title: Heterogeneous yet stable Vδ2(+) T-cell profiles define distinct cytotoxic effector potentials in healthy human individuals.
abstract: 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(+)], 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(+)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 Vδ2(+)T-cell biology. Here, we reveal previously unappreciated functional heterogeneity between the Vδ2(+)T-cell compartments of 63 healthy individuals. In this cohort, we identify distinct "Vδ2 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 Vδ2 profiles consist of variable proportions of two dominant but contrasting Vδ2(+)T-cell subsets that have divergent transcriptional programs and that display mechanistically distinct cytotoxic potentials. Importantly, an individual's Vδ2 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 Vδ2 profiles that have effector mechanisms compatible with tumor killing and suggest that tailored Vδ2-profile-specific activation protocols may maximize the chances of future treatment success.
authors.affiliation: Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, United Kingdom.|Centre for Adult Oral Health, Institute of Dentistry, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AD, United Kingdom.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Ryan
authors.affiliation: Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, United Kingdom.
authors.forename: Nital
authors.initials: N
authors.lastname: Sumaria
authors.affiliation: Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, United Kingdom.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Holland
authors.affiliation: Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, United Kingdom.
authors.forename: Claire M
authors.initials: CM
authors.lastname: Bradford
authors.affiliation: Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, United Kingdom.
authors.forename: Natalia
authors.initials: N
authors.lastname: Izotova
authors.affiliation: Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, United Kingdom.
authors.forename: Capucine L
authors.initials: CL
authors.lastname: Grandjean
authors.affiliation: Rheumatology Department, Royal London Hospital, London E1 1BB, United Kingdom.
authors.forename: Ali S
authors.initials: AS
authors.lastname: Jawad
authors.affiliation: Centre for Clinical and Diagnostic Oral Sciences, Institute of Dentistry, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, United Kingdom.
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Bergmeier
authors.affiliation: Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, United Kingdom; d.pennington@qmul.ac.uk.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Pennington
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000073883:CX3C Chemokine Receptor 1 / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D003602:Cytotoxicity, Immunologic; D005260:Female; D020869:Gene Expression Profiling; D019676:Genes, T-Cell Receptor delta; D064368:Healthy Volunteers; D006801:Humans; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics / Q000378:metabolism*; D054399:Receptors, CCR6 / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D055815:Young Adult
chemical_list: C106311:CCR6 protein, human; D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; D016692:Receptors, Antigen, T-Cell, gamma-delta; D054399:Receptors, CCR6
keywords: Vδ2(+) T cells; antitumor cytotoxicity; functional heterogeneity; human immunology; human γδ T cells