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• W2021057066 abstract "Crosstalk between T cells and renal tubular epithelial cells (TECs) in the pathogenesis of tubular lesions, the most important sign of progressive renal diseases, has not been clarified. Previous work has shown that TECs harbor co-stimulatory signals that promote T-cell activation, which induces tubular lesions. Nevertheless, the expression and functional role of B7-H4, a recently identified co-stimulatory ligand of the B7 superfamily, in pathologic human kidneys is unclear. We investigated the expression of B7-H4 on cryostat renal biopsies from patients with idiopathic membranous nephropathy (n=20), immunoglobulin A nephropathy (n=19), lupus nephritis (n=16), and acute renal allograft rejection (n=15) using immunohistochemistry. In addition, we also analyzed TEC-associated B7-H4 in the regulation of T-cell activation. Immunohistological staining revealed that B7-H4 antigen is restricted to tubular epithelium and that the protein is prominent in sections with severe tubular lesions, although no correlation was observed between tubular B7-H4 expression and levels of serum creatinine, serum urea nitrogen concentration, and 24-h proteinuria in each type of nephropathy. In vitro, mixed lymphocyte reactions revealed that TEC-related B7-H4 promotes cytokine (interleukin-2 and interferon-γ) production and proliferation of co-cultured T cells. Interestingly, the secretion of interleukin-2 by C10 T cell hybridomas also increased when C10 cells were co-cultured with the B7-H4-transgenic murine TEC line, 3M-1-secreting tubular epithelial cells (MCT) in the presence of the antigen hen egg lysozyme. Our results clearly show that TEC-associated B7-H4 induces T-cell activation and we propose that B7-H4 is a potential activator that promotes tubular lesion. Crosstalk between T cells and renal tubular epithelial cells (TECs) in the pathogenesis of tubular lesions, the most important sign of progressive renal diseases, has not been clarified. Previous work has shown that TECs harbor co-stimulatory signals that promote T-cell activation, which induces tubular lesions. Nevertheless, the expression and functional role of B7-H4, a recently identified co-stimulatory ligand of the B7 superfamily, in pathologic human kidneys is unclear. We investigated the expression of B7-H4 on cryostat renal biopsies from patients with idiopathic membranous nephropathy (n=20), immunoglobulin A nephropathy (n=19), lupus nephritis (n=16), and acute renal allograft rejection (n=15) using immunohistochemistry. In addition, we also analyzed TEC-associated B7-H4 in the regulation of T-cell activation. Immunohistological staining revealed that B7-H4 antigen is restricted to tubular epithelium and that the protein is prominent in sections with severe tubular lesions, although no correlation was observed between tubular B7-H4 expression and levels of serum creatinine, serum urea nitrogen concentration, and 24-h proteinuria in each type of nephropathy. In vitro, mixed lymphocyte reactions revealed that TEC-related B7-H4 promotes cytokine (interleukin-2 and interferon-γ) production and proliferation of co-cultured T cells. Interestingly, the secretion of interleukin-2 by C10 T cell hybridomas also increased when C10 cells were co-cultured with the B7-H4-transgenic murine TEC line, 3M-1-secreting tubular epithelial cells (MCT) in the presence of the antigen hen egg lysozyme. Our results clearly show that TEC-associated B7-H4 induces T-cell activation and we propose that B7-H4 is a potential activator that promotes tubular lesion. Tubular injury is the most reliable predictor of clinical outcome in chronic glomerular diseases.1.D'Amico G. Tubulointerstitium as predictor of progression of glomerular diseases.Nephron. 