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    Anti-programmed death-1 (PD-1) immunotherapy that aims to restore T cell activity in cancer patients frequently leads to immune-related adverse events such as colitis. However, the underlying mechanism is still elusive. Here, we find that Pdcd1-deficient mice exhibit disrupted gut microbiota and aggravated dextran sulfate sodium (DSS)-induced colitis. In addition to T cells, PD-1 is also substantially expressed in colonic lymphoid tissue inducer (LTi) cells. During DSS-induced colitis, LTi cell activation is accompanied by increased PD-1 expression, whereas PD-1 deficiency results in reduced interleukin-22 (IL-22) production by LTi cells and exacerbated inflammation. Mechanistically, activated LTi cells reprogram their metabolism toward carbohydrate metabolism and fatty acid synthesis, while fatty acid oxidation (FAO) is unchanged. However, PD-1 deficiency leads to significantly elevated FAO in LTi cells, which in turn attenuates their activation and IL-22 production. Consistently, FAO suppression efficiently restores IL-22 production in Pdcd1-/- LTi cells. Thus, our study provides unforeseen mechanistic insight into colitis occurrence during anti-PD-1 immunotherapy through LTi cell metabolic reconfiguration. © 2022. The Author(s), under exclusive licence to Springer Nature Limited.


    Di Wu, Luni Hu, Mengwei Han, Yichen Deng, Yime Zhang, Guanqun Ren, Xingyu Zhao, Zongxian Li, Peng Li, Yinlian Zhang, Shanwen Chen, Jun Li, Yanyan Shi, Jianxin Xue, Pengyuan Wang, Chao Zhong. PD-1 signaling facilitates activation of lymphoid tissue inducer cells by restraining fatty acid oxidation. Nature metabolism. 2022 Jul;4(7):867-882

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    PMID: 35788761

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