Details

Autor(en) / Beteiligte

• 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

Titel

Immunopeptidome mining reveals a novel ERS-induced target in T1D

Ist Teil von

• Cellular & molecular immunology, 2024-06, Vol.21 (6), p.604-619

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2024

Quelle

MEDLINE

Beschreibungen/Notizen

• 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, 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-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.