Thymus-specific deletion of insulin induces autoimmune diabetes
Open Access
- 13 August 2009
- journal article
- research article
- Published by Springer Science and Business Media LLC in The EMBO Journal
- Vol. 28 (18), 2812-2824
- https://doi.org/10.1038/emboj.2009.212
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 β‐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 β‐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. β‐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. There is a [Have you seen ...?][1] (September 2009) associated with this Article. [1]: http://dx.doi.org/10.1038/emboj.2009.251Keywords
This publication has 53 references indexed in Scilit:
- Thymus-homing peripheral dendritic cells constitute two of the three major subsets of dendritic cells in the steady-state thymusThe Journal of Experimental Medicine, 2009
- Deletional Tolerance Mediated by Extrathymic Aire-Expressing CellsScience, 2008
- Selective delivery of β cell antigen to dendritic cells in vivo leads to deletion and tolerance of autoreactive CD8 + T cells in NOD miceProceedings of the National Academy of Sciences of the United States of America, 2008
- Proliferative arrest and rapid turnover of thymic epithelial cells expressing AireThe Journal of Experimental Medicine, 2007
- Loss of Aire-dependent thymic expression of a peripheral tissue antigen renders it a target of autoimmunityProceedings of the National Academy of Sciences of the United States of America, 2007
- Differential Antigen Processing by Dendritic Cell Subsets in VivoScience, 2007
- Responses against islet antigens in NOD mice are prevented by tolerance to proinsulin but not IGRPJCI Insight, 2006
- Spontaneous autoimmunity prevented by thymic expression of a single self-antigenThe Journal of Experimental Medicine, 2006
- Self-antigen–presenting cells expressing diabetes-associated autoantigens exist in both thymus and peripheral lymphoid organsJCI Insight, 2001
- A disease-associated cellular immune response in type 1 diabetics to an immunodominant epitope of insulinJCI Insight, 2001