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However, the potential role of GPR65 in modulating CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cell immune responses in the pathogenesis of IBD stills not entirely understood. Here, we displayed that GPR65 expression was increased in inflamed intestinal mucosa of IBD patients and positively associated with disease activity. It was expressed in CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells and robustly upregulated through the TNF\u2010\u03b1\u2010caspase 3\/8 signalling pathway. Ectopic expression of GPR65 significantly promoted the differentiation of peripheral blood (PB) CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells from IBD patients and HC to Th1 and Th17 cells in vitro. Importantly, conditional knockout of\n                      <jats:italic>Gpr65<\/jats:italic>\n                      in CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells ameliorated trinitrobenzene sulfonic acid (TNBS)\u2010induced acute murine colitis and a chronic colitis in Rag1\n                      <jats:sup>\u2013\/\u2013<\/jats:sup>\n                      mice reconstituted with CD45RB\n                      <jats:sup>high<\/jats:sup>\n                      CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells in vivo, characterised by attenuated Th1 and Th17 cell immune response in colon mucosa and decreased infiltration of CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells, neutrophils and macrophages. RNA\u2010seq analysis of Gpr65\n                      <jats:sup>\u0394CD4<\/jats:sup>\n                      and Gpr65\n                      <jats:sup>flx\/flx<\/jats:sup>\n                      CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells revealed that NUAK family kinase 2 (\n                      <jats:italic>Nuak2<\/jats:italic>\n                      ) acts as a functional target of\n                      <jats:italic>Gpr65<\/jats:italic>\n                      to restrict Th1 and Th17 cell immune response. Mechanistically, GPR65 deficiency promoted NUAK2 expression via the cAMP\u2010PKA\u2010C\u2010Raf\u2010ERK1\/2\u2010LKB1\u2010mediated signalling pathway. Consistently, silencing of\n                      <jats:italic>Nuak2<\/jats:italic>\n                      facilitated the differentiation of Gpr65\n                      <jats:sup>\u0394CD4<\/jats:sup>\n                      and Gpr65\n                      <jats:sup>flx\/flx<\/jats:sup>\n                      CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells into Th1 and Th17 cells. Therefore, our data point out that GPR65 promotes Th1 and Th17 cell immune response and intestinal mucosal inflammation by suppressing NUAK2 expression, and that targeting GPR65 and NUAK2 in CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells may represent a novel therapeutic approach for IBD.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ctm2.771","type":"journal-article","created":{"date-parts":[[2022,3,28]],"date-time":"2022-03-28T03:38:44Z","timestamp":1648438724000},"source":"Crossref","is-referenced-by-count":56,"title":["GPR65 promotes intestinal mucosal Th1 and Th17 cell differentiation and gut inflammation through downregulating NUAK2"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3867-0061","authenticated-orcid":false,"given":"Ritian","family":"Lin","sequence":"first","affiliation":[{"name":"Center for Inflammatory Bowel Disease Research The Shanghai Tenth People's Hospital 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