Fas signaling-mediated T(H)9 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 T(H)9 cell differentiation by activating NF-κB via Ca(2+)-dependent PKC-β activation. In addition, PKC-β also phosphorylates p38 to inactivate NFAT1 and reduce NFAT1-NF-κB synergy to promote the Fas(-)induced T(H)9 transcription program. Fas ligation exacerbates inflammatory bowel disease by increasing T(H)9 cell differentiation, and promotes antitumor activity in p38 inhibitor-treated T(H)9 cells. Furthermore, low-dose p38 inhibitor suppresses tumor growth without inducing systemic adverse effects. In patients with tumor, relatively high T(H)9 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 T(H)9 cell induction and cancer therapy.