表位
瓜氨酸化
T细胞受体
人类白细胞抗原
自身免疫
抗原
免疫学
生物
人口
T细胞
细胞生物学
主要组织相容性复合体
免疫系统
瓜氨酸
遗传学
精氨酸
医学
氨基酸
环境卫生
作者
Jia Jia Lim,Claerwen M. Jones,Tiing Jen Loh,Yi Tian Ting,Pirooz Zareie,Khai Lee Loh,Nathan Felix,Anish Suri,Murray McKinnon,Frederik Stevenaert,Ravi Sharma,Lars Klareskog,Vivianne Malmström,Daniel Baker,Anthony W. Purcell,Hugh H. Reid,Nicole L. La Gruta,Jamie Rossjohn
出处
期刊:Science immunology
[American Association for the Advancement of Science (AAAS)]
日期:2021-04-02
卷期号:6 (58)
被引量:13
标识
DOI:10.1126/sciimmunol.abe0896
摘要
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-74cit69-81 peptide led to a population of HLA-DR4Fibβ-74cit69-81 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-72,74cit69-81) 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-74cit69-81 peptide was observed in healthy HLA-DR4+ individuals and patients with HLA-DR4+ RA, thereby suggesting a link to human RA.
科研通智能强力驱动
Strongly Powered by AbleSci AI