The Profiling of MHC-I and MHC-II peptide repertoire of Cytokine-Stressed Human Pancreatic Islets 3593

Description Type 1 diabetes (T1D) arises from T cell-mediated destruction of insulin-secreting pancreatic beta cells. Inflammation is hypothesized to induced presentation of new canonical or non-canonical epitopes or an imbalance of certain epitopes for pathogenic T cells. The naturally processed and presented MHC-bound peptides by primary human islet beta cells are largely unknown. We used mass spectrometry to identify native and post-translationally modified self-peptides presented by MHC proteins from human cadaveric islet samples treated in vitro with cytokines to identify epitopes emerging in an inflamed pancreas. Of > 4300 islet peptides presented by 60 different MHC molecules, we identified 28 new autoimmune epitopes that were recognized by CD4 or CD8 T cells in the peripheral blood or infiltrating the islets of T1D patients, 28 new epitopes from previously identified autoantigens, and 100 additional candidate autoantigens derived from inflammation, unfolded protein response, and secretory hormone processing pathways. These results identify novel naturally processed islet peptides targeted by autoimmune T cells in T1D and a large set of candidate autoantigens enriched in islet cells, upregulated by exposure to inflammatory cytokines, or derived from beta-cell transcripts upregulated in T1D. This study provides a resource for investigating T1D etiology and progression. Funding Sources This study was supported by NIH grants UC1DK104218 (SCK), UC4DK116284 (SCK, DMH, and LJS), R01AI137198 (LS and LJS). Topic Categories Antigen and Dendritic Cell Processing, Presentation, and Biology (AGDC)