Proteomics

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Ubiquitin Thioesterase OTUB2 is An Endoplasmic Reticulum Stress-associated β Cell Autoantigen Targeted by CD8+ T cells in Type 1 Diabetes


ABSTRACT: Autoreactive CD8+ T cell plays a key role in the pathogenesis of Type 1 diabetes (T1D), but the antigen spectrum that activate autoreactive CD8+ T cells is still not completely clear. Endoplasmic reticulum stress(ERS)has been implicated in the generation of β cell autoantigens and the enhanced immune visibility of β cells to autoreactive T cells. Here, we in-depth analyzed the major histocompatibility complex class I (MHC-I) associated immunopeptidome (MIP) of islets β cell under steady-state and ERS-state, and found couples of peptides exclusively present in the MIP of β cell line under ERS state. Among them, peptide OTUB258-66 derived from ubiquitin thioesterase OTUB2 showed immunodominance in NOD mice, and autoreactive CD8+ T cells targeting OTUB258-66 were diabetogenic in NOD mice. High glucose intake upregulated the expression of OTUB2 in the pancreas and amplified the OTUB258-66-specific CD8+ T cell response in NOD mice. Repeated administration with OTUB258-66 significantly reduced the incidence of T1D in NOD mice. This study not only provides an explanation for the role of ERS induced by environmental factors such as high glucose intake in promoting β cell autoimmune injury, but also provides a novel ERS-associated β cell autoantigens for developing specific immune intervention in prevention and treatment of T1D.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): B Cell, Blood

SUBMITTER: lina wang  

LAB HEAD: Li Wang

PROVIDER: PXD041227 | Pride | 2024-05-24

REPOSITORIES: Pride

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YA002LQ_HG_1b.raw Raw
YA002LQ_HG_1c.raw Raw
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Publications

Immunopeptidome mining reveals a novel ERS-induced target in T1D.

Wang Lina L   Yang Shushu S   Zhu Gaohui G   Li Jie J   Meng Gang G   Chen Xiaoling X   Zhang Mengjun M   Wang Shufeng S   Li Xiangqian X   Pan Yu Y   Huang Yi Y   Wang Li L   Wu Yuzhang Y  

Cellular & molecular immunology 20240430 6


Autoreactive CD8<sup>+</sup> T cells play a key role in type 1 diabetes (T1D), but the antigen spectrum that activates autoreactive CD8<sup>+</sup> 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  ...[more]

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