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Immunopeptidome mining reveals a novel ERS-induced target in T1D

Cellular & Molecular Immunology (2024)Cite this article

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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.

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Data availability

All data that support the findings of this study are available within the source data and supplementary information files. The raw mass spectrometry proteomics data have been deposited in the ProteomeXchange Consortium via the PRIDE [1] partner repository with the dataset identifier PXD041227.

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Acknowledgements

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.

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  1. These authors contributed equally: Lina Wang, Shushu Yang, Gaohui Zhu.

Authors and Affiliations

  1. Department of Immunology, College of Basic Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China

    Lina Wang, Shushu Yang, Jie Li, Xiaoling Chen, Shufeng Wang, Xiangqian Li, Li Wang & Yuzhang Wu

  2. Key Laboratory of Immune Microenvironment and Inflammatory Disease Research in Universities of Shandong Province, School of Basic Medical Sciences, Shandong Second Medical University, Weifang, 261053, China

    Lina Wang

  3. Department of Immunology, Medical College of Qingdao University, Qingdao, 266071, China

    Lina Wang

  4. Department of Endocrinology, Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, 400014, China

    Gaohui Zhu & Yu Pan

  5. Department of Pathology, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, China

    Gang Meng

  6. Department of Pharmaceutical Analysis, College of Pharmacy, Army Medical University (Third Military Medical University), Chongqing, 400038, China

    Mengjun Zhang

  7. National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, Children’s Hospital of Chongqing Medical University, Chongqing, 400014, China

    Yi Huang

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Contributions

Lina Wang, Shushu Yang and Gaohui Zhu designed and carried out the experiments and drafted the manuscript; Jie Li and Xiangqian Li performed the flow cytometry staining and data analysis; Gang Meng and Xiaoling Chen performed the HE and immunohistochemical staining of paraffin-embedded pancreas sections; Mengjun Zhang prepared the biological samples and isolated the MHC I-peptide complexes; Shufeng Wang analyzed the MS data and predicted the potential HLA-A*0201-restricted human OTUB2 peptides; Yu Pan collected the blood of all the subjects and performed the human IFN-γ ELISPOT; Yi Huang performed critical revision of the article for important intellectual content; Li Wang conceived the original ideas, designed the project, interpreted the results, evaluated the data and wrote the manuscript; Yuzhang Wu supervised and managed the research process, completed the manuscript and provided research funds. All authors contributed to the article and approved the submitted version.

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Correspondence to Li Wang or Yuzhang Wu.

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The authors declare no competing interests. Yuzhang Wu is an editorial board member of Cellular & Molecular Immunology, but he has not been involved in the peer review or the decision-making of the article.

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This study was approved by the Ethics Committee of the Army Medical University (Third Military Medical University) and Institutional Review Board of Children’s Hospital of Chongqing Medical University, and informed consent was obtained from all participants in this study.

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Wang, L., Yang, S., Zhu, G. et al. Immunopeptidome mining reveals a novel ERS-induced target in T1D. Cell Mol Immunol (2024). https://doi.org/10.1038/s41423-024-01150-0

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