Abstract
It has become well accepted that T cells require two signals for optimal activation (1–3). The first is generated by interactions of peptide-bearing major histocompatibility complex (MHC) molecules with the T-cell receptor (TCR). A second antigen-independent signal is generated through interactions of CD28 with members of the B7 family: B7-1 (CD80) and B7-2 (CD86). Antibodies to CD28 or B7 transfectants are both able to supply this second signal in vitro. Co-stimulation has also been demonstrated for T-cell activation in vivo. CTLA-4Ig, a fusion protein that binds B7 with high affinity, is efficient at inhibiting CD28-B7 blocking and blocking co-stimulation. For example, transfection of B7 into tumor cells augments T-cell- derived immune responses against the tumor, and CTLA-4Ig can block this effect. Recently, it has been demonstrated that members of the B7 family also bind to CTLA-4, a close relative of CD28. The function of this protein and the role of ligand interaction in T-cell activation remains obscure. We have shown that the consequences of CTLA-4 engagement is the delivery of a negative signal for T-cell response. Thus, the binary view of co-stimulation via B7 should be expanded to include a third signal generated by CTLA-4 signaling.
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References
June CH, Bluestone JA, Nadler LM, Thompson CB. The B7 and CD28 receptor families. Immunol Today 1994;15:321–31
Jenkins MK. The ups and downs of costimulation. Immunity 1994;1:443–6
Linsley PS, Ledbetter JA. The role of the CD28 receptor during T cell responses to antigen. Annu Rev Immunol 1993;11:191–212
Harding F, McArthur JG, Gross JA, Raulet DH, Allison JP. CD28 mediated signalling costimulates murine T cells and prevents the induction of anergy in T cell clones. Nature 1992;356:607–9
Holsti MA, McArthur J, Allison JP, Raulet DH. Role of IL-6, IL-1, and CD28 signaling in responses of mouse CD4+ T cells to immobilized anti-TCR monoclonal antibody. J Immunol 1994;152:1618–28
Linsley PS, Brady W, Grosmaire L, Aruffo A, Damle NK, Ledbetter JA. Binding of the B cell activation antigen B7 to CD28 costimulates T cell prolif¬eration and interleukin 2 mRNA accumulation. J Exp Med 1991;173:721–30
Gimmi CD, Freeman GJ, Gribben JG, et al. B-cell surface antigen B7 provides a costimulatory signal that induces T cells to proliferate and secret interleukin 2. Proc Natl Acad Sei USA 1991;88:6575–9
Reiser H, Freeman GJ, Razi-Wolf Z, Gimmi CD, Benacerraf B, Nadler LM. Murine B7 antigen provides an efficient costimulatory signal for activation of murine T lymphocytes via the T-cell receptor/CD3 complex. Proc Natl Acad Sei USA 1992;89:271–5
Murphy EE, Terres G, Macatonia SE, et al. B7 and interleukin-12 cooperate for proliferation and interferon y production by mouse T helper clones that are unresponsive to B7 costimulation. J Exp Med 1994;180:223–31
Harper K, Balzano C, Rouvier E, Mattei MG, Luciani MF, Golstein P. CTLA- 4 and CD28 activated lymphocyte molecules are closely related in both mouse and human as to sequence, message expression, gene structure, and chromo¬somal location. J Immunol 1991;147:1037–44
Lindsten T, Lee KP, Harris ES, et al. Characterization of CTLA-4 structure and expression on human T cells. J Immunol 1993;151:3489–99
Linsley PS, Brady W, Urnes M, Grosmaire LS, Damle NK, Ledbetter JA. CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med 1991;174:561–9
Linsley PS, Wallace PM, Johnson J, et al. Immunosuppression in vivo by a soluble form of the CTLA-4 T cell activation molecule. Science 1992;257:792–5
Lenschow DJ, Zeng Y, Thistlewaite JR, et al. Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA4Ig. Science 1992;257:789–92
Allison JP. CD28-B7 interactions in T-cell activation. Curr Opin Immunol 1994;6:414–9
Harding FA, Allison JP. CD28/B7 interactions allow the induction of CD8+ CTLs in the absence of exogenous help. J Exp Med 1993;177:1791–6
Linsley PS, Greene JL, Tan P, et al. Coexpression and functional cooperativity of CTLA-4 and CD28 on activated T lymphocytes. J Exp Med 1992;176:1595–1604
Walunas TL, Lenschow DJ, Bakker CY, et al. CTLA-4 can function as a negative regulator of T cell activation. Immunity 1994;1:405–13
Hathcock KS, Laszlo G, Pucillo C, Linsley P, Hodes RJ. Comparative analysis of B7-1 and B7-2 costimulatory ligands: expression and function. J Exp Med 1994;180:631–40
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Krummel, M., Allison, J.P. (1996). B7-Mediated Co-Stimulation of T Cells: CTLA-4 Can Deliver Inhibitory Signals. In: Abbas, A.K., Flavell, R.A. (eds) Genetic Models of Immune and Inflammatory Diseases. Serono Symposia USA. Springer, New York, NY. https://doi.org/10.1007/978-1-4612-2376-4_14
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DOI: https://doi.org/10.1007/978-1-4612-2376-4_14
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