Perinatal thymic-derived CD8αβ-expressing γδ T cells are innate IFN-γ producers that expand in IL-7R–STAT5B-driven neoplasms

© 2024 Springer Nature Limited. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The contribution of γδ T cells to immune responses is associated with rapid secretion of interferon-γ (IFN-γ). Here, we show a perinatal thymic wave of innate IFN-γ-producing γδ T cells that express CD8αβ heterodimers and expand in preclinical models of infection and cancer. Optimal CD8αβ+ γδ 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-STAT5B signaling promotes a supraphysiological accumulation of CD8αβ+ γδ T cells in the thymus and peripheral lymphoid organs in two mouse models of T cell neoplasia. Likewise, CD8αβ+ γδ T cells define a distinct subset of human T cell acute lymphoblastic leukemia pediatric patients. This work characterizes the normal and malignant development of CD8αβ+ γδ T cells that are enriched in early life and contribute to innate IFN-γ responses to infection and cancer. This work was supported by the BBSRC (BB/R017808/1; to D.J.P.); Fundação para a Ciência e Tecnologia (PTDC/MED-ONC/6829/2020 to B.S.-S.; SFRH/BD/145352/2019 to D.I. and SFRH/BD/147411/2019 to A.C.); European Molecular Biology Organization (ALTF 252-2017 to G.J.F.), European Commission Marie Sklodowska-Curie Individual Fellowship (752932 to G.J.F.); Neue Universitätsstiftung Freiburg (‘Come and STAY!’ to G.J.F.); European Research Council (ERC-PoC-101069429 to J.T.B.); ‘la Caixa’ Foundation (HR21-00761 to J.T.B.); and Worldwide Cancer Research (WWCR 24-0426 to J.T.B.) a