Fas signaling-mediated T9 cell differentiation favors bowel inflammation and antitumor functions.

Fas induces apoptosis in activated T cell to maintain immune homeostasis, but the effects of non-apoptotic Fas signaling on T cells remain unclear. Here we show that Fas promotes T9 cell differentiation by activating NF-κB via Ca-dependent PKC-β activation. In addition, PKC-β also phosphorylates p38 to inactivate NFAT1 and reduce NFAT1-NF-κB synergy to promote the Fasinduced T9 transcription program. Fas ligation exacerbates inflammatory bowel disease by increasing T9 cell differentiation, and promotes antitumor activity in p38 inhibitor-treated T9 cells. Furthermore, low-dose p38 inhibitor suppresses tumor growth without inducing systemic adverse effects. In patients with tumor, relatively high T9 cell numbers are associated with good prognosis. Our study thus implicates Fas in CD4 T cells as a target for inflammatory bowel disease therapy. Furthermore, simultaneous Fas ligation and low-dose p38 inhibition may be an effective approach for T9 cell induction and cancer therapy.