Specific elimination of effector memory CD4+ T cells due to enhanced Fas signaling complex formation and association...

Elimination of autoreactive CD4(+) T cells through the death receptor Fas/CD95 is an important mechanism of immunological self-tolerance. Fas deficiency results in systemic autoimmunity, yet does not affect the kinetics of T-cell responses to acute antigen exposure or infection. Here we show that Fas and TCR-induced apoptosis are largely restricted to CD4(+) T cells with an effector memory phenotype (effector memory T cells (T(EM))), whereas central memory and activated naïve CD4(+) T cells are relatively resistant to both. Sensitivity of T(EM) to Fas-induced apoptosis depends on enrichment of Fas in lipid raft microdomains, and is linked to more efficient formation of the Fas death-inducing signaling complex. These results explain how Fas can cull T cells reactive against self-antigens without affecting acute immune responses. This work also identifies Fas-induced apoptosis as a possible immunotherapeutic strategy to eliminate T(EM) linked to the pathogenesis of a number of autoimmune diseases.