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J Immunol. 2015 Nov 15;195(10):4641-9. doi: 10.4049/jimmunol.1501026. Epub 2015 Oct 9.

Ectopic Aire Expression in the Thymic Cortex Reveals Inherent Properties of Aire as a Tolerogenic Factor within the Medulla.

Author information

1
Division of Molecular Immunology, Institute for Enzyme Research, Tokushima University, Tokushima 770-8503, Japan;
2
Reproductive Engineering Team, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan;
3
Division of Molecular Immunology, Institute for Enzyme Research, Tokushima University, Tokushima 770-8503, Japan; Japan Agency for Medical Research and Development-Core Research for Evolutional Science and Technology, Tokyo 100-0004, Japan;
4
Department of Human Genetics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan; and.
5
Laboratory of Biological Protection, Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan.
6
Division of Molecular Immunology, Institute for Enzyme Research, Tokushima University, Tokushima 770-8503, Japan; Japan Agency for Medical Research and Development-Core Research for Evolutional Science and Technology, Tokyo 100-0004, Japan; mitsuru@tokushima-u.ac.jp.

Abstract

Cortical thymic epithelial cells (cTECs) and medullary thymic epithelial cells (mTECs) play essential roles in the positive and negative selection of developing thymocytes, respectively. Aire in mTECs plays an essential role in the latter process through expression of broad arrays of tissue-restricted Ags. To determine whether the location of Aire within the medulla is absolutely essential or whether Aire could also function within the cortex for establishment of self-tolerance, we used bacterial artificial chromosome technology to establish a semiknockin strain of NOD-background (β5t/Aire-transgenic) mice expressing Aire under control of the promoter of β5t, a thymoproteasome expressed exclusively in the cortex. Although Aire was expressed in cTECs as typical nuclear dot protein in β5t/Aire-Tg mice, cTECs expressing Aire ectopically did not confer transcriptional expression of either Aire-dependent or Aire-independent tissue-restricted Ag genes. We then crossed β5t/Aire-Tg mice with Aire-deficient NOD mice, generating a strain in which Aire expression was confined to cTECs. Despite the presence of Aire(+) cTECs, these mice succumbed to autoimmunity, as did Aire-deficient NOD mice. The thymic microenvironment harboring Aire(+) cTECs, within which many Aire-activated genes were present, also showed no obvious alteration of positive selection, suggesting that Aire's unique property of generating a self-tolerant T cell repertoire is functional only in mTECs.

PMID:
26453754
DOI:
10.4049/jimmunol.1501026
[Indexed for MEDLINE]
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