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J Immunol. 2018 Dec 1;201(11):3244-3257. doi: 10.4049/jimmunol.1800950. Epub 2018 Nov 2.

Aire Controls in Trans the Production of Medullary Thymic Epithelial Cells Expressing Ly-6C/Ly-6G.

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Division of Molecular Immunology, Institute for Enzyme Research, Tokushima University, Tokushima 770-8503, Japan.
Student Lab, Tokushima University Faculty of Medicine, Tokushima 770-8503, Japan.
Department of Molecular and Environmental Pathology, Institute of Biomedical Sciences, The University of Tokushima Graduate School, Tokushima 770-8503, Japan.
Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba 278-0022, Japan.
Department of Immunology, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan.
Department of Bioinformatics and Genomics, Graduate School of Medical Sciences, Kanazawa University, Ishikawa 920-0934, Japan; and.
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.


Medullary thymic epithelial cells (mTECs), which express a wide range of tissue-restricted Ags (TRAs), contribute to the establishment of self-tolerance by eliminating autoreactive T cells and/or inducing regulatory T cells. Aire controls a diverse set of TRAs within Aire-expressing cells by employing various transcriptional pathways. As Aire has a profound effect on transcriptomes of mTECs, including TRAs not only at the single-cell but also the population level, we suspected that Aire (Aire+ mTECs) might control the cellular composition of the thymic microenvironment. In this study, we confirmed that this is indeed the case by identifying a novel mTEC subset expressing Ly-6 family protein whose production was defective in Aire-deficient thymi. Reaggregated thymic organ culture experiments demonstrated that Aire did not induce the expression of Ly-6C/Ly-6G molecules from mTECs as Aire-dependent TRAs in a cell-intrinsic manner. Instead, Aire+ mTECs functioned in trans to maintain Ly-6C/Ly-6G+ mTECs. Thus, Aire not only controls TRA expression transcriptionally within the cell but also controls the overall composition of mTECs in a cell-extrinsic manner, thereby regulating the transcriptome from mTECs on a global scale.

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