γδ T cells are considered to be innate-like lymphocytes that respond rapidly to stress without clonal selection and differentiation. Here we use next-generation sequencing to probe how this paradigm relates to human Vδ2neg T cells, implicated in responses to viral infection and cancer. The prevalent Vδ1 T cell receptor (TCR) repertoire is private and initially unfocused in cord blood, typically becoming strongly focused on a few high-frequency clonotypes by adulthood. Clonal expansions have differentiated from a naive to effector phenotype associated with CD27 downregulation, retaining proliferative capacity and TCR sensitivity, displaying increased cytotoxic markers and altered homing capabilities, and remaining relatively stable over time. Contrastingly, Vδ2+ T cells express semi-invariant TCRs, which are present at birth and shared between individuals. Human Vδ1+ T cells have therefore evolved a distinct biology from the Vδ2+ subset, involving a central, personalized role for the γδ TCR in directing a highly adaptive yet unconventional form of immune surveillance.

Cancer Immunology and Immunotherapy Centre Institute for Immunology and Immunotherapy University of Birmingham Edgbaston Birmingham B15 2TT UK

Division of Infection and Immunity Cardiff University School of Medicine Heath Park Cardiff CF14 4XN UK

Shemyakin Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences Moscow 117997 Russia Pirogov Russian National Research Medical University Moscow 117997 Russia Central European Institute of Technology Masaryk University Brno 625 00 Czech Republic

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