γδ T cell receptor dependencies define a unique immunosurveillance modality

Abstract γδ T cells are one of three lymphocyte lineages that utilize gene rearrangement to diversify their antigen receptors. Nonetheless, the cells’ classification has remained uncertain, complicating our ability to understand the basis for their evolutionary conservation. Whereas many γδ T cells display hallmarks of adaptive immunity, others, including those in barrier tissues, make rapid, reportedly T cell receptor-independent responses that phenocopy innate immune cells 1 . Here we address this paradox and show that the phenotypes of tissue-intrinsic γδ T cells, including their rapid, innate-like responsiveness to tissue stress and carcinogenesis, acutely depend on the γδ T cell receptor (TCRγδ). Those dependencies emphasize the unique biology of γδ T cells and of the immunosurveillance modalities they mediate, with their clinical deployment evidently requiring environments conducive to TCRγδ signalling.