The human V\u03b42+ T-cell compartment comprises distinct innate-like V\u03b39+ and adaptive V\u03b39- subsets

Martin S Davey,Fiyaz Mohammed,Frederike J Bemelman,Dmitriy M Chudakov,Benjamin E Willcox,Ester B M Remmerswaal,Carrie R Willcox,Mahboob Salim,Sofya A Kasatskaya,Ye H Oo,Stuart Hunter

doi:10.1038/s41467-018-04076-0

Abstract

Vδ2+ T cells form the predominant human γδ T-cell population in peripheral blood and mediate T-cell receptor (TCR)-dependent anti-microbial and anti-tumour immunity. Here we show that the Vδ2+ compartment comprises both innate-like and adaptive subsets. Vγ9+ Vδ2+ T cells display semi-invariant TCR repertoires, featuring public Vγ9 TCR sequences equivalent in cord and adult blood. By contrast, we also identify a separate, Vγ9− Vδ2+ T-cell subset that typically has a CD27hiCCR7+CD28+IL-7Rα+ naive-like phenotype and a diverse TCR repertoire, however in response to viral infection, undergoes clonal expansion and differentiation to a CD27loCD45RA+CX3CR1+granzymeA/B+ effector phenotype. Consistent with a function in solid tissue immunosurveillance, we detect human intrahepatic Vγ9− Vδ2+ T cells featuring dominant clonal expansions and an effector phenotype. These findings redefine human γδ T-cell subsets by delineating the Vδ2+ T-cell compartment into innate-like (Vγ9+) and adaptive (Vγ9−) subsets, which have distinct functions in microbial immunosurveillance.

Highlights

Vδ2+ T cells form the predominant human γδ T-cell population in peripheral blood and mediate T-cell receptor (TCR)-dependent anti-microbial and anti-tumour immunity
Vγ9+ Vδ2+ T cells respond to prenyl pyrophosphate metabolites produced either by the host mevalonate pathway or microbial non-mevalonate pathway ((E)-4-Hydroxy-3methyl-but-2-enyl pyrophosphate, HMB-PP)[14], which are sensed in the context of butyrophilin 3A1 (BTN3A1)[15,16,17]
Our findings suggest Vδ2+ T cells can be delineated into two discrete subsets: Vγ9+ Vδ2+ T cells adopt a predominantly innate-like biology originating in neonatal development and allowing a degree of clonotypic plasticity, whereas Vγ9− Vδ2+ T cells adopt a distinct adaptive immunobiology, including focused clonal expansions and differentiation evident both in peripheral blood and solid tissues, and generated in response to acute viral infection

Summary

Introduction

Vδ2+ T cells form the predominant human γδ T-cell population in peripheral blood and mediate T-cell receptor (TCR)-dependent anti-microbial and anti-tumour immunity. T cells featuring dominant clonal expansions and an effector phenotype These findings redefine human γδ T-cell subsets by delineating the Vδ2+ T-cell compartment into innate-like (Vγ9+) and adaptive (Vγ9−) subsets, which have distinct functions in microbial immunosurveillance. Vγ9+ Vδ2+ T cells respond to prenyl pyrophosphate metabolites (phosphoantigens, or P-Ags) produced either by the host mevalonate pathway (isopentenyl pyrophosphate, IPP) or microbial non-mevalonate pathway ((E)-4-Hydroxy-3methyl-but-2-enyl pyrophosphate, HMB-PP)[14], which are sensed in the context of butyrophilin 3A1 (BTN3A1)[15,16,17] They mount important anti-microbial immune responses, including against Mycobacterium tuberculosis[13] and Plasmodium falciparum[18], and drive αβ T-cell responses[19,20]

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Results

Conclusion