytes, heart, brain, spleen, lung, liver, skeletal muscle, kidney, testis.

CD27 Ligand 477 Figure 1

Amino acid sequence for CD70.

Sequence Human CD70

1 MPEEGSGCSV RRRPYGCVLR AALVPLVAGL VICLVVCIQR FAQAQQQLPL 51 ESLGWDVAEL QLNHTGPQQD PRLYWQGGPA LGRSFLHGPE LDKGQLRIHR 101 DGIYMVHIQV TLAICSSTTA SRHHPTTLAV GICSPASRSI SLLRLSFHQG 151 CTIASQRLTP LARGDTLCTN LTGTLLPSRN TDETFFGVQW VRP Murine CD70

1 MPEEGRPCPW VRWSGTAFQR QWPWLLLVVF ITVFCCWFHC SGLLSKQQQR 51 LLEHPEPHTA ELQLNLTVPR KDPTLRWGAG PALGRSFTHG PELEEGHLRI 101 HQDGLYRLHI QVTLANCSSP GSTLQHRATL AVGICSPAAH GISLLRGRFG 151 QDCTVALQRL TYLVHGDVLC TNLTLPLLPS RNADETFFGV QWICP

Table 2 Biochemical characteristics of CD70 Human

Mouse

Number of amino acids

193

195

Protein

Type II transmembrane receptor

Type II transmembrane receptor

Protein backbone

21 kDa

21 kDa

Mature protein

29 kDa

29 kDa

Modifications

2 N-linked sugars

2 N-linked sugars

Binding affinity

1.83  108 Mÿ1 1.58  109 Mÿ1

resembling TNFR, an elongated structure held together with disulfide bridges, and lacking  helices or sheets. The human protein shares about 60% identity with the murine receptor protein (Goodwin et al., 1993; Tesselaar et al., 1997; Oshima et al., 1998).

Important homologies Related to the TNF superfamily in the extracellular domain. Relatives known to date include: CD40L (CD154), CD30L, Apo3L, LT , TRAIL, the HVEM/ ATAR ligand LIGHT, RANKL/TRANCE/ODF, CD95L (FasL), TNF, TNF /LT, 4-1BBL/ CD137L, Ox40L (Gravestein and Borst, 1998). CD70 has no known motifs in the cytoplasmic region.

Posttranslational modifications Two N-linked carbohydrates in the extracellular domain.

CELLULAR SOURCES AND TISSUE EXPRESSION

Cellular sources that produce The data on CD70 expression on normal tissue are summarized in Table 3 and Table 4; those on malignant cells in Table 5 (Goodwin et al., 1993; Gruss and Dower, 1995; Lens et al., 1998). CD70 is present on most activated B cells and a subpopulation of activated T cells and NK cells. There is weak expression on macrophages but it is reportedly absent on neutrophils, monocytes, and endothelial cells, either resting, or activated with IFN or TNF. Human CD70 is expressed on CD8+CD45RA+ CTLs upon interactions between CTLs, dendritic cells, and TH cells, and on memory CD4+CD45RO+ T cells, while its receptor CD27 is preferentially expressed on naõÈ ve CD4+CD45RA+ cells and absent on the memory T cells. A similar reciprocal expression of receptor and ligand has been reported on NK cells. Triggering of the antigen receptor on T or B cells plus TH1-type second signals induce high levels of CD70, while TH2-type cytokines such as IL-4 interfere with expression. Human B cells double positive for CD70 and its ligand CD27 comprise the recently activated memory population. CD70 is also expressed in the thymus on stromal cells and expected to play a role in

478 W. A. M. Loenen Table 3 Protein expression of CD70 in normal tissue Tissue

Cell types

Thymus

Scattered stromal medulla cells

Table 5 Examples of protein expression of human CD70 on B and T cell malignancies

Comments

Examples B cell lines

Medullary epithelial cells Tonsils

Some lymphocytes in germinal centers, skin, gut

Daudi JY

Cells with primed phenotype

BJAB SMS

10±25% B cells Peripheral blood

5±15% T cellsa

SB Cells with activated phenotype

10±25% B cellsb Other

T cell clones

CD27-negative

MP-1 Peripheral T and B cell lymphomas with lymphoblastic phenotypes

CD45RO, HLA-DR, IFN -producing cells. Double positive with CD27; IgG or IgM memory cells, some primed IgD+ cells

B cell chronic lymphocytic leukemia (B-CLL) (50±100%)

b

Virus-transformed cells

Functional subset

Comments

T cells

Activated CD4+ T helper cells

Helper cells and CTLs are double positive with CD27. See Figure 5 for model on interactions between T helper cells and CTLs with dendritic cells

Activated CD8+ cytotoxic T cells CD4+CD45RO+ memory T cells

Natural killer cells

Activated naõÈ ve B cells

Negative for CD27

Activated memory B cells

Double positive with CD27

Subset CD16+ CD56+

Reciprocal high level of expression of receptor and ligand?

the thymocyte selection via interaction with its ligand CD27. Potential interactions of CD70-positive cells with other cells expressing CD27 are indicated in Figure 2.

