Essential pro-survival role for caspase-8 during T-cell activation and embryonic development through inhibition of RIPK3-dependent necrosis (159.9)

Abstract

Abstract Caspase-8 is required for initiation of death receptor-mediated apoptosis, but counterintuitively is also required for normal T-cell proliferation and embryonic development. Recent work demonstrated that upon activation, caspase-8-deficient T cells fail to proliferate due to high rates of necroptosis, an alternative form of programmed cell death. To investigate these seemingly contradictory functions, we bred caspase-8 knockouts, which are embryonic lethal at E10.5, with necroptosis deficient RIPK3-/- animals. Unlike Casp8-/- animals, Casp8-/- RIPK3-/- double knockout (DKO) animals were generated at expected Mendelian frequencies and appeared grossly normal. DKO thymocytes responded normally to stimuli inducing intrinsic cell death, but resisted death induced by ligation of CD95. DKO animals, but not their normal littermates, were resistant to liver damage and death induced by injection of agonistic anti-Fas Ab Jo2. In contrast to casp8-/- T cells, DKO T cells proliferated normally in response to TCR ligation and displayed normal expansion and subsequent peripheral deletion in vivo when challenged with SEB. Interestingly, DKO animals display lymphoaccumulation of an aberrant B220+CD3+ population similar to that seen in gld or lpr mice. The survival of Casp8-/- RIPK3-/- mice and the normal proliferation of T cells from these animals point to an essential role for caspase-8 in limiting RIP3-dependent necrosis both during development and immune cell activation.