1999; 83: 289-295Crossref PubMed Scopus (58) Google Scholar, 2.Tipping P.G. Holdsworth S.R. T cells in glomerulonephritis.Springer Semin Immunopathol. 2003; 24: 377-393Crossref PubMed Scopus (38) Google Scholar, 3.Ikezumi Y. Kanno K. Karasawa T. et al.The role of lymphocytes in the experimental progressive glomerulonephritis.Kidney Int. 2004; 66: 1036-1048Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar Activated tubulointerstitial infiltrating T cells supply the local environment with proinflammatory factors such as tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), which have been demonstrated to actively participate in tubular pathogenesis.2.Tipping P.G. Holdsworth S.R. T cells in glomerulonephritis.Springer Semin Immunopathol. 2003; 24: 377-393Crossref PubMed Scopus (38) Google Scholar,4.Kelly C.J. T cell regulation of autoimmune interstitial nephritis.J Am Soc Nephrol. 1990; 1: 140-149PubMed Google Scholar It is now accepted that the optimal activation of T cells requires both co-stimulation and T-cell receptor engagement, and antigen presentation in the absence of co-stimulation may lead to T-cell anergy, tolerance, or apoptosis.5.Carreno B.M. Collins M. The B7 family of ligands and its receptors: new pathways for costimulation and inhibition of immune responses.Annu Rev Immunol. 2002; 20: 29-53Crossref PubMed Scopus (708) Google Scholar Renal tubular epithelial cells (TECs) become capable of effective antigen presentation and attract T cells into the tubulointerstitium, which has been confirmed by the contemporary aberrant expression of major histocompatibility complex II antigens (MHC-II) and intercellular adhesion molecule-1 (ICAM-1). Additionally, TECs are also induced to express several kinds of co-stimulatory molecules under inflammatory conditions, which supply secondary signals for T-cell activation. It has been confirmed that co-stimulatory molecules such as B7.1, B7.2, inducible co-stimulator ligand (ICOSL), or CD40 expressed by TECs actively take part in the pathogenesis of tubular lesions.6.Wahl P. Schoop R. Bilic G. et al.Renal tubular epithelial expression of the costimulatory molecule B7RP-1 (inducible costimulator ligand).J Am Soc Nephrol. 2002; 13: 1517-1526Crossref PubMed Scopus (75) Google Scholar, 7.Yamada A. Salama A.D. Sayegh M.H. The role of novel T cell costimulatory pathways in autoimmunity and transplantation.J Am Soc Nephrol. 2002; 13: 559-575PubMed Google Scholar, 8.Wu Q. Jinde K. Endoh M. et al.Clinical significance of costimulatory molecules CD80/CD86 expression in IgA nephropathy.Kidney Int. 2004; 65: 888-896Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 9.Wu Q. Jinde K. Endoh M. et al.Costimulatory molecules CD80 and CD86 in human crescentic glomerulonephritis.Am J Kidney Dis. 2003; 41: 950-961Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar Selective manipulation of CD28/B7.1, B7.2, CD154/CD40, or inducible co-stimulator ligand/inducible co-stimulator (ICOSL/ICOS) pathways have also been demonstrated to be beneficial in the therapy for autoimmune nephritis and renal allograft rejection.7.Yamada A. Salama A.D. Sayegh M.H. The role of novel T cell costimulatory pathways in autoimmunity and transplantation.J Am Soc Nephrol. 2002; 13: 559-575PubMed Google Scholar Recently, several members of the B7 superfamily have been identified, including B7-H1,10.Dong H. Zhu G. Tamada K. et al.B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion.Nat Med. 1999; 5: 1365-1369Crossref PubMed Scopus (1666) Google Scholar B7-DC,11.Latchman Y. Wood C.R. Chernova T. et al.PD-L2 is a second ligand for PD-1 and inhibits T cell activation.Nat Immunol. 