Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE155082 | GEO | 2022/03/21

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

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

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.

2024-04-18 | GSE244501 | GEO

Functionally diverse thymic medullary epithelial cells interplay to direct central tolerance

2024-03-08 | GSE243180 | GEO

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

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

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

Expression data from meduallar thymic epithelial cells and thymic or splenic B cells

Project description:Aire is a transcriptional regulator that induces promiscuous expression of thousands of tissue-restricted antigen (TRA) genes in medullary thymic epithelial cells (mTECs). While the target genes of Aire are well characterized, the transcriptional programs regulating its own expression remain elusive. We used Affymetrix microarrays to analyze the gene expression patterns of Aire expressing cells (mature mTECs and Thymic B cells) and compared them to control counterparts, namely immature mTECs, cortical Thymic epithelial cells and splenic B cells of tissue-restricted antigen (TRA) genes in medullary thymic epithelial cells (mTECs). While the target genes of Aire are well characterized, the transcriptional programs regulating its own expression remain elusive. We used Affymetrix microarrays to analyze the gene expression patterns of Aire expressing cells (mature mTECs and Thymic B cells) and compared them to control counterparts, namely immature mTECs, cortical Thymic epithelial cells and splenic B cells.

2016-12-12 | GSE89965 | GEO

The effect of the Autoimmune regulator (Aire) gene on microRNA transcriptional 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. Autoimmune regulator (Aire) is to date the best characterized transcriptional regulator known to at least partially coordinate PTA expression in mTECs. Furthermore the expression of Aire-dependent and -independent genes is also modulated by microRNAs. Given the transcriptional regulation exerted by Aire in mTEC cells and the role of miRNAs in post-transcriptional control, we used a Mus musculus mTEC cell line (3.10) which constitutively express Aire in culture) to knockdown Aire gene by means of siRNA transfection and then observe the effect of Aire knockdown in the transcriptional profile of miRNAs by means of oligomicroarrays. The Agilent oligomicroarrays were used to determine the large scale the miRNA transcriptional profiles of control or Aire-knockdown 3.10 mTECs.

2016-06-27 | E-MTAB-4596 | biostudies-arrayexpress

ATAC-seq profiling of medullary thymic epithelial cells from wildtype and Kat7-knockout mice

Project description:Thymic epithelial cells govern thymic T lymphocyte differentiation and selection. Medullary TECs (mTECs) facilitate the negative selection of self-reactive thymocytes and the differentiation of FOXP3+ regulatory T cells. Medullary TECs are also distinctive for their “promiscuous” gene expression, transcribing thousands of peripheral tissue genes (PTG) that are otherwise only expressed highly in one or two other organs. Much of this PTG expression by mTECs is controlled by the autoimmune regulator, AIRE. To probe the mechanism by which KAT7 promotes AIRE function, we performed ATAC-seq to compare chromatin accessibility in MHCII-high medullary thymic epithelial cells from Kat7-knockout and wildtype mice.

2021-12-21 | GSE188868 | GEO

In-depth profiling of transcriptional activity of Aire in mouse mTECs

Project description:Aire, a transcriptional regulator whose defect results in the development of autoimmunity, controls the transcriptome in medullary thymic epithelial cells (mTECs) including the genes for self-antigens. Here, we utilized a technique for profiling transcriptome from a single cell (RamDA-seq) to investigate bulk populations in mTECs deeply.

2023-01-07 | GSE222285 | GEO

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

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data