GSE108413
Conventional and neo-antigenic peptides naturally processed and presented by beta cells are targeted by circulating naïve CD8+ T cells in type 1 diabetic and healthy donors
Human CD8+ T cells are the final mediators of autoimmune ß-cell destruction in type 1 diabetes. However, their target epitopes have not been demonstrated to be naturally processed and presented by ß cells. We therefore performed an epitope discovery study combining HLA Class I peptidomics and transcriptomics strategies. Inflammatory cytokines increased ß-cell peptide presentation in vitro, paralleling upregulation of HLA Class I expression. Peptide sources included known ß-cell antigens and several insulin granule proteins. Preproinsulin yielded multiple previously described HLA-A2-restricted epitopes. Secretogranin V (SCG5/7B2), proconvertase-2, urocortin-3 and the insulin gene enhancer protein ISL-1 were identified as novel ß-cell antigens, which were processed into HLA-A2-restricted epitopes recognized by circulating naïve CD8+ T cells in type 1 diabetic and healthy donors. HLA-A2-bound neo-epitopes were also represented and originated from an alternative mRNA splice isoform (SCG5-009) and from an islet amyloid polypeptide transpeptidation product. This first description of the ß-cell HLA peptidome opens new avenues to understand the antigen processing pathways employed by ß cells and provides a valuable tool for developing T-cell biomarkers and tolerogenic vaccination strategies. Overall design: 5 human islet of Langerhans preparations examined under 2 conditions (control and cytokine treatment)