Foxp3 imparts regulatory T cell epigenetic identity through a transcription factor relay
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA647187 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12264700_1.fastq.gz | Fastqsanger.gz | |||
| SRR12264700_2.fastq.gz | Fastqsanger.gz | |||
| SRR12264701_1.fastq.gz | Fastqsanger.gz | |||
| SRR12264701_2.fastq.gz | Fastqsanger.gz | |||
| SRR12264702_1.fastq.gz | Fastqsanger.gz |
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Project description:RNA-seq, ATAC-seq, and CUT&RUN analysis in Foxp3+ regulatory T cells, Foxp3- conventional CD4 T cells and Foxp3 reporter-null cells subdivided based on cell surface activation markers CD44 and CD62L
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Project description:Regulatory T cells have been shown to adopt a catabolic metabolic programme with increased capacity for fatty acid oxidation fuelled oxidative phosphorylation (OXPHOS). The role of Foxp3 in this metabolic shift is poorly understood. Here we show that Foxp3 was sufficient to induce a significant increase in the spare respiratory capacity of the cell, the extra OXPHOS capacity available to a cell to increased demands on energy in response to work. Foxp3-expressing cells were enhanced in their ability to utilise palmitate for respiration and in addition the activity of electron transport complexes I, II and IV were enhanced following Foxp3 expression. ATP was secreted by both T effector and regulatory T cells and was reduced by mitochondrial respiration inhibitors. Thus Foxp3 imparts a selective advantage in ATP generation capacity to the cell and may exploit this as a source of adenosine for functional immunomodulation. In order to explore possible mechanisms for these differences in metabolism we conducted a comparative quantitative proteomics study to compare the contribution of TGFβ and the transcription factor Foxp3 to the Treg proteome. We used quantitative mass spectrometry to examine differences between proteomes of nuclear and cytoplasmic Foxp3-containing T cells and Foxp3 positive iTreg and Foxp3 negative activated CD4 T cells in addition to human peripheral blood natural Treg. Gene set enrichment analysis of our proteomic datasets demonstrated that Foxp3 drives a significant up regulation of several members of the mitochondrial electron transport chain.
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Project description:Regulatory T cells (Treg) have been shown to adopt a catabolic metabolic programme with increased capacity for fatty acid oxidation fuelled oxidative phosphorylation (OXPHOS). The role of Foxp3 in this metabolic shift is poorly understood. Here we show that Foxp3 was sufficient to induce a significant increase in the spare respiratory capacity of the cell, the extra OXPHOS capacity available to a cell to meet increased demands on energy in response to work. Foxp3-expressing cells were enhanced in their ability to utilise palmitate for respiration and, in addition, the activity of electron transport complexes I, II and IV were enhanced following Foxp3 expression. Foxp3 also imparts a selective advantage in ATP generation capacity, one that might be exploited as a source of adenosine for functional immunomodulation. In order to explore possible mechanisms for these differences in metabolism we conducted a quantitative proteomics study to compare the contribution of TGFβ and the transcription factor Foxp3 to the Treg proteome. We used quantitative mass spectrometry to examine differences between proteomes of nuclear and cytoplasmic Foxp3-containing CD4+ T cells from various sources with Foxp3- activated CD4 T cells, as well as Treg from human peripheral blood. Gene set enrichment analysis of our proteomic datasets demonstrated that Foxp3 expression is associated with a significant up regulation of several members of the mitochondrial electron transport chain. Not only does Foxp3 influence genes directly concerned with immune function, but also with the energy generating functions of Treg.
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Project description:Vertebrate cell identity depends on the combined activity of scores of transcription factors (TF). While TFs have often been studied in isolation, a systematic perspective on their integration has been missing. Focusing on FoxP3+ regulatory T cells (Tregs), key guardians of immune tolerance, we combined single-cell chromatin accessibility, machine learning, and high-density genetic variation, to resolve a validated framework of diverse Treg chromatin programs, each shaped by multi-TF inputs. This framework identified previously unrecognized Treg controllers (Smarcc1) and illuminated the mechanism of action of FoxP3, which amplified a pre-existing Treg identity, diversely activating or repressing distinct programs, dependent on different regulatory partners. Treg subpopulations in the colon relied variably on FoxP3, Helios+ Tregs being completely dependent, but RORγ+ Tregs largely independent. These differences were rooted in intrinsic biases decoded by the integrated framework. Moving beyond master regulators, this work unravels how overlapping TF activities coalesce into Treg identity and diversity.
