Abstract
During activation, T cells express receptors for receiving positive and negative costimulatory signals. Here we identify the B and T lymphocyte attenuator (BTLA), an immunoglobulin domain–containing glycoprotein with two immunoreceptor tyrosine-based inhibitory motifs. BTLA is not expressed by naive T cells, but it is induced during activation and remains expressed on T helper type 1 (TH1) but not TH2 cells. Crosslinking BTLA with antigen receptors induces its tyrosine phosphorylation and association with the Src homology domain 2 (SH2)-containing protein tyrosine phosphatases SHP-1 and SHP-2, and attenuates production of interleukin 2 (IL-2). BTLA-deficient T cells show increased proliferation, and BTLA-deficient mice have increased specific antibody responses and enhanced sensitivity to experimental autoimmune encephalomyelitis. B7x, a peripheral homolog of B7, is a ligand of BTLA. Thus, BTLA is a third inhibitory receptor on T lymphocytes with similarities to cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) and programmed death 1 (PD-1).
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References
Coyle, A.J. & Gutierrez-Ramos, J.C. The expanding B7 superfamily: increasing complexity in costimulatory signals regulating T cell function. Nat. Immunol. 2, 203–209 (2001).
Hutloff, A. et al. ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature 397, 263–266 (1999).
Swallow, M.M., Wallin, J.J. & Sha, W.C. B7h, a novel costimulatory homolog of B7.1 and B7.2, is induced by TNFα. Immunity 11, 423–432 (1999).
Yoshinaga, S.K. et al. T-cell co-stimulation through B7RP-1 and ICOS. Nature 402, 827–832 (1999).
Ling, V. et al. Cutting edge: identification of GL50, a novel B7-like protein that functionally binds to ICOS receptor. J. Immunol. 164, 1653–1657 (2000).
Wang, S. et al. Costimulation of T cells by B7-H2, a B7-like molecule that binds ICOS. Blood 96, 2808–2813 (2000).
Brodie, D. et al. LICOS, a primordial costimulatory ligand? Curr. Biol. 10, 333–336 (2000).
Liang, L. & Sha, W.C. The right place at the right time: novel B7 family members regulate effector T cell responses. Curr. Opin. Immunol. 14, 384–390 (2002).
Liang, L., Porter, E.M. & Sha, W.C. Constitutive expression of the B7h ligand for inducible costimulator on naive B cells is extinguished after activation by distinct B cell receptor and interleukin 4 receptor–mediated pathways and can be rescued by CD40 signaling. J. Exp. Med. 196, 97–108 (2002).
Ishida, Y. et al. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 11, 3887–3895 (1992).
Nishimura, H. et al. Immunological studies on PD-1 deficient mice: implication of PD-1 as a negative regulator for B cell responses. Int. Immunol. 10, 1563–1572 (1998).
Freeman, G.J. et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med. 192, 1027–1034 (2000).
Dong, H. et al. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat. Med. 5, 1365–1369 (1999).
Latchman, Y. et al. PD-L2 is a second ligand for PD-I and inhibits T cell activation. Nat. Immunol. 2, 261–268 (2001).
Tseng, S.Y. et al. B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells. J. Exp. Med. 193, 839–846 (2001).
Chapoval, A.I. et al. B7-H3: a costimulatory molecule for T cell activation and IFN-γ production. Nat. Immunol. 2, 269–274 (2001).
Sun, M. et al. Characterization of mouse and human B7-H3 genes. J. Immunol. 168, 6294–6297 (2002).
Yang, J. et al. IL-18-stimulated GADD45β required in cytokine-induced, but not TCR-induced, IFN-γ production. Nat. Immunol. 2, 157–164 (2001).
Tomasello, E. et al. Signaling pathways engaged by NK cell receptors: double concerto for activating receptors, inhibitory receptors and NK cells. Semin. Immunol. 12, 139–147 (2000).
Bolland, S. & Ravetch, J.V. Inhibitory pathways triggered by ITIM-containing receptors. Adv. Immunol. 72, 149–177 (1999).
Shiratori, T. et al. Tyrosine phosphorylation controls internalization of CTLA-4 by regulating its interaction with clathrin-associated adaptor complex AP-2. Immunity 6, 583–589 (1997).
Zhang, Y. & Allison, J.P. Interaction of CTLA-4 with AP50, a clathrin-coated pit adaptor protein. Proc. Natl. Acad. Sci. USA 94, 9273–9278 (1997).
Songyang, Z. et al. Specific motifs recognized by the SH2 domains of Csk, 3BP2, fps/fes, GRB-2, HCP, SHC, Syk, and Vav. Mol. Cell. Biol. 14, 2777–2785 (1994).
Nishimura, H. et al. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11, 141–151 (1999).
Shlapatska, L.M. et al. CD150 association with either the SH2-containing inositol phosphatase or the SH2-containing protein tyrosine phosphatase is regulated by the adaptor protein SH2D1A. J. Immunol. 166, 5480–5487 (2001).
