Interferon-α promotes HLA-B-restricted presentation of conventional and alternative antigens in human pancreatic β-cells

Interferon (IFN)-alpha is the earliest cytokine signature observed in individuals at risk for type 1 diabetes (T1D), but the effect of IFN-alpha on the antigen repertoire of HLA Class I (HLA-I) in pancreatic beta-cells is unknown. Here we characterize the HLA-I antigen presentation in resting and IFN-alpha-exposed beta-cells and find that IFN-alpha increases HLA-I expression and expands peptide repertoire to those derived from alternative mRNA splicing, protein cis-splicing and post-translational modifications. While the resting beta-cell immunopeptidome is dominated by HLA-A-restricted peptides, IFN-alpha largely favors HLA-B and only marginally upregulates HLA-A, translating into increased HLA-B-restricted peptide presentation and activation of HLA-B-restricted CD8+ T cells. Lastly, islets of patients with T1D show preferential HLA-B hyper-expression when compared with non-diabetic donors, and islet-infiltrating CD8+ T cells reactive to HLA-B-restricted granule peptides are found in T1D donors. Thus, the inflammatory milieu of insulitis may skew the autoimmune response toward alternative epitopes presented by HLA-B, hence recruiting T cells with a distinct repertoire that may be relevant to T1D pathogenesis.