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; K Christopher Garcia

doi:10.1038/s41586-022-05501-7

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

Nature. 2022 Dec;612(7941):771-777. doi: 10.1038/s41586-022-05501-7. Epub 2022 Dec 7.

Authors

Xinbo Yang^#^{1

2}, Lee I Garner^#^{3

4}, Ivan V Zvyagin^#^{5

6}, Michael A Paley^#⁷, Ekaterina A Komech^{5

6}, Kevin M Jude^{1

2}, Xiang Zhao^{1

2}, Ricardo A Fernandes^{1

2}, Lynn M Hassman⁸, Grace L Paley⁸, Christina S Savvides^{1

2}, Simon Brackenridge^{3

4}, Max N Quastel^{3

4}, Dmitriy M Chudakov^{5

6}, Paul Bowness⁹, Wayne M Yokoyama^{10

11}, Andrew J McMichael^{12

13}, Geraldine M Gillespie^{14

15}, K Christopher Garcia^{16

17

18}

Affiliations

¹ Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.
² Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.
³ NDM Research Building, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
⁴ Centre for Immuno-oncology, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
⁵ Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Institute of Translational Medicine, Pirogov Russian National Research Medical University, Moscow, Russian Federation.
⁶ Genomics of Adaptive Immunity Department, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russian Federation.
⁷ Rheumatology Division, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
⁸ Department of Ophthalmology, Washington University School of Medicine, St Louis, MO, USA.
⁹ Nuffield Department of Orthopaedics Rheumatology and Muscuoskeletal Science (NDORMS), Botnar Research Center, University of Oxford, Oxford, UK.
¹⁰ Rheumatology Division, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA. [email protected].
¹¹ Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St Louis, MO, USA. [email protected].
¹² NDM Research Building, Nuffield Department of Medicine, University of Oxford, Oxford, UK. [email protected].
¹³ Centre for Immuno-oncology, Nuffield Department of Medicine, University of Oxford, Oxford, UK. [email protected].
¹⁴ NDM Research Building, Nuffield Department of Medicine, University of Oxford, Oxford, UK. [email protected].
¹⁵ Centre for Immuno-oncology, Nuffield Department of Medicine, University of Oxford, Oxford, UK. [email protected].
¹⁶ Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. [email protected].
¹⁷ Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA. [email protected].
¹⁸ Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA. [email protected].

^# Contributed equally.

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) motif^2-4 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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Amino Acid Motifs
Autoantigens / chemistry
Autoantigens / immunology
Autoantigens / metabolism
Autoimmunity*
CD8-Positive T-Lymphocytes / immunology
CD8-Positive T-Lymphocytes / metabolism
Cross Reactions
HLA-B Antigens* / immunology
HLA-B Antigens* / metabolism
Humans
Peptide Library
Peptides* / chemistry
Peptides* / immunology
Peptides* / metabolism
Receptors, Antigen, T-Cell* / chemistry
Receptors, Antigen, T-Cell* / immunology
Receptors, Antigen, T-Cell* / metabolism
Spondylitis, Ankylosing / immunology
Synovial Fluid / immunology
Uveitis, Anterior / immunology

Substances

Autoantigens
HLA-B Antigens
Peptides
Receptors, Antigen, T-Cell
Peptide Library

Abstract

Publication types

MeSH terms

Substances

Grants and funding