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 promote survival of resting T lymphocytes, and others that control activation-induced cell death (AICD). In this study, we report on the use of a transgenic mouse model to test the role of CD4-MHC class H interactions for the susceptibility of CD4⁺ T lymphocytes to AICD, and for the survival of resting CD4⁺ T cells in peripheral lymphoid organs. The only I-A(β) gene expressed in these mice is an A(β)(k) transgene with a mutation that prevents MHC class H molecules from interacting with CD4. We show increased apoptosis in CD4⁺ T lymphocytes derived from wild-type, but not from mutant A(β)(k) transgenic mice following stimulation with staphylococcal enterotoxin A. Therefore, AICD may be impaired in CD4⁺ T cells derived from mutant A(β)(k) transgenic mice. Importantly, we observed much higher apoptosis in resting CD4⁺ T cells from mutant A(β)(k) transgenic mice than from wild-type mice. Furthermore, resting CD4⁺ T cells from mutant A(β)(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(β)(k) transgenic mice, but not from wild-type mice, suggesting apoptosis involved CD95 signaling. When cocultured with APC- expressing wild-type MHC class H molecules, apoptosis in resting CD4⁺ T lymphocytes from mutant A(β)(k) transgenic mice was reduced. Our results show for the first time that interactions between CD4 and MHC class H molecules are required for the survival of resting CD4⁺ T cells in peripheral lymphoid organs.