Epigenetic regulation of Treg specific genes by BATF in lymphoid tissues
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE229360 | GEO | 2025/09/19
REPOSITORIES: GEO
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Project description:Purpose: Identification of the differentially expressed genes and metabolic pathways in resting and activated WT and BATF-deficient Treg cells Methods: RNA was purified from resting of stimulated (aCD3-CD38/IL-2 for 48 h)Treg cells isolated from WT or Foxp3CreBatffl/fl mice Results: Loss of BATF promotes triacylglycerol biosynthesis in Treg cells. Conclusions: BATF is crucial to coordinate the suppressive function and triacylglycerol metabolism of Treg cells.
2021-03-02 | GSE149197 | GEO
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
Project description:Regulatory T (Treg) cells, as central mediators of immune suppression, play crucial roles in many aspects of immune system physiology and pathophysiology. Treg cells are characterized by a distinct pattern of gene expression, including upregulation of immune-suppressive genes and silencing of inflammatory cytokine genes. However, the molecular mechanisms that establish and/or maintain such gene regulation in Treg cells remain largely unknown. We recently reported that Nr4a family nuclear orphan receptors are essential for the development of Treg cells. The fact that Treg cells maintain high levels of expression of all Nr4a family components suggests that they may also play critical roles beyond Treg cell development. Here, we show that Nr4a factors are essential for maintaining Treg-specific gene expression programs, mediating two defined characteristics of Treg cells: lineage stability and suppressive activity. A compound knockout mouse strain in which all Nr4a genes were specifically deleted in Treg cells developed systemic immunopathology with accelerated Th2/Tfh/IgE reactions. Treg cells in these mice showed global reduction of 'Treg signature' gene expression, including Foxp3, Il2ra and Ikzf4. These findings demonstrate that Nr4a controls a genetic program indispensable for Treg cell maintenance and function. mRNA from wild-type and Nr4a-deficient Treg cells were analyzed.
2013-12-23 | E-GEOD-53574 | biostudies-arrayexpress
Project description:Human regulatory T cells (Tregs) are crucial regulators of tissue repair, autoimmune diseases, and cancer. However, it is challenging to inhibit the suppressive function of Tregs for cancer therapy, without impacting immune homeostasis. Identifying pathways that may distinguish tumor-restricted Tregs is important, yet the transcriptional programs that control intratumoral Treg gene expression, and that are distinct from Tregs in healthy tissues, remain largely unknown. We profiled single-cell transcriptomes of CD4+ T cells in tumors and peripheral blood from patients with head and neck squamous cell carcinomas (HNSCC), in non-tumor tonsil tissues and in peripheral blood from healthy donors. We identified a subpopulation of activated Tregs expressing multiple tumor necrosis factor receptor (TNFR) genes (TNFR+ Tregs) that is highly enriched in the tumor microenvironment (TME) compared with non-tumor tissue and the periphery. TNFR+ Tregs are associated with worse prognosis in HNSCC and across multiple solid tumor types. Mechanistically, the transcription factor BATF is a central component of a gene regulatory network that governs key aspects of TNFR+ Tregs. CRISPR/Cas9-mediated BATF knockout in human activated Tregs in conjunction with bulk RNA sequencing, immunophenotyping and in vitro functional assays, corroborated the central role of BATF in limiting excessive activation and promoting the survival of human activated Tregs. Finally, we identified a suite of surface molecules reflective of the BATF-driven transcriptional network on intratumoral Tregs in patients with HNSCC. These findings uncover a primary transcriptional regulator of highly suppressive intratumoral Tregs, highlighting potential opportunities for therapeutic intervention in cancer without impacting immune homeostasis.
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Project description:Analysis of the transcriptional correlates of FOXP3 expression in suppressive and non-suppressive primary human Treg cell clones. Individual CD4+CD25High or Cd4+CD25- T cells were isolated from human PBMCs and expanded in vitro. After 3 weeks of expansion, individual clones were analysed for FOXP3 expression and in vitro suppressive activity against freshly sorted allogeneic effector T cells. This study analyses the total RNA isolated from FOXP3+ clones with suppressive potency to their non-suppressive counterparts. The resutls of this study should provide insights into the molecular pathways linking FOXP3 expression to distinct aspects of Treg phenotype and function. Total RNA obtained from individual clones of primary human regulatory and effector CD4+T cells.
2015-05-06 | E-GEOD-65650 | biostudies-arrayexpress
Project description:Regulatory T (Treg) cells, as central mediators of immune suppression, play crucial roles in many aspects of immune system physiology and pathophysiology. Treg cells are characterized by a distinct pattern of gene expression, including upregulation of immune-suppressive genes and silencing of inflammatory cytokine genes. However, the molecular mechanisms that establish and/or maintain such gene regulation in Treg cells remain largely unknown. We recently reported that Nr4a family nuclear orphan receptors are essential for the development of Treg cells. The fact that Treg cells maintain high levels of expression of all Nr4a family components suggests that they may also play critical roles beyond Treg cell development. Thus, we compared mRNA expression pattern between wild-type Treg cells and Nr4a-deficietn Treg cells. As a result, we found that expression of 'Treg-signature genes' were globally down regulated in Nr4a-deficient Treg cells. mRNA from wild-type and Nr4a-deficient Treg cells were analyzed.
