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

Diabetes. 2020 Dec;69(12):2678-2690. doi: 10.2337/db20-0013. Epub 2020 Sep 14.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alternative Splicing
  • Animals
  • CD8-Positive T-Lymphocytes
  • Case-Control Studies
  • Chromogranins / genetics
  • Chromogranins / metabolism*
  • Computer Simulation
  • Data Mining
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / metabolism*
  • Epitopes
  • Female
  • Gene Expression Regulation
  • HLA-A3 Antigen
  • Humans
  • Insulin
  • Male
  • Mice
  • Mice, Inbred NOD
  • Neuroendocrine Secretory Protein 7B2 / genetics
  • Neuroendocrine Secretory Protein 7B2 / metabolism
  • Protein Binding
  • RNA, Messenger / genetics
  • Urocortins / genetics
  • Urocortins / metabolism
  • Young Adult

Substances

  • Chromogranins
  • Epitopes
  • HLA-A3 Antigen
  • Insulin
  • Neuroendocrine Secretory Protein 7B2
  • RNA, Messenger
  • Ucn3 protein, mouse
  • Urocortins

Associated data

  • figshare/10.2337/figshare.12899315