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We now report that encoding CD8 co-receptors in both\n                    <jats:italic>Cd4<\/jats:italic>\n                    and\n                    <jats:italic>Cd8<\/jats:italic>\n                    gene loci modulates major histocompatibility complex (MHC-I) class I T cell antigen receptor signaling duration to generate all potential CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell subsets. Strikingly, such mice revealed that functionally different CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells are selected by different MHC-I thymic peptides. Thymocytes signaled by \u03b25t-peptides produced by thymoproteasomes exclusively expressed in the thymic cortex invariably become cytotoxic CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells indicating their signaling ceases when thymocytes leave the cortex; whereas thymocytes signaled by non\u03b25t-peptides expressed throughout the thymus become either helper or innate memory CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells because their signaling persists or recurs outside the cortex. Thus, it is because of their different thymic distributions that different MHC-I peptides select functionally different CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells, integrating peptide specificity and CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell function during positive selection and thymocyte migration.\n                  <\/jats:p>","DOI":"10.1038\/s41590-025-02411-4","type":"journal-article","created":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T10:02:32Z","timestamp":1768816952000},"page":"786-798","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Unraveling CD8 lineage decisions reveals that functionally distinct CD8+ T cells are selected by different MHC-I thymic peptides"],"prefix":"10.1038","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7174-2464","authenticated-orcid":false,"given":"Miho","family":"Shinzawa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Ramos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khanh","family":"Bui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7796-6495","authenticated-orcid":false,"given":"William","family":"Hajjar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5746-0073","authenticated-orcid":false,"given":"Assiatu","family":"Crossman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiongfong","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret","family":"Cam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4992-9174","authenticated-orcid":false,"given":"Yousuke","family":"Takahama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6780-5108","authenticated-orcid":false,"given":"Alfred","family":"Singer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,19]]},"reference":[{"key":"2411_CR1","doi-asserted-by":"publisher","first-page":"1983","DOI":"10.4049\/jimmunol.1600032","volume":"196","author":"DR Littman","year":"2016","unstructured":"Littman, D. 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