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

Thymus-specific deletion of insulin induces autoimmune diabetes.

Author information

1
Division of Immunogenetics, Department of Pediatrics, University of Pittsburgh School of Medicine, Rangos Research Center, Children's Hospital of Pittsburgh, Pittsburgh, PA 15201, USA.

Abstract

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.

PMID:
19680229
PMCID:
PMC2750011
DOI:
10.1038/emboj.2009.212
[Indexed for MEDLINE]
Free PMC Article

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