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Aire is a cell intrinsic regulator of natural IgM-secreting cells

ABSTRACT: The Autoimmune Regulator (Aire) serves an essential role in T cell tolerance by promoting ‘promiscuous gene expression’ (PGE) in medullary thymic epithelial cells (mTECs). Several disease manifestations associated with Aire-deficiency, some apparently non-autoimmune, along with Aire expression beyond mTECs, suggest that Aire may regulate additional physiological processes. Here, we show that plasmablasts (PBs) and plasma cells (PCs) constitute a principal Aire-expressing population in the spleen, with highest expression in IgM+ cells and lower levels in class-switched PB/PCs. The Aire+IgM+ PB/PC compartment exhibits typical hallmarks of natural IgM secreting cells of extrafollicular origin: it is T cell-independent, exhibits distinct BCR features, and can originate from both peritoneal B1a cells and splenic marginal zone B cells, whereas follicular B cells may contribute to a lesser extent, at least under homeostatic conditions. While TLR-driven signals are sufficient in vitro to initiate PB differentiation from B1a and marginal zone B cells as previously described, we show that APRIL or BAFF synergize with TLR signaling to induce robust Aire expression, revealing a previously unrecognized TNF superfamily axis controlling Aire induction. Aire does not drive bona fide PGE in these cells, yet cell-intrinsically restrains their numbers, uncovering a role in homeostatic regulation of natural polyreactive IgM in steady state rather than classical maintenance of self-tolerance.

ORGANISM(S): Mus musculus

PROVIDER: GSE332886 | GEO | 2026/09/01

REPOSITORIES: GEO

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Aire is a cell intrinsic regulator of natural IgM-secreting cells

Project description:The Autoimmune Regulator (Aire) serves an essential role in T cell tolerance by promoting ‘promiscuous gene expression’ (PGE) in medullary thymic epithelial cells (mTECs). Several disease manifestations associated with Aire-deficiency, some apparently non-autoimmune, along with Aire expression beyond mTECs, suggest that Aire may regulate additional physiological processes. We show that plasmablasts (PBs) and plasma cells (PCs) constitute a principal Aire-expressing population in the spleen, with highest expression in IgM+ cells and lower levels in class-switched PB/PCs. The Aire+IgM+ PB/PC compartment exhibits typical hallmarks of natural IgM secreting cells of extrafollicular origin: it is T cell-independent, exhibits distinct BCR features, and can originate from both peritoneal B1a cells and splenic marginal zone B cells, whereas follicular B cells contribute minimally. While TLR-driven signals initiate PB differentiation as previously described, we find that subsequent stimulation through APRIL or BAFF - but not RANK or CD40 - induces Aire expression, uncovering a novel TNF superfamily axis upstream of Aire induction. Aire does not drive bona fide PGE in these cells, yet cell-intrinsically restrains their numbers, limiting steady-state serum levels of polyreactive IgM. These findings identify Aire as a B lineage-intrinsic regulator of natural IgM, raising the possibility that dysregulation of the IgM+ PB/PC compartment contributes to the pathological consequences of Aire-deficiency.

2026-08-31 | GSE310317 | GEO

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

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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

mRNA expression profile of medullary thymic epithelial cells-mTECs- of BALBc mice

Project description:The medullary thymic epithelial cells (mTECs) express virtually all autoantigens of the body. This phenomenon was then termed promiscuous gene expression (PGE). A large set of autoantigen genes (but not all) is controlled by the transcriptional modulator Autoimmune regulator (Aire) in mTECs. These autoantigens represent all tissues and organs in the thymus and it is implicated in the negative selection of autoreactive thymocytes, and consequantly preventing autoreactive autoimmune reactions and autoimmune diseases (e.g. type 1 diabetes mellitus, systemic lupus erythematosus). Thus, we are looking at gene expression in thse cells because it is very important to better understand the molecular basis of central immune tolerance to normal tissues and organs. The aim of this study is to evaluate the possible link between the expression of the transcriptional regulator Aire, the genetic background of mouse strains and the promiscuous gene expression in mTECs.

2014-04-18 | E-MEXP-3881 | biostudies-arrayexpress

Differential features of Aire-induced and Aire-independent promiscuous gene expression in thymic epithelial cells

Project description:Promiscuous gene expression (pGE) of numerous self-antigens in thymic epithelial cells (TEC) enables the elimination of self-reactive T cells. The autoimmune regulator (Aire) is the only known molecular determinant driving pGE in the thymus but the existence of Aire-independent mechanisms has been inferred. Here, we analyzed the poly(A)+ transcriptome of TEC populations by RNA-sequencing (RNA-seq) in order to reveal differential features of Aire-induced vs. –independent pGE. We report an unanticipated effect of Aire deletion on the proliferation and differentiation of cortical TEC. Moreover, the RNA-seq data reveal the breath of Aire-induced and –independent pGE in medullary TEC (mTEC) subsets and the extent of thymic peripheral tissue representation. The results suggest that Aire-induced promiscuously expressed transcripts affect several functions with far reaching biological consequences in mTEC. High-throughput characterization of TEC transcriptomes will enable progress in understanding TEC biology and the establishment of self-tolerance. The mRNA profiles of cTEC, mTEClo and mTEChi from 6-8 week-old wild type (WT) and Aire-/- (KO) mice were generated by RNA-sequencing using Illumina HiSeq2000.

2015-05-19 | E-GEOD-65617 | biostudies-arrayexpress

Differential features of Aire-induced and Aire-independent promiscuous gene expression in thymic epithelial cells

2015-05-19 | GSE65617 | GEO

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.

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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

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.

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