CD4 regulation of activation‐induced cell death

Abstract

Defects in FAS‐mediated activation induced cell death (AICD) are associated with the development of autoimmunity in both mouse models and human disease. We have previously found that mature T cells with a mutant CD4 co‐receptor unable to associate with Lck are resistant to AICD. Since activated CD4 mutant T cells express similar levels of FasL, Fas, and FADD compared to wild‐type cells, we hypothesize that the CD4‐dependent signaling pathways provide a “competency” signal required by T cells to become susceptible to AICD. In support of this hypothesis, mixing experiments indicate that FasL expression by wild type CD4 T cell blasts could not rescue the defect in AICD seen in CD4 mutant T cells. Additionally, we find that the AICD resistant phenotype in CD4 mutant T cells is primarily observed following peptide restimulation, while wild‐type and mutant CD4 T cells are similarly sensitive to AICD upon re‐stimulation with plate bound anti‐CD3. These experiments suggest that death receptor signaling pathways are compromised in mutant CD4 T cells following physiologic stimulation with peptide that involves CD4 signaling. Since CD4 association with Lck alters the compartmentalization of cellular Lck pools, these data suggest that that distinct pools of Lck may be differentially involved in modulating sensitivity to Fas signaling.Supported in part by a grant from the American Cancer Society.