Fas signaling-mediated TH9 cell differentiation favors bowel inflammation and antitumor functions

• Published in: Nature communications 2019-07, Vol.10 (1), p.1-14, Article 2924
• Main Authors: Shen, Yingying, Song, Zhengbo, Lu, Xinliang, Ma, Zeyu, Lu, Chaojie, Zhang, Bei, Chen, Yinghu, Duan, Meng, Apetoh, Lionel, Li, Xu, Guo, Jufeng, Miao, Ying, Zhang, Gensheng, Yang, Diya, Cai, Zhijian, Wang, Jianli
• Format: Article
• Language: English
• Subjects: 13/109; 13/21; 13/31; 13/51; 13/89; 14/34; 14/63; 38/77; 38/91; 631/250/1619/554/1898; 631/250/2152/1566/2493; 631/250/516; 631/67/1059/2325; 64/60; Anticancer properties; Antitumor activity; Apoptosis; Calcium; Calcium ions; CD4 antigen; Cell differentiation; Colon; Differentiation (biology); Homeostasis; Humanities and Social Sciences; Inflammatory bowel disease; Inflammatory bowel diseases; Inhibitors; Intestine; Kinases; Lymphocytes; Lymphocytes T; multidisciplinary; NF-AT1 protein; NF-κB protein; Protein kinase C; Science; Science (multidisciplinary); Signaling; Therapy; Transcription; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-10889-4

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. Fas signalling induces apoptosis of activated T cells to maintain immune homeostasis. Here the authors show that Fas also induces PKC-β activation to promote NF-κB-mediated T H 9 cell differentiation, while p38 activation by PKC-β antagonizes this effect, thereby supporting a synergy between p38 inhibitor and Fas for T H 9 differentiation.