: TCR recognition of antigen + MHC (signal 1) and T cell costimulation (signal 2) are essential for full T cell activation, differentiation, and survival. The prototypical T cell costimulatory receptor, CD28, is a constitutively expressed type I integral transmembrane protein displayed on naive CD4+ and CD8+ T cells. Following the identification of CD28 as a costimulatory receptor, a number of inducible receptors having similar function have been identified. Several of these receptor molecules, including 4-1BB receptors, are members of the tumor necrosis factor receptor (TNFR) superfamily. During the past 5 years our laboratory has been studying the costimulatory activity of 4-1BB receptors in T cell activation. During this period, we have characterized 4-1BB mediated signaling in T cell proliferation, 4-IBB mediated inhibition of T-dependent humoral immunity, its enhancement of CTL-mediated anti-tumor immunity, CU mediated anti-viral immunity; and T cell survival against apoptosis (AICD). The current application seeks to extend our earlier studies in defining potential clinical applications of anti-4-IBB mAbs for treating post-surgical metastatic cancer and to define structure/function relationships that enable 4-1BB receptors to mediate T cell immune responses. To accomplish these objectives the following specific aims will be pursued: (1) establish the optimal conditions for generating anti-4-IBB mAb mediated protective anti-tumor immunity against minimal residual disease, (2) determine whether 4-1BB mediated inhibition of T-dependent humoral immunity is essential for its ability to induce CU mediated anti-tumor immunity, (3) define structure/function relationships in 4-1BB receptor-mediated signal transduction and T cell effector function in establishing anti-tumor immunity through the use of lentiviral reconstitution approaches to express full-length 4-1BB wild type or cytoplasmic point or deletion mutants in mice that are deficient in 4-IBB expression.
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| Foell, Juergen; Strahotin, Simona; O'Neil, Shawn P et al. (2003) CD137 costimulatory T cell receptor engagement reverses acute disease in lupus-prone NZB x NZW F1 mice. J Clin Invest 111:1505-18 |
