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; Roberto Mallone

doi:10.1038/s41467-025-55908-9

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, Roberto Mallone

Cell Signalling and Immunology

Research output: Contribution to journal › Article › peer-review

12 Citations (Scopus)

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.

Original language	English
Article number	765
Number of pages	19
Journal	Nature Communications
Volume	16
DOIs	https://doi.org/10.1038/s41467-025-55908-9
Publication status	Published - 17 Jan 2025

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-025-55908-9Licence: CC BY

Final Published VersionFinal published version, 4.23 MBLicence: CC BY

Cite this

Carré, A., Samassa, F., Zhou, Z., Perez-Hernandez, J., Lekka, C., Manganaro, A., Oshima, M., Liao, H., Parker, R., Nicastri, A., Brandao, B., Colli, M. L., Eizirik, D. L., Aluri, J., Patel, D., Göransson, M., Burgos Morales, O., Anderson, A., Landry, L., ... Mallone, R. (2025). Interferon-α promotes HLA-B-restricted presentation of conventional and alternative antigens in human pancreatic β-cells. Nature Communications, 16, Article 765. https://doi.org/10.1038/s41467-025-55908-9

@article{949398203d4044c1a284c9f6799d0bec,

title = "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-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.",

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

note = " Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

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day = "17",

doi = "10.1038/s41467-025-55908-9",

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Carré, A, Samassa, F, Zhou, Z, Perez-Hernandez, J, Lekka, C, Manganaro, A, Oshima, M, Liao, H, Parker, R, Nicastri, A, Brandao, B, Colli, ML, Eizirik, DL, Aluri, J, Patel, D, Göransson, M, Burgos Morales, O, Anderson, A, Landry, L, Kobaisi, F, Scharfmann, R, Marselli, L, Marchetti, P, You, S, Nakayama, M, Hadrup, SR, Kent, SC, Richardson, SJ, Ternette, N & Mallone, R 2025, 'Interferon-α promotes HLA-B-restricted presentation of conventional and alternative antigens in human pancreatic β-cells', Nature Communications, vol. 16, 765. https://doi.org/10.1038/s41467-025-55908-9

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T1 - Interferon-α promotes HLA-B-restricted presentation of conventional and alternative antigens in human pancreatic β-cells

AU - Carré, Alexia

AU - Samassa, Fatoumata

AU - Zhou, Zhicheng

AU - Perez-Hernandez, Javier

AU - Lekka, Christiana

AU - Manganaro, Anthony

AU - Oshima, Masaya

AU - Liao, Hanqing

AU - Parker, Robert

AU - Nicastri, Annalisa

AU - Brandao, Barbara

AU - Colli, Maikel L.

AU - Eizirik, Decio L.

AU - Aluri, Jahnavi

AU - Patel, Deep

AU - Göransson, Marcus

AU - Burgos Morales, Orlando

AU - Anderson, Amanda

AU - Landry, Laurie

AU - Kobaisi, Farah

AU - Scharfmann, Raphael

AU - Marselli, Lorella

AU - Marchetti, Piero

AU - You, Sylvaine

AU - Nakayama, Maki

AU - Hadrup, Sine R.

AU - Kent, Sally C.

AU - Richardson, Sarah J.

AU - Ternette, Nicola

AU - Mallone, Roberto

PY - 2025/1/17

Y1 - 2025/1/17

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85216182735

U2 - 10.1038/s41467-025-55908-9

DO - 10.1038/s41467-025-55908-9

M3 - Article

C2 - 39824805

AN - SCOPUS:85216182735

SN - 2041-1723

VL - 16

JO - Nature Communications

JF - Nature Communications

M1 - 765

ER -

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

Abstract

ASJC Scopus subject areas

UN SDGs

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