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In this study, we identified CD4<jats:sup>+<\/jats:sup>Notch2<jats:sup>+<\/jats:sup>Foxp3<jats:sup>lo<\/jats:sup> T cells in the spinal cords of mice with experimental autoimmune encephalomyelitis (EAE), dextran sodium sulfate\u2212induced colitis model mice, and patients with ulcerative colitis as immune regulatory cells. These cells exhibited a nonproliferative, dysfunctional phenotype and demonstrated immune regulatory functions, including suppressive activity against activated CD4<jats:sup>+<\/jats:sup> T cells and marked Treg cell expansion activity. Our data revealed that Notch2 deletion in Foxp3\u2212expressing cells diminishes the ability of this population to reverse the clinical symptoms of EAE. Collectively, these findings suggest that Notch2 expression in dysfunctional CD4<jats:sup>+<\/jats:sup> T cells plays a crucial role in immune regulation.<\/jats:p>","DOI":"10.1038\/s41423-025-01318-2","type":"journal-article","created":{"date-parts":[[2025,7,23]],"date-time":"2025-07-23T08:00:24Z","timestamp":1753257624000},"page":"1077-1092","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Notch2\u2212expressing CD4+ T cells attain immunoregulatory functions during autoimmune inflammation"],"prefix":"10.1038","volume":"22","author":[{"given":"So-Eun","family":"Bae","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang-Heon","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chae Youn","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cho-Rong","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chanyeon","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7112-5957","authenticated-orcid":false,"given":"Rosah May","family":"Payumo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8538-1663","authenticated-orcid":false,"given":"So Yeon","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyu-Young","family":"Sim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ho Jin","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6632-1208","authenticated-orcid":false,"given":"Hyungseok","family":"Seo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seong-Joon","family":"Koh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seunghee","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3702-5765","authenticated-orcid":false,"given":"Sung-Gyoo","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,23]]},"reference":[{"key":"1318_CR1","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.cell.2020.03.007","volume":"181","author":"L Fugger","year":"2020","unstructured":"Fugger L, Jensen LT, Rossjohn J. 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