Immunopeptidome mining reveals a novel ERS-induced target in T1D
作者全名：Wang, Lina; Yang, Shushu; Zhu, Gaohui; Li, Jie; Meng, Gang; Chen, Xiaoling; Zhang, Mengjun; Wang, Shufeng; Li, Xiangqian; Pan, Yu; Huang, Yi; Wang, Li; Wu, Yuzhang
作者地址：[Wang, Lina; Yang, Shushu; Li, Jie; Chen, Xiaoling; Wang, Shufeng; Li, Xiangqian; Wang, Li; Wu, Yuzhang] Army Med Univ, Third Mil Med Univ, Coll Basic Med, Dept Immunol, Chongqing 400038, Peoples R China; [Wang, Lina] Shandong Second Med Univ, Sch Basic Med Sci, Key Lab Immune Microenvironm & Inflammatory Dis Re, Weifang 261053, Peoples R China; [Wang, Lina] Qingdao Univ, Med Coll, Dept Immunol, Qingdao 266071, Peoples R China; [Zhu, Gaohui; Pan, Yu] Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Key Lab Child Dev & Disorders, Dept Endocrinol,Childrens Hosp,Minist Educ,Chongqi, Chongqing 400014, Peoples R China; [Meng, Gang] Army Med Univ, Third Mil Med Univ, Southwest Hosp, Dept Pathol, Chongqing 400038, Peoples R China; [Zhang, Mengjun] Army Med Univ, Third Mil Med Univ, Coll Pharm, Dept Pharmaceut Anal, Chongqing 400038, Peoples R China; [Huang, Yi] Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Minist Educ Key Lab Child Dev & Disorders, Minist Educ,Key Lab Child Dev & Disorders,Children, Chongqing 400014, Peoples R China
通信作者：Wang, L; Wu, YZ (通讯作者)，Army Med Univ, Third Mil Med Univ, Coll Basic Med, Dept Immunol, Chongqing 400038, Peoples R China.
来源：CELLULAR & MOLECULAR IMMUNOLOGY
ESI学科分类：IMMUNOLOGY
WOS号：WOS:001211476000001
JCR分区：Q1
影响因子：21.8
年份：2024
卷号：21
期号：6
开始页：604
结束页：619
文献类型：Article
关键词：immunopeptidome; ERS; T1D; OTUB2; CD8(+) T cells
摘要：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 beta-cell autoantigen generation. Here, we analyzed the major histocompatibility complex class I (MHC-I)-associated immunopeptidome (MIP) of islet beta-cells under steady and ERS conditions and found that ERS reshaped the MIP of beta-cells and promoted the MHC-I presentation of a panel of conventional self-peptides. Among them, OTUB2(58-66) 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 OTUB2(58-66)-specific CD8(+) T-cell response in NOD mice. Repeated OTUB2(58-66) 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-gamma response to human OTUB2 peptides. This study provides not only a new explanation for the role of ERS in promoting beta-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.
基金机构：National Natural Science Foundation of China (National Science Foundation of China) [82071825, 81871301]; National Natural Science Foundation of China [2016YFA0502204]; National Key Research and Development Program [ZR2023MH201]; Shandong Provincial Natural Science Fund
基金资助正文：This work was supported by the National Natural Science Foundation of China (No. 82071825 and No. 81871301), the National Key Research and Development Program (No. 2016YFA0502204) and the Shandong Provincial Natural Science Fund (ZR2023MH201). We also thank Quan Zhou, Mingfu Ye and Xiaojun Peng (PTM-Biolabs, China) for their assistance in MS data analysis.
