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Peptides Derived From Insulin Granule Proteins Are Targeted by CD8 + T Cells Across MHC Class I Restrictions in Humans and NOD Mice

Abstract : 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.
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https://www.hal.inserm.fr/inserm-03312401
Contributor : Sylvaine You <>
Submitted on : Monday, August 2, 2021 - 12:44:13 PM
Last modification on : Saturday, August 7, 2021 - 3:16:44 AM

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Marie Eliane Azoury, Mahmoud Tarayrah, Georgia Afonso, Aurore Pais, Maikel Colli, et al.. Peptides Derived From Insulin Granule Proteins Are Targeted by CD8 + T Cells Across MHC Class I Restrictions in Humans and NOD Mice. Diabetes, American Diabetes Association, 2020, 69 (12), pp.2678-2690. ⟨10.2337/db20-0013⟩. ⟨inserm-03312401⟩

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