c-FLIPS reduces activation of caspase and NF-κB pathways and decreases T cell survival

Abstract

Effective stimulation of NF-κB in T cells following TCR ligation requires the activity of caspase-8. The active caspase-8 complex includes the paracaspase, MALT1, and Bcl-10, which connect to the NF-κB pathway. It has been less clear what regulates the level of caspase-8 activity during T cell activation. A likely candidate is cellular FLIP (c-FLIP), an enzymatically inert caspase-8 homologue. Two alternatively spliced forms of c-FLIP exist, a long form (c-FLIPL) and a short-form (c-FLIPs). The latter lacks the C-terminal caspase-like domain. c-FLIPL can heterodimerize with and activate caspase-8 through an activation loop in the C terminus of c-FLIPL. Here we show that, in contrast to c-FLIPL, c-FLIPs inhibits activation of caspase-8 in T cells, and consequently reduces recruitment of MALT1 and Bcl-10 to the active caspase complex. This results in reduced activity of NF-κB. Consequently, T cells from c-FLIPs-transgenic mice undergo more rapid cell death both spontaneously and after activation. The findings suggest that c-FLIPs functions to reduce the expansion of T cells during an immune response. © 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.