T1-ST2

T1/ST2 Karin Senn and Roman Klemenz* Division of Cancer Research, Department of Pathology, University Hospital ZuÈrich, Schmelzbergstrasse 12, ZuÈrich, CH-8091, Switzerland * corresponding author tel: 41-1-255-39-31, fax: 41-1-255-45-08, e-mail: [email protected] DOI: 10.1006/rwcy.2001.16016.

SUMMARY The T1/ST2 gene encodes two glycoproteins of the interleukin 1 receptor (IL-1R) family. The larger protein is a membrane-anchored orphan receptor, which is very similar to the type I IL-1R, and whose predominant sites of expression are mast cells and TH2 cells. The smaller, secreted protein corresponds to the extracellular domain of the T1/ST2 receptor and is produced by fibroblasts and osteoblasts in low quantities and in much higher amounts after stimulation with growth factors, proinflammatory cytokines, and in response to oncogene expression. A putative T1/ST2 ligand has been cloned, but was not able to trigger receptor activation. Two proteins of 18 kDa and 32 kDa have been identified that could bind the extracellular domain of T1/ST2 and induce NFB activation. The sequence of these proteins has not as yet been obtained. Studies of T1-deficient mice demonstrated that T1 is not crucial for the development and function of TH2 and mast cells, but suggested that it might be involved in the TH2specific cytokine production in response to certain parasitic infections.

cytoplasmic domains (Yanagisawa et al., 1993). Transcription of the murine T1/ST2 gene and its rat homolog Fit-1 results in the generation of a 2.7 kb and a 5 kb mRNA which arise from alternative 3 0 processing (Yanagisawa et al., 1993; Bergers et al., 1994). The 2.7 kb T1/ST2 transcript encodes the 38.5 kDa heavily glycosylated secreted protein (T1-S/ ST2) that is expressed in fibroblast and osteoblast cell lines (Klemenz et al., 1989; Tominaga, 1989; Werenskiold et al., 1989; Lanahan et al., 1992), in embryonic skin, bone, and retina (RoÈssler et al., 1993). The 5 kb mRNA is translated into a receptorlike molecule of about 65 kDa molecular weight (T1-M/ST2L). It shares the N-terminal, extracellular domain of T1-S/ST2, and contains in addition a transmembrane and cytoplasmic domain (Yanagisawa et al., 1993). This long transcript has been detected in rare cells of some hematopoietic organs (embryonic liver, spleen, bone marrow) (RoÈssler et al., 1995), including mast cells (RoÈssler et al., 1995; GaÈchter et al., 1996; Moritz et al., 1998a) and TH2 cells (Yanagisawa et al., 1997; LoÈhning et al., 1998; Xu et al., 1998).

Discovery BACKGROUND The T1/ST2 gene, also designated DER4, and Fit-1, encodes an orphan receptor belonging to the interleukin 1 receptor family (Klemenz et al., 1989; Tominaga, 1989; Werenskiold et al., 1989; Lanahan et al., 1992; Yanagisawa et al., 1993; Bergers et al., 1994). The T1/ST2 protein has been shown to exist as both a transmembrane molecule and as a soluble secreted protein lacking the transmembrane and

Cytokine Reference

The gene was originally isolated as an Ha-Ras and v-Mos oncoprotein-responsive and growth factor inducible gene in murine fibroblasts (Klemenz et al., 1989; Tominaga, 1989; Werenskiold et al., 1989). It was subsequently again isolated in a screen for delayed early serum-responsive genes (Lanahan et al., 1992). The human and rat homologs of murine T1/ ST2 have been cloned from human lymphocytes (Tominaga et al., 1992) and from rat fibroblasts (Fit-1), respectively (Bergers et al., 1994).

Copyright # 2001 Academic Press

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Alternative names The murine T1/ST2 gene was cloned independently by three groups. It was named T1 (Klemenz et al., 1989, Werenskiold et al., 1989), ST2 (Tominaga, 1989), and DER4 (Lanahan et al., 1992). A rat homolog has been identified and called Fit-1 (Bergers et al., 1994).

Structure The T1/ST2 gene encodes a membrane-bound glycoprotein (Yanagisawa et al., 1993) and a soluble variant (Klemenz et al., 1989; Tominaga, 1989; Werenskiold et al., 1989; Lanahan et al., 1992), which represents the ectodomain of the cell-associated receptor form. Both forms display three immunoglobulin-like domains (Tominaga, 1989).

Main activities and pathophysiological roles Despite the homology of T1/ST2 to IL-1R, the T1/ ST2 protein does not bind IL-1, IL-1 , or IL-1Ra (RoÈssler et al., 1995; Kumar et al., 1995; Gayle et al., 1996). Its natural ligand is not known as yet and the precise functions of T1/ST2 remain uncertain.

