title: The caspase 8 inhibitor c-FLIP(L) modulates T-cell receptor-induced proliferation but not activation-induced cell death of lymphocytes.
abstract: The caspase 8 inhibitor c-FLIP(L) can act in vitro as a molecular switch between cell death and growth signals transmitted by the death receptor Fas (CD95). To elucidate its function in vivo, transgenic mice were generated that overexpress c-FLIP(L) in the T-cell compartment (c-FLIP(L) Tg mice). As anticipated, FasL-induced apoptosis was inhibited in T cells from the c-FLIP(L) Tg mice. In contrast, activation-induced cell death of T cells in c-FLIP(L) Tg mice was unaffected, suggesting that this deletion process can proceed in the absence of active caspase 8. Accordingly, c-FLIP(L) Tg mice differed from Fas-deficient mice by showing no accumulation of B220(+) CD4(-) CD8(-) T cells. However, stimulation of T lymphocytes with suboptimal doses of anti-CD3 or antigen revealed increased proliferative responses in T cells from c-FLIP(L) Tg mice. Thus, a major role of c-FLIP(L) in vivo is the modulation of T-cell proliferation by decreasing the T-cell receptor signaling threshold.
authors.affiliation: Department of Biochemistry, University of Lausanne, Chemin des Boveresses 155, 1066 Epalinges, Switzerland.
authors.forename: Susanne M A
authors.initials: SM
authors.lastname: Lens
authors.forename: Takao
authors.initials: T
authors.lastname: Kataoka
authors.forename: Karen A
authors.initials: KA
authors.lastname: Fortner
authors.forename: Antoine
authors.initials: A
authors.lastname: Tinel
authors.forename: Isabel
authors.initials: I
authors.lastname: Ferrero
authors.forename: Robson H
authors.initials: RH
authors.lastname: MacDonald
authors.forename: Michel
authors.initials: M
authors.lastname: Hahne
authors.forename: Friedrich
authors.initials: F
authors.lastname: Beermann
authors.forename: Antoine
authors.initials: A
authors.lastname: Attinger
authors.forename: Hans-Acha
authors.initials: HA
authors.lastname: Orbea
authors.forename: Ralph C
authors.initials: RC
authors.lastname: Budd
authors.forename: Jürg
authors.initials: J
authors.lastname: Tschopp
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D017252:CD3 Complex / Q000494:pharmacology; D015704:CD4 Antigens / Q000096:biosynthesis; D016827:CD8 Antigens / Q000096:biosynthesis; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D053222:Fas Ligand Protein; D005434:Flow Cytometry; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000502:physiology; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D020033:Protein Isoforms / Q000378:metabolism / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; C506386:CFLAR protein, human; D002352:Carrier Proteins; D061945:Caspase Inhibitors; C506387:Cflar protein, mouse; D004791:Enzyme Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007376:Interleukin-2; D047908:Intracellular Signaling Peptides and Proteins; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins; D020033:Protein Isoforms; D011948:Receptors, Antigen, T-Cell; D017493:Leukocyte Common Antigens; C505530:CASP8 protein, human; C506433:CASP9 protein, human; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases