Aire controls the differentiation program of thymic epithelial cells in the medulla for the establishment of self-tolerance.
The roles of autoimmune regulator (Aire) in the expression of the diverse arrays of tissue-restricted antigen (TRA) genes from thymic epithelial cells in the medulla (medullary thymic epithelial cells [mTECs]) and in organization of the thymic microenvironment are enigmatic. We approached this issue by creating a mouse strain in which the coding sequence of green fluorescent protein (GFP) was inserted into the Aire locus in a manner allowing concomitant disruption of functional Aire protein expression. We found that Aire(+) (i.e., GFP(+)) mTECs were the major cell types responsible for the expression of Aire-dependent TRA genes such as insulin 2 and salivary protein 1, whereas Aire-independent TRA genes such as C-reactive protein and glutamate decarboxylase 67 were expressed from both Aire(+) and Aire(-) mTECs. Remarkably, absence of Aire from mTECs caused morphological changes together with altered distribution of mTECs committed to Aire expression. Furthermore, we found that the numbers of mTECs that express involucrin, a marker for terminal epidermal differentiation, were reduced in Aire-deficient mouse thymus, which was associated with nearly an absence of Hassall's corpuscle-like structures in the medulla. Our results suggest that Aire controls the differentiation program of mTECs, thereby organizing the global mTEC integrity that enables TRA expression from terminally differentiated mTECs in the thymic microenvironment.
Yano
Masashi
M
Division of Molecular Immunology, Institute for Enzyme Research, University of Tokushima, Tokushima, Japan.
Kuroda
Noriyuki
N
Han
Hongwei
H
Meguro-Horike
Makiko
M
Nishikawa
Yumiko
Y
Kiyonari
Hiroshi
H
Maemura
Kentaro
K
Yanagawa
Yuchio
Y
Obata
Kunihiko
K
Takahashi
Satoru
S
Ikawa
Tomokatsu
T
Satoh
Rumi
R
Kawamoto
Hiroshi
H
Mouri
Yasuhiro
Y
Matsumoto
Mitsuru
M
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D048430:Cell Shape; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D005260:Female; D018390:Gene Targeting; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D010641:Phenotype; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D017634:Self Tolerance / Q000502:physiology*; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology*; D000096927:AIRE Protein
D005968:Glutamate Decarboxylase; D049452:Green Fluorescent Proteins; D011498:Protein Precursors; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D000096927:AIRE Protein; C032253:involucrin; C402565:glutamate decarboxylase 1