For CD4+ T lymphocyte activation to occur, two distinct signals must be delivered by antigen presenting cells to resting T lymphocytes (Schwartz, R. H. (1990) Science 248:1349-1356; Williams, I. R. and Unanue, E. R. (1991) J. Immunol. 147:3752-3760; Mueller, D. L. et al., (1989) J. Immunol. 142:2617-2628). The first, or primary, activation signal is mediated physiologically by the interaction of the T cell receptor/CD3 complex (TcR/CD3) with MHC class II-associated antigenic peptide and gives specificity to the immune response. The second signal, the costimulatory signal, regulates the T cell proliferative response and induction of effector functions. Costimulatory signals appear pivotal in determining the functional outcome of T cell activation since delivery of an antigen-specific signal to a T cell in the absence of a costimulatory signal results in functional inactivation of mature T cells, leading to a state of tolerance (Schwartz, R. H. (1990) Science 248:1349-1356).
Molecules present on the surface of antigen presenting cells which are involved in T cell costimulation have been identified. These T cell costimulatory molecules include murine B7-1 (mB7-1; Freeman, G. J. et al., (1991) J. Exp. Med. 174:625-631), and the more recently identified murine B7-2 (mB7-2; Freeman, G. J. et al., (1993) J. Exp. Med. 178:2185-2192). Human counterparts to the murine B7-1 and B7-2 molecules have also been described (human B7-1 (hB7-1) Freedman, A. S. et al., (1987) J. Immunol. 137:3260-3267; Freeman, G. J. et al., (1989) J. Immunol. 143:2714-2722; and human B7-2 (hB7-2); Freeman, G. J. et al., (1993) Science 262:909-911; Azuma, M. et al. (1993) Nature 366:76-79). The B7-1 and B7-2 genes are members of the immunoglobulin gene superfamily.
B7-1 and B7-2 display a restricted pattern of cellular expression, which correlates with accessory cell potency in providing costimulation (Reiser, H. et al. (1992; Proc. Natl. Acad. Sci. USA 89:271-275; Razi-Wolf Z. et al., (1992) Proc. Natl. Acad. Sci. USA 89:4210-4214; Galvin, F. et al. (1992) J. Immunol. 149:3802-3808; Freeman, G. J. et al., (1993) J. Exp. Med. 178:2185-2192). For example, B7-1 has been observed to be expressed on activated B cells, T cells and monocytes but not on resting B cells, T cells or monocytes, and its expression can be regulated by different extracellular stimuli (Linsley, P. S. et al., (1990) Proc. Natl. Acad. Sci. USA 87:5031-5035; Linsley, P. S. et al., (1991) J. Exp. Med. 174:561-569; Reiser, H. et al. (1992); Proc. Natl. Acad. Sci. USA 89:271-275; Gimmi, C. D. et al. (1991) Proc. Natl. Acad. Sci. USA 88:6575-6579; Koulova, L. et al. (1991) J. Exp. Med. 173:759-762; Azuma, M. et al. (1993) J. Exp. Med. 177:845-850; Sansom, D. M. et al. (1993) Eur. J. Immunol. 23:295-298)
Both B7-1 and B7-2 are counter-receptors for two ligands, CD28 and CTLA4, expressed on T lymphocytes (Linsley, P. S. et al., (1990) Proc. Natl. Acad. Sci. USA 87:5031-5035; Linsley, P. S. et al., (1991) J. Exp. Med. 174:561-569). CD28 is constitutively expressed on T cells and, after ligation by a costimulatory molecule, induces IL-2 secretion and T cell proliferation (June, C. H. et al. (1990) Immunol. Today 11:211-216). CTLA4 is homologous to CD28 and appears on T cells after activation (Freeman, G. J. et al. (1992) J. Immunol. 149:3795-3801). Although CTLA4 has a significantly higher affinity for B7-1 than does CD28, its role in T cell activation remains to be determined. It has been shown that antigen presentation to T cells in the absence of the B7-1/CD28 costimulatory signal results in T cell anergy (Gimmi, C. D. et al. (1993) Proc. Natl. Acad. Sci. USA 90:6586-6590; Boussiotis, V. A. et al. (1993) J. Exp. Med. 178:1753). The ability of T cell costimulatory molecules such as B7-1 and B7-2 to bind to CD28 and/or CTLA4 on T cells and trigger a costimulatory signal in the T cells provides a functional role for these molecules in T cell activation.
USPTO Backgrounds
USPTO Backgrounds