2001; 2: 261-268Crossref PubMed Scopus (1916) Google Scholar B7-H3,12.Chapoval A.I. Ni J. Lau J.S. et al.B7-H3: a costimulatory molecule for T cell activation and IFN-gamma production.Nat Immunol. 2001; 2: 269-274Crossref PubMed Scopus (652) Google Scholar and B7-H4.13.Sica G.L. Choi I.H. Zhu G. et al.B7-H4, a molecule of the B7 family, negatively regulates T cell immunity.Immunity. 2003; 18: 849-861Abstract Full Text Full Text PDF PubMed Scopus (535) Google Scholar Elucidating the functional characteristics of these co-stimulatory ligands in renal diseases is currently the subject of intense research. B7-H4, also known as B7x14.Zang X. Loke P. Kim J. et al.B7x: a widely expressed B7 family member that inhibits T cell activation.Proc Natl Acad Sci USA. 2003; 100: 10388-10392Crossref PubMed Scopus (292) Google Scholar or B7S1,15.Prasad D.V. Richards S. Mai X.M. et al.B7S1, a novel B7 family member that negatively regulates T cell activation.Immunity. 2003; 18: 863-873Abstract Full Text Full Text PDF PubMed Scopus (331) Google Scholar is a recently identified member of the B7 family that is known to be critically involved in the downregulation of antigen-specific immune responses.13.Sica G.L. Choi I.H. Zhu G. et al.B7-H4, a molecule of the B7 family, negatively regulates T cell immunity.Immunity. 2003; 18: 849-861Abstract Full Text Full Text PDF PubMed Scopus (535) Google Scholar B7-H4 exerts its physiologic function by binding to a receptor on T cells which in turn induces cell cycle arrest and inhibits the secretion of cytokines and the development of cytotoxicity.13.Sica G.L. Choi I.H. Zhu G. et al.B7-H4, a molecule of the B7 family, negatively regulates T cell immunity.Immunity. 2003; 18: 849-861Abstract Full Text Full Text PDF PubMed Scopus (535) Google Scholar, 14.Zang X. Loke P. Kim J. et al.B7x: a widely expressed B7 family member that inhibits T cell activation.Proc Natl Acad Sci USA. 2003; 100: 10388-10392Crossref PubMed Scopus (292) Google Scholar, 15.Prasad D.V. Richards S. Mai X.M. et al.B7S1, a novel B7 family member that negatively regulates T cell activation.Immunity. 2003; 18: 863-873Abstract Full Text Full Text PDF PubMed Scopus (331) Google Scholar B7-H4 mRNA, but not protein expression, has been detected in a wide range of normal somatic tissues, including liver, skeletal muscle, pancreas, and the small bowel. Surface expression of B7-H4 protein, on the other hand, is restricted to activated T cells, B cells, monocytes, and dendritic cells (DCs). Recently, aberrant B7-H4 protein expression has also been reported in several human malignancies.16.Tringler B. Liu W. Corral L. et al.B7-H4 overexpression in ovarian tumors.Gynecol Oncol. 2006; 100: 44-52Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar, 17.Tringler B. Zhuo S. Pilkington G. et al.B7-H4 is highly expressed in ductal and lobular breast cancer.Clin Cancer Res. 2005; 11: 1842-1848Crossref PubMed Scopus (178) Google Scholar, 18.Ichikawa M. Chen L. Role of B7-H1 and B7-H4 molecules in down-regulating effector phase of T-cell immunity: novel cancer escaping mechanisms.Front Biosci. 2005; 1: 2856-2860Crossref Scopus (51) Google Scholar, 19.Choi I.H. Zhu G. Sica G.L. et al.Genomic organization and expression analysis of B7-H4, an immune inhibitory molecule of the B7 family.J Immunol. 