Aire Expression Is Inherent to Most Medullary Thymic Epithelial Cells during Their Differentiation Program

Kawano, Hiroshi; Nishijima, Hitoshi; Morimoto, Junko; Hirota, Fumiko; Morita, Ryoko; Mouri, Yasuhiro; Nishioka, Yasuhiko; Matsumoto, Machiko

doi:10.4049/jimmunol.1501000

Cited by 21 publications

(25 citation statements)

References 30 publications

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“…[16][17][18][19][20] It has been demonstrated that the expression of Aire is an inherent property of mTECs during their differentiation programme and may occur at specific stages and/or cell states. 21 Aire expression can be modulated by epigenetic factors, such as methylation, 22,23 or by molecular mechanisms, such as the induction of the nuclear factor-jB pathway through RANKL-RANK-mediated signalling, CD40L-CD40 or the leukotriene b-mediated pathway, that determine the fate of the differential expression of Aire only in a subset of mTEC cells. [24][25][26] Whether Aire might be post-transcriptionally controlled through micro-RNAs (miRNAs) remains an open question.…”

Section: Functional Marker Of Mtec Differentiationmentioning

confidence: 99%

Update on Aire and thymic negative selection

et al. 2017

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SummaryTwenty years ago, the autoimmune regulator (Aire) gene was associated with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, and was cloned and sequenced. Its importance goes beyond its abstract link with human autoimmune disease. Aire identification opened new perspectives to better understand the molecular basis of central tolerance and self-non-self distinction, the main properties of the immune system. Since 1997, a growing number of immunologists and molecular geneticists have made important discoveries about the function of Aire, which is essentially a pleiotropic gene. Aire is one of the functional markers in medullary thymic epithelial cells (mTECs), controlling their differentiation and expression of peripheral tissue antigens (PTAs), mTEC-thymocyte adhesion and the expression of microRNAs, among other functions. With Aire, the immunological tolerance became even more apparent from the molecular genetics point of view. Currently, mTECs represent the most unusual cells because they express almost the entire functional genome but still maintain their identity. Due to the enormous diversity of PTAs, this uncommon gene expression pattern was termed promiscuous gene expression, the interpretation of which is essentially immunological -i.e. it is related to self-representation in the thymus. Therefore, this knowledge is strongly linked to the negative selection of autoreactive thymocytes. In this update, we focus on the most relevant results of Aire as a transcriptional and post-transcriptional controller of PTAs in mTECs, its mechanism of action, and its influence on the negative selection of autoreactive thymocytes as the bases of the induction of central tolerance and prevention of autoimmune diseases.

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Section: Functional Marker Of Mtec Differentiationmentioning

confidence: 99%

Update on Aire and thymic negative selection

et al. 2017

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“…Neo r was removed by crossing the mice with a transgenic (Tg) line expressing the general deleter flippase. Aire/GFP-KI (26), Aire/ diphtheria toxin receptor (DTR)-GFP-KI (27), Aire/CreER BAC-Tg (28), and tdRFP reporter mice (kindly provided by Dr. H.J. Fehling) were reported previously.…”

Section: Micementioning

confidence: 99%

“…Thymic epithelial cells (TECs) were prepared via enzymatic digestion and subjected to flow cytometric analysis using a FACScalibur (BD Biosciences) and a FACSAria II (BD Biosciences) as described previously (26,27). mAbs against CD45 (clone 30-F11), EpCAM (clone G8.8), Ly-51 (clone 6C3), CD80 (clone 16-10A1), I-A/I-E (clone M5/114.15.2), H-2D b (clone KH95), Gr-1 (clone RB6-8C5), Ly-6C (clone HK1.4), Ly-6G (clone 1A8), CD11b (clone M1/70), CD11c (clone N418), PD-L1 (clone MIH5), ICAM-1 (clone YN1/1.7.4), and CD24 (clone M1/69) were purchased from BioLegend and eBioscience.…”

Section: Thymic Epithelial Cell Preparation and Flow Cytometric Analysismentioning

confidence: 99%

Aire Controls in Trans the Production of Medullary Thymic Epithelial Cells Expressing Ly-6C/Ly-6G

Morimoto

Nishikawa

Kakimoto

et al. 2018

The Journal of Immunology

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Medullary thymic epithelial cells (mTECs), which express a wide range of tissue-restricted Ags (TRAs), contribute to the establishment of self-tolerance by eliminating autoreactive T cells and/or inducing regulatory T cells. Aire controls a diverse set of TRAs within Aire-expressing cells by employing various transcriptional pathways. As Aire has a profound effect on transcriptomes of mTECs, including TRAs not only at the single-cell but also the population level, we suspected that Aire (Aire+ mTECs) might control the cellular composition of the thymic microenvironment. In this study, we confirmed that this is indeed the case by identifying a novel mTEC subset expressing Ly-6 family protein whose production was defective in Aire-deficient thymi. Reaggregated thymic organ culture experiments demonstrated that Aire did not induce the expression of Ly-6C/Ly-6G molecules from mTECs as Aire-dependent TRAs in a cell-intrinsic manner. Instead, Aire+ mTECs functioned in trans to maintain Ly-6C/Ly-6G+ mTECs. Thus, Aire not only controls TRA expression transcriptionally within the cell but also controls the overall composition of mTECs in a cell-extrinsic manner, thereby regulating the transcriptome from mTECs on a global scale.

