Thymic Treg TCR sequencing
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Project description:To investigate the role of Aire in thymic selection, we examined the cellular requirements for generation of ovalbumin (OVA)-specific CD4 and CD8 T cells in mice expressing OVA under the control of the rat insulin promoter (RIP). Aire-deficiency reduced the number of mature single positive (SP) OVA-specific CD4+ or CD8+ T cells in the thymus, independent of OVA expression. Importantly, it also contributed in two way to OVA-dependent negative selection depending on the T cell type. Aire-dependent negative selection of OVA-specific CD8 T cells correlated with Aire-regulated expression of OVA. By contrast, for OVA-specific CD4 T cells, Aire affected tolerance induction by a mechanism that operated independent of the level of OVA expression, controlling access of antigen presenting cells to mTEC-expressed OVA. This study supports the view that one mechanism by which Aire controls thymic negative selection is by regulating the indirect presentation of mTEC-derived antigens by thymic dendritic cells. It also indicates that mTEC can mediate tolerance by direct presentation of Aireregulated antigens to both CD4 and CD8 T cells. Total RNA was extracted from medullary thymic epithelial cells isolated from wildtype and Aire-deficient C57BL/6 mice for comparison of gene expression profiles.
2011-04-06 | E-GEOD-28393 | biostudies-arrayexpress
Project description:To investigate the role of Aire in thymic selection, we examined the cellular requirements for generation of ovalbumin (OVA)-specific CD4 and CD8 T cells in mice expressing OVA under the control of the rat insulin promoter (RIP). Aire-deficiency reduced the number of mature single positive (SP) OVA-specific CD4+ or CD8+ T cells in the thymus, independent of OVA expression. Importantly, it also contributed in two way to OVA-dependent negative selection depending on the T cell type. Aire-dependent negative selection of OVA-specific CD8 T cells correlated with Aire-regulated expression of OVA. By contrast, for OVA-specific CD4 T cells, Aire affected tolerance induction by a mechanism that operated independent of the level of OVA expression, controlling access of antigen presenting cells to mTEC-expressed OVA. This study supports the view that one mechanism by which Aire controls thymic negative selection is by regulating the indirect presentation of mTEC-derived antigens by thymic dendritic cells. It also indicates that mTEC can mediate tolerance by direct presentation of Aireregulated antigens to both CD4 and CD8 T cells.
2011-04-06 | GSE28393 | GEO
Project description:Aire in medullary thymic epithelial cells plays an essential role in the negative selection through expression of broad arrays of tissue-restricted antigens. We asked whether Aire could also activate the expression of tissue-restricted antigens in cortical thymic epithelial cells. We established a semi-knockin strain of NOD-background mice expressing Aire under control of the promoter of β5t, a thymoproteasome expressed exclusively in the cortex. We extracted RNA from cortical thymic epithelial cells ectopically expressing Aire and hybridization was performed on Affymetrix. microarrays.
2015-08-03 | E-GEOD-70326 | biostudies-arrayexpress
Project description:Aire in medullary thymic epithelial cells plays an essential role in the negative selection through expression of broad arrays of tissue-restricted antigens. We asked whether Aire could also activate the expression of tissue-restricted antigens in cortical thymic epithelial cells.
2015-08-03 | GSE70326 | GEO
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
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
Project description:Adaptive immunity requires multiple complementary mechanisms to maintain self-tolerance. Dedicated tolerogenic lymphoid populations and their key transcriptional regulators have been well characterized, but while recent evidence suggests some myeloid populations, particularly migratory dendritic cells (migDCs), may have similar functions, the identity of these populations and the transcriptional circuits regulating them remain obscure. The Autoimmune Regulator (Aire), well defined in medullary thymic epithelial cells (mTECs), is also expressed in extrathymic Aire-expressing cells (eTACs) in the secondary lymphoid organs. eTACs have been shown to have tolerogenic capabilities (ref), and recently work has shown them to be required for normal immune homeostasis in pregnancy (ref). But the precise identity and function of these cells remain unclear. Here using high-dimensional single-cell multiomics (scRNAseq/ASAPseq), we define the identity and biology of the principal extrathymic Aire-expressing populations at the transcriptional, genomic, and proteomic level, resulting in two related populations: CCR7+ Aire-regulated migratory dendritic cells (ArmDCs) and a novel population co-expressing RAR-related orphan receptor gamma-t (ROR-γt), with significant transcriptional and genomic homology to both migDCs and mTECs, which we termed Janus cells (JCs). We demonstrate these eTAC populations share a distinct transcriptional and genomic homology to medullary epithelium and, like mTECs, depend on RANK-RANK-ligand interactions to drive Aire expression. Lineage-tracing experiments suggest JCs are not a precursor population to the majority of ArmDCs. Further, self-antigen display by eTACs is sufficient to mediate negative selection of T cells that escape thymic selection. This remarkable central and peripheral homology suggests that a core Aire-associated transcriptional program may drive immune tolerance in both the thymus and periphery, and suggests a remarkable convergence of transcriptional programs in two disparate cell lineages in the thymus and periphery.
2021-12-15 | GSE176282 | GEO
Project description:STAT5 activation downstream of the Interleukin-2 receptor (IL-2R) facilitates Foxp3 expression, which is required for the differentiation and function of regulatory T (Treg) cells. However, due to the pleiotropic roles of IL-2R signaling, it is unclear how STAT5 acts on the Foxp3 locus to promote Treg cell lineage commitment. Here, we report that IL-2–STAT5 signaling converges on an enhancer (CNS4) during early Foxp3 induction. CNS4 facilitates and sustains the IL-2–dependent CD25+Foxp3– precursor to Treg cell transition in the thymus. Its deficiency results in markedly impaired Treg cell generation in neonates, which is partially mitigated with age. While the thymic Treg cell paucity caused by CNS4 deficiency did not result in autoimmunity on its own, it exacerbated autoimmune manifestations caused by disruption of the Aire gene. Thus, CNS4 enhancer activity ensures robust Treg cell differentiation early in postnatal life and, cooperatively with other tolerance mechanisms, minimizes autoimmunity.
2021-03-16 | GSE164117 | GEO
Project description:We use single-cell RNA-seq to determine distinct selection phenotypes of 2 rare thymic Treg cell progenitors as well as mature thymic Treg cells
2018-12-31 | GSE123067 | GEO
Project description:Gene expression in different thymic stromal cells and subsets thereof was analyzed in 6-12 week old wild type (C57BL/6) and Aire knock-out (mixed background) mice. Thymic stromal cells were purified by sequential enzymatic digestion (collagenase, collagenase/dispase and trypsin) followed by gradient centrifugation and FACS sorting. Sort criteria were as follows: dendritic cells (CD11c+, F4/80 -), macrophages (F4/80+, CD11c-), cTECs (CD45â/lo, CDR1/Ly51+, Ep-CAM+) and mTECs (CD45â/lo, CDR1/Ly51â, Ep-CAM+). mTECs of wild-type and Aire knock-out mice were further subdivided according to CD80 expression levels.,For microarray analysis total RNA from thymic stromal cell samples of two independent experiments was pre-amplified and biotinylated by two rounds of cDNA synthesis and in vitro transcription. Fluorescence readings were evaluated by using Microarray Suite 5.0 software.
2007-12-15 | E-GEOD-2585 | biostudies-arrayexpress