HTLV-I-positive T cell lines EBV-transformed B cell linesa

Table 4 Lymphocyte subsets expressing the CD70 surface receptor Cell type

Reed-Sternberg (RS) cells in Hodgkin's disease (96±100%) Large B cell non-Hodgkin's lymphoma (NHL) (60±80%)

a

B cells

Ramos

EBV-related undifferentiated nasopharyngeal carcinoma (UNPC) a

Most B cell lymphomas coexpress the CD70 ligand CD27.

Eliciting and inhibitory stimuli, including exogenous and endogenous modulators CD70 has a general stimulating effect on T cell, B cell, and NK cell growth and differentiation, in conjunction with primary activating signal (Figure 2). CD27/ CD70 interactions costimulate T, B, and NK cell proliferation, enhance cytokine production of all subsets analyzed, such as TNF secretion by CD4+ T cells, and cytotoxic activity of T and NK cells. CD70 binding on B cells acts as a weak costimulatory signal for B cell proliferation via SAC+IL-2, but strongly stimulates immunoglobulin production. CD70 synergizes with IL-2 and IL-10 in the transition of memory B cells (which can be identified by surface expression of its ligand CD27) into plasma cells. There are no known inhibitory functions (Lens et al., 1998; Nagumo et al., 1998).

CD27 Ligand 479 Expression of CD70 on resting cells is induced by triggering of the antigen receptor on T or B cells, which signal can be replaced by polyclonal activators or superantigen. Expression is enhanced by IL-12, or by triggering of the CD40 or CD28 routes. It is negatively affected by IL-4 and TGF (Lens et al., 1998; Figure 3).

RECEPTOR UTILIZATION CD27. Scatchard analysis of soluble CD27-Fc binding to the EBV-transformed B cell line MP-1 shows a biphasic curve with low and high binding affinities with reported Kd values of 1.83  108 Mÿ1

Figure 2 (a) Potential interactions of CD4+ memory T cells with lymphocytes expressing CD27. Interactions between the memory CD4+CD45RO+ T cell population with resting T and NK cells, activated T and NK cells, as well as resting and activated memory B cells, would allow extensive crosstalk between subsets. It should be noted that expression of the CD70 ligand CD27 strongly increases after activation of human cells (for simplicity reasons not included in the figure), concomitant with the generation of soluble CD27. The role of soluble CD27, which can also be found associated with T cell membranes, is not clear, as is coexpression on NK cells of CD70 and CD27. (b) Potential interactions of activated memory B cells with lymphocytes expressing CD27. Interactions of activated memory B cells with lymphocytes expressing CD70 and/or CD27 would allow crosstalk as extensive as that of memory T cells shown in Figure 2a. Resting memory B cells are single positive for CD27 and lack CD70, and potentially can be activated via the CD27 receptor by memory T and/or activated naõÈ ve T and NK cells, resulting in upregulation of CD70 on the memory B population. This is in line with reports that CD27+CD70+ B cells are recent immigrants in germinal centers. (a) Naive T-cell Activated T-cell

NK cell

Activated T-cell

CD4+ memory T-cell

Activated NK cell

Memory B-cell Soluble CD27 Activated memory B-cell

CD27 CD70

480 W. A. M. Loenen Figure 2 (Continued ) (b) Naive T-cell NK cell

Activated T-cell

Activated T-cell

Activated memory B-cell

Activated NK cell

Activated B-cell

Memory B-cell

Activated NK cell

Activated memory B-cell

Memory T-cell

Activated memory B-cell

Soluble CD27

CD27 CD70

Figure 3 Factors influencing induction of CD70 on naive T cells. Both CD28/B7(CD80/CD86) and CD40/ CD40L routes influence induction of CD70 upon antigenic stimuli. For simplicity reasons the presence of CD27 on resting cells and its concomitant enhanced expression after activation is not shown in this figure. See also Figure 5. IL-4

TGF-β –

Naive T-cell

–

Antigenic stimulation

+ CD28

+ CD40

+ IL-12

Activated T-cell

+ IL-1α

+ TNF-α CD70

and 1.58  109 Mÿ1, while that of recombinant sCD27 binding to 3T3 cells, transfected with the CD70 cDNA, gave values of 1.14  108 Mÿ1 and 1.25  109 Mÿ1 (Goodwin et al., 1993; Agematsu et al., 1994).

