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

Roberto Mallone, Orlando Burgos Morales, Deep Patel, Jahnavi Aluri, Farah Kobaisi, Zhicheng Zhou, Sylvaine You, Javier Perez-Hernandez, Decio L Eizirik, Raphael Scharfmann, Piero Marchetti, Lorella Marselli, Sine R Hadrup, Amanda Anderson, Sally C Kent, Alexia Carré, Robert Parker, Nicola Ternette, Sarah J Richardson, Maki Nakayama, Laurie Landry, Marcus Göransson, Maikel L Colli, Barbara Brandao, Annalisa Nicastri, Hanqing Liao, Masaya Oshima, Anthony Manganaro, Christiana Lekka, Fatoumata Samassa

Journal: Nature communications 2025;16(1):765

PMID: 39824805

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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.

Address: Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France.; Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France.; Department of Nutrition and Health, Valencian International University (VIU), Valencia, Spain.; Islet Biology Group, Exeter Centre of Excellence in Diabetes Research, University of Exeter Medical School, Exeter, UK.; Diabetes Center of Excellence, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.; Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford, Oxford, UK.; ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium.; Indiana Biosciences Research Institute, Indianapolis, IN, USA.; Department of Health Technology, Technical University of Denmark, Copenhagen, Denmark.; Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO, USA.; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.; Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France.; Indiana Biosciences Research Institute, Indianapolis, IN, USA.; Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France. [email protected].; Indiana Biosciences Research Institute, Indianapolis, IN, USA. [email protected].; Assistance Publique Hôpitaux de Paris, Service de Diabétologie et Immunologie Clinique, Cochin Hospital, Paris, France. [email protected].

DOI: 10.1038/s41467-025-55908-9

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MeSH Terms: Humans, Insulin-Secreting Cells, Diabetes Mellitus, Type 1, Antigen Presentation, CD8-Positive T-Lymphocytes, Interferon-alpha, HLA-B Antigens, Alternative Splicing, Male, Female, Peptides, Adult