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Bach2 represses effector programmes to stabilize Treg-mediated immune homeostasis

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE45975 | GEO | 2013/06/27

SECONDARY ACCESSION(S): PRJNA196832

REPOSITORIES: GEO

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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

The transcription factor BACH2 is required to establish immunosuppression within tumors

Project description:Through a diversity of functional lineages, cells of the innate and adaptive immune system either drive or constrain immune reactions within tumors. Thus, while the immune system has a powerful ability to recognize and kill cancer cells, this function is often suppressed preventing clearance of disease. The transcription factor (TF) BACH2 controls the differentiation and function of multiple innate and adaptive immune lineages, but its role in regulating tumor immunity is not known. Here, we demonstrate that BACH2 is required to establish immunosuppression within tumors. We found that growth of subcutaneously implanted tumors was markedly impaired in Bach2-deficient mice and coincided with intratumoral activation of both innate and adaptive immunity but was dependent upon adaptive immunity. Analysis of tumor-infiltrating lymphocytes in Bach2-deficient mice revealed high frequencies of CD4+ and CD8+ effector cells expressing the inflammatory cytokine IFN-Î³. Lymphocyte activation coincided with reduction in the frequency of intratumoral CD4+ Foxp3+ regulatory T (Treg) cells. Mechanistically, Treg-dependent inhibition of CD8+ T cells was required for BACH2-mediated tumor immunosuppression. These findings demonstrate that BACH2 is a key component of the molecular programme of tumor immunosuppression and identify a new target for development of therapies aimed at reversing immunosuppression in cancer. Analysis of tumor-infiltrating lymphocytes in Bach2-deficient mice revealed high frequencies of CD4+ and CD8+ effector cells expressing the inflammatory cytokine IFN-Î³. Lymphocyte activation coincided with reduction in the frequency of intratumoral CD4+ Foxp3+ regulatory T (Treg) cells. Mechanistically, Treg-dependent inhibition of CD8+ T cells was required for BACH2-mediated tumor immunosuppression.

2016-06-01 | E-GEOD-74653 | biostudies-arrayexpress

The transcription factor BACH2 is required to establish immunosuppression within tumors

Project description:Through a diversity of functional lineages, cells of the innate and adaptive immune system either drive or constrain immune reactions within tumors. Thus, while the immune system has a powerful ability to recognize and kill cancer cells, this function is often suppressed preventing clearance of disease. The transcription factor (TF) BACH2 controls the differentiation and function of multiple innate and adaptive immune lineages, but its role in regulating tumor immunity is not known. Here, we demonstrate that BACH2 is required to establish immunosuppression within tumors. We found that growth of subcutaneously implanted tumors was markedly impaired in Bach2-deficient mice and coincided with intratumoral activation of both innate and adaptive immunity but was dependent upon adaptive immunity. Analysis of tumor-infiltrating lymphocytes in Bach2-deficient mice revealed high frequencies of CD4+ and CD8+ effector cells expressing the inflammatory cytokine IFN-γ. Lymphocyte activation coincided with reduction in the frequency of intratumoral CD4+ Foxp3+ regulatory T (Treg) cells. Mechanistically, Treg-dependent inhibition of CD8+ T cells was required for BACH2-mediated tumor immunosuppression. These findings demonstrate that BACH2 is a key component of the molecular programme of tumor immunosuppression and identify a new target for development of therapies aimed at reversing immunosuppression in cancer.

2016-06-01 | GSE74653 | GEO

Transcription factor Bach2 attenuates T cell receptor induced transcription to control regulatory T cell differentiation and homeostasis [RNA-seq II]

Project description:The differentiation and homeostasis of Foxp3+ regulatory T (Treg) cells is strictly controlled by T cell receptor (TCR) signals; however, the molecular regulators of these processes are incompletely known. Here we found that Bach2 was a key regulator of Treg cell differentiation and homeostasis downstream of TCR signalling. Bach2 prevented premature differentiation of fully suppressive effector (e)Treg cells, limited IL-10 production and was required for the development of peripherally induced (p)Treg cells in the gastrointestinal tract. We found that Bach2 attenuated TCR signalling-induced and IRF4-dependent Treg cell differentiation programs. Deletion of IRF4 promoted inducible Treg cell differentiation and rescued pTreg cell differentiation in the absence of Bach2. In turn, loss of Bach2 normalised eTreg cell differentiation of IRF4-deficient Treg cells. Mechanistically, Bach2 counteracted DNA-binding activity of IRF4 and limited chromatin accessibility, thereby attenuating IRF4-dependent transcriptional programs. Thus, Bach2 balanced TCR signalling induced transcriptional activity of IRF4 to maintain Treg cell homeostasis.

2019-11-07 | GSE137243 | GEO

Transcription factor Bach2 attenuates T cell receptor induced transcription to control regulatory T cell differentiation and homeostasis [RNA-seq]

2019-11-07 | GSE126810 | GEO

Transcription factor Bach2 attenuates T cell receptor induced transcription to control regulatory T cell differentiation and homeostasis [ATAC-seq]

2019-11-07 | GSE126806 | GEO

Transcription factor Bach2 attenuates T cell receptor induced transcription to control regulatory T cell differentiation and homeostasis [ATAC-seq II]

2019-11-07 | GSE137246 | GEO

Transcription factor Bach2 attenuates T cell receptor induced transcription to control regulatory T cell differentiation and homeostasis [ChIP-seq]

2019-11-07 | GSE126800 | GEO

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