1. Fas signaling-mediated T H 9 cell differentiation favors bowel inflammation and antitumor functions.
- Author
-
Shen Y, Song Z, Lu X, Ma Z, Lu C, Zhang B, Chen Y, Duan M, Apetoh L, Li X, Guo J, Miao Y, Zhang G, Yang D, Cai Z, and Wang J
- Subjects
- Animals, Cytokines genetics, Cytokines immunology, Female, Humans, Inflammatory Bowel Diseases genetics, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Nude, NF-kappa B genetics, NF-kappa B immunology, NFATC Transcription Factors genetics, NFATC Transcription Factors immunology, Neoplasms genetics, Neoplasms immunology, Neoplasms therapy, Protein Kinase C beta genetics, Protein Kinase C beta immunology, T-Lymphocytes, Regulatory immunology, fas Receptor genetics, p38 Mitogen-Activated Protein Kinases genetics, p38 Mitogen-Activated Protein Kinases immunology, Cell Differentiation, Inflammatory Bowel Diseases immunology, Signal Transduction, T-Lymphocytes, Regulatory cytology, fas Receptor immunology
- 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 T
H 9 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 TH 9 transcription program. Fas ligation exacerbates inflammatory bowel disease by increasing TH 9 cell differentiation, and promotes antitumor activity in p38 inhibitor-treated TH 9 cells. Furthermore, low-dose p38 inhibitor suppresses tumor growth without inducing systemic adverse effects. In patients with tumor, relatively high TH 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 TH 9 cell induction and cancer therapy.- Published
- 2019
- Full Text
- View/download PDF