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J Exp Med. 2016 Jul 25;213(8):1441-58. doi: 10.1084/jem.20151780. Epub 2016 Jul 11.

Identification of embryonic precursor cells that differentiate into thymic epithelial cells expressing autoimmune regulator.

Author information

1
Division of Cellular and Molecular Biology, The Institute of Medical Science, The University of Tokyo, Shirokane-dai, Minato-ku, Tokyo 108-8639, Japan.
2
Division of Organic Chemistry, National Institute of Health Sciences, Kamiyoga, Setagaya, Tokyo 158-8501, Japan.
3
Nagahama Institute for Biochemical Science, Oriental Yeast Co., Ltd., 50, Kano-cho, Nagahama, Shiga 526-0804, Japan.
4
Laboratory of Cellular Biochemistry, Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
5
Division of Molecular Immunology, Institute for Enzyme Research, Tokushima University, Tokushima 770-8503, Japan.
6
Laboratory of Developmental Genetics, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, Shirokane-dai, Minato-ku, Tokyo 108-8639, Japan.
7
Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.
8
Institute for Oral Science, Matsumoto Dental University, Hiro-oka, Shiojiri-shi, Nagano 399-0781, Japan.
9
Division of Cellular and Molecular Biology, The Institute of Medical Science, The University of Tokyo, Shirokane-dai, Minato-ku, Tokyo 108-8639, Japan taishin@ims.u-tokyo.ac.jp.

Abstract

Medullary thymic epithelial cells (mTECs) expressing autoimmune regulator (Aire) are critical for preventing the onset of autoimmunity. However, the differentiation program of Aire-expressing mTECs (Aire(+) mTECs) is unclear. Here, we describe novel embryonic precursors of Aire(+) mTECs. We found the candidate precursors of Aire(+) mTECs (pMECs) by monitoring the expression of receptor activator of nuclear factor-κB (RANK), which is required for Aire(+) mTEC differentiation. pMECs unexpectedly expressed cortical TEC molecules in addition to the mTEC markers UEA-1 ligand and RANK and differentiated into mTECs in reaggregation thymic organ culture. Introduction of pMECs in the embryonic thymus permitted long-term maintenance of Aire(+) mTECs and efficiently suppressed the onset of autoimmunity induced by Aire(+) mTEC deficiency. Mechanistically, pMECs differentiated into Aire(+) mTECs by tumor necrosis factor receptor-associated factor 6-dependent RANK signaling. Moreover, nonclassical nuclear factor-κB activation triggered by RANK and lymphotoxin-β receptor signaling promoted pMEC induction from progenitors exhibiting lower RANK expression and higher CD24 expression. Thus, our findings identified two novel stages in the differentiation program of Aire(+) mTECs.

PMID:
27401343
PMCID:
PMC4986530
DOI:
10.1084/jem.20151780
[Indexed for MEDLINE]
Free PMC Article

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