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Gene expression in Bach2-deficient and wildtype CD4 single-positive thymocytes from mixed chimeric animals

ABSTRACT: The role of FoxP3+ regulatory T (Treg) cells in the maintenance of immunological tolerance is well established. Recently, genome-wide association studies (GWAS) in humans have associated polymorphisms within the BACH2 locus encoding the transcription factor BTB and CNC homology 1, basic leucine zipper transcription factor 2 (Bach2) with diverse allergic and autoimmune diseases including asthma, multiple sclerosis, Crohn's disease, celiac disease, generalized vitiligo and type 1 diabetes. Common to these diseases is a failure to adequately maintain immunological tolerance. However, a role for Bach2 in this process has not been established. Here, by assessing the phenotype of mice in which the Bach2 gene is disrupted, we demonstrate a non-redundant role for Bach2 in the prevention of a spontaneous lethal inflammatory disorder predominantly affecting the lung and gut with excessive T helper 2 (Th2) responses and formation of circulating autoantibodies. Bach2 was necessary for efficient induction of FoxP3 expression both during thymopoesis and upon stimulation of naïve peripheral CD4+ T cells under Treg polarizing conditions in vitro. Consequently, in bone marrow reconstitution experiments, Bach2 expression within the haematopoetic system was necessary for suppression of lethal autoimmunity in a manner that was FoxP3 dependent. These findings demonstrate a requirement for Bach2 in early lineage commitment of both thymic and induced Treg cells and point to shared mechanisms that underlie diverse allergic and autoimmune disorders that may serve as targets in the development of novel therapeutic strategies.

ORGANISM(S): Mus musculus

PROVIDER: GSE42598 | GEO | 2013/11/01

SECONDARY ACCESSION(S): PRJNA182359

REPOSITORIES: GEO

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Gene expression in Bach2-deficient and wildtype CD4 single-positive thymocytes from mixed chimeric animals

Project description:The role of FoxP3+ regulatory T (Treg) cells in the maintenance of immunological tolerance is well established. Recently, genome-wide association studies (GWAS) in humans have associated polymorphisms within the BACH2 locus encoding the transcription factor BTB and CNC homology 1, basic leucine zipper transcription factor 2 (Bach2) with diverse allergic and autoimmune diseases including asthma, multiple sclerosis, Crohn's disease, celiac disease, generalized vitiligo and type 1 diabetes. Common to these diseases is a failure to adequately maintain immunological tolerance. However, a role for Bach2 in this process has not been established. Here, by assessing the phenotype of mice in which the Bach2 gene is disrupted, we demonstrate a non-redundant role for Bach2 in the prevention of a spontaneous lethal inflammatory disorder predominantly affecting the lung and gut with excessive T helper 2 (Th2) responses and formation of circulating autoantibodies. Bach2 was necessary for efficient induction of FoxP3 expression both during thymopoesis and upon stimulation of naïve peripheral CD4+ T cells under Treg polarizing conditions in vitro. Consequently, in bone marrow reconstitution experiments, Bach2 expression within the haematopoetic system was necessary for suppression of lethal autoimmunity in a manner that was FoxP3 dependent. These findings demonstrate a requirement for Bach2 in early lineage commitment of both thymic and induced Treg cells and point to shared mechanisms that underlie diverse allergic and autoimmune disorders that may serve as targets in the development of novel therapeutic strategies. Six samples were collected from separate mice: three Ly5.1+ wildtype thymocyte samples (biological replicates) and three Ly5.1- Bach2 knockout thymocyte samples (biological replicates).

2013-11-01 | E-GEOD-42598 | biostudies-arrayexpress

Expression data from Treg cells expressing mutant FoxP3

2017-08-01 | GSE89654 | GEO

Expression data from mutant FoxP3-transduced CD4 T cells

2017-08-01 | GSE89645 | GEO

Expression data from BATF-deficient Treg cells

Project description:FoxP3 is a central regulator of immunological tolerance, controlling the development and function of regulatory T (Treg) cells. To dissect the complex processes orchestrated by FoxP3, we investigated impacts of three autoimmune disease-associated missense FoxP3 mutations in mice. The I363V and R397W mutations were loss-of-function mutations, causing multi-organ inflammation by globally compromising Treg cell physiology. By contrast, the A384T mutation induced a distinctive tissue-restricted inflammation by specifically impairing the ability of Treg cells to compete with pathogenic T cells in certain non-lymphoid tissues. Because BATF expression was down-regulated in A384T Treg cells, we hypothesized that its down-regulation could account for the A384T Treg cell phenotype and addressed whether BATF-deficient Treg cells are phenotypically similar to A384T Treg cells.