2015-06-27 | E-GEOD-70306 | biostudies-arrayexpress
Project description:Group 3 innate lymphoid cells (ILC3s) are crucial for the maintenance of host-microbiota homeostasis in gastrointestinal mucosal tissues. The mechanisms that maintain lineage identity of intestinal ILC3s, and ILC3s-mediated orchestration of microbiota and mucosal T cell immunity are elusive. Here, we identified BATF as a gatekeeper of ILC3s homeostasis in the gut. Depletion of BATF in ILC3s resulted in excessive interferon-γ production, dysbiosis, aberrant T cell immune responses and spontaneous inflammatory bowel disease (IBD), which was considerably ameliorated by removal of adaptive immunity or antibiotic treatment. Mechanistically, BATF directly regulates ILC3s identity by globally shapes chromatin landscape of ILC3s. BATF directly binds to the cis-regulatory elements of type 1 effector genes, restrains their chromatin accessibility and inhibits their expression. Conversely, BATF promotes chromatin accessibility of genes involved in MHCII antigen processing and presentation pathways. Collectively, our findings reveal BATF is a promising candidate to maintain ILC3s stability and coordinate ILC3s–mediated control of intestinal homeostasis.
2022-08-31 | GSE168077 | GEO
Project description:Nuclear factor Foxp3 determines regulatory T (Treg) cell fate and function via mechanisms that remain unclear. Here we investigate the nature of Foxp3-mediated gene regulation in suppressing autoimmunity and antitumor immune response. Contrasting with previous models, we find that Foxp3-chromatin binding is regulated by Treg activation states, tumor microenvironment, and antigen and cytokine stimulations. Proteomics studies uncovered dynamic proteins within the Foxp3 proximity upon TCR or IL-2 receptor signaling in vitro, reflecting intricate interactions among Foxp3, signal transducers, and chromatin. Pharmacological inhibition and genetic knockdown experiments indicate that NFAT and AP-1 protein Batf are required for enhanced Foxp3-chromatin binding in activated Treg cells and tumor-infiltrating Treg cells to modulate target gene expression. Furthermore, mutations at Foxp3 DNA-binding domain destabilize Foxp3-chromatin association. These representative settings delineate context-dependent Foxp3-chromatin interaction, suggesting that Foxp3 associates with chromatin by hijacking DNA-binding proteins resulting from Treg activation or differentiation, which is stabilized by direct Foxp3-DNA binding, to dynamically regulate Treg cell function according to immunological contexts.
2024-05-28 | GSE245100 | GEO
Project description:Regulatory T (Treg) cells, as central mediators of immune suppression, play crucial roles in many aspects of immune system physiology and pathophysiology. Treg cells are characterized by a distinct pattern of gene expression, including upregulation of immune-suppressive genes and silencing of inflammatory cytokine genes. However, the molecular mechanisms that establish and/or maintain such gene regulation in Treg cells remain largely unknown. We recently reported that Nr4a family nuclear orphan receptors are essential for the development of Treg cells. The fact that Treg cells maintain high levels of expression of all Nr4a family components suggests that they may also play critical roles beyond Treg cell development. Here, we show that Nr4a factors are essential for maintaining Treg-specific gene expression programs, mediating two defined characteristics of Treg cells: lineage stability and suppressive activity. A compound knockout mouse strain in which all Nr4a genes were specifically deleted in Treg cells developed systemic immunopathology with accelerated Th2/Tfh/IgE reactions. Treg cells in these mice showed global reduction of 'Treg signature' gene expression, including Foxp3, Il2ra and Ikzf4. These findings demonstrate that Nr4a controls a genetic program indispensable for Treg cell maintenance and function.
2013-12-23 | GSE53574 | GEO
Project description:Nuclear factor Foxp3 determines regulatory T (Treg) cell fate and function via mechanisms that remain unclear. Here we investigate the nature of Foxp3-mediated gene regulation in suppressing autoimmunity and antitumor immune response. Contrasting with previous models, we find that Foxp3-chromatin binding is regulated by Treg activation states, tumor microenvironment, and antigen and cytokine stimulations. Proteomics studies uncovered dynamic proteins within the Foxp3 proximity upon TCR or IL-2 receptor signaling in vitro, reflecting intricate interactions among Foxp3, signal transducers, and chromatin. Pharmacological inhibition and genetic knockdown experiments indicate that NFAT and AP-1 protein Batf are required for enhanced Foxp3-chromatin binding in activated Treg cells and tumor-infiltrating Treg cells to modulate target gene expression. Furthermore, mutations at Foxp3 DNA-binding domain destabilize Foxp3-chromatin association. These representative settings delineate context-dependent Foxp3-chromatin interaction, suggesting that Foxp3 associates with chromatin by hijacking DNA-binding proteins resulting from Treg activation or differentiation, which is stabilized by direct Foxp3-DNA binding, to dynamically regulate Treg cell function according to immunological contexts.
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