Evolution of the tuberculin skin test reveals generalisable Mtb-reactive T cell metaclones

TL;DR

This study uses T cell receptor sequencing at the site of the tuberculin skin test to identify common T cell responses to tuberculosis, which could help in vaccine development and patient stratification.

Contribution

The study introduces a computational pipeline, Metaclonotypist, to identify public Mtb-reactive T cell metaclones across individuals.

Findings

Initial T cell recruitment is non-selective, followed by enrichment of Mtb-reactive clones.

Ten metaclones were sufficient to identify Mtb reactivity across a large study population.

Public TCR-peptide interactions show population-level immunodominance in tuberculosis.

Abstract

T cells contribute to immune protection and pathogenesis in tuberculosis, but measurements of polyclonal responses have failed to resolve correlates of outcome. We report the temporal evaluation of the human in vivo clonal repertoire of Mycobacterium tuberculosis (Mtb)-reactive T cell responses, by T cell receptor (TCR) sequencing at the site of the tuberculin skin test, as a model for a standardised antigenic challenge. Initial non-selective recruitment of T cells is followed by enrichment of Mtb-reactive clones arising from oligoclonal T cell proliferation. We introduce a modular computational pipeline, Metaclonotypist, to sensitively cluster distinct TCRs with shared epitope specificity, which we apply here to establish a catalogue of public Mtb-reactive HLA-restricted T cell metaclones. Although most in vivo Mtb-reactive T cells are private, 10 metaclones were sufficient to identify Mtb-T cell reactivity across our study population (N≥128), indicating striking population level immunodominance of specific TCR-peptide interactions that may inform patient stratification and vaccine development.

T cells contribute to protection and pathogenesis in tuberculosis. Here the authors sequence T cell receptor repertoires in human skin biopsies from the site of the tuberculin skin test and show enrichment of clonotypes reactive to Mycobacterium tuberculosis using a computational pipeline metaclonotypist to identify distinct TCRs predicted to share peptide-MHC reactivity across participants, as an approach to explore T cell correlates of tuberculosis disease-risk stratification and vaccine efficacy.

Figures