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Bach2 inhibits Th2-type immune responses by regulating glutamine metabolism [expression array]

ABSTRACT: It is becoming clear that the acquisition of T cell functions is closely linked to the reprogramming of the metabolic pathway. However, the impact of metabolic changes on the differentiation of helper T cell subsets remains unclear. We herein demonstrate a critical role of glutamine metabolism in regulating type 2-immune response. Bach2, a transcriptional repressor, binds to an AP-1 motif, and suppresses Th2 cell differentiation and glutaminolysis. Glutaminase 2, which controls glutamine metabolism, was identified as a Bach2 target gene. The pharmacological inhibition of glutamine metabolism normalized allergic lung inflammation that developed spontaneously in T-cell specific Bach2-deficient mice. These findings reveal the importance of the Bach2-dependent modulation of glutamine metabolism in regulating Th2 cell differentiation and Th2 cell- mediated inflammation.

ORGANISM(S): Mus musculus

PROVIDER: GSE65083 | GEO | 2016/11/14

SECONDARY ACCESSION(S): PRJNA272912

REPOSITORIES: GEO

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Bach2 inhibits Th2-type immune responses by regulating glutamine metabolism [ChIP-seq]

Project description:It is becoming clear that the acquisition of T cell functions is closely linked to the reprogramming of the metabolic pathway. However, the impact of metabolic changes on the differentiation of helper T cell subsets remains unclear. We herein demonstrate a critical role of glutamine metabolism in regulating type 2-immune response. Bach2, a transcriptional repressor, binds to an AP-1 motif, and suppresses Th2 cell differentiation and glutaminolysis. Glutaminase 2, which controls glutamine metabolism, was identified as a Bach2 target gene. The pharmacological inhibition of glutamine metabolism normalized allergic lung inflammation that developed spontaneously in T-cell specific Bach2-deficient mice. These findings reveal the importance of the Bach2-dependent modulation of glutamine metabolism in regulating Th2 cell differentiation and Th2 cell- mediated inflammation.

2016-11-14 | GSE63380 | GEO

Bach2 represses effector programmes to stabilize Treg-mediated immune homeostasis

Project description:Through their functional diversification, CD4+ T cells play key roles in both driving and constraining immune-mediated pathology. Transcription factors are critical in the generation and maintenance of cellular diversity and negative regulators antagonistic to alternate fates often act in conjunction with positive regulators to stabilize lineage specification1. Polymorphisms within the locus encoding a transcription factor BACH2 are associated with diverse immune-mediated diseases including asthma2, multiple sclerosis3, Crohn¹s disease4-5, coeliac disease6, vitiligo7 and type 1 diabetes8. A role for Bach2 in maintaining immune homeostasis, however, has not been established. Here, we define Bach2 as a broad regulator of immune activation that stabilizes immunoregulatory capacity while repressing the differentiation programmes of multiple effector lineages in CD4+ T cells. Bach2 was required for efficient formation of regulatory (Treg) cells and consequently for suppression of lethal inflammation in a manner that was Treg cell dependent. Assessment of the genome-wide function of Bach2, however, revealed that it represses genes associated with effector cell differentiation. Consequently, its absence during Treg polarization resulted in inappropriate diversion to effector lineages. In addition, Bach2 constrained full effector differentiation within Th1, Th2 and Th17 cell lineages. These findings identify Bach2 as a key regulator of CD4+ T-cell differentiation that prevents inflammatory disease by controlling the balance between tolerance and immunity. The role of Bach2t to regulate immune homeostasis was investigated by mapping DNA binding profiles of Bach2 in iTreg condition. The function of Bach2 was also evaluated by comparing transcriptome in WT and Bach2-deficient iTreg cells and further comparison was done with transcriptome in naive, Th1, Th2, and Th17 conditions.

2013-06-27 | E-GEOD-45975 | biostudies-arrayexpress

Bach2-Batf interactions control Th2-type immune responses by regulating the IL-4 amplification loop

Project description:Although Bach2 plays an important role in regulating the Th2-type immune response, the underlying molecular mechanisms remain unclear. We herein demonstrate that Bach2 associates with Batf and binds to the regulatory regions of the Th2 cytokine gene loci. The Bach2-Batf complex antagonizes the recruitment of the Batf-Irf4 complex to AP-1 motifs and suppresses Th2 cytokine production. Furthermore, we found that Bach2 regulates the Batf and Batf3 expressions via two distinct pathways. First, Bach2 suppresses the maintenance of the Batf and Batf3 expression through the inhibition of IL-4 production. Second, the Bach2-Batf complex directly binds to the Batf and Batf3 gene loci and reduces transcription by interfering with the Batf-Irf4 complex. These findings suggest that IL-4 and Batf form a positive feedback amplification loop to induce Th2 cell differentiation and the subsequent Th2-type immune response, and Bach2-Batf interactions are required to prevent an excessive Th2 response.

