Transgenic overexpression of the Caspase-8 inhibitor FLIPshort leads to impaired T cell proliferation and an increased memory T cell pool after staphylococcal enterotoxin B injection

Abstract

The cellular homologues of the viral anti-apoptotic v-FLIP proteins exist as a long (c-FLIPL) and a short (c-FLIPS) splice variant. While c-FLIPS and v-FLIP are composed solely of two death effector domains, c-FLIPL contains an (inactive) caspase-like domain in addition to these two death effector domains, thereby structurally resembling pro-Caspase-8. Both c-FLIPL and c-FLIPS suppress apoptosis by inhibiting Caspase-8 activation, although at different levels of pro-Caspase-8 processing. To analyze the consequences of deregulated c-FLIPS expression in vivo, we established lck FLIPS-transgenic mice overexpressing the transgene in thymocytes and in mature T cells. As expected, CD95L-induced apoptosis was impaired in lck FLIPS-transgenic T cells, indicating the functionality of the FLIPS 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 FLIPS-transgenic animals, which in contrast to CD95-deficient mice do not accumulate Thy1+ B220+ CD4- CD8- peripheral T cells. c-FLIPS overexpression leads to a significant decrease in activation-induced T cell proliferation in vitro. Despite the capacity of FLIPS to inhibit CD95-induced apoptosis, T cell lymphomagenesis is not observed in lck FLIPS-transgenic mice. Interestingly, the Vβ8+ memory T cell pool is enlarged upon staphylococcal enterotoxin B injections, suggesting a specific in vivo function for FLIPS in the maintenance of restimulated T cells. © 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.