First Signature of Islet Beta-Cell-Derived Naturally Processed Peptides Selected by Diabetogenic Class II MHC Molecules

J Immunol. 2008 Mar 15;180(6):3849-56. doi: 10.4049/jimmunol.180.6.3849.

Abstract

The diversity of Ags targeted by T cells in autoimmune diabetes is unknown. In this study, we identify and characterize a limited number of naturally processed peptides from pancreatic islet beta-cells selected by diabetogenic I-A(g7) molecules of NOD mice. We used insulinomas transfected with the CIITA transactivator, which resulted in their expression of class II histocompatibility molecules and activation of diabetogenic CD4 T cells. Peptides bound to I-A(g7) were isolated and examined by mass spectrometry: some peptides derived from proteins present in secretory granules of endocrine cells, and a number were shared with cells of neuronal lineage. All proteins to which peptides were identified were expressed in beta cells from normal islets. Peptides bound to I-A(g7) molecules contained the favorable binding motif characterized by acidic amino acids at the P9 position. The draining pancreatic lymph nodes of prediabetic NOD mice contained CD4 T cells that recognized three different natural peptides. Furthermore, four different peptides elicited CD4 T cells, substantiating the presence of such self-reactive T cells. The overall strategy of identifying natural peptides from islet beta-cells opens up new avenues to evaluate the repertoire of self-reactive T cells and its role in onset of diabetes.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antigen Presentation / genetics
  • Antigen Presentation / immunology
  • Antigen-Presenting Cells / immunology
  • Antigen-Presenting Cells / metabolism
  • Autoimmune Diseases / immunology
  • Autoimmune Diseases / metabolism
  • Cell Line
  • Cell Line, Transformed
  • Cell Line, Tumor
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / metabolism
  • Histocompatibility Antigens Class II / biosynthesis
  • Histocompatibility Antigens Class II / genetics
  • Histocompatibility Antigens Class II / metabolism*
  • Humans
  • Insulin-Secreting Cells / immunology*
  • Insulin-Secreting Cells / metabolism*
  • Insulinoma / immunology
  • Insulinoma / metabolism
  • Mice
  • Mice, Inbred NOD
  • Molecular Sequence Data
  • Peptides / administration & dosage
  • Peptides / immunology
  • Peptides / metabolism*
  • Protein Binding / immunology
  • Protein Processing, Post-Translational / immunology*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism

Substances

  • Histocompatibility Antigens Class II
  • I-A g7 antigen
  • Peptides