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Title: Aire mediates thymic expression and tolerance of pancreatic antigens via an unconventional transcriptional mechanism
Authors: Danso-Abeam, Dina
Staats, Kim
Franckaert, Dean
Van Den Bosch, Ludo
Liston, Adrian
Gray, Daniel H D
Dooley, James # ×
Issue Date: Jan-2013
Publisher: Wiley-VCH
Series Title: European Journal of Immunology vol:43 issue:1 pages:75-84
Article number: 10.1002/eji.201242761
Abstract: The autoimmune regulator, Aire, mediates central tolerance of peripheral self. Its activity in thymic epithelial cells (TECs) directs the ectopic expression of thousands of tissue-restricted antigens (TRAs), causing the deletion of autoreactive thymocytes. The molecular mechanisms orchestrating the breadth of transcriptional regulation by Aire remain unknown. One prominent model capable of explaining both the uniquely high number of Aire-dependent targets and their specificity posits that tissue-specific transcription factors induced by Aire directly activate their canonical targets, exponentially adding to the total number of Aire-dependent TRAs. To test this "Hierarchical Transcription" model we analyzed mice deficient in the pancreatic master transcription factor Pdx1, specifically in TECs (Pdx1(ΔFoxn1) ), for the expression and tolerance of pancreatic TRAs. Surprisingly, we found that lack of Pdx1 in TECs did not reduce the transcription of insulin or somatostatin, or alter glucagon expression. Moreover, in a model of thymic deletion driven by a neo-TRA under the control of the insulin promoter, Pdx1 in TECs was not required to affect thymocyte deletion or the generation of regulatory T cells. These findings suggest that the capacity of Aire to regulate expression of a huge array of TRAs relies solely on an unconventional transcriptional mechanism, without intermediary transcription factors.
URI: 
ISSN: 0014-2980
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Genetics of Autoimmunity
Laboratory for Neurobiology (Vesalius Research Center)
× corresponding author
# (joint) last author

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