Requirement for efficient interactions between CD4 and MHC class II molecules for survival of resting CD4(+) T lymphocytes in vivo and for activation-induced cell death

Regulation of homeostasis in the immune system includes mechanisms that pro mote survival of resting T lymphocytes, and others that control activation- induced cell death (AICD), In this study, we report on the use of a transge nic mouse model to test the role of CD4-MHC class II interactions for the s usceptibility of CD4(+) T lymphocytes to AICD, and for the survival of rest ing CD4(+) T cells in peripheral lymphoid organs. The only I-A(beta) gene e xpressed in these mice is an A(beta)(k) transgene with a mutation that prev ents MHC class II molecules from interacting with CD4, We show increased ap optosis in CD4(+) T lymphocytes derived from wild-type, but not from mutant A(beta)k transgenic mice following stimulation with staphylococcal enterot oxin A. Therefore, AICD may be impaired in CD4(+) T cells derived from muta nt A(beta)(k) transgenic mice. Importantly, we observed much higher apoptos is in resting CD4(+) T cells from mutant A(beta)(k) transgenic mice than fr om wild-type mice. Furthermore, resting CD4(+) T cells from mutant A(beta)( k) transgenic mice expressed higher levels of cell surface CD95 (Fas, APO-1 ). Ab-mediated cross-linking of CD95 further increased apoptosis in CD4+ T cells from mutant A(beta)(k) transgenic mice, but not from wild-type mice, suggesting apoptosis involved CD95 signaling. When cocultured with APC-expr essing wild-type MHC class II molecules; apoptosis in resting CD4(+) T lymp hocytes from mutant A(beta)(k) transgenic mice was reduced. Our results sho w for the first time that interactions between CD4 and MHC class II molecul es are required for the survival of resting CD4(+) T cells in peripheral ly mphoid organs.