Conventional and Neo-antigenic Peptides Presented by β Cells Are Targeted by Circulating Naïve CD8+ T Cells in Type 1 Diabetic and Healthy Donors

Cell Metab. 2018 Dec 4;28(6):946-960.e6. doi: 10.1016/j.cmet.2018.07.007. Epub 2018 Aug 2.


Although CD8+ T-cell-mediated autoimmune β cell destruction occurs in type 1 diabetes (T1D), the target epitopes processed and presented by β cells are unknown. To identify them, we combined peptidomics and transcriptomics strategies. Inflammatory cytokines increased peptide presentation in vitro, paralleling upregulation of human leukocyte antigen (HLA) class I expression. Peptide sources featured several insulin granule proteins and all known β cell antigens, barring islet-specific glucose-6-phosphatase catalytic subunit-related protein. Preproinsulin yielded HLA-A2-restricted epitopes previously described. Secretogranin V and its mRNA splice isoform SCG5-009, proconvertase-2, urocortin-3, the insulin gene enhancer protein ISL-1, and an islet amyloid polypeptide transpeptidation product emerged as antigens processed into HLA-A2-restricted epitopes, which, as those already described, were recognized by circulating naive CD8+ T cells in T1D and healthy donors and by pancreas-infiltrating cells in T1D donors. This peptidome opens new avenues to understand antigen processing by β cells and for the development of T cell biomarkers and tolerogenic vaccination strategies.

Keywords: antigen; autoimmunity; epitope; human leukocyte antigen (HLA); preproinsulin; proconvertase; secretogranin; transpeptidation; type 1 diabetes; urocortin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen Presentation*
  • Biomarkers / metabolism
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Case-Control Studies
  • Cell Line
  • Corticotropin-Releasing Hormone / metabolism
  • Cytokines / metabolism
  • Diabetes Mellitus, Type 1 / immunology*
  • Epitopes, T-Lymphocyte / immunology*
  • HLA Antigens / metabolism
  • Humans
  • Insulin / metabolism
  • Islet Amyloid Polypeptide / metabolism
  • Mice
  • Neuroendocrine Secretory Protein 7B2 / metabolism
  • Proprotein Convertase 2 / metabolism
  • Protein Precursors / metabolism
  • Proteomics / methods
  • Transcriptome / immunology*
  • Urocortins / metabolism


  • Biomarkers
  • Cytokines
  • Epitopes, T-Lymphocyte
  • HLA Antigens
  • Insulin
  • Islet Amyloid Polypeptide
  • Neuroendocrine Secretory Protein 7B2
  • Protein Precursors
  • SCG5 protein, human
  • UCN3 protein, human
  • Urocortins
  • preproinsulin
  • Corticotropin-Releasing Hormone
  • PCSK2 protein, human
  • Proprotein Convertase 2