IN VITRO ACTIVITIES

In vitro findings In vitro experiments demonstrate mutual crosstalk and bidirectional signaling in both CD70- and CD27positive cells, as also reported for other relatives (see chapters on CD40L, Fas ligand, CD30L, Ox40, 4-1BB) (Vogel and Noelle, 1998; Moulian and BerrihAknin, 1998; Horie and Watanabe, 1998; Weinberg et al., 1998; Vinay and Kwon, 1998). Their activity appears to overlap as well as synergize with the CD28 and CD40 routes, and thus contribute to a carefully controlled expansion of the immune cascade involving interactions with antigen-presenting cells. CD70 coprecipitates with an uncharacterized 122 kDa protein. Ligation of CD70 with its receptor CD27 enhances proliferation of lymphocytes stimulated in various ways (CD3 mAb, TCR mAb, CD2 mAb, lectins, phorbol esters) and reactions can be blocked by CD70 mAb. Fixed or irradiated cell lines expressing CD70 either naturally, such as the human B cell line Ramos, or after transfection with the CD70 cDNA,

CD27 Ligand 481 Table 6 Induction of expression of human CD70 in vitro Cell type

Expression

Type of stimulation

+

PHA+PMA or CD2 or CD3 mAb (*)

++

(*)+CD28 or TNF, IL-1, or IL-12

ÿ

(*)+IL-4

Human CD70 T cells

B cells

+

LPS or CD40 mAb (**)

++

(**)+IgM mAb

ÿ

(**)+IL-4

++/+

Comment: Most CD70++ clones are CD27ÿ and vice versa

Resting T cells

ÿ

Immobilized CD3 mAb+CD28 mAb; peak 2±4 days

Activated T cells

+

Immobilized CD3 mAb+CD28 mAb; peak 2±4 days

Resting B cells

ÿ

CD40 mAb+IL-4, or LPS (Oshima et al., 1998)

Low

LPS or IgM mAbs (Hartwig et al., 1997)

+

CD40 mAb+IL-4, or LPS (Oshima et al., 1998)

++

CD40 mAb+IgM mAb (Oshima et al., 1998)

+

LPS or IgM mAb (Hartwig et al., 1997)

ÿ

CD40 mAb+IL-4 or LPS (Hartwig et al., 1997)

Some NK clones Murine CD70 in spleen

Activated B cells

e.g. COS-7, CV-1, CHO cells, have been used in proliferation assays, mixed lymphocyte reactions, and cytotoxicity assays. Data on human and mouse CD70 are listed in Table 6. Recombinant soluble CD70 trimerizes and Scatchard analysis indicates two binding affinities perhaps indicative of sequential recruiting of CD27 molecules, as described for its relative Ox40L (Al-Shamkhani et al., 1997). Activation of T cells via the TCR/CD3 complex leads to the gradual appearance of CD70 on about 20% of the cells over a period of 3±4 days, with a large proportion of weakly to highly positive cells after 5 days. In dendritic cell-mediated events the early CD70+ cells appear to be CD8+ CTLs, the later CD70+ cells CD4+CD27-, presumably leading to the memory T population (Stuhler et al., 1999). These data allow addition of CD70 to the model on interactions between dendritic cells, helper and cytotoxic T cells as discussed by Toes et al. (1998) (Figure 4). Triggering of B cells induces CD70 on the majority (70±90%) of B cells. In mouse, mCD70 can be induced on splenic T cells with CD3 and CD28 mAbs, that on splenic B cells by CD40 mAb. The latter is enhanced by crosslinking of surface Ig by IgM mAb (Table 6).

Figure 4 Synergism between CD40 and CD70 during differentiation of memory B cells into plasma cells. Activation of memory B cells, which appear to be the only B cells expressing the CD27 receptor, leads to induction of CD70 on the memory cells, involving the CD40/CD40L (CD154) route. Subsequently helper T cells stimulate differentiation into plasma cells and production of immunoglobulin, in which process the role of IL-2 and IL-10 has been established.

Memory B-cell

Antigenic stimulation

Activated memory B-cell

+ CD40

IL-2 IL-10

Activated Th-cell

Plasma cells CD27 CD70

482 W. A. M. Loenen Figure 5 Synergism between the CD40 and CD70 routes during T cell help to cytotoxic T cells. The CD40 model, as discussed by Toes et al. (1998) is based on the emerging importance of the role in T cell help by CD40L (CD154), induced shortly after activation of T cells, and CD40 (present on dendritic cells). Information on the involvement of CD70 in this process (see text) allows addition of the CD70/CD27 pair to this model in interactions between the lymphocytes. For simplicity reasons the CD28 and B7 receptors, which are involved in the initial interactions between and activation of both the T cells and dendritic cells, have not been included in this figure. The CD28 route is also involved in upregulation of CD70 (see Figure 3). CD40 model

Cytokines

CD4+ Th

CD8+ CTL

Activation

Dendritic cell

interactions can influence autocrine growth of these B and T cell lines.

