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They can be generated either centrally in the thymus or in peripheral organs. Metabolites such as short\u2010chain fatty acids produced by intestinal microbiota can induce peripheral Treg differentiation, by activating G\u2010protein\u2010coupled\u2010receptors like GPR109A. In this study, we identified a novel role for GPR109A in thymic Treg development. We found that <jats:italic>Gpr109a<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mice had increased Treg under basal conditions in multiple organs compared with WT mice. GPR109A was not expressed on T cells but on medullary thymic epithelial cells (mTECs), as revealed by single\u2010cell RNA sequencing in both mice and humans and confirmed by flow cytometry in mice. mTECs isolated from <jats:italic>Gpr109a<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mice had higher expression of autoimmune regulator (AIRE), the key regulator of Treg development, while the subset of mTECs that did not express <jats:italic>Gpr109a<\/jats:italic> in the WT displayed increased <jats:italic>Aire<\/jats:italic> expression and also enhanced signaling related to mTEC functionality. Increased thymic Treg in <jats:italic>Gpr109a<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mice was associated with protection from experimental autoimmune encephalomyelitis, with ameliorated clinical signs and reduced inflammation. This work identifies a novel role for GPR109A and possibly the gut microbiota, on thymic Treg development via its regulation of mTECs.<\/jats:p>","DOI":"10.1002\/eji.202350521","type":"journal-article","created":{"date-parts":[[2023,8,19]],"date-time":"2023-08-19T07:37:26Z","timestamp":1692430646000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["GPR109A expressed on medullary thymic epithelial cells affects thymic Treg development"],"prefix":"10.1002","volume":"53","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3902-2843","authenticated-orcid":false,"given":"Duan","family":"Ni","sequence":"first","affiliation":[{"name":"Charles Perkins Centre The University of Sydney  The University of Sydney New South Wales Australia"},{"name":"School of Medical Sciences Faculty of Medicine and Health The University of Sydney  Sydney New South Wales 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