Transgenic overexpression of the Caspase-8 inhibitor FLIP(short) leads to impaired T cell proliferation and an increased memory T cell pool after staphylococcal enterotoxin B injection.
The cellular homologues of the viral anti-apoptotic v-FLIP proteins exist as a long (c-FLIP(L)) and a short (c-FLIP(S)) splice variant. While c-FLIP(S) and v-FLIP are composed solely of two death effector domains, c-FLIP(L) contains an (inactive) caspase-like domain in addition to these two death effector domains, thereby structurally resembling pro-Caspase-8. Both c-FLIP(L) and c-FLIP(S) suppress apoptosis by inhibiting Caspase-8 activation, although at different levels of pro-Caspase-8 processing. To analyze the consequences of deregulated c-FLIP(S) expression in vivo, we established lck FLIP(S)-transgenic mice overexpressing the transgene in thymocytes and in mature T cells. As expected, CD95L-induced apoptosis was impaired in lck FLIP(S)-transgenic T cells, indicating the functionality of the FLIP(S) transgene. Remarkably, activation-induced cell death of transgenic T cells was unaffected, despite the observed inhibition of CD95-induced T cell death. Thymic and splenic cell numbers as well as CD4/CD8 cellularity were normal in lck FLIP(S)-transgenic animals, which in contrast to CD95-deficient mice do not accumulate Thy1(+) B220(+) CD4(-) CD8(-) peripheral T cells. c-FLIP(S) overexpression leads to a significant decrease in activation-induced T cell proliferation in vitro. Despite the capacity of FLIP(S) to inhibit CD95-induced apoptosis, T cell lymphomagenesis is not observed in lck FLIP(S)-transgenic mice. Interestingly, the Vbeta8(+) memory T cell pool is enlarged upon staphylococcal enterotoxin B injections, suggesting a specific in vivo function for FLIP(S) in the maintenance of restimulated T cells.
Oehme
Ina
I
Georg-Speyer-Haus, Frankfurt, Germany.
Neumann
Frank
F
Bösser
Susanne
S
Zörnig
Martin
M
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D053181:Caspase 8; D061945:Caspase Inhibitors; D002455:Cell Division / Q000187:drug effects*; D004768:Enterotoxins / Q000494:pharmacology*; D053222:Fas Ligand Protein; D007156:Immunologic Memory / Q000187:drug effects* / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D013154:Spleen / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000378:metabolism
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D061945:Caspase Inhibitors; C506387:Cflar protein, mouse; D004768:Enterotoxins; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C031818:enterotoxin B, staphylococcal; C505526:Casp8 protein, mouse; D053181:Caspase 8