title: Biphasic Aire expression in early embryos and in medullary thymic epithelial cells before end-stage terminal differentiation.
abstract: The roles of autoimmune regulator (Aire)-expressing medullary thymic epithelial cells (mTECs) in the organization of the thymic microenvironment for establishing self-tolerance are enigmatic. We sought to monitor the production and maintenance of Aire-expressing mTECs by a fate-mapping strategy in which bacterial artificial chromosome transgenic (Tg) mice expressing Cre recombinase under the control of the Aire regulatory element were crossed with a GFP reporter strain. We found that, in addition to its well recognized expression within mature mTECs, Aire was expressed in the early embryo before emergence of the three germ cell layers. This observation may help to explain the development of ectodermal dystrophy often seen in patients with AIRE deficiency. With the use of one Tg line in which Cre recombinase expression was confined to mTECs, we found that Aire(+)CD80(high) mTECs further progressed to an Aire(-)CD80(intermediate) stage, suggesting that Aire expression is not constitutive from after its induction until cell death but instead is down-regulated at the beginning of terminal differentiation. We also demonstrated that many mTECs of Aire-expressing lineage are in close contact with thymic dendritic cells. This close proximity may contribute to transfer of tissue-restricted self-antigens expressed by mTECs to professional antigen-presenting cells.
authors.affiliation: Division of Molecular Immunology, Institute for Enzyme Research, University of Tokushima, Tokushima 770-8503, Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Nishikawa
authors.forename: Fumiko
authors.initials: F
authors.lastname: Hirota
authors.forename: Masashi
authors.initials: M
authors.lastname: Yano
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kitajima
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Miyazaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawamoto
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Mouri
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Matsumoto
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D047108:Embryonic Development / Q000235:genetics; D004847:Epithelial Cells / Q000166:cytology* / Q000502:physiology; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics; D008221:Lymphoid Tissue / Q000502:physiology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D013091:Spermatogenesis / Q000502:physiology; D013737:Testis / Q000502:physiology; D013950:Thymus Gland / Q000166:cytology* / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics*; D000096927:AIRE Protein
chemical_list: D049452:Green Fluorescent Proteins; D014157:Transcription Factors; D000096927:AIRE Protein
references.citation: EMBO Rep. 2000 Sep;1(3):239-43
references.pmid: 11256606
references.citation: Annu Rev Immunol. 2009;27:287-312
references.pmid: 19302042
references.citation: J Exp Med. 2009 Jul 6;206(7):1505-13
references.pmid: 19564355
references.citation: J Exp Med. 2007 Oct 29;204(11):2521-8
references.pmid: 17908938
references.citation: J Immunol. 2008 Oct 15;181(8):5225-32
references.pmid: 18832676
references.citation: J Exp Med. 2005 Jul 4;202(1):15-9
references.pmid: 15983067
references.citation: Cell. 2007 May 4;129(3):523-36
references.pmid: 17482546
references.citation: Science. 2008 Aug 8;321(5890):843-7
references.pmid: 18687966
references.citation: J Immunol. 2009 Mar 15;182(6):3902-18
references.pmid: 19265170
references.citation: Biochem Biophys Res Commun. 2006 Jul 7;345(3):926-32
references.pmid: 16707099
references.citation: Hum Mol Genet. 2002 Feb 15;11(4):397-409
references.pmid: 11854172
references.citation: Annu Rev Immunol. 2004;22:457-83
references.pmid: 15032585
references.citation: Nat Immunol. 2007 Feb;8(2):181-90
references.pmid: 17195844
references.citation: Science. 2002 Nov 15;298(5597):1395-401
references.pmid: 12376594
references.citation: J Exp Med. 2007 Jun 11;204(6):1267-72
references.pmid: 17502664
references.citation: J Exp Med. 2004 Oct 18;200(8):1039-49
references.pmid: 15492126
references.citation: Immunogenetics. 2008 Feb;60(2):105-14
references.pmid: 18214467
references.citation: Annu Rev Immunol. 2006;24:571-606
references.pmid: 16551260
references.citation: Annu Rev Immunol. 2003;21:335-76
references.pmid: 12524386
references.citation: Annu Rev Immunol. 2008;26:355-88
references.pmid: 18304000
references.citation: FEBS Lett. 2000 Mar 31;470(3):263-8
references.pmid: 10745079
references.citation: Trends Immunol. 2007 Jul;28(7):321-7
references.pmid: 17556019
references.citation: Arch Immunol Ther Exp (Warsz). 2007 Jan-Feb;55(1):27-34
references.pmid: 17277892
references.citation: J Immunol. 2004 Feb 15;172(4):2067-75
references.pmid: 14764671
references.citation: J Immunol. 2005 Feb 15;174(4):1862-70
references.pmid: 15699112
references.citation: Nat Rev Immunol. 2008 Dec;8(12):948-57
references.pmid: 19008896
references.citation: J Immunol. 2008 Feb 1;180(3):1338-43
references.pmid: 18209027
references.citation: Eur J Immunol. 2007 Dec;37(12):3363-72
references.pmid: 18000951
references.citation: J Exp Med. 2008 Nov 24;205(12):2827-38
references.pmid: 19015306
references.citation: J Immunol. 2008 Apr 15;180(8):5344-51
references.pmid: 18390716