2017-08-01 | GSE89656 | GEO

Foxp3 expression is required for the induction of therapeutic tissue tolerance

Project description:CD4+Foxp3+ regulatory T cells (Treg) are essential for immune homeostasis and maintenance of self-tolerance. They are produced in the thymus and also generated de novo in the periphery in a TGFB dependent manner. Foxp3+ Treg are also required to achieve tolerance to transplanted tissues when induced by co-receptor or costimulation blockade. Using TCR transgenic mice to avoid issues of autoimmune pathology we show that Foxp3 expression is necessary and sufficient for tissue tolerance by coreceptor blockade. Moreover, the known need in tolerance induction for TGFB signalling to T cells, can wholly be explained by its role in induction of Foxp3, as such signalling proved dispensable for the suppressive process. We analysed the relative contribution of TGFB and Foxp3 on the transcriptome of TGFB induced Treg. TGFB elicited a large set of downregulated signature genes. The number of genes uniquely modulated due to the influence of Foxp3 alone was surprisingly limited. Retroviral conditional Foxp3 expression proved sufficient to confer transplant-suppressive potency on CD4+ T cells, and was lost once nuclear Foxp3 expression was extinguished. Thus despite the large genetic influence of TGFB exposure on iTreg the crucial Foxp3 influenced signature independent of TGFB is small. These data support a dual role for TGFB and Foxp3 in induced tolerance, where TGFB stimulates Foxp3 expression whose sustained expression is associated with acquisition of tolerance 21 samples were analyzed. 5 replicates of Marilyn.Foxp3hCD2 activated (HY)(Untreated) and TGFB-induced (HYT) cells sorted as CD4+hCD2+ and CD4+hCD2- and 3 replicates of Marilyn.Foxp3-/- activated and TGFβ-experienced (but Foxp3-) cells sorted as CD4+CD2. Pairwise comparisons were generated for the Marilyn Foxp3hCD2 UT versus TGFB induced populations and also for the Marilyn Foxp3-/- UT versus the TGFB experienced cells sorted as CD4+CD2

2012-10-03 | E-GEOD-39529 | biostudies-arrayexpress

Gene expression profiling of thymically-derived regulatory T cells from miR-142-deficient versus wild-type mice

Project description:Regulatory T cells (Tregs) play a fundamental role in immune tolerance via control of self-reactive effector T cells (Teffs). The development and function of the Treg lineage is critically dependent on the transcription factor Forkhead box P3 (Foxp3). Mice with a Treg-specific deletion of miRNAs, also develop a spontaneous, lethal autoimmune disease virtually indistinguishable from that seen in Foxp3-decicient mice demonstrating that miRNAs are critical for establishment of Treg-mediated peripheral tolerance. However, the set of miRNAs responsible for this functional deficiency has yet to be fully defined. Using Foxp3 ChIP-seq data we identified Mir142 as the only miRNA gene associated with a super-enhancer bound by FOXP3 suggesting that miR-142 is important for Treg function. To identify genes directly regulated by miR-142 in Tregs we profiled the changes in gene expression upon conditional deletion of miR-142 in thymically-derived Treg cells.

2019-06-28 | GSE122881 | GEO

Foxp3 expression is required for the induction of therapeutic tissue tolerance

2012-10-03 | GSE39529 | GEO

mRNA expression in CD4+ CD25+ GITR+ regulatory T cells from WT and Bach2 KO mice

Project description:Bach2 regulates homeostasis of foxp3+ regulatory T cells and protects against fatal lung disease in mice. Cells from WT and Bach2 KO spleen were isolated. CD4+ CD25+ GITR+ (Treg) cells were sorted by FACS sorting. Total RNAs were extracted from sorted Treg cells using by Rneasy Kit (Qiagen).

2013-11-14 | E-GEOD-52337 | biostudies-arrayexpress

Antigen specific human conventional T cells (CD154+) or regulatory T cells (CD137+) directed agains A. fumigatus or Birch pollen lysate isolated from Birch pollen allergic patients or healthy controls.

Project description:Foxp3+ regulatory T cells (Treg) play a central role for tolerance against self and innocuous environmental antigens. However, the role of antigen-specificity for Treg-mediated tolerance is only incompletely understood. Here we show by direct ex vivo characterization of human CD4+ T cells, that the response against innocuous airborne antigens, such as plant pollen or fungal spores, is dominated by memory-like antigen-specific Treg. Surprisingly, breakdown of tolerance in atopic donors was not accompanied by a quantitatively or qualitatively altered Treg response, but instead correlated with a striking dichotomy of Treg versus Th2 target specificity. Allergenic proteins, are selectively targeted by Th2 cells, but not Treg. Thus human Treg specific for airborne antigens maintain tolerance at mucosal sites and the failure to generate specific Treg against a subgroup of antigens provides a window of opportunity for allergy development. PBMCs from sex and age matched birch pollen allergic patients and healthy controls, were stimulated (7h) with airborne fungal (A. fumigatus) or birch pollen antigen (birch) and sorted into antigen specific conventional and regulatory T cells according to their expression of CD154+ and CD137+ on CD4+ T cells, respectively. Number of samples per group in parentheses: Healthy controls stimulated with A. fumigatus (n=5), allergic patients stimulated with A. fumigatus (n=6), healthy controls stimulated with birch (n=6), allergic patients stimulated with birch (n=4).

2016-10-25 | E-GEOD-77018 | biostudies-arrayexpress

Continuous requirement for the T cell receptor for regulatory T cell function

Project description:Foxp3+ regulatory T cells (Treg cells) maintain immunological tolerance and their deficiency results in fatal multi-organ autoimmunity. Although heightened T cell receptor (TCR) signaling is critical for the differentiation of Treg cells, the role of TCR signaling in Treg cell function remains largely unknown. Here we demonstrate inducible ablation of the TCR results in Treg cell dysfunction which cannot be attributed to impaired Foxp3 expression, decreased expression of Treg cell signature genes or altered ability to sense and consume interleukin 2. Rather, TCR signaling was required for maintaining the expression of a limited subset of genes comprising 25% of the activated Treg cell transcriptional signature. Our results reveal a critical role for the TCR in Treg cell suppressor capacity. Array expression of Foxp3-CreERT2 CalphaFL/WT mice

2014-09-08 | E-GEOD-61077 | biostudies-arrayexpress

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