Autoimmunity-associated T cell receptors recognize HLA-B*27-bound peptides

Xinbo Yang, Lee I. Garner, Ivan V. Zvyagin, Michael A. Paley, Ekaterina A. Komech, Kevin M. Jude, Xiang Zhao, Ricardo A. Fernandes, Lynn M. Hassman, Grace L. Paley, Christina S. Savvides, Simon Brackenridge, Max N. Quastel, Dmitriy M. Chudakov, Paul Bowness, Wayne M. Yokoyama (), Andrew J. McMichael (), Geraldine M. Gillespie () and K. Christopher Garcia ()
Additional contact information
Xinbo Yang: Stanford University School of Medicine
Lee I. Garner: University of Oxford
Ivan V. Zvyagin: Pirogov Russian National Research Medical University
Michael A. Paley: Washington University School of Medicine
Ekaterina A. Komech: Pirogov Russian National Research Medical University
Kevin M. Jude: Stanford University School of Medicine
Xiang Zhao: Stanford University School of Medicine
Ricardo A. Fernandes: Stanford University School of Medicine
Lynn M. Hassman: Washington University School of Medicine
Grace L. Paley: Washington University School of Medicine
Christina S. Savvides: Stanford University School of Medicine
Simon Brackenridge: University of Oxford
Max N. Quastel: University of Oxford
Dmitriy M. Chudakov: Pirogov Russian National Research Medical University
Paul Bowness: University of Oxford
Wayne M. Yokoyama: Washington University School of Medicine
Andrew J. McMichael: University of Oxford
Geraldine M. Gillespie: University of Oxford
K. Christopher Garcia: Stanford University School of Medicine

Nature, 2022, vol. 612, issue 7941, 771-777

Abstract: Abstract Human leucocyte antigen B*27 (HLA-B*27) is strongly associated with inflammatory diseases of the spine and pelvis (for example, ankylosing spondylitis (AS)) and the eye (that is, acute anterior uveitis (AAU))1. How HLA-B*27 facilitates disease remains unknown, but one possible mechanism could involve presentation of pathogenic peptides to CD8+ T cells. Here we isolated orphan T cell receptors (TCRs) expressing a disease-associated public β-chain variable region–complementary-determining region 3β (BV9–CDR3β) motif2–4 from blood and synovial fluid T cells from individuals with AS and from the eye in individuals with AAU. These TCRs showed consistent α-chain variable region (AV21) chain pairing and were clonally expanded in the joint and eye. We used HLA-B*27:05 yeast display peptide libraries to identify shared self-peptides and microbial peptides that activated the AS- and AAU-derived TCRs. Structural analysis revealed that TCR cross-reactivity for peptide–MHC was rooted in a shared binding motif present in both self-antigens and microbial antigens that engages the BV9–CDR3β TCRs. These findings support the hypothesis that microbial antigens and self-antigens could play a pathogenic role in HLA-B*27-associated disease.

Date: 2022
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DOI: 10.1038/s41586-022-05501-7

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