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Natural killer (NK) and T cells have evolved to detect and destroy cells infected with pathogens and to provide an early response to malignancies. While it is known that NMRs lack NK cells, likely lost during evolution, little is known about their T-cell subsets in terms of the evolution of the genes that regulate their function, their clonotypic diversity, and the thymus where they mature. Here we find, using single-cell transcriptomics, that NMRs have a large circulating population of \u03b3\u03b4T cells, which in mice and humans mostly reside in peripheral tissues and induce anti-cancer cytotoxicity. Using single-cell-T-cell-receptor sequencing, we find that a cytotoxic \u03b3\u03b4T-cell subset of NMRs harbors a dominant clonotype, and that their conventional CD8 \u03b1\u03b2T cells exhibit modest clonotypic diversity. Consistently, perinatal NMR thymuses are considerably smaller than those of mice yet follow similar involution progression. Our findings suggest that NMRs have evolved under a relaxed intracellular pathogenic selective pressure that may have allowed cancer resistance and longevity to become stronger targets of selection to which the immune system has responded by utilizing \u03b3\u03b4T cells.<\/jats:p>","DOI":"10.1038\/s41467-024-47264-x","type":"journal-article","created":{"date-parts":[[2024,4,11]],"date-time":"2024-04-11T10:01:55Z","timestamp":1712829715000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Evolution of T cells in the cancer-resistant naked mole-rat"],"prefix":"10.1038","volume":"15","author":[{"given":"Tzuhua D.","family":"Lin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7818-7868","authenticated-orcid":false,"given":"Nimrod D.","family":"Rubinstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole L.","family":"Fong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy","family":"Craft","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baby","family":"Martin-McNulty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Perry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martha A.","family":"Delaney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret A.","family":"Roy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3285-8311","authenticated-orcid":false,"given":"Rochelle","family":"Buffenstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,4,11]]},"reference":[{"key":"47264_CR1","unstructured":"Janeway, J. 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