Responses against islet antigens in NOD mice are prevented by tolerance to proinsulin but not IGRP

J Clin Invest. 2006 Dec;116(12):3258-65. doi: 10.1172/JCI29602.


Type 1 diabetes (T1D) is characterized by immune responses against several autoantigens expressed in pancreatic beta cells. T cells specific for proinsulin and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) can induce T1D in NOD mice. However, whether immune responses to multiple autoantigens are caused by spreading from one to another or whether they develop independently of each other is unknown. As cytotoxic T cells specific for IGRP were not detected in transgenic NOD mice tolerant to proinsulin, we determined that immune responses against proinsulin are necessary for IGRP-specific T cells to develop. On the other hand, transgenic overexpression of IGRP resulted in loss of intra-islet IGRP-specific T cells but did not protect NOD mice from insulitis or T1D, providing direct evidence that the response against IGRP is downstream of the response to proinsulin. Our results suggest that pathogenic proinsulin-specific immunity in NOD mice subsequently spreads to other antigens such as IGRP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoantigens / immunology
  • Autoantigens / metabolism
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / metabolism
  • Female
  • Glucose-6-Phosphatase / genetics
  • Glucose-6-Phosphatase / immunology*
  • Glucose-6-Phosphatase / metabolism
  • Immune Tolerance / immunology*
  • Islets of Langerhans / immunology
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Mice, Transgenic
  • Peptide Fragments / immunology
  • Proinsulin / immunology*
  • Proinsulin / metabolism
  • Proteins / genetics
  • Proteins / immunology*
  • Proteins / metabolism
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism


  • Autoantigens
  • Peptide Fragments
  • Proteins
  • Proinsulin
  • Glucose-6-Phosphatase
  • G6pc2 protein, mouse