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“…Recent studies using a novel Aire-reporter strain suggest that this is indeed the case: Bona fide Aire + mTECs account for a larger fraction of mTECs than has been appreciated previously [30]. Furthermore, most, if not all, individual mTECs express Aire at least once in their lifetime [30,31]. Based on these observations, a defect of a single Aire transcription regulator resulting in global alteration of TRA expression at the mTEC population level might not be so unlikely.…”

mentioning

confidence: 93%

“…The latter situation is possible if we consider that the medulla is composed of a mixture of mTECs in different developmental stages and/or activation states [29]. Recent studies using a novel Aire-reporter strain suggest that this is indeed the case: Bona fide Aire + mTECs account for a larger fraction of mTECs than has been appreciated previously [30]. Furthermore, most, if not all, individual mTECs express Aire at least once in their lifetime [30,31].…”

mentioning

confidence: 94%

Switching on the Aire conditioner

Matsumoto

2015

Eur J Immunol

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If it becomes evident that a molecule is important for immune regulation, its mode of action immediately becomes a focus of interest. Sometimes, however, the issue of how it is produced to begin with may be overlooked. Aire, a gene responsible for a hereditary type of autoimmune disease, known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), may represent one such example, because of its well-known role in the establishment of self-tolerance. Since the cloning of Aire in 1997, researchers have found that it functions in two essential events within the thymus, through the representation of a wide array of tissue-restricted Ags (TRAs) from medullary thymic epithelial cells (mTECs) [1]: clonal deletion [2,3] and the production of functional Treg cells [3][4][5][6]. Furthermore, the means by which the nonorthodox transcription regulator Aire produces so many TRAs have been thoroughly investigated at the molecular Correspondence: Prof. Mitsuru Matsumoto e-mail: mitsuru@tokushima-u.ac.jp level [7, 8]. In contrast to these efforts to clarify the cellular immunology and molecular biology of Aire, our understanding of the mechanisms controlling Aire expression itself is still far from complete. In particular, we have only limited information on the promoter/enhancer element(s) for Aire within the mammalian genome.In this issue, Haljasorg et al. [9] investigate the molecular regulation of Aire expression by focusing on the region ß3 kb upstream of Aire, which was highlighted by in silico analysis: the corresponding sequence was highly conserved among many mammalian species, containing two putative NF-κB binding sites spaced less than 10 bp apart. Using a reporter gene assay together with an electrophoretic mobility shift assay (EMSA), the authors confirm that these NF-κB-binding motifs indeed bind to classical (RelA and p50) and nonclassical (RelB and p52) NF-κB components. The authors named this region "conserved noncoding sequences" (CNS1), with possible enhancer activity for Aire. In order to prove their hypothesis, they adopted the tough approach of generating mice lacking CNS1 (CNS1-KO) through a targeted deletion. Sure enough, CNS1-KO mice showed no Aire expression in the thymus or secondary organs [9]. Furthermore, CNS1-KO mice showed many characteristic features of Aire-deficient mice, including reduced expression of many so-called Aire-dependent TRAs, such as salivary protein 1 and insulin 2, and altered development of mTECs (i.e. changes in the composition of immature and mature mTECs), although no obvious autoimmune phenotypes were observed on a C57BL/6 background [9].Given that it was demonstrated that mice deficient in various TNF receptor superfamily members activating the NF-κB signal pathway have defective Aire expression, Haljasorg et al.[9] next examined the possible cytokine signals responsible for NF-κB-mediated Aire expression. The authors found that Aire was induced from wild-type (WT) mouse thymi but not from CNS1-KO thymi upon stimulation with RANKL (receptor activator o...

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Aire Expression Is Inherent to Most Medullary Thymic Epithelial Cells during Their Differentiation Program

Cited by 21 publications

References 30 publications

Update on Aire and thymic negative selection

Update on Aire and thymic negative selection

Aire Controls in Trans the Production of Medullary Thymic Epithelial Cells Expressing Ly-6C/Ly-6G

Switching on the Aire conditioner

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