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. The meachanism of signal transduction mediating T cell activation and costimulation has been studied. TCR mediated activation of T cells to proliferation and IL2 secretion was enhanced in mice deficient in cbl-b, suggesting a negative regulatory role for cbl-b under these conditions. Cbl-b deletion in fact reversed the inability of CD28-deficient mice to generate T cell-dependent Ig class switched primary and secondary antibody responses. Surprisingly, however, cbl-b deletion did not reverse the functional defect of B7 (CD80/CD86) deficient mice, indicating an unexpected difference bewtween the requirement for CD28 and for CD28 ligand B7 molecules. The mechanism underlying this difference is under study. Additional studies have been initiated to study the molecular pathways of T cell activation and costimulatory signaling. The relationship between members of the cbl family and another critical adapter molecule, SLP-76, are being studied using additional strategies of genetically manipulated expresssion. Preliminary experiments have indicated that altered expression of cbl members reverses some, but not other, of the defects caused by SLP-76 deficiency. 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.
