• 1
    Brunet, J. F., Denizot, F., Luciani, M. F., Roux-Dosseto, M., Suzan, M., Mattei, M. G. and Golstein, P., A new member of the immunoglobulin superfamily: CTLA-4. Nature 1987. 328: 267270.
  • 2
    Lenschow, D. J., Zeng, Y., Thistlethwaite, J. R., Montag, A., Brady, W., Gibson, M. G., Linsley, P. S. et al., Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA4lg. Science 1992. 257: 789792.
  • 3
    Linsley, P. S., Wallace, P. M., Johnson, J., Gibson, M. G., Greene, J. L., Ledbetter, J. A., Singh, C. et al., Immunosuppression in vivo by a soluble form of the CTLA-4 T cell activation molecule. Science 1992. 257: 792795.
  • 4
    Krummel, M. F. and Allison, J. P., CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J. Exp. Med. 1995. 182: 459465.
  • 5
    Tivol, E. A., Borriello, F., Schweitzer, A. N., Lynch, W. P., Bluestone, J. A. and Sharpe, A. H., Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 1995. 3: 541547.
  • 6
    Waterhouse, P., Penninger, J. M., Timms, E., Wakeham, A., Shahinian, A., Lee, K. P., Thompson, C. B. et al., Lymphoproliferative disorders with early lethality in mice deficient in CTLA-4. Science 1995. 270: 985988.
  • 7
    Alegre, M. L., Frauwirth, K. A. and Thompson, C. B., T-cell regulation by CD28 and CTLA-4. Nat. Rev. Immunol. 2001. 1: 220228.
  • 8
    Bour-Jordan, H. and Blueston, J. A., CD28 function: a balance of costimulatory and regulatory signals. J. Clin. Immunol. 2002. 22: 17.
  • 9
    Bachmann, M. F., Kohler, G., Ecabert, B., Mak, T. W. and Kopf, M., Cutting edge: lymphoproliferative disease in the absence of CTLA-4 is not T cell autonomous. J. Immunol. 1999. 163: 11281131.
  • 10
    Tivol, E. A. and 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. 2002. 169: 18521858.
  • 11
    Takahashi, T., Tagami, T., Yamazaki, S., Uede, T., Shimizu, J., Sakaguchi, N., Mak, T. W. et al., Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J. Exp. Med. 2000. 192: 303310.
  • 12
    Read, S., Malmstrom, V. and Powrie, F., Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J. Exp. Med. 2000. 192: 295302.
  • 13
    Manzotti, C. N., Tipping, H., Perry, L. C., Mead, K. I., Blair, P. J., Zheng, Y. and Sansom, D. M., Inhibition of human T cell proliferation by CTLA-4 utilizes CD80 and requires CD25+ regulatory T cells. Eur. J. Immunol. 2002. 32: 28882896. 2-F.
  • 14
    Wing, K., Onishi, Y., Prieto-Martin, P., Yamaguchi, T., Miyara, M., Fehervari, Z., Nomura, T. et al., CTLA-4 control over Foxp3+ regulatory T cell function. Science 2008. 322: 271275.
  • 15
    Zheng, Y., Manzotti, C. N., Burke, F., Dussably, L., Qureshi, O., Walker, L. S. and Sansom, D. M., Acquisition of suppressive function by activated human CD4 +CD25- T cells is associated with the expression of CTLA-4 not FoxP3. J. Immunol. 2008. 181: 16831691.
  • 16
    Peggs, K. S., Quezada, S. A., Chambers, C. A., Korman, A. J. and Allison, J. P., Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J. Exp. Med. 2009. 206: 17171725.
  • 17
    Grohmann, U., Orabona, C., Fallarino, F., Vacca, C., Calcinaro, F., Falorni, A., Candeloro, P. et al., CTLA-4-ig regulates tryptophan catabolism in vivo. Nat. Immunol. 2002. 3: 10971101.
  • 18
    Dejean, A. S., Beisner, D. R., Ch'en, I. L., Kerdiles, Y. M., Babour, A., Arden, K. C., Castrillon, D. H. et al., Transcription factor Foxo3 controls the magnitude of T cell immune responses by modulating the function of dendritic cells. Nat. Immunol. 2009. 10: 504513.
