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.

γδ T cells: an immunotherapeutic approach for HIV cure strategies

“…Unfortunately, due to the difficulty in recruiting women (31), our study only included men. However, we acknowledge that gender differences may exist, given controversial findings in previous work according to γδ T cell frequencies (32)(33)(34), that may potentially translate into functional differences. Current work is focused towards this end.…”

Human γδ T‐cell receptor repertoire is shaped by influenza viruses, age and tissue compartmentalisation

“…In contrast, γδ T cells within the CB lacked gzm A, B and K expression, with only gzm M being moderately expressed (̃15%, n = 3; Figure a). As Vδ2 + and Vδ2 − TCRγδ + subsets have previously shown to have differential functional capacities and phenotypic profiles, we further segregated gzm and perforin staining into Vδ2 + and Vδ2 − TCRγδ + subsets. Indeed, our frequency analyses of individual single cytotoxic molecules in healthy adults verified the previous findings and showed that the Vδ2 + T cells had significantly higher frequency of all molecules with the exception of Gzm B, as compared to Vδ2 − TCRγδ + cells (Figure b; P = Gzm A, K, M = 0.008, perforin = 0.023).…”

PD-1 signaling modulates interferon-γ production by Gamma Delta (γδ) T-Cells in response to leukemia

“…Studies analyzing the immune cell repertoire in healthy adults found that PD-1 expression is higher in Vδ1+, compared to Vδ2 + T-cells 15 but similar within several functionally distinctive subsets of Vδ2 T-cells. 16 Others reported differences in PD-1 expression depending on CD27 and CD45RA status with preferential expression in the effector-memory subsets. 9 We found a mean of 40% PD-1(+) on γδ T-cells in unstimulated human peripheral blood (Figure 1(a)) while three earlier studies found lower fractions of PD-1(+) cells (< 10%) 7,10,15 and others reported higher values.…”