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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 Death¹

Department of Microbiology and Immunology and Sealy Center for Molecular Science, University of Texas Medical Branch, Galveston, TX 77555

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 II 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_ß gene expressed in these mice is an A_ß^k transgene with a mutation that prevents MHC class II molecules from interacting with CD4. We show increased apoptosis in CD4⁺ T lymphocytes derived from wild-type, but not from mutant A_ß^k transgenic mice following stimulation with staphylococcal enterotoxin A. Therefore, AICD may be impaired in CD4⁺ T cells derived from mutant A_ß^k transgenic mice. Importantly, we observed much higher apoptosis in resting CD4⁺ T cells from mutant A_ß^k transgenic mice than from wild-type mice. Furthermore, resting CD4⁺ T cells from mutant A_ß^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_ß^k transgenic mice, but not from wild-type mice, suggesting apoptosis involved CD95 signaling. When cocultured with APC-expressing wild-type MHC class II molecules, apoptosis in resting CD4⁺ T lymphocytes from mutant A_ß^k transgenic mice was reduced. Our results show for the first time that interactions between CD4 and MHC class II molecules are required for the survival of resting CD4⁺ T cells in peripheral lymphoid organs.

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