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 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<sup>+</sup> T cells. Several peptides were recognized by CD8<sup>+</sup>
T cells within a narrow frequency (1-50/10<sup>6</sup>), 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
neo-epitopes, generated either via peptide <i>cis</i>-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-2K<sup>d</sup>-restricted CD8<sup>+</sup> T cells recognizing the murine orthologues
of SCG5, urocortin-3, and proconvertase-2 infiltrated the islets of NOD mice
and transferred diabetes into NOD/<i>scid</i>
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.