Interferon-α promotes HLA-B-restricted presentation of conventional and alternative antigens in human pancreatic β-cells
peer-reviewed · Nature Communications · 2025
| Date | 2025-01-17 |
| Type | peer-reviewed |
| Venue | Nature Communications |
| Publisher | Springer Science and Business Media LLC |
| Contribution | downstream-application |
| DOI | 10.1038/s41467-025-55908-9 |
| Citations (OpenAlex) | 37 |
| Venue 2-year citedness | 17.60 |
Abstract
Interferon (IFN)-α is the earliest cytokine signature observed in individuals at risk for type 1 diabetes (T1D), but the effect of IFN-α on the antigen repertoire of HLA Class I (HLA-I) in pancreatic β-cells is unknown. Here we characterize the HLA-I antigen presentation in resting and IFN-α-exposed β-cells and find that IFN-α 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 β-cell immunopeptidome is dominated by HLA-A-restricted peptides, IFN-α 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.
Methods and tools
- IFN-alpha beta-cell HLA-I immunopeptidome: A de novo sequencing-based immunopeptidomics pipeline showed that interferon-alpha expands the beta-cell HLA-I repertoire toward HLA-B and toward non-canonical peptides from alternative and cis-splicing.
Methods it uses
- PEAKS: Commercial DP-based de novo