小柯机器人

美国斯坦福大学医学院K. Christopher Garcia等研究人员合作发现，自身免疫相关的T细胞受体识别HLA-B*27结合的多肽。这一研究成果于2022年12月7日在线发表在国际学术期刊《自然》上。

研究人员表示，人类白细胞抗原B*27（HLA-B*27）与脊柱和骨盆（如强直性脊柱炎AS）和眼睛（即急性前葡萄膜炎AAU）的炎症性疾病密切相关。HLA-B*27如何促进疾病的发生仍是未知数，但一个可能的机制可能涉及致病肽对CD8⁺T细胞的呈递。

研究人员从AS患者的血液和滑膜液T细胞以及AAU患者的眼睛中分离出了表达疾病相关的公共β链可变区-互补决定区3β（BV9-CDR3β）模体的孤儿T细胞受体（TCR）。这些TCR显示出一致的α-链可变区（AV21）链配对，并在关节和眼睛中克隆性地扩展。研究人员使用HLA-B*27:05酵母展示肽库来确定了激活AS和AAU延伸的TCR的共享自体肽和微生物肽。

结构分析显示，TCR对肽-MHC的交叉反应性源于存在于自我抗原和微生物抗原中的一个共享的结合模体，该模体与BV9-CDR3β TCR相结合。这些发现支持微生物抗原和自我抗原可能在HLA-B*27相关疾病中发挥致病作用的假设。

附：英文原文

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

Author: 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

Issue&Volume: 2022-12-07

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) motif2,3,4 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.

DOI: 10.1038/s41586-022-05501-7

Source: https://www.nature.com/articles/s41586-022-05501-7

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
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