Autoimmunity as a consequence of retrovirus-mediated expression of C-FLIP in lymphocytes.
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.
Van Parijs
L
L
Department of Biology, California Institute of Technology, Pasadena 91125, USA.
Refaeli
Y
Y
Abbas
A K
AK
Baltimore
D
D
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
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