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In this study, we found that infusions of orthogonal (ortho) IL-2 failed to enhance Tregs expressing a corresponding orthoIL-2 receptor (IL-2R) in a mouse model of autoimmune diabetes. Engineering Tregs with an orthoIL-2 tethered to its receptor achieved selective autocrine signaling; increased CD25, CTLA-4, and Foxp3 expression; supported Treg persistence without exogenous IL-2 in vivo; and improved the efficacy of Treg prevention of autoimmune diabetes. Inserting the tethered orthoIL-2 construct into the Foxp3 locus enabled Treg-specific self-reinforced expression through the activation of the Foxp3 locus by increased IL-2 signaling. Together, these results illustrate a safe and effective cell-engineering solution for overcoming Tregs\u2019 dependency on exogenous IL-2, thereby achieving superior therapeutic efficacy.<\/jats:p>","DOI":"10.1084\/jem.20251480","type":"journal-article","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T06:20:52Z","timestamp":1783491652000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Receptor-tethered orthogonal IL-2 enhances regulatory T cell therapy"],"prefix":"10.1084","volume":"223","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2662-0964","authenticated-orcid":true,"given":"Alyssa C.","family":"Indart","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043mz5j54","id-type":"ROR","asserted-by":"publisher"}],"name":"Diabetes Center, University of California, San Francisco 1 , San Francisco, 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