biostudies-literatureShen YNational Natural Science Foundation of ChinaNational Natural Science Foundation of China (National Science Foundation of China)2924https://www.ebi.ac.uk/biostudies/studies/S-EPMC6606754biostudies-literatureUnknown10(1)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 nuNature communicationsFas signaling-mediated T_H9 cell differentiation favors bowel inflammation and antitumor functions.PMC660675431670877Zhang GDuan MLu XLu CMa ZYang DWang JLi XGuo JApetoh LCai ZMiao YChen YShen YZhang BSong ZfalseFas 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 nu2019-01-01T00:00:00Z2019 Jul2026-05-06T22:50:19.57Z2019-07-25T07:03:00ZS-EPMC66067543126695010.1038/s41467-019-10889-4