2003; 171: 4650-4654Crossref PubMed Scopus (207) Google Scholar, 20.Krambeck A.E. Thompson R.H. Dong H. et al.B7-H4 expression in renal cell carcinoma and tumor vasculature: associations with cancer progression and survival.Proc Natl Acad Sci USA. 2006; 103: 10391-10396Crossref PubMed Scopus (252) Google Scholar, 21.Kryczek I. Zou L. Rodriguez P. et al.B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma.J Exp Med. 2006; 203: 871-881Crossref PubMed Scopus (516) Google Scholar Nevertheless, the significance of B7-H4 expression in human kidneys has not been described. Herein, we investigate B7-H4 expression on cryostat sections from patients with various nephropathies and define its clinical significance. Moreover, we also performed mixed lymphocyte reactions (MLRs) to detect the potential role of TEC-associated B7-H4 in the regulation of T-cell activation in vitro. Double labeling with B7-H4-PE (phycoerythrin) and CK-18-FITC (fluorescein isothiocyanate) monoclonal antibodies (mAbs) indicated that B7-H4 antigen was restricted to tubule epithelium and the expression was absent on cells within the tubulointerstitial space or glomeruli of diseased kidneys (Figure 1). Immunohistochemical assays indicated that B7-H4 expression in sections with severe tubular lesions (tubular lesions of Grades 2 and 3) was much stronger than in sections with minor tubular lesions (Grade 1). Moreover, only two cases of immunoglobulin A (IgA) nephropathy and two cases of idiopathic membranous nephropathy (IMN) without detectable tubular lesions (Grade 0) were faintly positive for B7-H4 antigen. Interestingly, we did not find B7-H4 expression by normal kidneys (Figure 2).Figure 2Immunohistochemical assay of B7-H4 antigen on diseased and normal cryostat renal tissues. Data evidenced that strong B7-H4 protein was detected in the tubular epithelium of sections with severe tubular lesions (Grade 3) of patients with (a) IMN, (b) acute renal allograft rejection, (c) IgA nephropathy, and (d) a representative patient with lupus nephritis with Grade 2 tubular lesions. (e) Slight B7-H4 expression on tubular epithelium was detected in sections from IgA nephropathy without tubular lesions (Grade 0). (f) B7-H4 protein expression was absent in normal renal tissues. Original magnification × 200.View Large Image Figure ViewerDownload (PPT) The percentage of B7-H4+ tubules in IMN was 16.26±20.82% (mean±s.d.; median, 13.7%), whereas in IgA nephropathy it was 14.67±21.12% (mean±s.d.; median, 11.3%). The percentage of B7-H4+ tubules in acute renal allograft rejection was slightly larger (mean±s.d., 37.6±23.2%; median, 15.6%) than that in lupus nephritis (mean±s.d., 26.5±35.2%; median, 9.7%; Figure 3a). The mean percentage of B7-H4+ tubules in all calculated sections was 11.6%. Statistical analysis revealed B7-H4 expression was not significantly different among these five types of nephropathies (data not shown). We further compared B7-H4 expression with clinicopathological variables. Patients were divided into two groups using the median percentage number of B7-H4+ tubules as the distinguishing factor. Results showed that no correlation was observed between tubular B7-H4 expression and levels of serum creatinine, blood urea nitrogen, albumin, or 24-h proteinuria for each type of nephropathy (Table 1). In addition, no correlation was found between B7-H4 expression and patients' age or gender (data not shown).Table 1Expression of B7-H4 on renal tubules has no statistically significant correlation with clinicopathological characteristics of patients with different renal diseasesClinical/histologic diagnosisNumber of casesB7-H4 statusaThe median percentage of B7-H4 positive tubules in IMN was 13.7%, in IgA nephropathy 11.3%, in lupus nephritis 9.7%, and in acute renal allograft rejection 15.6%.Serum creatinine (μmol/l)Urea nitrogen (mg/l)24-h proteinuria (g/day)IMN11≥Median107.20±22.4525.32±7.692.29±1.359<Median131.27±17.1220.13±6.733.82±2.49IgA nephropathy8≥Median131.21±26.1120.02±5.202.21±1.6411<Median122.33±28.7923.17±5.661.43±0.96Lupus