Fas induced apoptosis and Restimulation Induced Cell Death (RICD) is restricted to human effector memory CD4+ T subsets (46.8)

Abstract

Abstract FasL, a member of the TNF super family and its receptor Fas, are critical for peripheral tolerance of T cells via a mechanism of TCR-induced apoptosis of activated cells, termed RICD. Studies of RICD have shown that human CD4+T cells require TCR crosslinking to maximally undergo apoptosis when stimulated with Fas. However, the relative sensitivity of different CD4+ T cells subsets to Fas stimulation have not been addressed. We found that essentially all cells sensitive to Fas stimulation derive from human memory CD4+ T cells and within the memory T cell pool, 'effector' cells lacking CCR7 and CD27 were consistently the most sensitive to Fas-induced apoptosis. Fas resistant 'central memory' as well as Fas-sensitive 'effector' cells had similar levels of Fas, induced FasL as well as pro-survival Bcl2/BCLxL levels. Biochemical studies indicate a highly efficient formation of the death-inducing signaling complex (DISC) in memory and effector T cells, which correlates with their apoptotic response. Finally, in ALPS patients with Fas mutations, resistance to Fas apoptosis was found predominantly in the effector memory subsets. These results suggest for the first time that within a heterogeneous population of CD4+ T cells, effector memory T cells are specifically programmed for sensitivity to Fas-induced apoptosis compared with activated naïve T cells.