Journal
DIABETES
Volume 69, Issue 12, Pages 2678-2690Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db20-0013
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Funding
- Legs Borel
- Region Ile-de-France CORDDIM
- Aide aux Jeunes Diabetiques
- Societe Francophone di Diabete
- JDRF [2-SRA-2016-164-Q-R]
- Fondation Francophone pour la Recherche sur le Diabete
- EFSD/JDRF/Lilly European Programme in Type 1 Diabetes Research 2015
- Agence Nationale de la Recherche [ANR-19-CE15-0014-01]
- Fondation pour la Recherche Medicale [EQU20193007831]
- Association pour la Recherche sur le Diabete
- Inserm-Transfert Proof of Concept 2018
- Welbio/FRFS (Wallonia, Belgium) [WELBIO-CR-2019C-04]
- Conseil Regional d'Ile-de-France
- H2020 European Research Council Innovative Medicines Initiative 2 Joint Undertaking - European Federation of Pharmaceutical Industries and Associations [INNODIA 115797, INNODIA HARVEST 945268]
- JDRF
- Leona M. and Harry B. Helmsley Charitable Trust
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The antigenic peptides processed by beta-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 beta-cell immunogenicity. Building on our previous description of the HLA-A2/A3 peptidome of beta-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 (1-50/10(6)), 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 beta-cell granule proteins (e.g., SCG3, SCG5, and urocortin-3). Similarly, H-2K(d)-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.
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