期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：50
页码：14378-14383
DOI：10.1073/pnas.1611098113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceA type of human white blood cell, known as the V{delta}2(+) T cell, has shown promise in immunotherapies against a range of tumors. However, in recent clinical trials patient responses and clinical outcomes have been variable and unpredictable. To address this, we here reveal a significant variability in V{delta}2(+) T-cell functional potential between individuals in the general population, which develops shortly after birth, is stable over time, and is manifested by differential mechanistic capacities to kill tumor targets. These results support personalized clinical approaches to identify patients with "V{delta}2 profiles" that are compatible with killing of their particular tumor and suggest that tailored V{delta}2-profile-specific activation protocols may maximize the chances of future treatment success. 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 V{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 individuals 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.
关键词：human γδ T cells ; Vδ2(+) T cells ; antitumor cytotoxicity ; functional heterogeneity ; human immunology
