title: The induction of Bim expression in human T-cell blasts is dependent on nonapoptotic Fas/CD95 signaling.
abstract: The BH3-only protein Bim is required for maintaining the homeostasis of the immune system, since Bim regulates the down-modulation of T-cell responses, mainly through cytokine deprivation. Using T-cell blasts from healthy donors and also from patients with autoimmune lymphoproliferative syndromes (ALPSs) due to homozygous loss-of-function mutation of FasL (ALPS-Ic) or heterozygous mutation in the Fas/CD95 death domain (ALPS-Ia), it is shown that the induction of Bim expression during the process of human T-cell blast generation is strictly dependent on FasL/Fas-mediated signaling. The main pathway by which Fas signaling regulates the levels of Bim expression in human T-cell blasts is the death-domain- and caspase-independent generation of discrete levels of H2O2, which results in the net increase of Foxo3a levels. The present results connect the 2 main pathways described until the moment for the control of T-cell responses: death receptor-mediated activation-induced cell death and apoptosis by cytokine deprivation.
authors.affiliation: Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, and Servicio de Inmunología, Hospital 12 de Octubre, Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bosque
authors.forename: Juan Ignacio
authors.initials: JI
authors.lastname: Aguiló
authors.forename: M Angeles
authors.initials: MA
authors.lastname: Alava
authors.forename: Estela
authors.initials: E
authors.lastname: Paz-Artal
authors.forename: Javier
authors.initials: J
authors.lastname: Naval
authors.forename: Luis M
authors.initials: LM
authors.lastname: Allende
authors.forename: Alberto
authors.initials: A
authors.lastname: Anel
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D000072224:Bcl-2-Like Protein 11; D001752:Blast Crisis / Q000473:pathology*; D016923:Cell Death; D016207:Cytokines / Q000172:deficiency; D005786:Gene Expression Regulation; D006801:Humans; D008232:Lymphoproliferative Disorders / Q000209:etiology / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D053218:Receptors, Death Domain / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000473:pathology*; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000235:genetics / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D016207:Cytokines; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D053218:Receptors, Death Domain; D019014:fas Receptor