  • 19
    Qureshi, O. S., Zheng, Y., Nakamura, K., Attridge, K., Manzotti, C., Schmidt, E. M., Baker, J. et al., Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science 2011. 332: 600603.
  • 20
    Magistrelli, G., Jeannin, P., Herbault, N., Benoit De Coignac, A., Gauchat, J. F., Bonnefoy, J. Y. and Delneste, Y., A soluble form of CTLA-4 generated by alternative splicing is expressed by nonstimulated human T cells. Eur. J. Immunol. 1999. 29: 35963602.
  • 21
    Oaks, M. K., Hallett, K. M., Penwell, R. T., Stauber, E. C., Warren, S. J. and Tector, A. J., A native soluble form of CTLA-4. Cell. Immunol. 2000. 201: 144153.
  • 22
    Oaks, M. K. and Hallett, K. M., Cutting edge: a soluble form of CTLA-4 in patients with autoimmune thyroid disease. J. Immunol. 2000. 164: 50155018.
  • 23
    Ueda, H., Howson, J. M., Esposito, L., Heward, J., Snook, H., Chamberlain, G., Rainbow, D. B. et al., Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 2003. 423: 506511.
  • 24
    Pearce, S. H. and Merriman, T. R., Genetic progress towards the molecular basis of autoimmunity. Trends Mol. Med. 2006. 12: 9098.
  • 25
    Seddiki, N., Santner-Nanan, B., Martinson, J., Zaunders, J., Sasson, S., Landay, A., Solomon, M. et al., Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J. Exp. Med. 2006. 203: 16931700.
  • 26
    Liu, W., Putnam, A. L., Xu-Yu, Z., Szot, G. L., Lee, M. R., Zhu, S., Gottlieb, P. A. et al., CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J. Exp. Med. 2006. 203: 17011711.
  • 27
    Peters, J. H., Preijers, F. W., Woestenenk, R., Hilbrands, L. B., Koenen, H. J. and Joosten, I., Clinical grade Treg: GMP isolation, improvement of purity by CD127 depletion, Treg expansion, and Treg cryopreservation. PLoS One 2008. 3: e3161.
  • 28
    Codarri, L., Vallotton, L., Ciuffreda, D., Venetz, J. P., Garcia, M., Hadaya, K., Buhler, L. et al., Expansion and tissue infiltration of an allospecific CD4+CD25+CD45RO+IL-7Ralphahigh cell population in solid organ transplant recipients. J. Exp. Med. 2007. 204: 15331541.
  • 29
    Finney, O. C., Riley, E. M. and Walther, M., Phenotypic analysis of human peripheral blood regulatory T cells (CD4+FOXP3+CD127lo/-) ex vivo and after in vitro restimulation with malaria antigens. Eur. J. Immunol. 2010. 40: 4760.
  • 30
    van Elsas, A., Hurwitz, A. A. and Allison, J. P., Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation. J. Exp. Med. 1999. 190: 355366.
  • 31
    Chambers, C. A., Kuhns, M. S., Egen, J. G. and Allison, J. P., CTLA-4-mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy. Annu. Rev. Immunol. 2001. 19: 565594.
  • 32
    van Elsas, A., Sutmuller, R. P., Hurwitz, A. A., Ziskin, J., Villasenor, J., Medema, J. P., Overwijk, W. W. et al., Elucidating the autoimmune and antitumor effector mechanisms of a treatment based on cytotoxic T lymphocyte antigen-4 blockade in combination with a B16 melanoma vaccine: comparison of prophylaxis and therapy. J. Exp. Med. 2001. 194: 481489.
  • 33
    Pruitt, S. K., Boczkowski, D., de Rosa, N., Haley, N. R., Morse, M. A., Tyler, D. S., Dannull, J. and Nair, S., Enhancement of anti-tumor immunity through local modulation of CTLA-4 and GITR by dendritic cells. Eur. J. Immunol. 2011. 41: 35533563.
  • 34
    Hodi, F. S., O'Day, S. J., McDermott, D. F., Weber, R. W., Sosman, J. A., Haanen, J. B., Gonzalez, R. et al., Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 2010. 363: 711723.
