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

Author

Listed:
  • Alexia Carré

    (INSERM)

  • Fatoumata Samassa

    (INSERM)

  • Zhicheng Zhou

    (INSERM)

  • Javier Perez-Hernandez

    (INSERM
    Valencian International University (VIU))

  • 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
    Indiana Biosciences Research Institute)

  • 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
    Indiana Biosciences Research Institute
    Cochin Hospital)

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.

Suggested Citation

  • Alexia Carré & Fatoumata Samassa & Zhicheng Zhou & Javier Perez-Hernandez & Christiana Lekka & Anthony Manganaro & Masaya Oshima & Hanqing Liao & Robert Parker & Annalisa Nicastri & Barbara Brandao & , 2025. "Interferon-α promotes HLA-B-restricted presentation of conventional and alternative antigens in human pancreatic β-cells," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-55908-9
    DOI: 10.1038/s41467-025-55908-9
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    References listed on IDEAS

    as
    1. Vikash Chandra & Hazem Ibrahim & Clémentine Halliez & Rashmi B. Prasad & Federica Vecchio & Om Prakash Dwivedi & Jouni Kvist & Diego Balboa & Jonna Saarimäki-Vire & Hossam Montaser & Tom Barsby & Väin, 2022. "The type 1 diabetes gene TYK2 regulates β-cell development and its responses to interferon-α," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
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