Neoself-antigens are the primary target for autoreactive T cells in human lupus

IF 45.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Cell Pub Date : 2024-09-13 DOI:10.1016/j.cell.2024.08.025

Shunsuke Mori, Masako Kohyama, Yoshiaki Yasumizu, Asa Tada, Kaito Tanzawa, Tatsuya Shishido, Kazuki Kishida, Hui Jin, Masayuki Nishide, Shoji Kawada, Daisuke Motooka, Daisuke Okuzaki, Ryota Naito, Wataru Nakai, Teru Kanda, Takayuki Murata, Chikashi Terao, Koichiro Ohmura, Noriko Arase, Tomohiro Kurosaki, Hisashi Arase

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Abstract

Major histocompatibility complex class II (MHC-II) is the most significant genetic risk factor for systemic lupus erythematosus (SLE), but the nature of the self-antigens that trigger autoimmunity remains unclear. Unusual self-antigens, termed neoself-antigens, are presented on MHC-II in the absence of the invariant chain essential for peptide presentation. Here, we demonstrate that neoself-antigens are the primary target for autoreactive T cells clonally expanded in SLE. When neoself-antigen presentation was induced by deleting the invariant chain in adult mice, neoself-reactive T cells were clonally expanded, leading to the development of lupus-like disease. Furthermore, we found that neoself-reactive CD4⁺ T cells were significantly expanded in SLE patients. A high frequency of Epstein-Barr virus reactivation is a risk factor for SLE. Neoself-reactive lupus T cells were activated by Epstein-Barr-virus-reactivated cells through downregulation of the invariant chain. Together, our findings imply that neoself-antigen presentation by MHC-II plays a crucial role in the pathogenesis of SLE.

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新自身抗原是人类狼疮中自身反应性 T 细胞的主要靶标

主要组织相容性复合体II类（MHC-II）是系统性红斑狼疮（SLE）最重要的遗传风险因素，但引发自身免疫的自身抗原的性质仍不清楚。不寻常的自身抗原被称为新自身抗原（neoself-antigens），它们呈现在MHC-II上时缺少肽呈现所必需的不变链。在这里，我们证明了新自身抗原是系统性红斑狼疮中克隆扩增的自身反应性 T 细胞的主要靶标。当通过删除成年小鼠的不变链诱导新自身抗原呈递时，新自身反应性T细胞会克隆扩增，从而导致狼疮样疾病的发生。此外，我们还发现，系统性红斑狼疮患者的新自身反应性 CD4+ T 细胞显著扩增。高频率的爱泼斯坦-巴氏病毒再激活是系统性红斑狼疮的一个危险因素。新自身反应性狼疮T细胞通过下调不变链被Epstein-Barr病毒活化的细胞激活。总之，我们的研究结果表明，MHC-II呈递的新自身抗原在系统性红斑狼疮的发病机制中起着至关重要的作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell 生物-生化与分子生物学

CiteScore

110.00

自引率

0.80%

发文量

396

审稿时长

2 months

期刊介绍： Cells is an international, peer-reviewed, open access journal that focuses on cell biology, molecular biology, and biophysics. It is affiliated with several societies, including the Spanish Society for Biochemistry and Molecular Biology (SEBBM), Nordic Autophagy Society (NAS), Spanish Society of Hematology and Hemotherapy (SEHH), and Society for Regenerative Medicine (Russian Federation) (RPO). The journal publishes research findings of significant importance in various areas of experimental biology, such as cell biology, molecular biology, neuroscience, immunology, virology, microbiology, cancer, human genetics, systems biology, signaling, and disease mechanisms and therapeutics. The primary criterion for considering papers is whether the results contribute to significant conceptual advances or raise thought-provoking questions and hypotheses related to interesting and important biological inquiries. In addition to primary research articles presented in four formats, Cells also features review and opinion articles in its "leading edge" section, discussing recent research advancements and topics of interest to its wide readership.