Thymus-specific deletion of insulin induces autoimmune diabetes

EMBO J. 2009 Sep 16;28(18):2812-24. doi: 10.1038/emboj.2009.212. Epub 2009 Aug 13.


Insulin expression in the thymus has been implicated in regulating the negative selection of autoreactive T cells and in mediating the central immune tolerance towards pancreatic beta-cells. To further explore the function of this ectopic insulin expression, we knocked out the mouse Ins2 gene specifically in the Aire-expressing medullary thymic epithelial cells (mTECs), without affecting its expression in the beta-cells. When further crossed to the Ins1 knockout background, both male and female pups (designated as ID-TEC mice for insulin-deleted mTEC) developed diabetes spontaneously around 3 weeks after birth. beta-cell-specific autoimmune destruction was observed, as well as islet-specific T cell infiltration. The presence of insulin-specific effector T cells was shown using ELISPOT assays and adoptive T cell transfer experiments. Results from thymus transplantation experiments proved further that depletion of Ins2 expression in mTECs was sufficient to break central tolerance and induce anti-insulin autoimmunity. Our observations may explain the rare cases of type 1 diabetes onset in very young children carrying diabetes-resistant HLA class II alleles. ID-TEC mice could serve as a new model for studying this pathology.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alleles
  • Animals
  • Diabetes Mellitus, Experimental / genetics*
  • Diabetes Mellitus, Experimental / immunology
  • Diabetes Mellitus, Type 1 / genetics*
  • Diabetes Mellitus, Type 1 / immunology
  • Disease Models, Animal
  • Female
  • Immune Tolerance / genetics
  • Insulin / metabolism*
  • Insulin-Secreting Cells / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • Models, Genetic
  • T-Lymphocytes / metabolism
  • Thymus Gland / cytology
  • Thymus Gland / pathology*


  • Insulin