Regulatory molecules: Inhibitors and enhancers The CD27/CD70 pathway is sensitive to pertussis toxin and to cyclosporin A. CD70 can be induced with monoclonal antibodies that stimulate the antigen receptor, lectins such as PHA or Con A, or phorbol ester such as PMA. CD28 mAb and proinflammatory cytokines (IL-1, TNF, IL-12) enhance induction CD70 on CD70-negative T cells upon stimulation with CD2 or CD3 mAb. CD40 mAb have a similar effect on CD70 expression on B cells. IL-4 has been reported to downregulate expression in human and mouse (Table 6) (Hartwig et al., 1997; Lens et al., 1998; Oshima et al., 1998).

Dendritic cell

Bioassays used New CD40 + CD70 model

CD4+ Th

Bioassays used include enhancement of lymphocyte proliferation, cytokine secretion, immunoglobulin production, and cytotoxicity (Lens et al., 1998).

CD8+ CTL

Dendritic cell

Dendritic cell

MHC I

MHC II

CD70

CD40

CD27

CD40L

TCR

There is some evidence that CD70 may be involved in growth of malignant cells. In a subgroup of B cell chronic lymphocytic leukemia (B-CLL) patients, CD70 mAb in conjunction with phorbol ester can induce proliferation of these malignant cells (Lens et al., 1998). Transfection of the CD70 cDNA in the (CD27low/CD70-negative) human T cell acute lymphoblastic leukemia (T-ALL) Jurkat leads to apoptosis, as does addition of recombinant soluble CD27 to the human B cell line Ramos (Prasad et al., 1997; Loenen, 1998). These results may indicate, that CD70-CD27

IN VIVO BIOLOGICAL ACTIVITIES OF LIGANDS IN ANIMAL MODELS

Normal physiological roles CD70 is presumably involved in lymphocyte development from early on in the thymus, as judged by CD27 mAb studies in vitro. Recent evidence on interactions in vitro between CTLs, dendritic cells, and TH cell clusters involving mutual stimulation via the CD28, CD40, and CD70 routes (Stuhler et al., 1999), suggests that such events may normally take place in lymph nodes upon antigenic triggering. CD70 is present on B cells that have recently migrated to germinal centers, which ties in with the in vitro data on its role in the differentiation from memory into plasma cells. There have been no reports on the presence of CD70 or its ligand on the antigen-presenting dendritic cells themselves, suggesting that the role of the CD70/ CD27 pair may be confined to interactions between the different lymphocyte subsets that interact with the dendritic cells via CD28 and CD40.

CD27 Ligand 483

PATHOPHYSIOLOGICAL ROLES IN NORMAL HUMANS AND DISEASE STATES AND DIAGNOSTIC UTILITY In X-linked hyper-IgM syndrome, in which patients' class switching is impaired due to a defect in the CD40L gene, the IgD-CD27+ B cell memory population has been reported to be greatly decreased. IgG production by cells from these patients could be induced by stimulation of the antigen receptor and CD40 plus IL-2 and IL-10 (Agematsu et al., 1998).

IN THERAPY

Preclinical ± How does it affect disease models in animals? Currently three reports have been published on the use of CD70 in tumor models, suggesting their potential usefulness in human clinical trials. In the first paper, the authors provide evidence that CD70 may augment antitumor effects mediated by IL-12 (Couderc et al., 1998). MCA207 fibrosarcoma or TS/ A mammary adenocarcinoma cells transfected with CD70 can elicit an antitumor response both in vitro (as measured by stimulation of spleen cell proliferation) and in vivo, leading to a reduction in tumor growth at a level similar to that of the CD28/CTLA-4 ligand B7.1 (CD80), either in the presence or absence of IL-12. CD70 was tested in parallel with its relative CD154 (CD40L) and both were able to slow down tumor growth. The second report (Nieland et al., 1998) tallies with the first. The authors show enhanced antitumor immunity in their vaccination model using P815 mastocytoma cells. CD70 may be a better alternative to a long-lived memory response in vivo as defined both by the induction of tumor-specific cytotoxic T lymphocytes and the rejection of wild-type tumor cells. The third report (Lorenz et al., 1999) uses recombinant vaccinia virus rather than retroviral delivery as used by the above authors, with the advantage of high-level rapid delivery of the receptor, and supports further feasibility studies of the use of CD70 in human tumor therapy.

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