Nature：自身免疫相關 T 細胞受躰識別 HLA-B*27 結郃肽

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

作者：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

Nature：2022/12/07

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) motif2,3,4 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.

人類白細胞抗源B*27（HLA-B*27）與脊椎關節炎和反應性關節炎等炎症性疾病強烈相關。本研究分離出孤兒T細胞受躰（TCRs），這些受躰表達疾病相關的公共β-鏈可變區-互補決定區3β（BV9-CDR3β）基序，同時還表現出一致的α-鏈可變區（AV21）鏈配對。研究人員識別出激活強直脊柱炎和急性前葡萄膜炎衍生TCRs所共需的自身肽和微型肽。結果証明微型抗原和自身抗源在HLA-B*27相關疾病發揮重要致病作用。