Identifying Fas/CD95 non-apoptotic signaling pathways associated with T cell differentiation

Abstract

Abstract Fas (CD95, TNFRSF6), a member of the TNF cytokine superfamily, triggers apoptosis through recruitment of FADD and Caspase 8. However, Fas can also induce other responses besides cell death, including costimulating T-cell activation and promoting tumor cell growth and metastasis. We have found that Fas accelerates the differentiation of naïve T cells into effector memory cells. In vivo, Fas deficiency is known to cause autoimmunity, which has been attributed to a lack of Fas-induced cell death. Interestingly, we observed that palmitoylation-defective Fas C194V transgenic mice, in which Fas cannot induce apoptosis but can signal for differentiation, did not present with autoimmunity. This led us to hypothesize that non-apoptotic Fas signaling plays a role in autoimmunity and investigate the signaling pathways underlying Fas-induced differentiation. Primary T cells lacking FADD or Caspase 8 and cells treated with caspase inhibitor z-VAD did not differentiate suggesting that Fas-induced T cell differentiation depends on FADD, Caspase 8 and caspase activity. Moreover, we observed that cells undergoing Fas-induced differentiation had increased pAkt and pS6, and that Akt inhibition blocked differentiation. Although Fas does not directly activate Akt, activation of this pathway by Fas in the context of T cell activation is dependent on IL-2, suggesting that instead of directly activating Akt, Fas potentiates the IL-2 initiated PI3K/Akt pathway. Together, our data show that Fas potentiates the induction of PI3K/AKT signaling by IL-2 to accelerate naïve T cell differentiation via a FADD and Caspase 8 dependent mechanism.