Disabling an Integral CTL Epitope Allows Suppression of Autoimmune Diabetes by Intranasal Proinsulin Peptide

J Clin Invest. 2003 May;111(9):1365-71. doi: 10.1172/JCI17166.

Abstract

Insulin is a major target of the autoimmune response associated with destruction of pancreatic beta cells in type 1 diabetes. A peptide that spans the junction of the insulin B chain and the connecting (C) peptide in proinsulin has been reported to stimulate T cells from humans at risk for type 1 diabetes and autoimmune diabetes-prone NOD mice. Here we show that proinsulin B24-C36 peptide binds to I-A(g7), the MHC class II molecule of the NOD mouse, and, after intranasal administration, induces regulatory CD4(+) T cells that, in the absence of CD8(+) T cells, block the adoptive transfer of diabetes. Curiously, however, intranasal B24-C36 did not inhibit development of spontaneous diabetes in treated mice. We then determined that B24-C36, and its core sequence B25-C34, bind to K(d), the NOD mouse MHC class I molecule, and elicit CD8(+) CTLs. When the CD8(+) T lymphocyte epitope was truncated at the C34 valine anchor residue for binding to K(d), the residual CD4(+) T cell epitope, B24-C32/33, significantly inhibited diabetes development after a single intranasal dose. This study identifies a novel CTL epitope in proinsulin and demonstrates that the therapeutic potential of a "tolerogenic" autoantigen peptide can be compromised by the presence of an integral CTL epitope.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intranasal
  • Adoptive Transfer
  • Animals
  • Cells, Cultured
  • Diabetes Mellitus, Type 1 / drug therapy*
  • Diabetes Mellitus, Type 1 / immunology
  • Diabetes Mellitus, Type 1 / metabolism
  • Epitopes*
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Inbred NOD
  • Models, Molecular
  • Peptides / administration & dosage
  • Peptides / therapeutic use*
  • Proinsulin / chemistry
  • Proinsulin / genetics
  • Proinsulin / metabolism
  • Proinsulin / therapeutic use*
  • Protein Binding
  • Protein Structure, Tertiary
  • Spleen / cytology
  • Spleen / immunology
  • T-Lymphocytes, Cytotoxic / immunology*
  • T-Lymphocytes, Cytotoxic / physiology

Substances

  • Epitopes
  • Peptides
  • Proinsulin