Heterogeneous yet stable Vδ2(+) T-cell profiles define distinct cytotoxic effector potentials in healthy human individuals

Human gamma delta T cells display potent responses to pathogens and malignancies. Of particular interest are those expressing a gamma delta T-cell receptor (TCR) incorporating TCR delta-chain variable-region-2 [V delta 2((+))], which are activated by pathogen-derived phosphoantigens (pAgs), or host-derived pAgs that accumulate in transformed cells or in cells exposed to aminobisphosphonates. Once activated, V delta 2((+)) T cells exhibit multiple effector functions that have made them attractive candidates for immunotherapy. Despite this, clinical trials have reported mixed patient responses, highlighting a need for better understanding of Vd delta 2((+)) T-cell biology. Here, we reveal previously unappreciated functional heterogeneity between the V delta 2((+)) T-cell compartments of 63 healthy individuals. In this cohort, we identify distinct "V delta 2 profiles" that are stable over time; that do not correlate with age, gender, or history of phosphoantigen activation; and that develop after leaving the thymus. Multiple analyses suggest these V delta 2 profiles consist of variable proportions of two dominant but contrasting V delta 2((+)) T-cell subsets that have divergent transcriptional programs and that display mechanistically distinct cytotoxic potentials. Importantly, an individual's V delta 2 profile predicts defined effector capacities, demonstrated by contrasting mechanisms and efficiencies of killing of a range of tumor cell lines. In short, these data support patient stratification to identify individuals with V delta 2 profiles that have effector mechanisms compatible with tumor killing and suggest that tailored V delta 2-profile-specific activation protocols may maximize the chances of future treatment success.