TY  - JOUR
AU  - Azoury, Marie Eliane
AU  - Tarayrah, Mahmoud
AU  - Afonso, Georgia
AU  - Pais, Aurore
AU  - Colli, Maikel L
AU  - Maillard, Claire
AU  - Lavaud, Cassandra
AU  - Alexandre-Heymann, Laure
AU  - Gonzalez-Duque, Sergio
AU  - Verdier, Yann
AU  - Vinh, Joelle
AU  - Pinto, Sheena
AU  - Buus, Soren
AU  - Dubois-Laforgue, Danièle
AU  - Larger, Etienne
AU  - Beressi, Jean-Paul
AU  - Bruno, Graziella
AU  - Eizirik, Decio L
AU  - You, Sylvaine
AU  - Mallone, Roberto
TI  - Peptides Derived From Insulin Granule Proteins Are Targeted by CD8+ T Cells Across MHC Class I Restrictions in Humans and NOD Mice.
JO  - Diabetes
VL  - 69
IS  - 12
SN  - 1939-327X
CY  - Alexandria, Va
PB  - Assoc.
M1  - DKFZ-2021-00212
SP  - 2678 - 2690
PY  - 2020
N1  - Division of Developmental Immunology
AB  - 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.
KW  - Adult
KW  - Alternative Splicing
KW  - Animals
KW  - CD8-Positive T-Lymphocytes
KW  - Case-Control Studies
KW  - Chromogranins: genetics
KW  - Chromogranins: metabolism
KW  - Computer Simulation
KW  - Data Mining
KW  - Diabetes Mellitus, Type 1: genetics
KW  - Diabetes Mellitus, Type 1: metabolism
KW  - Epitopes
KW  - Female
KW  - Gene Expression Regulation
KW  - HLA-A3 Antigen
KW  - Humans
KW  - Insulin
KW  - Male
KW  - Mice
KW  - Mice, Inbred NOD
KW  - Neuroendocrine Secretory Protein 7B2: genetics
KW  - Neuroendocrine Secretory Protein 7B2: metabolism
KW  - Protein Binding
KW  - RNA, Messenger: genetics
KW  - Urocortins: genetics
KW  - Urocortins: metabolism
KW  - Young Adult
KW  - Chromogranins (NLM Chemicals)
KW  - Epitopes (NLM Chemicals)
KW  - HLA-A3 Antigen (NLM Chemicals)
KW  - Insulin (NLM Chemicals)
KW  - Neuroendocrine Secretory Protein 7B2 (NLM Chemicals)
KW  - RNA, Messenger (NLM Chemicals)
KW  - Ucn3 protein, mouse (NLM Chemicals)
KW  - Urocortins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:32928873
DO  - DOI:10.2337/db20-0013
UR  - https://inrepo02.dkfz.de/record/167227
ER  -