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Sirt1 is essential for Aire-mediated induction of central immunological tolerance

ABSTRACT: Autoimmune regulator (Aire) is a unique transcriptional regulator that induces promiscuous expression of thousands of tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs), a step critical for induction of immunological self-tolerance. Although several recent studies provided very important molecular insights into how Aire operates, a more comprehensive understanding of this process still remains elusive. Here we demonstrate that a lysine deacetylase Sirtuin-1 (Sirt1) is predominantly expressed in mature Aire+ mTECs, where it is required for expression of Aire-dependent TRA genes and a subsequent induction of immunological self-tolerance. Our study elucidates a previously unknown molecular mechanism for Aire-mediated transcriptional regulation and uncovers a unique functional role for Sirt1 in preventing organ-specific autoimmunity. ~100ng of total RNA isolated by Trizol extraction from MHC-II low and high mTECs (pool of 3 mice) was used to generate poly-A-selected transcriptome libraries using the non-directionnal TruSeq V3 RNA Sample Prep Kit (without additional pre-amplification) following the manufacturer's protocols. Enrichment of DNA fragment with adapter molecules on both ends was done using 15 cycles of PCR amplification using the Illumina PCR mix and primer cocktail. Paired-end (2 × 100 bp) sequencing was performed using the Illumina HiSeq2000 machine.

ORGANISM(S): Mus musculus

SUBMITTER: Matthieu Giraud

PROVIDER: E-GEOD-68190 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Sirt1 is essential for Aire-mediated induction of central immunological tolerance

Project description:Autoimmune regulator (Aire) is a unique transcriptional regulator that induces promiscuous expression of thousands of tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs), a step critical for induction of immunological self-tolerance. Although several recent studies provided very important molecular insights into how Aire operates, a more comprehensive understanding of this process still remains elusive. Here we demonstrate that a lysine deacetylase Sirtuin-1 (Sirt1) is predominantly expressed in mature Aire+ mTECs, where it is required for expression of Aire-dependent TRA genes and a subsequent induction of immunological self-tolerance. Our study elucidates a previously unknown molecular mechanism for Aire-mediated transcriptional regulation and uncovers a unique functional role for Sirt1 in preventing organ-specific autoimmunity.

2015-05-25 | GSE68190 | GEO

Identification of a novel Aire-regulating cis-regulatory element using H3K27ac ChIP-seq

Project description:Thymic central tolerance is essential to preventing autoimmunity. In medullary thymic epithelial cells (mTECs), the Autoimmune regulator (Aire) gene plays an essential role in this process by driving the expression of a diverse set of tissue-specific antigens (TSAs), which are presented and help tolerize self-reactive thymocytes. Interestingly, Aire has a highly tissue-restricted pattern of expression, with only mTECs and peripheral extrathymic Aire-expressing cells (eTACs) known to express detectable levels in adults. Despite this high level of tissue specificity, the cis-regulatory elements that control Aire expression have remained obscure. We used sequence conservation analysis and ChIP-seq against the enhancer-associated histone mark H3K27ac to identify a candidate Aire cis-regulatory element. There is enrichment of H3K27ac near this element, ACNS1, in mTECs and the element also has characteristics of being NF-ÎºB-responsive. Finally, we find that this element is essential for Aire expression in vivo and necessary to prevent spontaneous autoimmunity, reflecting the importance of this regulatory DNA element in promoting immune tolerance. Two experimental groups (GFP neg mTECs and GFP pos mTECs), each with three samples, and one control sample (D10 Th2 cells).

2015-10-23 | E-GEOD-74257 | biostudies-arrayexpress

Transcriptional regulation by Aire in medullary thymic epithelial cells revisited

Project description:The deficiency of Aire, a transcriptional regulator whose defect results in the development of autoimmunity, is associated with reduced expression of tissue-restricted self-Ags (TRAs) in medullary thymic epithelial cells (mTECs). Although the mechanisms underlying Aire-dependent expression of TRAs need to be explored, the physical identification of the target(s) of Aire has been hampered by the low and promiscuous expression of TRAs. We have tackled this issue by engineering mice with augmented Aire expression. Integration of the transcriptomic data from Aire-augmented and Aire-deficient mTECs revealed that a large proportion of so-called Aire-dependent genes, including those of TRAs, may not be direct transcriptional targets downstream of Aire. Rather, Aire induces TRA expression indirectly through controlling the heterogeneity of mTECs, as revealed by single-cell analyses. In contrast, Ccl25 emerged as a canonical target of Aire, and we verified this both in vitro and in vivo. Our approach has illuminated the Aire?s primary targets while distinguishing them from the secondary targets.

2021-10-13 | GSE155331 | GEO

Aire suppresses CTLA-4 expression from thymic stroma to control autoimmunity

Project description:We show that thymic epithelial cells in the medulla (mTECs) that present self-antigens (self-Ags) to developing thymocytes for establishing immunological self-tolerance also express CTLA-4 if Aire, loss of which is responsible for the hereditary autoimmunity, is nonfunctional. Upon binding with its ligand, CD80 and CD86, expressed on thymic DCs, CTLA-4/ligand complex was internalized by Aire-deficient mTECs. This attenuated the ability of DCs to provide costimulatory signals and to present self-Ags, resulting in the reduced production of Tregs.

