Human CD4+ memory T cells are pre-sensitized to Fas-mediated apoptosis due to increased receptor localization to lipid raft microdomains (35.38)

Abstract

Abstract Fas-FasL interactions play a critical role in TCR-induced apoptosis of activated CD4+ T cells. However, naïve T cells activated through antigen stimulation expand and contract independent of the presence of the death receptor Fas. Fas deficiency promotes accumulation of CD44+ memory phenotype T cells in mice, suggesting Fas may play a critical role in memory T cell apoptosis. The differential sensitivity of memory versus naïve CD4+ T cells to Fas-induced apoptosis has not been investigated. We compared the sensitivity of purified memory versus naïve human CD4+ T cells, both directly ex vivo and after in vitro activation and expansion, to undergo Fas-mediated apoptosis. Interestingly, effector memory phenotype (CD27- CCR7-) cells were the most sensitive to non-crosslinked anti-Fas induced cell death. We have previously shown a correlation between lipid raft-associated Fas and sensitivity to apoptosis. Memory cells have increased lipid raft-associated Fas protein versus naïve cells, which could explain the increased Fas sensitivity. In both primary human CD4+ T cells and transformed cell lines, addition of a competitive inhibitor to palmitoylation abrogates Fas-mediated cell death. These results suggest that effector memory cells are intrinsically more sensitive to Fas-induced apoptosis, possibly due to post-translational palmitoylation and lipid raft localization of Fas.