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

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

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-...

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Main Authors: Alexia Carré, Fatoumata Samassa, Zhicheng Zhou, Javier Perez-Hernandez, Christiana Lekka, Anthony Manganaro, Masaya Oshima, Hanqing Liao, Robert Parker, Annalisa Nicastri, Barbara Brandao, Maikel L. Colli, Decio L. Eizirik, Jahnavi Aluri, Deep Patel, Marcus Göransson, Orlando Burgos Morales, Amanda Anderson, Laurie Landry, Farah Kobaisi, Raphael Scharfmann, Lorella Marselli, Piero Marchetti, Sylvaine You, Maki Nakayama, Sine R. Hadrup, Sally C. Kent, Sarah J. Richardson, Nicola Ternette, Roberto Mallone
Format: Article
Language:English
Published: Nature Portfolio 2025-01-01
Series:Nature Communications
Online Access:https://doi.org/10.1038/s41467-025-55908-9
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Summary: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.
ISSN:2041-1723

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