Costimulatory B7 molecules (B7-1 or CD80; and B7-2 or CD86) are known to bind to T cell costimulatory receptors CD28 and CTLA4. Engagement of CD28 is know to transduce signals in T cells that play a critical role in T cell activation; however, little is known of the ability of B7 molecules to themselves act as signal transducing molecules. The role of CD28/B7 interactions has been analyzed in host responses to antigenic tumor. EL4 tumor cells grew progressively in syngeneic B6 mice. However, transfection of EL4 with B7-1 or B7-2 costimulatory ligands resulted in tumor rejection and the induction of tumor-specific immunity. Tumor rejection under these conditions was dependent upon the presence of the B7 receptor CD28 as demonstrated using CD28-deficient B6 mice for tumor challenge. These results demonstrated for the first time the requirement for CD28 as a B7 receptor in tumor rejection. The role of B7 cytoplasmic domains in tumor rejection was tested by transfection of EL4 cells with cytoplasmic deletion mutants of B7-1 and B7-2, and it was found that tumor rejection was not influenced by the presence or absence of B7 cytoplasmic domains. These results indicate that CD28 interaction with extracellular B7-1 or B7-2 domains can mediate costimulatory function for syngeneic tumor rejection. The effect of costimulus in T cell development and repertoire selection was studied using transgenic mice that over-express B7-1(CD80) or B7-2 (CD86). Initial data indicate that expression of costimulatory B7 ligands has a substantial effect on CD4 and CD8 differentiation. Further studies are in progress to assess the mechanism of this effect. TCR mediated activation of T cells to proliferation and IL2 secretion is enhanced in mice deficient in cbl-b, suggesting a negative regulatory role for cbl-b under these conditions. Studies are in progress using cbl-b deficient mice to assess the role of cbl-b in susceptibility to apoptosis and to anergy induction, as well the effect on T cell repertoire selection. The function of B7 in T-dependent B cell activation is being analyzed using B cells from mice that are genetically engineered to be deficient in B7 expression or to express mutated or truncated B7 products. Studies in these mice and in radiation chimeras generated from these mice will determine whether expression of B7 and signal transduction through the B7 cytoplasmic tail are required for T-dependent antibody responses, Ig class switching, and generation of memory B cells.