GENE

Accession numbers Mouse: M24843, Y07519, X60184 Rat: U04319 Human: E07716

Chromosome location and linkages The mouse T1/ST2 gene is located on chromosome 1 in close proximity to the IL-1R genes (Tominaga et al., 1991; Parnet et al., 1996), whereas the human T1/ST2 gene is located on chromosome 2 at q11.2 (Sims et al., 1995; Tominaga et al., 1996). The T1/ST2 locus is tightly linked to the IL-1R1 locus in mouse as well as in human species (Tominaga et al., 1991). In murine fibroblasts, expression of the T1/ST2 gene is regulated by transcription factors of the AP-1 family and by E binding proteins and gives rise to an

abundant 2.7 kb mRNA and a rare 5 kb mRNA (Kalousek et al., 1994; TruÈb et al., 1994; Kumar et al., 1997; Laursen et al., 1998). Within the 148 bp T1/ST2 enhancer, 3.6 kb upstream of the transcription initiation site used in fibroblasts, there is an essential tetradecanoyl phorbol acetate-responsive element (TRE), the binding site for AP proteins, and three E boxes which are important for efficient gene expression in fibroblasts (TruÈb et al., 1994). Overexpression of c-Fos and FosB was sufficient for T1/ST2 gene induction in these cells (Kalousek et al., 1994). Similarly the rat homolog of T1/ST2, Fit-1, was shown to be a c-Fos-responsive gene (Bergers et al., 1994). The induced expression of the Ha-ras oncogene results in the transient accumulation of cFos and consequently of T1-S/ST2. In contrast, sustained Ha-ras oncogene expression leads to the accumulation of Fra-1, which represses c-fos gene activation and in turn results in T1/ST2 gene repression. Thus, in ras-transformed fibroblasts the T1/ST2 gene is refractory to induction by various growth factors. However, IL-1 and TNF-mediated T1/ST2 gene induction is not affected by the ras oncogene (Kessler et al., 1999). In mast cells, transcription initiates at an alternative exon 1, 10.5 kb further upstream than the exon 1 which is used in fibroblasts. Both of the alternative exons 1 used in mast cells and in fibroblasts are spliced to the common exon 2 where the ATG initiation codon is located. T1/ST2 gene expression in mast cells is regulated by GATA transcription factors. The enhancer element which is essential for fibroblast-specific T1/ST2 gene activation is dispensable for expression in mast cells (GaÈchter et al., 1996). Under normal growth conditions accumulation of the 5 kb transcript occurs. However Ca2+ ionophore treatment and, to a lesser extent, Fc"RI ligation resulted in the rapid disappearance of the 5 kb T1 transcript and the massive accumulation of the 2.7 kb T1/ST2 mRNA followed by the secretion of T1-S/ST2 (GaÈchter et al., 1998; Moritz et al., 1998a). The different promoter usage is strictly tissuespecific whereas the distal and the proximal promoters are used by hematopoietic cells and fibroblasts, respectively (Figure 1) (GaÈchter et al., 1996).

PROTEIN

Accession numbers SwissProt: Mouse: P14719 ST2 protein precursor (T1/ST2 protein) (lymphocyte antigen 84).

T1/ST2 3 Figure 1 Genomic organization of the T1/ST2 gene. Coding and noncoding exons are indicated by filled and open boxes. The enhancer used in fibroblasts and the region containing three essential GATA elements for mast cellspecific expression are indicated by an open circle and a diamond, respectively. The splicing pattern in mast cells and fibroblasts is given above and below the line, respectively. The gene structure is taken from GaÈchter et al. (1998), Tominaga et al. (1991), and unpublished results.

the two forms of T1/ST2 are identical at the N-terminus and differ only nine amino acids before the C-terminal end of the small protein. The large T1/ST2 protein consists of an additional transmembrane and a cytoplasmic domain (Yanagisawa et al., 1993). Both forms of the T1/ST2 protein are heavily glycosylated. The ectodomain contains nine potential N-glycosylation sites (Werenskiold, 1992; Takagi et al., 1993). Due to heterogeneity of protein glycosylation, the molecular weight of the soluble T1/ST2 glycoprotein varies between 45 and 65 kDa. The membrane-bound form exhibits a lower molecular weight in fibroblasts (95 kDa) than in mast cells (110±120 kDa) (Moritz et al., 1998a).

Relevant homologies and species differences

Figure 2 Amino acid sequence for ST2 protein precursor. Signal peptide sequence is underlined.

Sequence See Figure 2.

