Participation of FLIP, RIP and Bcl-x(L) in Fas-mediated T-cell death.
Apart from the conventional Fas signalling pathway, alternative pathways including the mitochondrial caspase-dependent and RIP-mediated cell death routes have been proposed to operate during Fas-mediated cell death. To evaluate the contribution of different Fas signalling pathways, mice overexpressing FLIP(L), Bcl-x(L), a kinase-deficient form of RIP (RIPDeltakin) or combinations thereof were generated by retroviral gene transfer of haematopoietic stem cells. Such mice did not show overt abnormalities in haematopoietic development, defects in thymic deletion, accumulation of double-negative T cells or signs of autoimmunity. Fas-mediated death of mitogen-activated T cells was caspase dependent and could be blocked by FLIP(L) overexpression only with the minor involvement of Bcl-x(L) or RIPDeltakin inhibitable pathways. Fas-mediated death of resting CD4(+) and CD8(+) T cells was mainly caspase dependent but could only partly be blocked by FLIP(L) overexpression. Both Bcl-x(L) or RIPDeltakin expression resulted in partial protection of CD8(+) T cells against Fas-mediated cell death. These results indicate that yet uncharacterized signalling pathways from the Fas receptor are critically involved in lymphoproliferative and autoimmune disease observed in lpr mice and autoimmune lymphoproliferative syndrome patients.
Djerbi
M
M
Department of Immunology, The Wenner-Gren Institute, University of Stockholm, Stockholm, Sweden.
Malinowski
M M
MM
Yagita
H
H
Zhivotovsky
B
B
Grandien
A
A
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D015153:Blotting, Western; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D061945:Caspase Inhibitors; D020169:Caspases / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D051379:Mice; D008811:Mice, Inbred DBA; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D014161:Transduction, Genetic; D051020:bcl-X Protein / Q000276:immunology*; D019014:fas Receptor / Q000276:immunology*
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D051020:bcl-X Protein; D019014:fas Receptor; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D020169:Caspases