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

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.

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Publication Details

Journal
Nature Communications
Published
2026-01-21
DOI
https://doi.org/10.1038/s41467-026-68678-9
Primary Topic
vaccines and immunoinformatics approaches
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Paul Ogongo, Werner Smidt, M. I. K. Berkeley, S Lozewicz et al.
Nature Communications
vaccines and immunoinformatics approaches
article

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

Paul Ogongo, Werner Smidt, M. I. K. Berkeley, S Lozewicz, Aneesh Chandran, Gabriele Pollara, Veron Ramsuran, Rachel Byng-Maddick, Gayathri Nageswaran, H Kunst, Jana Jiang, Santino Capocci, Alasdair J. Leslie, Carolin T. Turner, Ritin Saxena, Flora Pang, Suzanne Byrne, Benjamin M. Chain, Akshay Karthikeyan, Julian C. Knight, Imran Uddin, Andreas Tiffeau-Mayer, Marc Lipman, Mahdad Noursadeghi, Ping Zhang, Joshua Rosenheim
article en

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.

Nature CommunicationsVol. 17(1)
University of Copenhagen (DK), Centre for Human Genetics (GB), University College London Hospitals NHS Foundation Trust (GB), University of Freiburg (DE), Queen Mary University of London (GB), Royal Free London NHS Foundation Trust (GB), University of California, San Francisco (US), Centre for the AIDS Programme of Research in South Africa (ZA), University Medical Center Freiburg (DE), University of Oxford (GB), Africa Health Research Institute (ZA), Whittington Health NHS Trust (GB), North Middlesex Hospital (GB), Institute of Infection and Immunity (CA), University College London (GB), Middlesex University London (GB), University of KwaZulu-Natal (ZA)
Wellcome Trust, National Institute for Health and Care Research, University College London, Deutsche Forschungsgemeinschaft, NIHR Oxford Biomedical Research Centre
Good health and well-being
Openalex Percentile: Top 82%
vaccines and immunoinformatics approaches
DOIOpen Access PDFOpenAlex
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