Description of protein The 2.7 kb mRNA encodes a secreted protein of 337 amino acids with a hydrophobic N-terminal leader peptide (Klemenz et al., 1989). The predicted signal peptidase cleavage site is at position 26. The molecular weight of the protein backbone is 38.5 kDa. There are nine potential N-linked glycosylation sites. The mature protein migrates on SDS polyacrylamide gel with an apparent molecular weight of 45±65 kDa. The 5 kb mRNA is translated into a receptor-like protein of 567 amino acids with a calculated molecular weight of 65 kDa. It is heavily glycosylated and migrates on SDS page gel with a molecular weight of 95±110 kDa. The ectodomains of

The whole murine T1/ST2 protein shows significant sequence identity with the type I IL-1 receptor. The ectodomain of T1/ST2 and IL-1R type I are 25% identical, whereas their cytoplasmic portions share 38% identity (Yanagisawa et al., 1993). The highly conserved exon/intron structure of the type I and type II IL-1R and T1/ST2 gene suggests a common ancestor (Sims et al., 1995). Furthermore, it displays sequence similarity to other proteins related to the immunoglobulin superfamily, such as mouse neural cell adhesion molecule (22.7%), mouse basement membrane proteoglycan (19.0%), HLA-6±2 (20.8%), constant region of secreted form of chicken IgM heavy chain (16.5%) (Tominaga, 1989), and the carcinoembryonic antigen (20.0%) (Klemenz et al., 1989). The murine and human T1/ST2 share 67.7% identity in a 327 amino acid overlapping domain (Tominaga, 1989).

Affinity for ligand(s) T1/ST2 is an orphan receptor with over 25% sequence homology to the IL-1R type I (Yanagisawa et al., 1993; Mitcham et al., 1996; Parnet et al., 1996), but it does not bind IL-1, IL-1 or IL-1Ra (RoÈssler et al., 1995; Kumar et al., 1995; Gayle et al., 1996). A putative T1/ST2 ligand has been cloned by Gayle et al. but it has not been shown to trigger receptor activation. Kumar et al. have isolated two proteins of 18 kDa and 32 kDa that bind the extracellular domain of T1/ST2 and thereby induce NFB activation. The cloning of these candidate T1/ST2 ligands is awaited.

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Another report describes the specific binding of a recombinant human T1/ST2 protein to myelomaderived RPMI8226 cells, indicating that these cells carry a membrane-anchored T1 ligand and suggesting a possible involvement of T1/ST2 in T cell/B cell interaction (Yanagisawa et al., 1997).

Cell types and tissues expressing the receptor The two T1/ST2 transcripts differ in their expression pattern. The short 2.7 kb mRNA has been detected in the embryonic skin, retina, and bone (RoÈssler et al., 1995), in the developing mammary gland, in Ha-rasinduced murine mammary adenocarcinomas (RoÈssler et al., 1993), and in fibroblast cell lines (Klemenz et al., 1989; Tominaga, 1989; Werenskiold et al., 1989; Lanahan et al., 1992). The long 5 kb mRNA was detected in major hematopoietic organs such as fetal liver, spleen, and bone marrow (RoÈssler et al., 1995), in the lung (Bergers et al., 1994), as well as in several cell lines derived from macrophages, erythroid progenitors, and T cells (Yanagisawa et al., 1997), in a mast cell line (Bergers et al., 1994; RoÈssler et al., 1995), in primary mast cells (RoÈssler et al., 1995; GaÈchter et al., 1996; Moritz et al., 1998a) as well as in TH2 effector cells (Yanagisawa et al., 1997; LoÈhning et al., 1998; Xu et al., 1998). In mouse tissues the membrane-anchored form of T1/ST2 was found in single cells of the hematopoietic system (RoÈssler et al., 1995) including mast cells (GaÈchter et al., 1996), mast cell progenitors in fetal blood (Moritz et al., 1998b), and TH2 effector cells (Yanagisawa et al., 1997; LoÈhning et al., 1998; Xu et al., 1998).

Regulation of receptor expression T1/ST2 synthesis in fibroblasts is asssociated with proliferation. A marked increase in T1/ST2 production is observed when quiescent cells enter the cell cycle either in response to stimulation with serum or various mitogens such as PDGF, bFGF, cAMP, and TPA or by diluting confluent cells. Members of the fos family of transcription factors were shown to be involved in T1 gene induction (Kalousek et al., 1994; Kessler et al., 1999). Sustained ras expression abrogates the induction of the T1/ST2 gene by mitogens, but not by IL-1, TNF, or anisomycin (Laursen et al., 1998; Kessler et al., 1999).

Release of soluble receptors The secreted, soluble form has been detected in nonhematopoietic tissues during embryonic development such as in skin, bone, and retina (RoÈssler et al., 1995). In addition, stimulation of quiescent fibroblasts with serum, growth factors, and proinflammatory cytokines or in response to oncogene expression leads to transient expression of the T1/ST2 gene (Kalousek et al., 1994; TruÈb et al., 1994; Laursen et al., 1998).