nephritis7≥Median112.19±20.0313.91±3.062.85±1.399<Median109.15±27.2712.79±3.112.37±1.66Acute allograft rejection8≥Median96.08±20.2217.67±7.542.01±1.687<Median89.31±17.5722.08±7.091.69±1.87IgA, immunoglobulin A; IMN, idiopathic membranous nephropathy.a The median percentage of B7-H4 positive tubules in IMN was 13.7%, in IgA nephropathy 11.3%, in lupus nephritis 9.7%, and in acute renal allograft rejection 15.6%. Open table in a new tab IgA, immunoglobulin A; IMN, idiopathic membranous nephropathy. We also examine a possible relationship between B7-H4 expression and the severity of tubular lesions. Here, patients were divided into four groups using the scores of tubular lesions as a cutoff. As shown in Figure 3b, although occasional expression of B7-H4 was found in sections with slight tubular lesions, significant B7-H4 protein was detected in severe cases. Statistical analysis indicates they are significantly different (P<0.05). These results suggest that tubular-associated B7-H4 might be a suitable marker for predicting tubular lesions. To induce B7-H4 antigen on TECs, human primary TECs were stimulated with proinflammatory factors including TNF-α (10 ng/ml), IFN-γ (200 U/ml), lipopolysaccharide (LPS) (10 ng/ml), and interleukin (IL)-10 (10 pg/ml) in combination for the indicated duration. The total RNA from 3 × 105 collected TECs was isolated and B7-H4 mRNA transcription was measured by semiquantitative reverse transcriptase polymerase chain reaction analysis (RT-PCR). As shown in Figure 4a, RT-PCR indicated that the upregulation of B7-H4 mRNA transcription was already detectable after 24 h of treatment with the inflammatory factor cocktail, reach a maximum at 72 h, and gradually decline thereafter. Flow cytometry as well as Western blotting assays also revealed that B7-H4 protein expression on TECs was driven by these inflammatory factors (Figure 4b and c). MLRs were used to test the effect of TEC-related B7-H4 on T-cell activation. Confluent TECs (1 × 104) were preincubated with the inflammatory factor cocktail to induce B7-H4 antigen. After 72 h, purified CD3+ T cells (1 × 105) were added to the culture in the presence of anti-CD3 mAb (2 μg/ml), B7-H4-blocking mAb (hH4.1, 20 μg/ml), or isotype control mAb (mouse IgG1, 20 μg/ml). Supernatants were collected to assay the secretion of cytokines by enzyme-linked immunosorbent assay (ELISA) after 72 h. As shown in Figure 5a, the production of IFN-γ and IL-2 was increased when T cells were co-cultured with TECs compared to T cells cultured alone in the presence of anti-CD3 (2 μg/ml). Interestingly, the secretion of both cytokines was decreased when TEC-associated B7-H4 signals were blocked using anti-B7-H4 mAbs (the level of IL-2 decreased from 215.3 to 107.7 pg/ml (P<0.05), and IFN-γ decreased from 121.7 to 65.4 pg/ml (P<0.05)). Similar results for the TEC-related B7-H4 promotion of T-cell proliferation were also detected in the MLRs (Figure 5b). These results confirmed that B7-H4 mediates stimulatory signal, which upregulates T-cell proliferation and cytokine production in our experimental system. MLRs were also used to assay B7-H4 function in antigen presentation. Figure 6 indicates that B7-H4 protein is absent in the murine TEC cell line MCT. Before co-culture experiments, MCT cells were transfected to stably express B7-H4 protein, as confirmed by flow cytometry as well as Western blot analysis. MCT cells were co-cultured with C10 T cells in the presence or absence of foreign antigen hen-egg lysozyme (6 mg/ml). After 48 h, supernatants were collected to detect IL-2 production. As shown in Figure 6c, transfection of B7-H4 significantly promoted the production of IL-2 by C10 T hybridoma cells. Additionally, blocking