%0 Journal Article
%A Azoury, Marie Eliane
%A Tarayrah, Mahmoud
%A Afonso, Georgia
%A Pais, Aurore
%A Colli, Maikel L
%A Maillard, Claire
%A Lavaud, Cassandra
%A Alexandre-Heymann, Laure
%A Gonzalez-Duque, Sergio
%A Verdier, Yann
%A Vinh, Joelle
%A Pinto, Sheena
%A Buus, Soren
%A Dubois-Laforgue, Danièle
%A Larger, Etienne
%A Beressi, Jean-Paul
%A Bruno, Graziella
%A Eizirik, Decio L
%A You, Sylvaine
%A Mallone, Roberto
%T Peptides Derived From Insulin Granule Proteins Are Targeted by CD8+ T Cells Across MHC Class I Restrictions in Humans and NOD Mice.
%J Diabetes
%V 69
%N 12
%@ 1939-327X
%C Alexandria, Va
%I Assoc.
%M DKFZ-2021-00212
%P 2678 - 2690
%D 2020
%Z Division of Developmental Immunology
%X The antigenic peptides processed by β-cells and presented through surface HLA class I molecules are poorly characterized. Each HLA variant (e.g., the most common being HLA-A2 and HLA-A3) carries some peptide-binding specificity. Hence, features that, despite these specificities, remain shared across variants may reveal factors favoring β-cell immunogenicity. Building on our previous description of the HLA-A2/A3 peptidome of β-cells, we analyzed the HLA-A3-restricted peptides targeted by circulating CD8+ T cells. Several peptides were recognized by CD8+ T cells within a narrow frequency (1-50/106), which was similar in donors with and without type 1 diabetes and harbored variable effector/memory fractions. These epitopes could be classified as conventional peptides or neoepitopes, generated either via peptide cis-splicing or mRNA splicing (e.g., secretogranin-5 [SCG5]-009). As reported for HLA-A2-restricted peptides, several epitopes originated from β-cell granule proteins (e.g., SCG3, SCG5, and urocortin-3). Similarly, H-2Kd-restricted CD8+ T cells recognizing the murine orthologs of SCG5, urocortin-3, and proconvertase-2 infiltrated the islets of NOD mice and transferred diabetes into NOD/scid recipients. The finding of granule proteins targeted in both humans and NOD mice supports their disease relevance and identifies the insulin granule as a rich source of epitopes, possibly reflecting its impaired processing in type 1 diabetes.
%K Adult
%K Alternative Splicing
%K Animals
%K CD8-Positive T-Lymphocytes
%K Case-Control Studies
%K Chromogranins: genetics
%K Chromogranins: metabolism
%K Computer Simulation
%K Data Mining
%K Diabetes Mellitus, Type 1: genetics
%K Diabetes Mellitus, Type 1: metabolism
%K Epitopes
%K Female
%K Gene Expression Regulation
%K HLA-A3 Antigen
%K Humans
%K Insulin
%K Male
%K Mice
%K Mice, Inbred NOD
%K Neuroendocrine Secretory Protein 7B2: genetics
%K Neuroendocrine Secretory Protein 7B2: metabolism
%K Protein Binding
%K RNA, Messenger: genetics
%K Urocortins: genetics
%K Urocortins: metabolism
%K Young Adult
%K Chromogranins (NLM Chemicals)
%K Epitopes (NLM Chemicals)
%K HLA-A3 Antigen (NLM Chemicals)
%K Insulin (NLM Chemicals)
%K Neuroendocrine Secretory Protein 7B2 (NLM Chemicals)
%K RNA, Messenger (NLM Chemicals)
%K Ucn3 protein, mouse (NLM Chemicals)
%K Urocortins (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:32928873
%R 10.2337/db20-0013
%U https://inrepo02.dkfz.de/record/167227