Non-apoptotic signaling through Fas activates Akt and promotes T cell differentiation through Caspase-8

Abstract

Abstract The TNF receptor Fas (CD95, TNFRSF6) is known for inducing apoptosis in primary cells via binding with Fas ligand (FasL) and activation of caspase-8 through the adapter protein FADD. In addition, recent research showed that the apoptotic signaling requires palmitoylation of Fas near its transmembrane region to localize on the lipid rafts. Fas palmitoylation-defective mutant is unable to induce apoptosis in primary cells but continues to enhance T cell differentiation into effector memory cells (CD44hiCD62Llo), indicating that Fas can also trigger non-apoptotic signaling in primary T cells. Fas non-apoptotic signaling has unexpected roles in modulating T cell tumor immunotherapy and autoimmunity (Klebanoff et al. 2016; Cruz et al. 2016). We have investigated the signaling pathways underlying non-apoptotic Fas signaling in T cells. Co-stimulation with oligomerized Fas Ligand activates Akt and ribosomal S6 protein phosphorylation, and Fas induced T cell differentiation is blocked by Akt or mTOR inhibitors. Further studies showed that T cells from RIP3−/− and Caspase-8−/− double deficient mice, but not mice deficient in RIP3, were refractory to Fas-induced differentiation, indicating that Caspase 8 is essential for Fas non-apoptotic signaling. Similar results were obtained with FADD. Our findings suggest that in addition to apoptotic functions, Fas also promotes non-apoptotic signaling via Caspase-8 and induces T cell differentiation by activating the Akt pathway. These results reveal a common role for Caspase-8 in non-apoptotic and apoptotic functions of Fas, with potentially different caspase-8 substrates mediating these diverse functions of a single receptor.