Sensitivity of CD4+ effector memory T cells to Fas-induced apoptosis is due to increased localization of Fas to lipid raft microdomains (104.9)

Abstract

Abstract Fas-FasL interactions play a critical role in TCR-induced apoptosis of activated CD4+ T cells. Fas deficiency prompts accumulation of CD44+ memory T cells and autoimmunity in mice, suggesting Fas plays a role in memory and/or autoreactive T cell apoptosis. We have recently shown that CD4+ effector memory cells were sensitive to Fas-induced cell death, and also a correlation between lipid raft-associated Fas and sensitivity to apoptosis. A critical cysteine residue near the transmembrane helix of Fas has been shown to be responsible for its association with lipid rafts. Whether the lipid raft association of Fas is regulated in different primary cell types is not known. We have compared the post-translational modification state and membrane localization of Fas receptor in purified naïve versus memory human CD4+ T cells. Memory T cells have increased lipid raft-associated Fas receptor versus naïve cells, which could explain the increased Fas sensitivity in the memory pool. Using a competitive inhibitor to palmitoylation, we found the sensitivity of effector memory T cells to Fas-induced apoptosis depended on Fas palmitoylation. Utilizing click chemistry to analyze the palmitoylation state of Fas showed increased receptor palmitoylation in cells sensitive to Fas-mediated apoptosis compared to resistant cells. These results suggest post-translational palmitoylation and lipid raft localization of Fas as a regulatory mechanism in Fas-induced apoptosis in memory T cells.