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.