Interferon-α promotes HLA-B-restricted presentation of conventional and alternative antigens in human pancreatic β-cells
Abstract
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.
Article Details
Authors (30)
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
Cardiovascular Research Institute, Weill Cornell Medicine
Sine R. Hadrup
Sally C. Kent
Sarah J. Richardson
Nicola Ternette
Roberto Mallone