Lim Jia Jia, Jones Claerwen M, Loh Tiing Jen, Ting Yi Tian, Zareie Pirooz, Loh Khai L, Felix Nathan J, Suri Anish, McKinnon Murray, Stevenaert Frederik, Sharma Ravi K, Klareskog Lars, Malmström Vivianne, Baker Daniel G, Purcell Anthony W, Reid Hugh H, La Gruta Nicole L, Rossjohn Jamie
Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.
Janssen Research & Development LLC, Horsham, Philadelphia, PA, USA.
Sci Immunol. 2021 Apr 16;6(58). doi: 10.1126/sciimmunol.abe0896.
Individuals expressing HLA-DR4 bearing the shared susceptibility epitope (SE) have an increased risk of developing rheumatoid arthritis (RA). Posttranslational modification of self-proteins via citrullination leads to the formation of neoantigens that can be presented by HLA-DR4 SE allomorphs. However, in T cell-mediated autoimmunity, the interplay between the HLA molecule, posttranslationally modified epitope(s), and the responding T cell repertoire remains unclear. In HLA-DR4 transgenic mice, we show that immunization with a Fibβ-74cit peptide led to a population of HLA-DR4 tetramer T cells that exhibited biased T cell receptor (TCR) β chain usage, which was attributable to selective clonal expansion from the preimmune repertoire. Crystal structures of pre- and postimmune TCRs showed that the SE of HLA-DR4 represented a main TCR contact zone. Immunization with a double citrullinated epitope (Fibβ-72,74cit) altered the responding HLA-DR4 tetramer T cell repertoire, which was due to the P2-citrulline residue interacting with the TCR itself. We show that the SE of HLA-DR4 has dual functionality, namely, presentation and a direct TCR recognition determinant. Analogous biased TCR β chain usage toward the Fibβ-74cit peptide was observed in healthy HLA-DR4 individuals and patients with HLA-DR4 RA, thereby suggesting a link to human RA.
表达带有共享易感性表位（SE）的HLA - DR4的个体患类风湿性关节炎（RA）的风险增加。通过瓜氨酸化对自身蛋白进行翻译后修饰会导致新抗原的形成，这些新抗原可由HLA - DR4 SE同种异型呈现。然而，在T细胞介导的自身免疫中，HLA分子、翻译后修饰的表位与反应性T细胞库之间的相互作用仍不清楚。在HLA - DR4转基因小鼠中，我们发现用Fibβ - 74cit肽免疫会导致一群HLA - DR4四聚体T细胞，这些细胞表现出偏向性的T细胞受体（TCR）β链使用情况，这归因于来自免疫前库的选择性克隆扩增。免疫前和免疫后TCR的晶体结构表明，HLA - DR4的SE代表了一个主要的TCR接触区。用双瓜氨酸化表位（Fibβ - 72,74cit）免疫改变了反应性HLA - DR4四聚体T细胞库，这是由于P2 - 瓜氨酸残基与TCR本身相互作用所致。我们表明，HLA - DR4的SE具有双重功能，即呈递和直接的TCR识别决定因素。在健康的HLA - DR4个体和HLA - DR4 RA患者中观察到了类似的针对Fibβ - 74cit肽的偏向性TCR β链使用情况，从而提示与人类RA存在联系。