2022-03-21 | GSE155082 | GEO

The role of Autoimmune regulator (Aire) gene in the control of adhesion between medullary thymic epithelial cells and thymocytes

Project description:The crosstalk between thymocytes and thymic epithelial cells is critical for T cell development and establishment of central tolerance. Although the role of Autoimmune Regulator (Aire) gene in the induction of central tolerance is well known, the precise cellular and molecular mechanisms by which Aire controls the ectopic expression of tissue restricted antigens (TRAs) in medullary thymic epithelial cells (mTECS) remain unclear. In this study we performed a functional assay with fresh thymocytes dissociated from a normal mouse thymus co-cultured with a Mus musculus mTEC cell line - named 3.10 mTEC line - , in which we had previously knocked-down Aire gene by means of siRNA transfection. Agilent Mouse Gene Expression microarrays were used to determine the large scale transcriptional expression profiles of control and Aire-knockdown 3.10 mTECs co-cultured with thymocytes.

2016-06-27 | E-MTAB-4595 | biostudies-arrayexpress

Functionally diverse thymic medullary epithelial cells interplay to direct central tolerance

Project description:Medullary thymic epithelial cells (mTECs) are essential for the establishment of self-tolerance in T cells. Promiscuous gene expression by a subpopulation of mTECs regulated by nuclear protein Aire contributes to the display of self-genomic products to newly generated T cells. Recent reports have highlighted additional self-antigen-displaying mTEC subpopulations; namely, Fezf2-expressing mTECs and a mosaic of self-mimetic mTECs including thymic tuft cells. In addition, a functionally different subset of mTECs produces chemokine CCL21 that attracts developing thymocytes to the medullary region. Here we report that CCL21+ mTECs and Aire+ mTECs non-redundantly cooperate to direct self-tolerance to prevent autoimmune pathology by optimizing the deletion of self-reactive T cells and the generation of regulatory T cells. We also detected a cooperation for self-tolerance between Aire and Fezf2, which unexpectedly regulates thymic tuft cells. Our results indicate an indispensable interplay among functionally diverse mTECs for the establishment of central self-tolerance.

2024-03-08 | GSE243180 | GEO

Functionally diverse thymic medullary epithelial cells interplay to direct central tolerance II

2024-04-18 | GSE244501 | GEO

The effect of the autoimmune regulator (Aire) gene on the transcriptional expression profile of 3.10 mTEC cell line.

Project description:Medullary thymic epithelial cells (mTECs) contribute to self-tolerance through the ectopic expression of peripheral tissue antigens (PTAs) in the thymus. PTA expression in mTECs is largely dependent on the autoimmune regulator (Aire) gene. Here we used a Mus musculus mTEC cell line (3.10 mTEC line, which constitutively express Aire in culture) to knockdown Aire gene by means of siRNA transfection. Aire knockdown was confirmed by means of qRT-PCR and RNA-FISH (for Aire mRNA levels), immunofluorescence and western blot (for AIRE protein levels).The Agilent oligo microarrays were used to determine the large scale transcriptional expression profiles of control or Aire-knockdown 3.10 mTECs.

2015-12-31 | E-MTAB-3879 | biostudies-arrayexpress

Expression data of Sirt1-deficient and sufficient medullary thymic epithelial cells (mTECs)

2015-05-25 | GSE68363 | GEO

Expression data of Sirt1-deficient and sufficient medullary thymic epithelial cells (mTECs)

Project description:Medullary thymic epithelial cells play essential role for induction of central self-tolerance. This functional capacity is mediated through a phenomenon known as promiscuous gene expression (pGE) of various tissue-restricted antigen (TRA) genes. pGE was previously shown to be mediated by a single factor called the Autoimmune regulator (Aire), which is specically expressed by mTECs. The aim of this study was to analyze the impact of deacetylase Sirtuin1, which is also highly expressed by mTECs, on mTEC gene expression profile and compare it with the impact of Aire. We used Affymetrix mouse 1ST arrays to analyze the impact of the Sirt1 gene on the gene expression profile of MHC-II high medullary thymic epithelial cells Mature MHC-II high mTECs were flow-sorted from thymi isolated from B6.Sirt1fl/fl, B6.Sirt1fl/flFoxn1-Cre and B6.Aire–/– 6weeks old mice. Typically, 3 mice were pooled to obtain 30-60 thousand sorted mTECs, which were then analyzed by gene expression profiling. Specifically, total RNA was extracted from ~30,000 pooled sorted cells using Trizol. Purified total RNA was then amplified using the MessageAmp RNA kit (Ambion). Biotinylated cRNA was then hybridized to Affymetrix Mouse Gene 1-ST arrays by the genomics core at the Weizmann Institute

2015-05-25 | E-GEOD-68363 | biostudies-arrayexpress

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