TCR and Fas-mediated apoptosis targets Effector Memory T cells (85.14)

Abstract

Abstract The death receptor Fas plays an essential role in TCR-induced apoptosis of activated CD4+ T cells, in a process termed restimulation-induced cell death (RICD). However, within a heterogeneous population of human CD4+ T cells, we have found that cells with an effector memory phenotype (CCR7-CD27-) are specifically programmed for sensitivity to Fas-induced apoptosis and RICD. Similary, mouse effector memory T cells (CD44hiCD62Llo) are the most sensitive to cells are very sensitive to RICD and direct killing by Fas receptor ligation. Fas resistant ‘central memory’ as well as Fas-sensitive ‘effector’ cells had similar levels of induced FasL, surface Fas, as well as pro-survival Bcl2/BCLxL levels. In ALPS patients with Fas mutations, resistance to Fas apoptosis was found predominantly in the effector memory subsets. Biochemical studies show a preponderance of lipid raft localized Fas and highly efficient formation of the death-inducing signaling complex (DISC) in memory and effector T cells. Thus sensitivity to TCR and Fas-mediated apoptoisis is mediated at the level of early signaling events in the Fas pathway. These observations may explain the specificity of the Fas/FasL system in T cell homeostasis toward chronically expressed and endogenous antigens to check autoreactivity and responses to chronic infections.