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However, ISCs are particularly sensitive to various stressors and primary targets of overwhelming immune responses, such as interferon \u03b3 (IFN\u03b3)-mediated killing. In mouse models of radiation therapy-induced gut damage and in biopsies from patients who underwent allogeneic hematopoietic stem cell transplantation, we observed IFN\u03b3 expression by intestinal T\n                    <jats:sub>reg<\/jats:sub>\n                    cells. T\n                    <jats:sub>reg<\/jats:sub>\n                    cells leverage combined IFN\u03b3 and interleukin 10 (IL-10) stimulation of ISCs to nurture the growth of intestinal organoids through the activation of the mTORC1 and Myc pathways. Similarly, T\n                    <jats:sub>reg<\/jats:sub>\n                    cells or the combined addition of recombinant IFN\u03b3 and IL-10 promoted the regeneration of organoids after irradiation, and both cytokines were essential for ensuring epithelial regeneration following acute intestinal tissue injury in vivo. The exposure of organoids to growth factor-free culture conditions revealed distinct EGF-like properties of IFN\u03b3 and Wnt-like properties of IL-10. While IFN\u03b3 rapidly induced epithelial proliferation, it depleted the pool of ISCs in vitro. Only the combination of IFN\u03b3 and IL-10 led to epithelial proliferation and organoid growth while simultaneously ensuring ISC maintenance over time. Our results reveal a context-dependent role of inflammatory signaling in ISCs, through which T\n                    <jats:sub>reg<\/jats:sub>\n                    cells promote epithelial repair following therapy-induced injury.\n                  <\/jats:p>","DOI":"10.1038\/s41392-025-02476-5","type":"journal-article","created":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T23:02:56Z","timestamp":1764111776000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Tissue-adapted Tregs harness inflammatory signals to promote intestinal repair from therapy-related injury"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6951-3416","authenticated-orcid":false,"given":"Julius 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S.H. is a consultant for Bristol Myers-Squibb, Novartis, Merck, AbbVie, and Roche and has received research funding from Bristol Myers-Squibb and Novartis. S.H. is an employee of and holds equity interest in Roche\/Genentech. M. B-H. received honoraria for lectures or articles from Sanofi, Pfizer, Springer, Thieme, and Novartis. K.S. is a consultant for TRIMT GmBH and has filed a patent for a radiopharmaceutical target. D. Wolff received a research grant from Novartis and honoraria from Novartis, Incyte, Syndax, Mallinckrodt, Takeda, Behring, Neovii and Sanofi. S.E.C.: Consulting fees from Icotec AG (Switzerland), HMG Systems Engineering GmbH (Germany), and Bristol Myers Squibb BMS (Germany). Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events (most speaking appointments include reimbursement of travel costs\u2014does not apply for virtual appointments): Roche, BMS, Brainlab, AstraZeneca, Accuray, Dr. Sennewald, Daiichi Sankyo, Elekta, Medac, med update GmbH. G.K. has been holding research contracts with Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Sutro, Tollys, and Vascage. G.K. is on the Board of Directors of the Bristol Myers Squibb Foundation France. G.K. is a scientific co-founder of everImmune, Osasuna Therapeutics, Samsara Therapeutics and Therafast Bio. G.K. is in the scientific advisory boards of Hevolution, Institut Servier, Longevity Vision Funds and Rejuveron Life Sciences. G.K. is the inventor of patents covering therapeutic targeting of aging, cancer, cystic fibrosis and metabolic disorders. G.K.\u2019s wife, Laurence Zitvogel, has held research contracts with Glaxo Smyth Kline, Incyte, Lytix, Kaleido, Innovate Pharma, Daiichi Sankyo, Pilege, Merus, Transgene, 9\u2009m, Tusk and Roche, was on the Board of Directors of Transgene, is a cofounder of everImmune, and holds patents covering the treatment of cancer and the therapeutic manipulation of the microbiota. G.K.\u2019s brother, Romano Kroemer, was an employee of Sanofi and now consults for Boehringer-Ingelheim. The funders had no role in the design of the study, in the writing of the manuscript, or in the decision to publish the results. O.Ke. is a cofounder of Samsara Therapeutics. The remaining authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"384"}}