  • 35
    Walker, L. S. and Sansom, D. M., The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses. Nat. Rev. Immunol. 2011. 11: 852863.
  • 36
    Wing, K., Yamaguchi, T. and Sakaguchi, S., Cell-autonomous and -non-autonomous roles of CTLA-4 in immune regulation. Trends Immunol. 2011. 32: 428433.
  • 37
    Takahashi, T., Kuniyasu, Y., Toda, M., Sakaguchi, N., Itoh, M., Iwata, M., Shimizu, J. and Sakaguchi, S., Immunologic self-tolerance maintained by CD25+CD4 +naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state. Int. Immunol. 1998. 10: 19691980.
  • 38
    Thornton, A. M. and Shevach, E. M., CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J. Exp. Med. 1998. 188: 287296.
  • 39
    Krummel, M. F. and Allison, J. P., CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T cells. J. Exp. Med. 1996. 183: 25332540.
  • 40
    Walunas, T. L., Bakker, C. Y. and Bluestone, J. A., CTLA-4 ligation blocks CD28-dependent T cell activation. J. Exp. Med. 1996. 183: 25412550.
  • 41
    Blair, P. J., Riley, J. L., Levine, B. L., Lee, K. P., Craighead, N., Francomano, T., Perfetto, S. J. et al., CTLA-4 ligation delivers a unique signal to resting human CD4 T cells that inhibits interleukin-2 secretion but allows bcl-X(L) induction. J. Immunol. 1998. 160: 1215.
  • 42
    Brunner, M. C., Chambers, C. A., Chan, F. K., Hanke, J., Winoto, A. and Allison, J. P., CTLA-4-mediated inhibition of early events of T cell proliferation. J. Immunol. 1999. 162: 58135820.
  • 43
    Griffin, M. D., Hong, D. K., Holman, P. O., Lee, K. M., Whitters, M. J., O'Herrin, S. M., Fallarino, F. et al., Blockade of T cell activation using a surface-linked single-chain antibody to CTLA-4 (CD152). J. Immunol. 2000. 164: 44334442.
  • 44
    Fife, B. T., Griffin, M. D., Abbas, A. K., Locksley, R. M. and Bluestone, J. A., Inhibition of T cell activation and autoimmune diabetes using a B cell surface-linked CTLA-4 agonist. J. Clin. Invest. 2006. 116: 22522261.
  • 45
    Karman, J., Jiang, J. L., Gumlaw, N., Zhao, H., Campos-Rivera, J., Sancho, J., Zhang, J. et al., Ligation of cytotoxic T lymphocyte antigen-4 to the TCR inhibits T cell activation and directs differentiation into FOXP3+ regulatory T cells. J. Biol. Chem. 2012. 287: 1109811107.
  • 46
    Tivol, E. A., Boyd, S. D., McKeon, S., Borriello, F., Nickerson, P., Strom, T. B. and Sharpe, A. H., CTLA4Ig prevents lymphoproliferation and fatal multiorgan tissue destruction in CTLA-4-deficient mice. J. Immunol. 1997. 158: 50915094.
  • 47
    Shevach, E. M., Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity 2009. 30: 636645.
  • 48
    Laurent, S., Carrega, P., Saverino, D., Piccioli, P., Camoriano, M., Morabito, A., Dozin, B. et al., CTLA-4 is expressed by human monocyte-derived dendritic cells and regulates their functions. Hum. Immunol. 2010. 71: 934941.
  • 49
    Gerold, K. D., Zheng, P., Rainbow, D. B., Zernecke, A., Wicker, L. S. and Kissler, S., The soluble CTLA-4 splice variant protects from type 1 diabetes and potentiates regulatory T-cell function. Diabetes 2011. 60: 19551963.
  • 50
    Hall, A. M., Ward, F. J., Vickers, M. A., Stott, L. M., Urbaniak, S. J. and Barker, R. N., Interleukin-10-mediated regulatory T-cell responses to epitopes on a human red blood cell autoantigen. Blood 2002. 100: 45294536.
  • 51
    Barker, R. N., Hall, A. M., Standen, G. R., Jones, J. and Elson, C. J., Identification of T-cell epitopes on the rhesus polypeptides in autoimmune hemolytic anemia. Blood 1997. 90: 27012715.