Immunopeptidome mining reveals a novel ERS-induced target in T1D

IF 21.8 1区 医学 Q1 IMMUNOLOGY
Lina Wang, Shushu Yang, Gaohui Zhu, Jie Li, Gang Meng, Xiaoling Chen, Mengjun Zhang, Shufeng Wang, Xiangqian Li, Yu Pan, Yi Huang, Li Wang, Yuzhang Wu
{"title":"Immunopeptidome mining reveals a novel ERS-induced target in T1D","authors":"Lina Wang, Shushu Yang, Gaohui Zhu, Jie Li, Gang Meng, Xiaoling Chen, Mengjun Zhang, Shufeng Wang, Xiangqian Li, Yu Pan, Yi Huang, Li Wang, Yuzhang Wu","doi":"10.1038/s41423-024-01150-0","DOIUrl":null,"url":null,"abstract":"Autoreactive CD8+ T cells play a key role in type 1 diabetes (T1D), but the antigen spectrum that activates autoreactive CD8+ T cells remains unclear. Endoplasmic reticulum stress (ERS) has been implicated in β-cell autoantigen generation. Here, we analyzed the major histocompatibility complex class I (MHC-I)-associated immunopeptidome (MIP) of islet β-cells under steady and ERS conditions and found that ERS reshaped the MIP of β-cells and promoted the MHC-I presentation of a panel of conventional self-peptides. Among them, OTUB258-66 showed immunodominance, and the corresponding autoreactive CD8+ T cells were diabetogenic in nonobese diabetic (NOD) mice. High glucose intake upregulated pancreatic OTUB2 expression and amplified the OTUB258-66-specific CD8+ T-cell response in NOD mice. Repeated OTUB258-66 administration significantly reduced the incidence of T1D in NOD mice. Interestingly, peripheral blood mononuclear cells (PBMCs) from patients with T1D, but not from healthy controls, showed a positive IFN-γ response to human OTUB2 peptides. This study provides not only a new explanation for the role of ERS in promoting β-cell-targeted autoimmunity but also a potential target for the prevention and treatment of T1D. The data are available via ProteomeXchange with the identifier PXD041227.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":null,"pages":null},"PeriodicalIF":21.8000,"publicationDate":"2024-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cellular &Molecular Immunology","FirstCategoryId":"3","ListUrlMain":"https://www.nature.com/articles/s41423-024-01150-0","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Autoreactive CD8+ T cells play a key role in type 1 diabetes (T1D), but the antigen spectrum that activates autoreactive CD8+ T cells remains unclear. Endoplasmic reticulum stress (ERS) has been implicated in β-cell autoantigen generation. Here, we analyzed the major histocompatibility complex class I (MHC-I)-associated immunopeptidome (MIP) of islet β-cells under steady and ERS conditions and found that ERS reshaped the MIP of β-cells and promoted the MHC-I presentation of a panel of conventional self-peptides. Among them, OTUB258-66 showed immunodominance, and the corresponding autoreactive CD8+ T cells were diabetogenic in nonobese diabetic (NOD) mice. High glucose intake upregulated pancreatic OTUB2 expression and amplified the OTUB258-66-specific CD8+ T-cell response in NOD mice. Repeated OTUB258-66 administration significantly reduced the incidence of T1D in NOD mice. Interestingly, peripheral blood mononuclear cells (PBMCs) from patients with T1D, but not from healthy controls, showed a positive IFN-γ response to human OTUB2 peptides. This study provides not only a new explanation for the role of ERS in promoting β-cell-targeted autoimmunity but also a potential target for the prevention and treatment of T1D. The data are available via ProteomeXchange with the identifier PXD041227.

Abstract Image

Abstract Image

免疫肽组挖掘揭示 T1D 中 ERS 诱导的新靶点
自反应性 CD8+ T 细胞在 1 型糖尿病(T1D)中起着关键作用,但激活自反应性 CD8+ T 细胞的抗原谱仍不清楚。内质网应激(ERS)与β细胞自身抗原的产生有关。在这里,我们分析了胰岛β细胞在稳定和ERS条件下的主要组织相容性复合体I类(MHC-I)相关免疫肽组(MIP),发现ERS重塑了β细胞的MIP,促进了一组常规自身肽的MHC-I呈现。其中,OTUB258-66表现出免疫优势,相应的自反应CD8+ T细胞对非肥胖糖尿病(NOD)小鼠具有致糖尿病作用。高糖摄入会上调胰腺 OTUB2 的表达,并增强 NOD 小鼠对 OTUB258-66 特异性 CD8+ T 细胞的反应。重复给药 OTUB258-66 能显著降低 NOD 小鼠 T1D 的发病率。有趣的是,T1D 患者的外周血单核细胞(PBMCs)对人 OTUB2 肽的 IFN-γ 反应呈阳性,而健康对照组则没有。这项研究不仅为 ERS 在促进以 β 细胞为靶点的自身免疫中的作用提供了新的解释,还为预防和治疗 T1D 提供了潜在的靶点。这些数据可通过蛋白质组交换(ProteomeXchange)获得,其标识符为 PXD041227。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
CiteScore
31.20
自引率
1.20%
发文量
903
审稿时长
1 months
期刊介绍: Cellular & Molecular Immunology, a monthly journal from the Chinese Society of Immunology and the University of Science and Technology of China, serves as a comprehensive platform covering both basic immunology research and clinical applications. The journal publishes a variety of article types, including Articles, Review Articles, Mini Reviews, and Short Communications, focusing on diverse aspects of cellular and molecular immunology.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信