Non-apoptotic caspase-8 activation balances T lymphocyte autophagy (82.14)

Abstract

Abstract Apoptosis and autophagy are critical mediators of a functional immune response. FADD and caspase-8 (casp8) were originally discovered to transduce apoptotic signals delivered through TNF family members. Paradoxically, lymphocytes lacking FADD or casp8 function have impaired clonal expansion following antigen receptor crosslinking and succumb to a caspase-independent cell death. We show that T cells lacking FADD or casp8 are subject to hyperactive autophagy. T cell autophagy induces casp8 activation through its interaction with FADD:Atg5:Atg12 complexes. Blockade of autophagic signaling with shRNA knockdown of the autophagy-dependent protein Atg7 leads to a rescue of T cells lacking FADD and casp8. Similarly, inhibition of RIPK1 kinase activity with necrostatin-1 completely restored T cell cycle and survival. We hypothesize that the non-apoptotic casp8 activity serves to dampen the autophagic response of proliferating T cells through direct cleavage of RIPK1 or the casp8 homolog, c-FLIP, which may secondarily inhibit RIPK1-dependent authophagic signaling. While rapidly dividing T cells require autophagy, this negative feedback loop can prevent hyperactive autophagy. Linking apoptotic proteins to this signaling paradigm may serve to prevent an inflammatory response driven by autophagic cell death in lymphocytes during an immune response. (Funded by NIH T32CA09054 to B.D.B. and R01AI63419 to C.M.W.)