{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T06:29:15Z","timestamp":1790058555642,"version":"4.0.1"},"reference-count":60,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2020,11,24]],"date-time":"2020-11-24T00:00:00Z","timestamp":1606176000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006364","name":"Institut National Du Cancer","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006364","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Mechanisms driving acute graft-versus-host disease (aGVHD) onset in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) are still poorly understood. To provide a detailed characterization of tissue-infiltrating T lymphocytes (TL) and search for eventual site-specific specificities, we developed a xenogeneic model of aGVHD in immunodeficient mice. Phenotypic characterization of xenoreactive T lymphocytes (TL) in diseased mice disclosed a massive infiltration of GVHD target organs by an original CD4<jats:sup>+<\/jats:sup>CD8<jats:sup>+<\/jats:sup>TL subset. Immunophenotypic and transcriptional profiling shows that CD4<jats:sup>+<\/jats:sup>CD8<jats:sup>+<\/jats:sup>TL comprise a major PD1<jats:sup>+<\/jats:sup>CD62L<jats:sup>\u2212\/+<\/jats:sup>transitional memory subset (&amp;gt;60%) characterized by low level expression of cytotoxicity-related transcripts. CD4<jats:sup>+<\/jats:sup>CD8<jats:sup>+<\/jats:sup>TL produce high IL-10 and IL-13 levels, and low IL-2 and IFN-\u03b3, suggestive of regulatory function. In vivo tracking of genetically labeled CD4<jats:sup>+<\/jats:sup>or CD8<jats:sup>+<\/jats:sup>TL subsequently found that CD4<jats:sup>+<\/jats:sup>CD8<jats:sup>+<\/jats:sup>TL mainly originate from chronically activated cytotoxic TL (CTL). On the other hand, phenotypic profiling of CD3<jats:sup>+<\/jats:sup>TL from blood, duodenum or rectal mucosa in a cohort of allo-HSCT patients failed to disclose abnormal expansion of CD4<jats:sup>+<\/jats:sup>CD8<jats:sup>+<\/jats:sup>TL independent of aGVHD development. Collectively, our results show that acquisition of surface CD4 by xenoreactive CD8<jats:sup>+<\/jats:sup>CTL is associated with functional diversion toward a regulatory phenotype, but rule out a central role of this subset in the pathogenesis of aGVHD in allo-HSCT patients.<\/jats:p>","DOI":"10.3389\/fimmu.2020.579776","type":"journal-article","created":{"date-parts":[[2020,11,24]],"date-time":"2020-11-24T10:21:24Z","timestamp":1606213284000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["CD4+CD8+ T-Lymphocytes in Xenogeneic and Human Graft-versus-Host Disease"],"prefix":"10.3389","volume":"11","author":[{"given":"Kutaiba","family":"Alhaj 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