Autoimmunity-associated T cell receptors recognize HLA-B27-bound peptides

• Published in: Nature (London) Vol. 612; no. 7941; pp. 771 - 777
• Main Authors: Yang, Xinbo, Garner, Lee I., Zvyagin, Ivan V., Paley, Michael A., Komech, Ekaterina A., Jude, Kevin M., Zhao, Xiang, Fernandes, Ricardo A., Hassman, Lynn M., Paley, Grace L., Savvides, Christina S., Brackenridge, Simon, Quastel, Max N., Chudakov, Dmitriy M., Bowness, Paul, Yokoyama, Wayne M., McMichael, Andrew J., Gillespie, Geraldine M., Garcia, K. Christopher
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22-12-2022; Nature Publishing Group
• Subjects: 38/23; 631/250/38; 692/699/1670/2766; 82/103; 82/47; 82/83; Amino Acid Motifs; Ankylosing spondylitis; Antigens; Autoantigens; Autoantigens - chemistry; Autoantigens - immunology; Autoantigens - metabolism; Autoimmunity; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Chains; Chlamydia; Cross Reactions; Cross-reactivity; Disease; Histocompatibility antigen HLA; HLA-B Antigens - immunology; HLA-B Antigens - metabolism; Humanities and Social Sciences; Humans; Hypotheses; Inflammatory diseases; Leukocytes; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Microorganisms; multidisciplinary; Patients; Pelvis; Peptide libraries; Peptide Library; Peptides; Peptides - chemistry; Peptides - immunology; Peptides - metabolism; Receptors; Receptors, Antigen, T-Cell - chemistry; Receptors, Antigen, T-Cell - immunology; Receptors, Antigen, T-Cell - metabolism; Salmonella; Science; Science & Technology - Other Topics; Science (multidisciplinary); Spine; Spondylitis, Ankylosing - immunology; Structural analysis; Synovial fluid; Synovial Fluid - immunology; T cell receptors; Uveitis; Uveitis, Anterior - immunology; Variable region; Yeast; Yeasts
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-022-05501-7

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.
A study shows that cross-reactivity of microbial antigens and self-antigens presented by HLA-B*27 may be important in the pathogenesis of diseases associated with HLA-B*27 and identifies the shared binding motif responsible.