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<p>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 <i>cis-</i>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<sup>+</sup> T cells. Lastly, islets of patients with T1D show preferential HLA-B hyper-expression when compared with non-diabetic donors, and islet-infiltrating CD8<sup>+</sup> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月17日

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  • 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

摘要

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.