title: Specific elimination of effector memory CD4+ T cells due to enhanced Fas signaling complex formation and association with lipid raft microdomains.
abstract: 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.
authors.affiliation: Immunoregulation Section, Autoimmunity Branch, NIAMS, NIH, Bethesda, MD 20892, USA.
authors.forename: M
authors.initials: M
authors.lastname: Ramaswamy
authors.forename: A C
authors.initials: AC
authors.lastname: Cruz
authors.forename: S Y
authors.initials: SY
authors.lastname: Cleland
authors.forename: M
authors.initials: M
authors.lastname: Deng
authors.forename: S
authors.initials: S
authors.lastname: Price
authors.forename: V K
authors.initials: VK
authors.lastname: Rao
authors.forename: R M
authors.initials: RM
authors.lastname: Siegel
mesh_terms: D000818:Animals; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000145:classification / Q000276:immunology*; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000378:metabolism; D006801:Humans; D007156:Immunologic Memory; D021962:Membrane Microdomains / Q000378:metabolism*; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D019014:fas Receptor / Q000032:analysis / Q000378:metabolism*
chemical_list: D053418:Death Domain Receptor Signaling Adaptor Proteins; D011948:Receptors, Antigen, T-Cell; D019014:fas Receptor