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¹ Division of Molecular Immunology, Institute for Enzyme Research, University of Tokushima, Tokushima 770-8503, Japan
² Laboratory for Animal Resources and Genetic Engineering, Center for Developmental Biology, Institute of Physical and Chemical Research (RIKEN) Kobe, Kobe 650-0047, Japan
³ Department of Anatomy and Cell Biology, Division of Basic Medicine I, Osaka Medical College, Osaka, 569-8686, Japan
⁴ Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan
⁵ Neuronal Circuit Mechanisms Research Group, RIKEN Brain Science Institute, Saitama 351-0198, Japan
⁶ Institute of Basic Medical Sciences and Laboratory Animal Resource Center, Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba 305-8575, Japan
⁷ Laboratory for Lymphocyte Development, RIKEN Research Center for Allergy and Immunology, Kanagawa 230-0045, Japan

CORRESPONDENCE Mitsuru Matsumoto: mitsuru{at}ier.tokushima-u.ac.jp

The roles of autoimmune regulator (Aire) in the expression of the diverse arrays of tissue-restricted antigen (TRA) genes from thymic epithelial cells in the medulla (medullary thymic epithelial cells [mTECs]) and in organization of the thymic microenvironment are enigmatic. We approached this issue by creating a mouse strain in which the coding sequence of green fluorescent protein (GFP) was inserted into the Aire locus in a manner allowing concomitant disruption of functional Aire protein expression. We found that Aire⁺ (i.e., GFP⁺) mTECs were the major cell types responsible for the expression of Aire-dependent TRA genes such as insulin 2 and salivary protein 1, whereas Aire-independent TRA genes such as C-reactive protein and glutamate decarboxylase 67 were expressed from both Aire⁺ and Aire^– mTECs. Remarkably, absence of Aire from mTECs caused morphological changes together with altered distribution of mTECs committed to Aire expression. Furthermore, we found that the numbers of mTECs that express involucrin, a marker for terminal epidermal differentiation, were reduced in Aire-deficient mouse thymus, which was associated with nearly an absence of Hassall's corpuscle-like structures in the medulla. Our results suggest that Aire controls the differentiation program of mTECs, thereby organizing the global mTEC integrity that enables TRA expression from terminally differentiated mTECs in the thymic microenvironment.

© 2008 Yano et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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This article has been cited by other articles:

• Yano, M., Kuroda, N., Han, H., Meguro-Horike, M., Nishikawa, Y., Kiyonari, H., Maemura, K., Yanagawa, Y., Obata, K., Takahashi, S., Ikawa, T., Satoh, R., Kawamoto, H., Mouri, Y., Matsumoto, M. (2008). Aire controls the differentiation program of thymic epithelial cells in the medulla for the establishment of self-tolerance. JCB 183: i11-i11 [Full Text]  

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