The induction of Bim expression in human T-cell blasts is dependent on nonapoptotic Fas/CD95 signaling.
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.
Bosque
Alberto
A
Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, and Servicio de Inmunología, Hospital 12 de Octubre, Madrid, Spain.
Aguiló
Juan Ignacio
JI
Alava
M Angeles
MA
Paz-Artal
Estela
E
Naval
Javier
J
Allende
Luis M
LM
Anel
Alberto
A
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*
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