Immunopeptidome mining reveals a novel ERS-induced target in T1D

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-state and ERS conditions and found a small number of peptides that were exclusively present in the MIP of the ERS-exposed β cell line. Among them, OTUB2₅₈ − ₆₆ showed immunodominance, and the corresponding autoreactive CD8⁺ T cells were diabetogenic in 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 T1D incidence in these mice. This study provides novel β cell autoantigens for developing specific immune interventions for T1D prevention and treatment. Data are available via ProteomeXchange with identifier PXD041227.