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Nat Commun. 2019 Jul 2;10(1):2924. doi: 10.1038/s41467-019-10889-4.

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

Shen Y1,2,3, Song Z4, Lu X1, Ma Z1, Lu C1, Zhang B1, Chen Y5, Duan M6, Apetoh L7,8, Li X9, Guo J10, Miao Y11, Zhang G12, Yang D13, Cai Z14, Wang J15,16.

Author information

1
Institute of Immunology and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, 310058, Hangzhou, China.
2
Institute of Hematology, Zhejiang University and Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, 310003, Hangzhou, China.
3
Institute of Immunology and Department of Orthopaedics of the Second Affiliated Hospital, Zhejiang University School of Medicine, 310058, Hangzhou, China.
4
Department of Medical Oncology, Zhejiang Cancer Hospital, 310022, Hangzhou, China.
5
Division of Infection Disease, Zhejiang Key Laboratory for Neonatal Diseases, Children's Hospital, Zhejiang University School of Medicine, 310006, Hangzhou, China.
6
Chronic Disease Research Institute, School of Public Health, School of Medicine, Zhejiang University, 310058, Hangzhou, China.
7
INSERM, U866, Dijon, France.
8
Faculté de Médecine, Université de Bourgogne, Dijon, 21000, France.
9
School of Life Science, Westlake University, 310024, Hangzhou, China.
10
Department of Breast Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, 310006, Hangzhou, China.
11
Clinical Trial Center, Qingdao Municipal Hospital, 266011, Qingdao, China.
12
Department of Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China.
13
Xinyuan Institute of Medicine and Biotechnology, School of Life Sciences, Zhejiang Sci-Tech University, 310018, Hangzhou, China.
14
Institute of Immunology and Department of Orthopaedics of the Second Affiliated Hospital, Zhejiang University School of Medicine, 310058, Hangzhou, China. caizj@zju.edu.cn.
15
Institute of Immunology and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, 310058, Hangzhou, China. jlwang@zju.edu.cn.
16
Institute of Hematology, Zhejiang University and Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, 310003, Hangzhou, China. jlwang@zju.edu.cn.

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.

PMID:
31266950
PMCID:
PMC6606754
DOI:
10.1038/s41467-019-10889-4
[Indexed for MEDLINE]
Free PMC Article

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