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This study aimed to investigate the underlying mechanisms of GITRL in primary Sj\u00f6gren syndrome (pSS).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Patients with pSS and healthy controls were recruited. Serum GITRL and Th17\u2010related cytokines were determined. RNA sequencing was performed to decipher key signal pathways. Nonobese diabetes (NOD) mice were adopted as experimental Sj\u00f6gren models and recombinant adeno\u2010associated virus (rAAV) transduction was conducted to verify the therapeutic potentials of targeting GITRL in vivo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Serum GITRL was significantly higher in patients with pSS and showed a positive correlation with leukopenia, thrombocytopenia, autoantibodies, lung involvement, and disease activity. Serum GITRL was correlated with Th17\u2010related cytokines. GITRL promoted the expansion of Th17 and Th17.1 cells. Expansion of granulocyte\u2010macrophage colony\u2010stimulating factor positive (GM\u2010CSF<jats:sup>+<\/jats:sup>) CD4<jats:sup>+<\/jats:sup> T cells induced by GITRL could be inhibited by blockade of GITRL. Moreover, GM\u2010CSF could stimulate GITRL expression on monocytes. RNA sequencing revealed mammalian target of rapamycin complexes 1 (mTORC1) might be the key modulator. The increased phosphorylation of S6 and STAT3 and the expansion of Th17 and Th17.1 cells induced by GITRL were effectively inhibited by rapamycin, suggesting a GITRL\u2013mTORC1\u2013GM\u2010CSF positive loop in pathogenic Th17 response in pSS. Administration of an rAAV vector expressing short hairpin RNA targeting GITRL alleviated disease progression in NOD mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our results identified the pathogenic role of GITRL in exacerbating disease activity and promoting pathogenic Th17 response in pSS through a GITRL\u2013mTORC1\u2013GM\u2010CSF loop. These findings suggest GITRL might be a promising therapeutic target in the treatment of pSS.<\/jats:p><jats:p><jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/art42859-toc-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec>","DOI":"10.1002\/art.42859","type":"journal-article","created":{"date-parts":[[2024,4,8]],"date-time":"2024-04-08T22:24:39Z","timestamp":1712615079000},"page":"1419-1430","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["<scp>A GITRL\u2010mTORC1\u2010GM\u2010CSF Positive Loop<\/scp> Promotes Pathogenic Th17 Response in Primary Sj\u00f6gren Syndrome"],"prefix":"10.1002","volume":"76","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8885-7452","authenticated-orcid":false,"given":"Yuzhou","family":"Gan","sequence":"first","affiliation":[{"name":"Department of Rheumatology and Immunology, Beijing Key Laboratory for Rheumatism and Immune Diagnosis (BZ0135) Peking University People's Hospital  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haotian","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Beijing Key Laboratory for Rheumatism and Immune Diagnosis (BZ0135) Peking University People's Hospital  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6348-5074","authenticated-orcid":false,"given":"Yixue","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Beijing Key Laboratory for Rheumatism and Immune Diagnosis (BZ0135) 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