title: Autoimmunity as a consequence of retrovirus-mediated expression of C-FLIP in lymphocytes.
abstract: The induction of apoptosis by death receptors serves to regulate immune responses by eliminating unwanted and harmful cells. Mature lymphocytes express FLICE inhibitory proteins (FLIPs) that block death receptor-induced cell death. Here, we show that both B and T cells downregulate c-FLIP upon activation in vitro. Retrovirus-mediated expression of c-FLIP blocks Fas-induced apoptosis of activated lymphocytes but does not affect cell death resulting from cytokine withdrawal. In vivo, c-FLIP expression results in defective superantigen-mediated elimination of T cells, the accumulation of activated B cells, the production of autoantibodies, and the development of autoimmune disease. No effect was seen on negative selection of thyomocytes. These results suggest that activation-dependent downregulation of c-FLIP renders mature lymphocytes sensitive to death receptor-mediated apoptosis and is required to maintain self-tolerance.
authors.affiliation: Department of Biology, California Institute of Technology, Pasadena 91125, USA.
authors.forename: L
authors.initials: L
authors.lastname: Van Parijs
authors.forename: Y
authors.initials: Y
authors.lastname: Refaeli
authors.forename: A K
authors.initials: AK
authors.lastname: Abbas
authors.forename: D
authors.initials: D
authors.lastname: Baltimore
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis; D001327:Autoimmune Diseases / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D015536:Down-Regulation; D004768:Enterotoxins / Q000276:immunology; D053200:Fas-Associated Death Domain Protein; D015870:Gene Expression; D005822:Genetic Vectors / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D012190:Retroviridae / Q000235:genetics; D013211:Staphylococcus aureus / Q000276:immunology; D018089:Superantigens / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D019014:fas Receptor / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins; C506387:Cflar protein, mouse; D004768:Enterotoxins; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D047908:Intracellular Signaling Peptides and Proteins; D011993:Recombinant Fusion Proteins; D018089:Superantigens; D019014:fas Receptor; C038600:trinitrophenyl-ovalbumin; C031818:enterotoxin B, staphylococcal; D010047:Ovalbumin