title: Identification of embryonic precursor cells that differentiate into thymic epithelial cells expressing autoimmune regulator.
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.
authors.affiliation: Division of Cellular and Molecular Biology, The Institute of Medical Science, The University of Tokyo, Shirokane-dai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Nobuko
authors.identifier: 0000-0003-1085-5996
authors.initials: N
authors.lastname: Akiyama
authors.affiliation: Division of Cellular and Molecular Biology, The Institute of Medical Science, The University of Tokyo, Shirokane-dai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Nobukazu
authors.initials: N
authors.lastname: Takizawa
authors.affiliation: Division of Cellular and Molecular Biology, The Institute of Medical Science, The University of Tokyo, Shirokane-dai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Miyauchi
authors.affiliation: Division of Cellular and Molecular Biology, The Institute of Medical Science, The University of Tokyo, Shirokane-dai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Yanai
authors.affiliation: Division of Cellular and Molecular Biology, The Institute of Medical Science, The University of Tokyo, Shirokane-dai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Tateishi
authors.affiliation: Division of Cellular and Molecular Biology, The Institute of Medical Science, The University of Tokyo, Shirokane-dai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Shinzawa
authors.affiliation: Division of Cellular and Molecular Biology, The Institute of Medical Science, The University of Tokyo, Shirokane-dai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Riko
authors.initials: R
authors.lastname: Yoshinaga
authors.affiliation: Division of Organic Chemistry, National Institute of Health Sciences, Kamiyoga, Setagaya, Tokyo 158-8501, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Kurihara
authors.affiliation: Division of Organic Chemistry, National Institute of Health Sciences, Kamiyoga, Setagaya, Tokyo 158-8501, Japan.
authors.forename: Yosuke
authors.identifier: 0000-0001-7521-4861
authors.initials: Y
authors.lastname: Demizu
authors.affiliation: Nagahama Institute for Biochemical Science, Oriental Yeast Co., Ltd., 50, Kano-cho, Nagahama, Shiga 526-0804, Japan.
authors.forename: Hisataka
authors.initials: H
authors.lastname: Yasuda
authors.affiliation: Laboratory of Cellular Biochemistry, Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
authors.forename: Shintaro
authors.identifier: 0000-0002-1598-7923
authors.initials: S
authors.lastname: Yagi
authors.affiliation: Laboratory of Cellular Biochemistry, Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
authors.forename: Guoying
authors.identifier: 0000-0003-1840-5244
authors.initials: G
authors.lastname: Wu
authors.affiliation: Division of Molecular Immunology, Institute for Enzyme Research, Tokushima University, Tokushima 770-8503, Japan.
authors.forename: Mitsuru
authors.identifier: 0000-0003-3844-8110
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: 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.
authors.forename: Reiko
authors.initials: R
authors.lastname: Sakamoto
authors.affiliation: 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.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Yoshida
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.
authors.forename: Josef M
authors.identifier: 0000-0002-8194-3777
authors.initials: JM
authors.lastname: Penninger
authors.affiliation: Institute for Oral Science, Matsumoto Dental University, Hiro-oka, Shiojiri-shi, Nagano 399-0781, Japan.
authors.forename: Yasuhiro
authors.identifier: 0000-0002-0903-3226
authors.initials: Y
authors.lastname: Kobayashi
authors.affiliation: Division of Cellular and Molecular Biology, The Institute of Medical Science, The University of Tokyo, Shirokane-dai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Jun-Ichiro
authors.identifier: 0000-0001-6389-7036
authors.initials: J
authors.lastname: Inoue
authors.affiliation: 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.
authors.forename: Taishin
authors.identifier: 0000-0002-0341-6154
authors.initials: T
authors.lastname: Akiyama
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology*; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000276:immunology*; D037121:Plant Lectins / Q000235:genetics / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology*; D000096927:AIRE Protein
chemical_list: D037121:Plant Lectins; D014157:Transcription Factors; D000096927:AIRE Protein; C036850:Ulex europaeus lectins