Abstract
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 TH9 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 TH9 transcription program. Fas ligation exacerbates inflammatory bowel disease by increasing TH9 cell differentiation, and promotes antitumor activity in p38 inhibitor-treated TH9 cells. Furthermore, low-dose p38 inhibitor suppresses tumor growth without inducing systemic adverse effects. In patients with tumor, relatively high TH9 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 TH9 cell induction and cancer therapy.
Highlights
Fas induces apoptosis in activated T cell to maintain immune homeostasis, but the effects of non-apoptotic Fas signaling on T cells remain unclear
To determine the role of Fas signaling in TH9 cell differentiation, we differentiated naive CD4+ T cells from wild-type (WT) and Faslpr mice into TH1, TH2, TH9, and TH17 cells and T regulatory cell (Treg) in vitro
There were no obvious differences in apoptosis or proliferation between WT-TH9 and Faslpr-TH9 after transfer into inflammatory bowel disease (IBD) mice
Summary
Fas induces apoptosis in activated T cell to maintain immune homeostasis, but the effects of non-apoptotic Fas signaling on T cells remain unclear. We show that Fas promotes TH9 cell differentiation by activating NF-κB via Ca2+-dependent PKC-β activation. Fas ligation exacerbates inflammatory bowel disease by increasing TH9 cell differentiation, and promotes antitumor activity in p38 inhibitor-treated TH9 cells. Simultaneous Fas ligation and low-dose p38 inhibition may be an effective approach for TH9 cell induction and cancer therapy. DR3, another member of the TNF-R family, enhances TH9 cell differentiation through a STAT5-dependent mechanism[19]. A member of the TNF-R family, plays a critical role in programmed cell death[20]. A recent publication demonstrated that Fas promotes TH17 cell differentiation and inhibits TH1 cell development[24]. Whether non-apoptotic Fas signaling participates in regulating TH9 cell differentiation remains unknown
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