Cellular FLIP (long form) regulates CD8+ T cell activation through caspase-8-dependent NF-κB activation

Cellular FLIP long form (c-FLIPL) was originally identified as an inhibitor of Fas (CD95/Apo-1). Subsequently, additional functions of c-FLIP, were identified through its association with receptor-interacting protein (RIP)l and TNFR-associated factor 2 to activate NF-kappa B, as well as by its association with and activation of caspase-8. T cells from c-FLIPL-transgenic (Tg) mice manifest hyperproliferation upon activation, although it was not clear which of the various functions of c-FLIPL was involved. We have further explored the effect of c-FLIPL on CD8(+) effector T cell function and its mechanism of action. c-FLIPL-Tg CD8(+) T cells have increased proliferation and IL-2 responsiveness to cognate Ags as well as to low-affinity Ag variants, due to increased CD25 expression. They also have a T cytotoxic 2 cytokine phenotype. c-FLIPL-Tg CD8' T cells manifest greater caspase activity and NF-kappa B acitivity upon activation. Both augmented proliferation and CD25 expression are blocked by caspase inhibition. c-FLIPL itself is a substrate of the caspase activity in effector T cells, being cleaved to a p43(FLIP) form. p43(FLIP) more efficiently recruits RIP1 than full-length c-FLIPL to activate NF-kappa B. c-FLIPL and RIP1 also coimmunoprecipitate with active caspase-8 in effector CD8' T cells. Thus, one mechanism by which c-FLIPL influences effector T cell function is through its activation of caspase-8, which in turn cleaves c-FLIPL to allow RIP1 recruitment and NF-kappa B activation. This provides a partial explanation of why caspase activity is required to initiate proliferation of resting T cells.