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Here we uncover a previously unrecognized role for MHC class I in modulating CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cell-mediated immunity. In allogeneic graft-versus-host disease and tumor models, we demonstrate that the absence of MHC class I on target cells significantly increases their susceptibility to CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cell cytotoxicity. Transcriptomic and functional studies suggest that this was because of heightened sensitivity to enhanced ferroptosis of the target cells. In large human transcriptomic and sequencing datasets, a role for CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells in enhancing immune checkpoint blocker-mediated responses in persons with melanoma and mismatch-repair-deficient colon cancers that have downregulated MHC class I was suggested. These findings revise and expand the known role of MHC class I in CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell and natural killer cell immunity and demonstrate a previously unrecognized role in CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cell-mediated cancer and alloimmunity.\n                  <\/jats:p>","DOI":"10.1038\/s41590-026-02480-z","type":"journal-article","created":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T10:01:41Z","timestamp":1774346501000},"page":"1000-1012","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["MHC class I on target cells regulates CD4+ T cell-mediated immunity"],"prefix":"10.1038","volume":"27","author":[{"given":"Emma","family":"Lauder","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahnoor","family":"Gondal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-1204-7887","authenticated-orcid":false,"given":"Meng-Chih","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7574-6446","authenticated-orcid":false,"given":"Akira","family":"Yamamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0044-5395","authenticated-orcid":false,"given":"Laure","family":"Maneix","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongchang","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaping","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcin","family":"Cieslik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9282-3415","authenticated-orcid":false,"given":"Arul M.","family":"Chinnaiyan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7264-8429","authenticated-orcid":false,"given":"Pavan","family":"Reddy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,24]]},"reference":[{"key":"2480_CR1","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1038\/251547a0","volume":"251","author":"RM Zinkernagel","year":"1974","unstructured":"Zinkernagel, R. 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