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

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.