Haskins, K. et al. The major histocompatibility complex–restricted antigen receptor on T cells. I. Isolation with a monoclonal antibody. J. Exp. Med. 157, 1149–1169 (1983).
Okazaki, T. et al. PD-1 immunoreceptor inhibits B cell receptor–mediated signaling by recruiting Src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. Proc. Natl. Acad. Sci. USA 98, 13866–13871 (2001).
Chambers, C.A. et al. Secondary but not primary T cell responses are enhanced in CTLA-4-deficient CD8+ T cells. Eur. J. Immunol. 28, 3137–3143 (1998).
Oosterwegel, M.A. et al. The role of CTLA-4 in regulating Th2 differentiation. J. Immunol. 163, 2634–2639 (1999).
Greenwald, R.J. et al. CTLA-4 regulates induction of anergy in vivo. Immunity 14, 145–155 (2001).
Sabelko-Downes, K.A., Cross, A.H. & Russell, J.H. Dual role for Fas ligand in the initiation of and recovery from experimental allergic encephalomyelitis. J. Exp. Med. 189, 1195–1205 (1999).
Sharpe, A.H. & Freeman, G.J. The B7-CD28 superfamily. Nat. Rev. Immunol. 2, 116–126 (2002).
Tivol, E.A. et al. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity. 3, 541–547 (1995).
Khattri, R. et al. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat. Immunl. 4, 337–342 (2003).
Bachmann, M.F. et al. Cutting edge: lymphoproliferative disease in the absence of CTLA-4 is not T cell autonomous. J. Immunol. 163, 1128–1131 (1999).
Bachmann, M.F. et al. Normal pathogen-specific immune responses mounted by CTLA-4-deficient T cells: a paradigm reconsidered. Eur. J. Immunol. 31, 450–458 (2001).
Tivol, E.A. & Gorski, J. Re-establishing peripheral tolerance in the absence of CTLA-4: complementation by wild-type T cells points to an indirect role for CTLA-4. J. Immunol. 169, 1852–1858 (2002).
Grohmann, U. et al. CTLA-4-Ig regulates tryptophan catabolism in vivo. Nat. Immunol. 3, 1097–1101 (2002).
Finger, E.B. & Bluestone, J.A. When ligand becomes receptor—tolerance via B7 signaling on DCs. Nat. Immunol. 3, 1056–1057 (2002).
Nishimura, H. et al. Autoimmune dilated cardiomyopathy in PD-1 receptor–deficient mice. Science 291, 319–322 (2001).
Bennett, F. et al. Program death-1 engagement upon TCR activation has distinct effects on costimulation and cytokine-driven proliferation: attenuation of ICOS, IL-4, and IL-21, but not CD28, IL-7, and IL-15 responses. J. Immunol. 170, 711–718 (2003).
Carter, L. et al. PD-1:PD-L inhibitory pathway affects both CD4+ and CD8+ T cells and is overcome by IL-2. Eur. J. Immunol. 32, 634–643 (2002).
Brunner, M.C. et al. CTLA-4-mediated inhibition of early events of T cell proliferation. J. Immunol. 162, 5813–5820 (1999).
Luhder, F. et al. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) regulates the unfolding of autoimmune diabetes. J. Exp. Med. 187, 427–432 (1998).
Luhder, F. et al. Pinpointing when T cell costimulatory receptor CTLA-4 must be engaged to dampen diabetogenic T cells. Proc. Natl. Acad. Sci. USA 97, 12204–12209 (2000).
Abiru, N., Kawasaki, E. & Eguch, K. Current knowledge of Japanese type 1 diabetic syndrome. Diabetes Metab. Res. Rev. 18, 357–366 (2002).
Ueda, H. et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature; advance online publication 30 April 2003/ doi 10.1038/nature01621.
Ranganath, S. et al. GATA-3-dependent enhancer activity in IL-4 gene regulation. J. Immunol. 161, 3822–3826 (1998).
Afkarian, M. et al. T-bet is a STAT1-induced regulator of IL-12R expression in naive CD4+ T cells. Nat. Immunol. 3, 549–557 (2002).
Hsieh, C.S. et al. Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science 260, 547–549 (1993).
Sha, W.C. et al. Selective expression of an antigen receptor on CD8-bearing T lymphocytes in transgenic mice. Nature 335, 271–274 (1988).
Acknowledgements
We thank B. Sleckman for help with gene targeting; M. White for generating chimeric mice; M. Gimenez for help with immunohistochemistry; and W. Sha for discussions. This work was supported in part by grants from the National Institutes of Health. J.P.A. and K.M.M. are Investigators of the Howard Hughes Medical Institute.
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Watanabe, N., Gavrieli, M., Sedy, J. et al. BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1. Nat Immunol 4, 670–679 (2003). https://doi.org/10.1038/ni944
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DOI: https://doi.org/10.1038/ni944