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Heterogeneous yet stable V?2(+) T-cell profiles define distinct cytotoxic effector potentials in healthy human individuals.

ABSTRACT: Human ?? T cells display potent responses to pathogens and malignancies. Of particular interest are those expressing a ?? T-cell receptor (TCR) incorporating TCR?-chain variable-region-2 [V?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?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 V?2(+) T-cell biology. Here, we reveal previously unappreciated functional heterogeneity between the V?2(+) T-cell compartments of 63 healthy individuals. In this cohort, we identify distinct "V?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?2 profiles consist of variable proportions of two dominant but contrasting V?2(+) T-cell subsets that have divergent transcriptional programs and that display mechanistically distinct cytotoxic potentials. Importantly, an individual's V?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?2 profiles that have effector mechanisms compatible with tumor killing and suggest that tailored V?2-profile-specific activation protocols may maximize the chances of future treatment success.

SUBMITTER: Ryan PL

PROVIDER: S-EPMC5167212 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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

Ryan Paul L PL Sumaria Nital N Holland Christopher J CJ Bradford Claire M CM Izotova Natalia N Grandjean Capucine L CL Jawad Ali S AS Bergmeier Lesley A LA Pennington Daniel J DJ

Proceedings of the National Academy of Sciences of the United States of America 20161128 50

Human γδ T cells display potent responses to pathogens and malignancies. Of particular interest are those expressing a γδ T-cell receptor (TCR) incorporating TCRδ-chain variable-region-2 [Vδ2<sup>(+)</sup>], 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, Vδ2<sup>(+)</sup> T cells exhibit multiple effector functions that have made them attractive candidates for i ...[more]

PMID: 27911793

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Heterogeneous yet stable V?2(+) T-cell profiles define distinct cytotoxic effector potentials in healthy human individuals.

Publications

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

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