SIGNAL TRANSDUCTION

Associated or intrinsic kinases Growth factor- and oncoprotein-mediated T1/ST2 gene expression is a delayed early event, requiring ongoing protein synthesis. The involvement of c-Fos and the Erk signal transduction pathway has been demonstrated (Kalousek et al., 1994; Kessler et al., 1999). In contrast, IL-1-, TNF-, and anisomycinmediated T1/ST2 gene induction is an immediate early event which does not require ongoing protein synthesis and which occurs via the MAP kinase p38/ RK pathway (Laursen et al., 1998). Studies with chimeric proteins consisting of the extracellular domain of the IL-1R and the intracellular part of T1/ST2, revealed that T1/ST2 and IL-1R trigger the same or a similar signal transduction cascade, namely the activation of NFB, the MAP kinase p38/RK, and transcription from the IL-8 promoter upon IL-1 or IL-1 stimulation (Kumar et al., 1995; Reikersdorfer et al., 1995; Mitcham et al., 1996).

BIOLOGICAL CONSEQUENCES OF ACTIVATING OR INHIBITING RECEPTOR AND PATHOPHYSIOLOGY

Unique biological effects of activating the receptors A defined function has not been yet ascribed to the T1/ST2 protein. In view of the selective expression of T1/ST2 on TH2 lymphocytes, the role of this molecule in TH2 responses has been studied using anti-T1/ST2 antibodies or a T1/ST2-Ig fusion protein. In a murine model of TH2-dependent allergic airway inflammation it was shown that administration of

T1/ST2 5 either mAb against T1/ST2 or recombinant T1/ST2 fusion protein reduced the induction of a lung mucosal TH2 immune response in vivo. Furthermore, in vitro polarization of CD4+ T cells in the presence of a T1/ ST2-Ig fusion protein blocked differentiation and activation of TH2 but not TH1 effector cells (LoÈhning et al., 1998; Coyle et al., 1999). Administration of an anti-T1/ST2 antibody to Leishmania major-infected Balb/c mice was shown to lead to increased resistance, as revealed by a reduced parasite load and the occurrence of smaller lesions, indicating that the TH2 response was decreased (Xu et al., 1998). In addition, the severity of collagen-induced arthritis was enhanced when susceptible DBA/1 mice were immunized with type II collagen in Freund's complete adjuvant (Xu et al., 1998). The above findings therefore suggest that the T1/ST2 molecule may be involved in the induction of a TH2 response and that blockade of T1/ST2 signaling by an antibody or fusion protein may inhibit the differentiation or activation of TH2 effector cells. However, anti-T1/ST2 antibody was also shown to enhance complement-mediated lysis of TH2 cells in vitro (Xu et al., 1998), raising the concern that the above findings involving anti-T1 mAb might have been caused by TH2 depletion. Analyses of the T1/ ST2 knockout phenotype revealed some conflicting results concerning the involvement of T1/ST2 in TH2 cytokine responses (see below).

Phenotypes of receptor knockouts and receptor overexpression mice Different reports concerning the T1/ST2 knockout phenotype have been published. Hoshino et al. (1999) described T1/ST2 knockouts to have normal TH2 responses after infection with the nematode Nippostrongylus brasiliensis as well as in allergen-induced airway inflammation. Furthermore, differentiation and function of bone marrow-derived cultured mast cells were unaffected (Hoshino et al., 1999). T1/ST2deficient mice generated in our laboratory showed a reduction in IL-5 production by lung lymphocytes and a slight decrease in the recruitment of eosinophils into lung tissue after infection with Nippostrongylus brasiliensis (Senn et al., 2000). The primary pulmonary granuloma model, induced by Schistosoma mansoni eggs, was applied by Townsend et al. (2000) to investigate the role of T1/ST2. T1/ST2-deficient mice abrogate granuloma formation, characterized by lack of eosinophil infiltration, and show a reduced TH2 cytokine production by the draining lymph nodes during secondary granuloma development (Townsend et al., 2000).

T1/ST2-Fc transgenic mice, which constitutively express high levels of a T1/ST2-Fc fusion protein under the liver-specific 1-antitrypsin promoter, show a comparable phenotype to T1/ST2-deficient mice after infection with Nippostrongylus brasiliensis (Senn et al., 2000). IL-5-deficient C57/B6 mice exhibit an approximately 3-fold reduced T1/ST2 expression on isolated spleen cells as compared with wild-type mice (LoÈhning et al., 1998). Therefore, it is possible that regulation of IL-5 production and T1/ST2 expression might be interdependent.

THERAPEUTIC UTILITY

Effect of treatment with soluble receptor domain Transgenic mice harboring an Ha-ras transgene under control of the mammary-specific whey acidic protein (WAP) promoter induce T1/ST2 gene activation in mammary adenocarcinomas. T1/ST2 mRNA was also expressed in undifferentiated nude mouse tumors produced from Ha-ras-transformed mammary epithelial cells (RoÈssler et al., 1993).

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