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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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-55908-9 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Alexia Carré |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-06a75ef863fc41ad96ea4efa7765eb58 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-06a75ef863fc41ad96ea4efa7765eb582025-01-19T12:30:39ZengNature PortfolioNature Communications2041-17232025-01-0116111910.1038/s41467-025-55908-9Interferon-α promotes HLA-B-restricted presentation of conventional and alternative antigens in human pancreatic β-cellsAlexia Carré0Fatoumata Samassa1Zhicheng Zhou2Javier Perez-Hernandez3Christiana Lekka4Anthony Manganaro5Masaya Oshima6Hanqing Liao7Robert Parker8Annalisa Nicastri9Barbara Brandao10Maikel L. Colli11Decio L. Eizirik12Jahnavi Aluri13Deep Patel14Marcus Göransson15Orlando Burgos Morales16Amanda Anderson17Laurie Landry18Farah Kobaisi19Raphael Scharfmann20Lorella Marselli21Piero Marchetti22Sylvaine You23Maki Nakayama24Sine R. Hadrup25Sally C. Kent26Sarah J. Richardson27Nicola Ternette28Roberto Mallone29Université Paris Cité, Institut Cochin, CNRS, INSERMUniversité Paris Cité, Institut Cochin, CNRS, INSERMUniversité Paris Cité, Institut Cochin, CNRS, INSERMUniversité Paris Cité, Institut Cochin, CNRS, INSERMIslet Biology Group, Exeter Centre of Excellence in Diabetes Research, University of Exeter Medical SchoolDiabetes Center of Excellence, Department of Medicine, University of Massachusetts Chan Medical SchoolUniversité Paris Cité, Institut Cochin, CNRS, INSERMCentre for Immuno-Oncology, Nuffield Department of Medicine, University of OxfordCentre for Immuno-Oncology, Nuffield Department of Medicine, University of OxfordCentre for Immuno-Oncology, Nuffield Department of Medicine, University of OxfordUniversité Paris Cité, Institut Cochin, CNRS, INSERMULB Center for Diabetes Research, Université Libre de BruxellesULB Center for Diabetes Research, Université Libre de BruxellesIndiana Biosciences Research InstituteIndiana Biosciences Research InstituteDepartment of Health Technology, Technical University of DenmarkUniversité Paris Cité, Institut Cochin, CNRS, INSERMBarbara Davis Center for Diabetes, University of Colorado School of MedicineBarbara Davis Center for Diabetes, University of Colorado School of MedicineUniversité Paris Cité, Institut Cochin, CNRS, INSERMUniversité Paris Cité, Institut Cochin, CNRS, INSERMDepartment of Clinical and Experimental Medicine, University of PisaDepartment of Clinical and Experimental Medicine, University of PisaUniversité Paris Cité, Institut Cochin, CNRS, INSERMBarbara Davis Center for Diabetes, University of Colorado School of MedicineDepartment of Health Technology, Technical University of DenmarkDiabetes Center of Excellence, Department of Medicine, University of Massachusetts Chan Medical SchoolIslet Biology Group, Exeter Centre of Excellence in Diabetes Research, University of Exeter Medical SchoolCentre for Immuno-Oncology, Nuffield Department of Medicine, University of OxfordUniversité Paris Cité, Institut Cochin, CNRS, INSERMAbstract 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.https://doi.org/10.1038/s41467-025-55908-9 |
| spellingShingle | 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 Interferon-α promotes HLA-B-restricted presentation of conventional and alternative antigens in human pancreatic β-cells Nature Communications |
| title | Interferon-α promotes HLA-B-restricted presentation of conventional and alternative antigens in human pancreatic β-cells |
| title_full | Interferon-α promotes HLA-B-restricted presentation of conventional and alternative antigens in human pancreatic β-cells |
| title_fullStr | Interferon-α promotes HLA-B-restricted presentation of conventional and alternative antigens in human pancreatic β-cells |
| title_full_unstemmed | Interferon-α promotes HLA-B-restricted presentation of conventional and alternative antigens in human pancreatic β-cells |
| title_short | Interferon-α promotes HLA-B-restricted presentation of conventional and alternative antigens in human pancreatic β-cells |
| title_sort | interferon α promotes hla b restricted presentation of conventional and alternative antigens in human pancreatic β cells |
| url | https://doi.org/10.1038/s41467-025-55908-9 |
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