Abstract
T cell-mediated immunity in the intestine is stringently controlled to ensure proper immunity against pathogenic microbes and to prevent autoimmunity, a known cause of inflammatory bowel disease. However, precisely how T cells regulate intestine immunity remains to be fully understood. In this study, we found that mitogen-activated protein kinase kinase kinase 2 (MAP3K2) is required for the CD4+ T cell-mediated inflammation in the intestine. Using a T cell transfer colitis model, we found that MAP3K2-deficient naïve CD4 T cells had a dramatically reduced ability to induce colitis compared to wild type T cells. In addition, significantly fewer IFN-γ- but more IL-17A-producing CD4+ T cells in the intestines of mice receiving MAP3K2-deficient T cells than in those from mice receiving wild type T cells was observed. Interestingly, under well-defined in vitro differentiation conditions, MAP3K2-deficient naïve T cells were not impaired in their ability to differentiate into Th1, Th17 and Treg. Furthermore, the MAP3K2-regulated colitis severity was mediated by Th1 but not Th17 cells in the intestine. At the molecular level, we showed that MAP3K2-mediated Th1 cell differentiation in the intestine was regulated by IL-18 and required specific JNK activation. Together, our study reveals a novel regulatory role of MAP3K2 in intestinal T cell immunity via the IL-18-MAP3K2-JNK axis and may provide a novel target for intervention in T cell-mediated colitis.
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This work was supported by the National Natural Science Foundation of China (81430033, 81871269, 91942311 and 31930035). We want to thank Dr. Fang Wang for kindly reading the manuscript and providing helpful comments. We also want to thank Dr. Lei Shen for assisting with T cell differentiation experiment.
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Compliance and ethics The author(s) declare that they have no conflict of interest. All animal experiments were performed according to the guidelines for the use and care of laboratory animals as provided by Shanghai JiaoTong University School of Medicine Institutional Animal Care and Use Committees (IACUC).
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Wu, N., Chen, D., Sun, H. et al. MAP3K2 augments Th1 cell differentiation via IL-18 to promote T cell-mediated colitis. Sci. China Life Sci. 64, 389–403 (2021). https://doi.org/10.1007/s11427-020-1720-9
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DOI: https://doi.org/10.1007/s11427-020-1720-9