title: Perforin-dependent apoptosis functionally compensates Fas deficiency in activation-induced cell death of human T lymphocytes.
abstract: Activation-induced cell death (AICD) is involved in peripheral tolerance by controlling the expansion of repeatedly stimulated T cells via an apoptotic Fas (CD95; APO-1)-dependent pathway. The TNFRSF-6 gene encoding Fas is mutated in children suffering from autoimmune lymphoproliferative syndrome (ALPS), which is characterized by lymphoproliferation and autoimmunity. We examined AICD in Fas-deficient T cells from ALPS patients. We showed that primary activated Fas-deficient T cells die by apoptosis after repeated T cell antigen receptor (TCR) stimulation despite resistance to Fas-mediated cell death. This Fas-independent AICD was found to be mediated through a cytotoxic granules-dependent pathway. Cytotoxic granules-mediated AICD was also detected in normal T lymphocytes though to a lesser extent. As expected, the cytotoxic granules-dependent AICD was abolished in T cells from Rab27a- or perforin-deficient patients who exhibited defective granules-dependent cytotoxicity. Supporting an in vivo relevance of the cytotoxic granules-dependent AICD in ALPS patients, we detected an increased number of circulating T lymphocytes expressing granzymes A and B. Altogether, these data indicated that the cytotoxic granules-dependent cell death in ALPS may compensate for Fas deficiency in T lymphocytes. Furthermore, they identified a novel AICD pathway as a unique alternative to Fas apoptosis in human peripheral T lymphocytes.
authors.affiliation: INSERM, U768, Paris, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Mateo
authors.forename: Michael
authors.initials: M
authors.lastname: Ménager
authors.forename: Geneviève
authors.initials: G
authors.lastname: de Saint-Basile
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Stolzenberg
authors.forename: Bertrand
authors.initials: B
authors.lastname: Roquelaure
authors.forename: Nicolas
authors.initials: N
authors.lastname: André
authors.forename: Benoit
authors.initials: B
authors.lastname: Florkin
authors.forename: Françoise
authors.initials: F
authors.lastname: le Deist
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Frédéric
authors.initials: F
authors.lastname: Rieux-Laucat
mesh_terms: D017209:Apoptosis; D001327:Autoimmune Diseases / Q000276:immunology; D016022:Case-Control Studies; D016923:Cell Death; D002478:Cells, Cultured; D002648:Child; D006801:Humans; D007108:Immune Tolerance; D008213:Lymphocyte Activation; D008232:Lymphoproliferative Disorders / Q000276:immunology*; D009154:Mutation; D054353:Perforin / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000473:pathology*; D019014:fas Receptor / Q000172:deficiency* / Q000235:genetics
chemical_list: D011948:Receptors, Antigen, T-Cell; D019014:fas Receptor; D054353:Perforin