B7-H4 signals with a specific, blocking mAb (clone 188, 20 μg/ml) reversed the stimulatory effect of B7-H4 and resulted in decreased antigen-specific IL-2 production by C10 cells. In addition, the activation of C10 cells required antigen presentation by major histocompatibility complex molecules, as evidenced by the inhibition of IL-2 secretion by blocking I-Ak with a major histocompatibility complex II-specific mAb (clone 10-3.6). These results further indicated that TEC-associated B7-H4 is a stimulator of T-cell responses. It is well established that members of the B7 family of co-stimulatory ligands provide positive and negative signals and play a central role in the regulation of antigen-specific, T-cell-mediated immune responses.22.Collins M. Ling V. Carreno B.M. The B7 family of immune-regulatory ligands.Genome Biol. 2005; 6: 223Crossref PubMed Scopus (185) Google Scholar,23.Greenwald R.J. Freeman G.J. Sharpe A.H. The B7 family revisited.Annu Rev Immunol. 2005; 23: 515-548Crossref PubMed Scopus (1804) Google Scholar B7-H4 is a recently discovered co-stimulatory molecule of the B7 family that regulates T-cell activation.13.Sica G.L. Choi I.H. Zhu G. et al.B7-H4, a molecule of the B7 family, negatively regulates T cell immunity.Immunity. 2003; 18: 849-861Abstract Full Text Full Text PDF PubMed Scopus (535) Google Scholar,15.Prasad D.V. Richards S. Mai X.M. et al.B7S1, a novel B7 family member that negatively regulates T cell activation.Immunity. 2003; 18: 863-873Abstract Full Text Full Text PDF PubMed Scopus (331) Google Scholar Based on flow cytometric analysis, expression of B7-H4 protein was reported to be inducible upon stimulation of T cells, B cells, monocytes, and DCs, whereas immunohistochemistry revealed little expression in several peripheral tissues with the exception of positive staining on some carcinomas.18.Ichikawa M. Chen L. Role of B7-H1 and B7-H4 molecules in down-regulating effector phase of T-cell immunity: novel cancer escaping mechanisms.Front Biosci. 2005; 1: 2856-2860Crossref Scopus (51) Google Scholar, 19.Choi I.H. Zhu G. Sica G.L. et al.Genomic organization and expression analysis of B7-H4, an immune inhibitory molecule of the B7 family.J Immunol. 2003; 171: 4650-4654Crossref PubMed Scopus (207) Google Scholar, 24.Simon I. Zhuo S. Corral L. et al.B7-H4 is a novel membrane-bound protein and a candidate serum and tissue biomarker for ovarian cancer.Cancer Res. 2006; 66: 1570-1575Crossref PubMed Scopus (153) Google Scholar In this study, an abundance of renal biopsies were tested for B7-H4 protein expression and the results show that although B7-H4 antigen is absent in normal kidneys, significant B7-H4 antigen is detected in diseased cases included IMN, IgA nephropathy, lupus nephritis, and acute renal allograft rejection. Double labeling indicated that B7-H4 antigen is only detected on tubule epithelium but not on cells within the tubulointerstitial space or glomeruli. Moreover, vascular endothelial cells did not express B7-H4 in these tissues (data not shown). These results are inconsistent with the results from renal cell carcinoma reported by Krambeck et al.,20.Krambeck A.E. Thompson R.H. Dong H. et al.B7-H4 expression in renal cell carcinoma and tumor vasculature: associations with cancer progression and survival.Proc Natl Acad Sci USA. 2006; 103: 10391-10396Crossref PubMed Scopus (252) Google Scholar who found B7-H4 expression on tumor cells and the tumor vasculature of renal cell carcinoma. In vitro, B7-H4 protein is profoundly induced in primary human TECs upon stimulation with IL-10, LPS, TNF-α, and IFN-γ in combination. Our results are the first to demonstrate that B7-H4 is a co-stimulatory ligand that can be