Deviation of islet autoreactivity to cryptic epitopes protects NOD mice from diabetes

Eur J Immunol. 2003 Feb;33(2):546-55. doi: 10.1002/immu.200310031.


To better understand loss of self-tolerance in diabetes-prone NOD mice, we are generating ICA69 transgenes under control of the tetracycline-regulated tet07 minimal promoter. In vitro pilot studies showed leaky transgene expression, but addition of beta-globin genomic insulator flanks prevented leakage and dramatically enhanced transgene expression even in transient transfection, with excellent suppression by Doxycycline. In vivo, the accidental loss of insulator flanks during transgene insertion in one transgenic NOD founder, tet1, re-established leakiness with high level, exclusive ICA69-transgene expression in stromal elements of thymus and spleen. This led to persistent deletion of T cells targeting the immunodominant ICA69 epitope, Tep69, but emergence of T cell pools targeting cryptic ICA69 epitopes not normally generated in sufficient density to select and maintain ICA69-autoreactive T cells. This subtle modification of T cell repertoires reduced insulitis, and protected from diabetes in transgenics and in wild-type mice carrying irradiated tet1 thymus grafts. The low pathogenicity of T cells targeting cryptic epitopes likely reflects the fact that the major ICA69 determinant presented in the islet milieu remains Tep69, while cryptic epitopes are under-represented. Deviation of T cell autoreactivity from major to cryptic target epitopes in tet1 mice provides a fortuitous model to explain previously observed diabetes protection by immunotherapy or autoantigen transgenes despite apparent failure to achieve tolerance to the full length islet antigens.

MeSH terms

  • Adoptive Transfer
  • Animals
  • Autoantigens / genetics
  • Autoantigens / immunology*
  • Clonal Deletion
  • DNA, Complementary / genetics
  • Diabetes Mellitus, Type 1 / immunology*
  • Disease Models, Animal
  • Epitopes / immunology*
  • Female
  • Genetic Vectors / chemistry
  • Genetic Vectors / genetics
  • Immunodominant Epitopes / immunology
  • Inflammation
  • Islets of Langerhans / immunology*
  • Islets of Langerhans / pathology
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, Transgenic
  • Promoter Regions, Genetic / genetics
  • Radiation Chimera
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / immunology
  • Self Tolerance / immunology
  • Spleen / immunology
  • Spleen / pathology
  • Spleen / transplantation
  • Stromal Cells / metabolism
  • T-Lymphocyte Subsets / immunology*
  • Thymus Gland / immunology
  • Thymus Gland / pathology
  • Thymus Gland / transplantation
  • Transgenes


  • Autoantigens
  • DNA, Complementary
  • Epitopes
  • Ica1 protein, mouse
  • Immunodominant Epitopes
  • Recombinant Fusion Proteins