Spontaneous T-cell proliferation in the non-obese diabetic mouse to a peptide from the unique class II MHC molecule, I-Ag7, which is also protective against the development of autoimmune diabetes

Diabetologia. 1999 May;42(5):560-5. doi: 10.1007/s001250051195.

Abstract

Aims/hypothesis: Major histocompatibility complex class II molecules present antigenic peptides to T-cells and have an important role in T-cell thymic education. The mechanism by which major histocompatibility complex alleles confer a high genetic risk for autoimmune diabetes is not known. One hypothesis is that during positive thymic selection, the peripheral T-cell repertoire is modelled by major histocompatibility complex-restricted presentation of self major histocompatibility complex molecule-derived peptides, some of which mimic tissue autoantigens. The sequence similarity between a known T-cell epitope of glutamic acid decarboxylase-65, 509:VPPSLRTLED and the non-obese diabetic mouse class II major histocompatibility complex molecule I-Ag7 86:VPTSLRRLEQ is consistent with this.

Methods: We measured spontaneous proliferation of peripheral T-cells from non-obese diabetic mice and other, non-diabetes-prone strains, to the I-Ag7 86-101 and glutamic acid decarboxylase-65(509-524) peptides, binding of these peptides to intact I-Ag7 and assessed the effect of tolerance induction on diabetes development, by injecting young non-obese diabetic mice with high doses of peptide.

Results: T-cells from non-obese diabetic, but not other mice strains, spontaneously proliferate to the I-Ag7 86-101 and glutamic acid decarboxylase-65(509-524) peptides, but not control peptides. Both test peptides bind I-Ag7. Tolerance induction prolongs diabetes-free survival in non-obese diabetic mice when either the I-Ag7 86-101 or glutamic acid decarboxylase-65(509-524) peptide, but not control peptide, is used.

Conclusion/interpretation: A peptide from the unique class II major histocompatibility complex, diabetes-susceptibility molecule, I-Ag7, presented by I-Ag7 is a target of T-cell responses in diabetes-prone nonobese diabetic mice and tolerance induction against the peptide offers appreciable protection against the development of diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Autoimmune Diseases / immunology*
  • Diabetes Mellitus, Type 1 / immunology*
  • Epitopes
  • Female
  • Histocompatibility Antigens Class II / chemistry
  • Histocompatibility Antigens Class II / immunology*
  • Lymphocyte Activation
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Mice, Inbred NOD
  • Molecular Sequence Data
  • Peptide Fragments / chemistry
  • Peptide Fragments / immunology
  • T-Lymphocytes / immunology*

Substances

  • Epitopes
  • Histocompatibility Antigens Class II
  • Peptide Fragments