induced in TECs in vivo and in vitro. Sections with severe tubular lesion observed in many renal autoimmune diseases and acute renal transplant rejection are associated with T cells infiltrating into tubulointerstitium, and these infiltrating T cells could secrete inflammatory cytokines to promote tubular atrophy and interstitial fibrosis.25.Remuzzi G. Ruggenenti P. Benigni A. Understanding the nature of renal disease progression.Kidney Int. 1997; 51: 2-15Abstract Full Text PDF PubMed Scopus (584) Google Scholar On the other hand, it is well known that co-stimulatory molecules CD80, CD86, and CD40 on TECs also play a central role in the pathogenesis of such tubular lesions, they favor direct interactions between tubular cells and interstitial T cells.23.Greenwald R.J. Freeman G.J. Sharpe A.H. The B7 family revisited.Annu Rev Immunol. 2005; 23: 515-548Crossref PubMed Scopus (1804) Google Scholar We here show that B7-H4 is majored in sections with severe tubular lesion, a similar pattern of T-cell infiltration in diseased kidneys reported previously.25.Remuzzi G. Ruggenenti P. Benigni A. Understanding the nature of renal disease progression.Kidney Int. 1997; 51: 2-15Abstract Full Text PDF PubMed Scopus (584) Google ScholarIn vitro, B7-H4 mRNA transcription and protein expression is also induced by proinflammatory factors. These results indicate that B7-H4 expression is possibly induced by factors secreted by infiltrating T cells within tubulointerstitium. B7-H4 binds to a putative receptor expressed on activated but not naive T cells and thereby leads to inhibition of T-cell activation and IL-2 production.13.Sica G.L. Choi I.H. Zhu G. et al.B7-H4, a molecule of the B7 family, negatively regulates T cell immunity.Immunity. 2003; 18: 849-861Abstract Full Text Full Text PDF PubMed Scopus (535) Google Scholar, 14.Zang X. Loke P. Kim J. et al.B7x: a widely expressed B7 family member that inhibits T cell activation.Proc Natl Acad Sci USA. 2003; 100: 10388-10392Crossref PubMed Scopus (292) Google Scholar, 15.Prasad D.V. Richards S. Mai X.M. et al.B7S1, a novel B7 family member that negatively regulates T cell activation.Immunity. 2003; 18: 863-873Abstract Full Text Full Text PDF PubMed Scopus (331) Google Scholar B7-H4 does not interact with receptors for other B7 family members including CD28, ICOS, cytotoxic T-lymphocyte antigen 4 (CTLA-4), or program death-1 (PD-1) and, to date, the specific identity of the cell-surface receptor that binds B7-H4 has not been identified. A receptor named B and T lymphocyte attenuator (BLTA) has been proposed for B7-H4 based on indirect evidence.14.Zang X. Loke P. Kim J. et al.B7x: a widely expressed B7 family member that inhibits T cell activation.Proc Natl Acad Sci USA. 2003; 100: 10388-10392Crossref PubMed Scopus (292) Google Scholar,26.Watanabe N. Gavrieli M. Sedy J.R. et al.BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1.Nat Immunol. 2003; 4: 670-679Crossref PubMed Scopus (611) Google Scholar However, B7-H4 and BTLA do not interact with each other in direct binding experiments, and herpesvirus entry mediator is regarded as the ligand for BLTA.27.Sedy J.R. Gavrieli M. Potter K.G. et al.B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator.Nat Immunol. 2005; 6: 90-98Crossref PubMed Scopus (458) Google Scholar Despite the lack of a defined B7-H4 receptor, our results described here provide clear evidence that B7-H4 binding to a receptor expressed on co-cultured T cells or C10 T hybridoma cells. MLRs indicated that TEC-related B7-H4 is a stimulator that promotes co-cultured T-cell activation, as confirmed by the secretion of IFN-γ and IL-2 as well as the proliferation was decreased when B7-H4 is blocked using antibodies. In addition, transfected expression of B7-H4 by the murine TEC cell line MCT also promoted antigen presentation. Our results are inconsistent with the concept of an overall negative regulatory function for B7-H4 in T-cell activation13.Sica G.L. Choi I.H. Zhu G. et al.B7-H4, a molecule of the B7 family, negatively regulates T cell immunity.Immunity. 