Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Australia.
Janssen Research & Development, LLC, Horsham, Philadelphia, PA, USA.
Nat Commun. 2024 Jul 23;15(1):6201. doi: 10.1038/s41467-024-50511-w.
CD4 T cells recognising citrullinated self-epitopes presented by HLA-DRB1 bearing the shared susceptibility epitope (SE) are implicated in rheumatoid arthritis (RA). However, the underlying T cell receptor (TCR) determinants of epitope specificity towards distinct citrullinated peptide antigens, including vimentin-64cit and α-enolase-15cit remain unclear. Using HLA-DR4-tetramers, we examine the T cell repertoire in HLA-DR4 transgenic mice and observe biased TRAV6 TCR gene usage across these two citrullinated epitopes which matches with TCR bias previously observed towards the fibrinogen β-74cit epitope. Moreover, shared TRAV26-1 gene usage is evident in four α-enolase-15cit reactive T cells in three human samples. Crystal structures of mouse TRAV6 and human TRAV26-1 TCR-HLA-DR4 complexes presenting vimentin-64cit and α-enolase-15cit, respectively, show three-way interactions between the TCR, SE, citrulline, and the basis for the biased selection of TRAV genes. Position 2 of the citrullinated epitope is a key determinant underpinning TCR specificity. Accordingly, we provide a molecular basis of TCR specificity towards citrullinated epitopes.
CD4 T 细胞识别由携带共享易感性表位 (SE) 的 HLA-DRB1 呈递的瓜氨酸化自身表位与类风湿关节炎 (RA) 有关。然而，针对不同瓜氨酸化肽抗原（包括 vimentin-64cit 和 α-烯醇酶-15cit）的表位特异性的 T 细胞受体 (TCR) 决定因素尚不清楚。我们使用 HLA-DR4-四聚体，检查 HLA-DR4 转基因小鼠中的 T 细胞库，并观察到这两个瓜氨酸化表位的 TRAV6 TCR 基因使用存在偏向性，这与先前观察到的针对纤维蛋白原 β-74cit 表位的 TCR 偏向性相匹配。此外，在三个人类样本中的四个对 α-烯醇酶-15cit 有反应的 T 细胞中，明显存在共享的 TRAV26-1 基因使用。分别呈现 vimentin-64cit 和 α-烯醇酶-15cit 的小鼠 TRAV6 和人 TRAV26-1 TCR-HLA-DR4 复合物的晶体结构显示 TCR、SE、瓜氨酸之间的三向相互作用，以及 TRAV 基因的偏性选择的基础。瓜氨酸化表位的位置 2 是决定 TCR 特异性的关键决定因素。因此，我们为 TCR 对瓜氨酸化表位的特异性提供了分子基础。
