Localization of Fas/CD95 to lipid raft microdomains sensitizes human CD4+ effector memory T cells to Fas-induced apoptosis (85.13)

Abstract

Abstract Fas-FasL interactions play a critical role in TCR-induced apoptosis of activated CD4+ T cells. However, naïve T cells activated through acute antigen stimulation expand and contract independently of the presence of the death receptor Fas. Fas deficiency prompts the accumulation of CD44+ memory phenotype T cells and autoimmunity in mice, suggesting Fas may play a critical role in memory and/or autoreactive T cell apoptosis. We have previously shown a correlation between lipid raft-associated Fas and sensitivity to apoptosis. Whether or not lipid raft microdomains influence Fas signaling in primary T cells, and whether lipid raft association of Fas is regulated in different primary cell types is unknown. Therefore, we have compared the sensitivity of purified naïve versus memory human CD4+ T cells to undergo Fas-mediated apoptosis. Effector memory phenotype cells lacking both the chemokine receptor CCR7 and the TNFSFR CD27 were the most sensitive to both anti-Fas antibody as well as FasL-induced cell death. 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 sensitivity of effector memory T cells to Fas-induced apoptosis depended on Fas palmitoylation. These results suggest that effector memory cells are intrinsically more sensitive to Fas-induced apoptosis, possibly due to lipid raft localization of Fas.