TY - JOUR
T1 - Autoimmunity-associated T cell receptors recognize HLA-B*27-bound peptides
AU - Yang, Xinbo
AU - Garner, Lee I.
AU - Zvyagin, Ivan V.
AU - Paley, Michael A.
AU - Komech, Ekaterina A.
AU - Jude, Kevin M.
AU - Zhao, Xiang
AU - Fernandes, Ricardo A.
AU - Hassman, Lynn M.
AU - Paley, Grace L.
AU - Savvides, Christina S.
AU - Brackenridge, Simon
AU - Quastel, Max N.
AU - Chudakov, Dmitriy M.
AU - Bowness, Paul
AU - Yokoyama, Wayne M.
AU - McMichael, Andrew J.
AU - Gillespie, Geraldine M.
AU - Garcia, K. Christopher
N1 - Funding Information:
The study received support from the National Institutes of Health (NIH; 5R01AI103867 (K.C.G.) and U19AI057229 (K.C.G.)), the Howard Hughes Medical Institute (K.C.G.), the UK Medical Research Council (MR/M019837/1; G.M.G., A.J.M. and P.B.), Oxford University McMichael Trust Fund (G.M.G and L.I.G), the Rosetrees Trust (M455; G.M.G.), Oxford University John Fell Fund and Medical Sciences Division Internal Funds (G.M.G. and L.I.G.), the UK National Institute for Health Research Oxford Biomedical Research Centre (BRC) (P.B.), the Ministry of Science and Higher Education of the Russian Federation (075-15-2019-1789; E.A.K., I.V.Z. and D.M.C.), the Rheumatology Research Foundation (M.A.P.), the Arthritis National Research Foundation (M.A.P.), the Rheumatic Diseases Research Resource-based Center at Washington University (NIH P30-AR073752; M.A.P. and W.M.Y.), the Bursky Center for Human Immunology and Immunotherapy Programs (W.M.Y.) and the Barnes-Jewish Hospital Foundation (W.M.Y.). The views expressed are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. We thank the Oxford Genomics Centre at the Wellcome Centre for Human Genetics (Wellcome Trust grant reference 203141/Z/16/Z) for the generation and initial processing of sequencing data and J. Webber (Cell Sorting Facility, Kennedy Institute of Rheumatology, University of Oxford) for conducting cell sorting. We also thank N. Ternette, W. Paes and R. Inman for data analysis advice and scientific discussions. The Berkeley Center for Structural Biology is supported in part by the Howard Hughes Medical institute. The Advanced Light Source is a Department of Energy Office of Science User Facility under Contract No. DE-AC02-05CH11231. The ALS-ENABLE beamlines are supported in part by the NIH, National institute of General Medical Sciences (grant P30 GM124169). The schematic cartoon figures in Fig. and Extended Data Fig. were created with BioRender.com .
Funding Information:
The study received support from the National Institutes of Health (NIH; 5R01AI103867 (K.C.G.) and U19AI057229 (K.C.G.)), the Howard Hughes Medical Institute (K.C.G.), the UK Medical Research Council (MR/M019837/1; G.M.G., A.J.M. and P.B.), Oxford University McMichael Trust Fund (G.M.G and L.I.G), the Rosetrees Trust (M455; G.M.G.), Oxford University John Fell Fund and Medical Sciences Division Internal Funds (G.M.G. and L.I.G.), the UK National Institute for Health Research Oxford Biomedical Research Centre (BRC) (P.B.), the Ministry of Science and Higher Education of the Russian Federation (075-15-2019-1789; E.A.K., I.V.Z. and D.M.C.), the Rheumatology Research Foundation (M.A.P.), the Arthritis National Research Foundation (M.A.P.), the Rheumatic Diseases Research Resource-based Center at Washington University (NIH P30-AR073752; M.A.P. and W.M.Y.), the Bursky Center for Human Immunology and Immunotherapy Programs (W.M.Y.) and the Barnes-Jewish Hospital Foundation (W.M.Y.). The views expressed are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. We thank the Oxford Genomics Centre at the Wellcome Centre for Human Genetics (Wellcome Trust grant reference 203141/Z/16/Z) for the generation and initial processing of sequencing data and J. Webber (Cell Sorting Facility, Kennedy Institute of Rheumatology, University of Oxford) for conducting cell sorting. We also thank N. Ternette, W. Paes and R. Inman for data analysis advice and scientific discussions. The Berkeley Center for Structural Biology is supported in part by the Howard Hughes Medical institute. The Advanced Light Source is a Department of Energy Office of Science User Facility under Contract No. DE-AC02-05CH11231. The ALS-ENABLE beamlines are supported in part by the NIH, National institute of General Medical Sciences (grant P30 GM124169). The schematic cartoon figures in Fig. 1 and Extended Data Fig. 1 were created with BioRender.com.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/12/22
Y1 - 2022/12/22
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85143436762&partnerID=8YFLogxK
U2 - 10.1038/s41586-022-05501-7
DO - 10.1038/s41586-022-05501-7
M3 - Article
C2 - 36477533
AN - SCOPUS:85143436762
SN - 0028-0836
VL - 612
SP - 771
EP - 777
JO - Nature
JF - Nature
IS - 7941
ER -