Aire Expression Is Inherent to Most Medullary Thymic Epithelial Cells during Their Differentiation Program.
Aire in medullary thymic epithelial cells (mTECs) plays an important role in the establishment of self-tolerance. Because Aire(+) mTECs appear to be a limited subset, they may constitute a unique lineage(s) among mTECs. An alternative possibility is that all mTECs are committed to express Aire in principle, but Aire expression by individual mTECs is conditional. To investigate this issue, we established a novel Aire reporter strain in which endogenous Aire is replaced by the human AIRE-GFP-Flag tag (Aire/hAGF-knockin) fusion gene. The hAGF reporter protein was produced and retained very efficiently within mTECs as authentic Aire nuclear dot protein. Remarkably, snapshot analysis revealed that mTECs expressing hAGF accounted for >95% of mature mTECs, suggesting that Aire expression does not represent a particular mTEC lineage(s). We confirmed this by generating Aire/diphtheria toxin receptor-knockin mice in which long-term ablation of Aire(+) mTECs by diphtheria toxin treatment resulted in the loss of most mature mTECs beyond the proportion of those apparently expressing Aire. These results suggest that Aire expression is inherent to all mTECs but may occur at particular stage(s) and/or cellular states during their differentiation, thus accounting for the broad impact of Aire on the promiscuous gene expression of mTECs.
Division of Molecular Immunology, Institute for Enzyme Research, Tokushima University, Tokushima 770-8503, Japan; Department of Respiratory Medicine and Rheumatology, Institute of Biomedical Sciences, University of Tokushima Graduate School, Tokushima 770-8503, Japan; and.
Hiroshi
H
Kawano
Division of Molecular Immunology, Institute for Enzyme Research, Tokushima University, Tokushima 770-8503, Japan;
Hitoshi
H
Nishijima
Division of Molecular Immunology, Institute for Enzyme Research, Tokushima University, Tokushima 770-8503, Japan;
Junko
J
Morimoto
Division of Molecular Immunology, Institute for Enzyme Research, Tokushima University, Tokushima 770-8503, Japan; Japan Agency for Medical Research and Development-Core Research for Evolutional Science and Technology, Tokyo 100-0004, Japan.
Fumiko
F
Hirota
Division of Molecular Immunology, Institute for Enzyme Research, Tokushima University, Tokushima 770-8503, Japan; Japan Agency for Medical Research and Development-Core Research for Evolutional Science and Technology, Tokyo 100-0004, Japan.
Ryoko
R
Morita
Division of Molecular Immunology, Institute for Enzyme Research, Tokushima University, Tokushima 770-8503, Japan;
Yasuhiro
Y
Mouri
Department of Respiratory Medicine and Rheumatology, Institute of Biomedical Sciences, University of Tokushima Graduate School, Tokushima 770-8503, Japan; and.
Yasuhiko
Y
Nishioka
Division of Molecular Immunology, Institute for Enzyme Research, Tokushima University, Tokushima 770-8503, Japan; Japan Agency for Medical Research and Development-Core Research for Evolutional Science and Technology, Tokyo 100-0004, Japan mitsuru@tokushima-u.ac.jp.
Mitsuru
M
Matsumoto
D000818:Animals; D002454:Cell Differentiation; D004167:Diphtheria Toxin / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D015870:Gene Expression; D005786:Gene Expression Regulation; D055879:Gene Knock-In Techniques; D049452:Green Fluorescent Proteins / Q000235:genetics; D066257:Heparin-binding EGF-like Growth Factor / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism*; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D000096927:AIRE Protein
D004167:Diphtheria Toxin; D049452:Green Fluorescent Proteins; D066257:Heparin-binding EGF-like Growth Factor; D014157:Transcription Factors; D000096927:AIRE Protein