2003; 18: 849-861Abstract Full Text Full Text PDF PubMed Scopus (535) Google Scholar,14.Zang X. Loke P. Kim J. et al.B7x: a widely expressed B7 family member that inhibits T cell activation.Proc Natl Acad Sci USA. 2003; 100: 10388-10392Crossref PubMed Scopus (292) Google Scholar and we propose that B7-H4 might play a stimulatory role in TEC-mediated immune activation and immunopathology within kidneys. The existence of two different receptors with opposing signaling outcomes has been documented for all B7 super family members until now. B7.1 and B7.2 bind to CTLA-4 on activated T cells to mediate a negative signal and to CD28 on resting cells to provide a co-stimulatory signal.23.Greenwald R.J. Freeman G.J. Sharpe A.H. The B7 family revisited.Annu Rev Immunol. 2005; 23: 515-548Crossref PubMed Scopus (1804) Google Scholar Overwhelming evidence suggests that B7-H1 (PD-L1) and B7-DC (PD-L2), two members of the B7 family which are normally expressed by macrophage lineage cells and are also abundant in a variety of cancers,28.Khoury S.J. Sayegh M.H. The roles of the new negative T cell costimulatory pathways in regulating autoimmunity.Immunity. 2004; 20: 529-538Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar are negative regulators of T-cell responses through engagement with PD-1.29.Rodig N. Ryan T. Allen J.A. et al.Endothelial expression of PD-L1 and PD-L2 down-regulates CD8+ T cell activation and cytolysis.Eur J Immunol. 2003; 33: 3117-3126Crossref PubMed Scopus (324) Google Scholar, 30.Carter L. Fouser L.A. Jussif J. et al.PD-1:PD-L inhibitory pathway affects both CD4(+) and CD8(+) T cells and is overcome by IL-2.Eur J Immunol. 2002; 32: 634-643Crossref PubMed Scopus (526) Google Scholar, 31.Keir M.E. Liang S.C. Guleria I. et al.Tissue expression of PD-L1 mediates peripheral T cell tolerance.J Exp Med. 2006; 203: 883-895Crossref PubMed Scopus (812) Google Scholar, 32.Saunders P.A. Hendrycks V.R. Lidinsky W.A. et al.PD-L2:PD-1 involvement in T cell proliferation, cytokine production, and integrin-mediated adhesion.Eur J Immunol. 2005; 35: 3561-3569Crossref PubMed Scopus (85) Google Scholar Nevertheless, several studies indicate that B7-H1 and B7-DC can stimulate T-cell activation through engagement with as yet unidentified receptors.33.Chen L. Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity.Nat Rev Immunol. 2004; 4: 336-347Crossref PubMed Scopus (972) Google Scholar Moreover, TEC-associated B7RP-1 provides an inhibitory signal to downregulate T-cell activation,6.Wahl P. Schoop R. Bilic G. et al.Renal tubular epithelial expression of the costimulatory molecule B7RP-1 (inducible costimulator ligand).J Am Soc Nephrol. 2002; 13: 1517-1526Crossref PubMed Scopus (75) Google Scholar although robust evidence indicates that B7RP-1 is a co-stimulator.34.Yoshinaga S.K. Whoriskey J.S. Khare S.D. et al.T-cell co-stimulation through B7RP-1 and ICOS.Nature. 1999; 402: 827-832Crossref PubMed Scopus (657) Google Scholar,35.Coyle A.J. Gutierrez-Ramos J.C. The expanding B7 superfamily: increasing complexity in costimulatory signals regulating T cell function.Nat Immunol. 2001; 2: 203-209Crossref PubMed Scopus (358) Google Scholar Interestingly, double functions for B7-H3 in T-cell activation have also been reported.33.Chen L. Co-inhibito" @default.
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