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The prevalence of the disease is increasing, and there is an urgent need to better understand its pathogenic mechanisms to improve treatment. We show that GPR15\u2014a G-protein-coupled receptor expressed in immune cells and described previously as an entry co-factor for human and simian immunodeficiency viruses\n                    <jats:sup>3<\/jats:sup>\n                    \u2014is a marker and homing receptor for a subset of intramucosal GPR15-guided regulatory CD8\n                    <jats:sup>+<\/jats:sup>\n                    T lymphocytes (CD8\n                    <jats:sup>+<\/jats:sup>\n                    T\n                    <jats:sub>IGR<\/jats:sub>\n                    \u00a0cells). Deleterious GPR15 gene variants in humans cause defective homing of CD8\n                    <jats:sup>+<\/jats:sup>\n                    T\n                    <jats:sub>IGR<\/jats:sub>\n                    cells\u00a0and are associated with severe early-onset IBD. Moreover, CD8\n                    <jats:sup>+<\/jats:sup>\n                    T\n                    <jats:sub>IGR<\/jats:sub>\n                    cells are reduced in the intestinal mucosa of individuals with\u00a0sporadic IBD. In mice, GPR15 deficiency impairs colonic homing of CD8\n                    <jats:sup>+<\/jats:sup>\n                    T\n                    <jats:sub>IGR<\/jats:sub>\n                    cells, leading to accumulation of inflammatory macrophages and increased susceptibility to colitis. CD8\n                    <jats:sup>+<\/jats:sup>\n                    T\n                    <jats:sub>IGR<\/jats:sub>\n                    cells potently kill macrophages activated by intestinal damage or disease using Fas ligand and TNF-related weak inducer of apoptosis\u00a0(TWEAK). The identification of CD8\n                    <jats:sup>+<\/jats:sup>\n                    T\n                    <jats:sub>IGR<\/jats:sub>\n                    cells yields new insights into organ-specific immune regulation and potential therapeutics for IBD.\n                  <\/jats:p>","DOI":"10.1038\/s41586-026-10749-4","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T15:03:14Z","timestamp":1780930994000},"page":"1003-1012","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["GPR15-guided CD8+ T regulatory cells control intestinal inflammation"],"prefix":"10.1038","volume":"656","author":[{"given":"Jing","family":"Cui","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuojia","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan 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