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

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 and Roberto Mallone ()
Additional contact information
Alexia Carré: INSERM
Fatoumata Samassa: INSERM
Zhicheng Zhou: INSERM
Javier Perez-Hernandez: INSERM
Christiana Lekka: University of Exeter Medical School
Anthony Manganaro: University of Massachusetts Chan Medical School
Masaya Oshima: INSERM
Hanqing Liao: University of Oxford
Robert Parker: University of Oxford
Annalisa Nicastri: University of Oxford
Barbara Brandao: INSERM
Maikel L. Colli: Université Libre de Bruxelles
Decio L. Eizirik: Université Libre de Bruxelles
Jahnavi Aluri: Indiana Biosciences Research Institute
Deep Patel: Indiana Biosciences Research Institute
Marcus Göransson: Technical University of Denmark
Orlando Burgos Morales: INSERM
Amanda Anderson: University of Colorado School of Medicine
Laurie Landry: University of Colorado School of Medicine
Farah Kobaisi: INSERM
Raphael Scharfmann: INSERM
Lorella Marselli: University of Pisa
Piero Marchetti: University of Pisa
Sylvaine You: INSERM
Maki Nakayama: University of Colorado School of Medicine
Sine R. Hadrup: Technical University of Denmark
Sally C. Kent: University of Massachusetts Chan Medical School
Sarah J. Richardson: University of Exeter Medical School
Nicola Ternette: University of Oxford
Roberto Mallone: INSERM

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-55908-9

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