Fas signaling-mediated T_H9 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_H9 cell differentiation by activating NF-κB via Ca²⁺-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_H9 transcription program. Fas ligation exacerbates inflammatory bowel disease by increasing T_H9 cell differentiation, and promotes antitumor activity in p38 inhibitor-treated T_H9 cells. Furthermore, low-dose p38 inhibitor suppresses tumor growth without inducing systemic adverse effects. In patients with tumor, relatively high T_H9 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_H9 cell induction and cancer therapy.