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Here, we show a perinatal thymic wave of innate IFN-\u03b3-producing \u03b3\u03b4 T cells that express CD8\u03b1\u03b2 heterodimers and expand in preclinical models of infection and cancer. Optimal CD8\u03b1\u03b2<jats:sup>+<\/jats:sup> \u03b3\u03b4 T cell development is directed by low T cell receptor signaling and through provision of interleukin (IL)-4 and IL-7. This population is pathologically relevant as overactive, or constitutive, IL-7R\u2013STAT5B signaling promotes a supraphysiological accumulation of CD8\u03b1\u03b2<jats:sup>+<\/jats:sup> \u03b3\u03b4 T cells in the thymus and peripheral lymphoid organs in two mouse models of T cell neoplasia. Likewise, CD8\u03b1\u03b2<jats:sup>+<\/jats:sup> \u03b3\u03b4 T cells define a distinct subset of human T cell acute lymphoblastic leukemia pediatric patients. This work characterizes the normal and malignant development of CD8\u03b1\u03b2<jats:sup>+<\/jats:sup> \u03b3\u03b4 T cells that are enriched in early life and contribute to innate IFN-\u03b3 responses to infection and cancer.<\/jats:p>","DOI":"10.1038\/s41590-024-01855-4","type":"journal-article","created":{"date-parts":[[2024,5,27]],"date-time":"2024-05-27T10:01:49Z","timestamp":1716804109000},"page":"1207-1217","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Perinatal thymic-derived CD8\u03b1\u03b2-expressing \u03b3\u03b4 T cells are innate IFN-\u03b3 producers that expand in IL-7R\u2013STAT5B-driven neoplasms"],"prefix":"10.1038","volume":"25","author":[{"given":"Nital","family":"Sumaria","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8226-5584","authenticated-orcid":false,"given":"Gina J.","family":"Fiala","sequence":"additional","affiliation":[]},{"given":"Daniel","family":"In\u00e1cio","sequence":"additional","affiliation":[]},{"given":"Marta","family":"Curado-Avelar","sequence":"additional","affiliation":[]},{"given":"Ana","family":"Cachucho","sequence":"additional","affiliation":[]},{"given":"R\u00faben","family":"Pinheiro","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2079-4413","authenticated-orcid":false,"given":"Robert","family":"Wiesheu","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2158-467X","authenticated-orcid":false,"given":"Shunsuke","family":"Kimura","sequence":"additional","affiliation":[]},{"given":"Lucien","family":"Courtois","sequence":"additional","affiliation":[]},{"given":"Birte","family":"Blankenhaus","sequence":"additional","affiliation":[]},{"given":"Julie","family":"Darrigues","sequence":"additional","affiliation":[]},{"given":"Tobias","family":"Suske","sequence":"additional","affiliation":[]},{"given":"Afonso R. 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