2016-11-14 | GSE65084 | GEO

Bach2 represses effector programmes to stabilize Treg-mediated immune homeostasis

2013-06-27 | GSE45975 | GEO

The Menin–Bach2 axis is critical for regulating CD4 T cell senescence and homeostasis

Project description:Although CD4 T cell senescence plays an important role in immunosenescence, the mechanisms remain unclear. We found that T cell-specific Menin deficiency results in the premature senescence of CD4 T cells, accompanied by the senescence-associated secretory phenotype (SASP) after antigenic stimulation. TH1 and TH2 differentiation was dysregulated in Menin-knockout CD4 T cells. Bach2, which regulates SASP and TH differentiation, was identified as a Menin target. Menin binds to the Bach2 locus, and controls its expression through maintenance of histone acetylation. These findings reveal a critical role of the Menin-Bach2 pathway in regulating CD4 T cell senescence and homeostasis, thus indicating the involvement of this pathway in the inhibition of age-associated development of inflammatory diseases, which are induced by immunosenescence. Examination of transcriptional factor Menin binding and histone modefications in Menin WT and KO CD4 T cells

2014-03-27 | E-GEOD-53831 | biostudies-arrayexpress

GLS2 links glutamine metabolism and atherosclerosis by remodelling artery walls (aorta).

Project description:Metabolic dysregulation, including perturbed glutamine-glutamate homeostasis, is common in atherosclerotic cardiovascular disease. Here, we reveal that modulation of glutaminolysis or glutamate availability in culture media is critical for smooth muscle cell line (MOVAS) phenotypic switching. Cells were treated for 24 hours with glutaminase inhibitors (50mM DON, Sigma-SML0601) in presence or absence of 2mM glutamate suplementation (Gibco-35050061). High-throughput transcriptional profiling revealed that modulation of glutamine and glutamate homeostasis impacted genes involved in protein and extracellular matrix organization, cell motility and microtubule. Thus, we uncovered a novel role for glutamine metabolism in the phenotypic switch in SMCs, a hallmark of vascular remodelling.

2024-10-17 | GSE270058 | GEO

GLS2 links glutamine metabolism and atherosclerosis by remodelling artery walls (MOVAS).

2024-10-17 | GSE270056 | GEO

Super-killer CTLs are generated by single gene deletion of Bach2

Project description:Bach2 codes for a transcriptional regulator exerting major influences on T cell mediated immune regulation. Effector CTLs derived from in vitro activation of murine CD8+ T cells showed increased proliferative and cytolytic capacity in the absence of BACH2. Before activation, BACH2-deficient CD8+ T cells had a higher abundance of memory and reduced abundance of naïve cells compared to wild-type. CTLs derived from central memory T cells were more potently cytotoxic than those derived from naïve T cells, but even within separated subsets, BACH2-deficiency conferred a cytotoxic advantage. Immunofluorescence and electron microscopy revealed larger granules in BACH2-deficient compared to wild-type CTLs, and proteomic analysis showed an increase in granule content, including perforin and granzymes. Thus, the enhanced cytotoxicity observed in effector CTLs lacking BACH2 arises not only from differences in their initial differentiation state but also inherent production of enlarged cytolytic granules. These results demonstrate how a single gene deletion can produce a CTL super-killer.

2022-09-02 | PXD036457 | Pride

The Menin–Bach2 axis is critical for regulating CD4 T cell senescence and homeostasis

2014-03-27 | GSE53831 | GEO

BACH2 in human plasma cell fate decision

Project description:We report here the broad transcriptomic program regulated by BACH2 transcription factor. We used a well suited in vitro model of B cell differentiation to evaluate transcriptomic program governed by BACH2 leading to Plasmocyte (PC) differentiation. In this model B cells were cultured with anti-BCR, CpG, CD40L and Interleukin-2 (IL2). This Interleukin triggers PC differentiation by directly repressing BACH2 expression. We artificially inhibit BACH2 expression by siRNA and found that this condition is sufficient to trigger PC differentiation without IL2. To understand global changes induced by enforced BACH2 downregulation we compared Chip-Sequencing data between activated B Cells and BACH2 deficient B cells (siBACH2). We found that BACH2 binds more than 3000 genes across the human genome. RNAsequencing comparing IL2 drivent committed cells and siBACH2 committed cells highlighs a large common trasncriptional program shared by both conditions and involved in B cell destiny. This study provides evidence that BACH2 is a guardian of B cell fate.

2017-08-29 | GSE102460 | GEO

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