Biphasic Aire expression in early embryos and in medullary thymic epithelial cells before end-stage terminal differentiation.
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.
Nishikawa
Yumiko
Y
Division of Molecular Immunology, Institute for Enzyme Research, University of Tokushima, Tokushima 770-8503, Japan.
Hirota
Fumiko
F
Yano
Masashi
M
Kitajima
Hiroyuki
H
Miyazaki
Jun-ichi
J
Kawamoto
Hiroshi
H
Mouri
Yasuhiro
Y
Matsumoto
Mitsuru
M
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
D049452:Green Fluorescent Proteins; D014157:Transcription Factors; D000096927:AIRE Protein
EMBO Rep. 2000 Sep;1(3):239-43
11256606
Annu Rev Immunol. 2009;27:287-312
19302042
J Exp Med. 2009 Jul 6;206(7):1505-13
19564355
J Exp Med. 2007 Oct 29;204(11):2521-8
17908938
J Immunol. 2008 Oct 15;181(8):5225-32
18832676
J Exp Med. 2005 Jul 4;202(1):15-9
15983067
Cell. 2007 May 4;129(3):523-36
17482546
Science. 2008 Aug 8;321(5890):843-7
18687966
J Immunol. 2009 Mar 15;182(6):3902-18
19265170
Biochem Biophys Res Commun. 2006 Jul 7;345(3):926-32
16707099
Hum Mol Genet. 2002 Feb 15;11(4):397-409
11854172
Annu Rev Immunol. 2004;22:457-83
15032585
Nat Immunol. 2007 Feb;8(2):181-90
17195844
Science. 2002 Nov 15;298(5597):1395-401
12376594
J Exp Med. 2007 Jun 11;204(6):1267-72
17502664
J Exp Med. 2004 Oct 18;200(8):1039-49
15492126
Immunogenetics. 2008 Feb;60(2):105-14
18214467
Annu Rev Immunol. 2006;24:571-606
16551260
Annu Rev Immunol. 2003;21:335-76
12524386
Annu Rev Immunol. 2008;26:355-88
18304000
FEBS Lett. 2000 Mar 31;470(3):263-8
10745079
Trends Immunol. 2007 Jul;28(7):321-7
17556019
Arch Immunol Ther Exp (Warsz). 2007 Jan-Feb;55(1):27-34
17277892
J Immunol. 2004 Feb 15;172(4):2067-75
14764671
J Immunol. 2005 Feb 15;174(4):1862-70
15699112
Nat Rev Immunol. 2008 Dec;8(12):948-57
19008896
J Immunol. 2008 Feb 1;180(3):1338-43
18209027
Eur J Immunol. 2007 Dec;37(12):3363-72
18000951
J Exp Med. 2008 Nov 24;205(12):2827-38
19015306
J Immunol. 2008 Apr 15;180(8):5344-51
18390716