Perinatal thymic-derived CD8αβ-expressing γδ T cells are innate IFN-γ producers that expand in IL-7R–STAT5B-driven neoplasms
Nital Sumaria, Gina J. Fiala, Daniel Inácio, Marta Curado-Avelar, Ana Cachucho, Rúben Pinheiro, Robert Wiesheu, Shunsuke Kimura, Lucien Courtois, Birte Blankenhaus, Julie Darrigues, Tobias Suske, Afonso R. M. Almeida, Susana Minguet, Vahid Asnafi, Ludovic Lhermitte, Charles G. Mullighan, Seth B. Coffelt, Richard Moriggl, João T. Barata, Daniel J. Pennington, Bruno Silva‐Santos
Abstract
Abstract 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.