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Project description:Regulatory T (Treg) cells, characterized by expression of the lineage-defining transcription factor Foxp3, are critical gatekeepers of immune homeostasis. While Foxp3’s essential role in Treg cell development is well established, the precise mechanisms by which Foxp3 governs the Treg-specific transcriptional network remain incompletely understood. Here, we employed a novel chemogenetic model that enables inducible, time-controlled degradation of Foxp3 protein in vivo to dissect its stage-specific functions. We show that Foxp3 is indispensable for the establishment of the Treg transcriptional program and the acquisition of suppressive function during thymic differentiation and in newly generated peripheral Treg cells. In contrast, degradation of Foxp3 in fully differentiated, mature Treg cells resulted in surprisingly minimal transcriptional changes and largely preserved suppressive capacity, affecting only a small subset of genes highly enriched for direct Foxp3 targets. Strikingly, intratumoral Treg cells were uniquely sensitive to Foxp3 loss, leading to impaired suppressive function and enhanced tumor rejection. These findings uncover a differential, context-dependent requirement for Foxp3 across Treg cell ontogeny, highlighting a distinct, largely indirect mechanism by which Foxp3 establishes — and to a more limited extent maintains — Treg identity and function.
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Project description:Foxp3+ regulatory T (Treg) cells restrict immune pathology in inflamed tissues; however, an inflammatory environment presents a threat to Treg cell identity and function. We here establish a transcriptional signature of central nervous system (CNS) Treg cells that accumulate during experimental autoimmune encephalitis (EAE) and identify a pathway that maintains Treg cell function and identity during severe inflammation. This pathway was dependent on the transcriptional regulator Blimp1, which prevented dismantling of Foxp3 expression and "toxic" gain-of-function of Treg cells in the inflamed CNS. Blimp1 negatively regulated IL-6- and STAT3-mediated methylation of Treg cell-specific conserved non-coding sequence 2 (CNS2) in the Foxp3 locus. Consequently, CNS2 was heavily methylated when Blimp1 was ablated, leading to loss of Foxp3 expression and severe disease. These findings identify a Blimp1-dependent epigenetic pathway that preserves Treg cell stability in inflamed non-lymphoid tissues.
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Project description:Foxp3 Orchestrates Reorganization of Chromatin Architecture to Establish Regulatory T Cell Identity
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Project description:Regulatory T (Treg) cells, characterized by expression of the lineage-defining transcription factor Foxp3, are critical gatekeepers of immune homeostasis. While Foxp3’s essential role in Treg cell development is well established, the precise mechanisms by which Foxp3 governs the Treg-specific transcriptional network remain incompletely understood. Here, we employed a novel chemogenetic model that enables inducible, time-controlled degradation of Foxp3 protein in vivo to dissect its stage-specific functions. We show that Foxp3 is indispensable for the establishment of the Treg transcriptional program and the acquisition of suppressive function during thymic differentiation and in newly generated peripheral Treg cells. In contrast, degradation of Foxp3 in fully differentiated, mature Treg cells resulted in surprisingly minimal transcriptional changes and largely preserved suppressive capacity, affecting only a small subset of genes highly enriched for direct Foxp3 targets. Strikingly, intratumoral Treg cells were uniquely sensitive to Foxp3 loss, leading to impaired suppressive function and enhanced tumor rejection. These findings uncover a differential, context-dependent requirement for Foxp3 across Treg cell ontogeny, highlighting a distinct, largely indirect mechanism by which Foxp3 establishes — and to a more limited extent maintains — Treg identity and function.
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Project description:Regulatory T (Treg) cells, characterized by expression of the lineage-defining transcription factor Foxp3, are critical gatekeepers of immune homeostasis. While Foxp3’s essential role in Treg cell development is well established, the precise mechanisms by which Foxp3 governs the Treg-specific transcriptional network remain incompletely understood. Here, we employed a novel chemogenetic model that enables inducible, time-controlled degradation of Foxp3 protein in vivo to dissect its stage-specific functions. We show that Foxp3 is indispensable for the establishment of the Treg transcriptional program and the acquisition of suppressive function during thymic differentiation and in newly generated peripheral Treg cells. In contrast, degradation of Foxp3 in fully differentiated, mature Treg cells resulted in surprisingly minimal transcriptional changes and largely preserved suppressive capacity, affecting only a small subset of genes highly enriched for direct Foxp3 targets. Strikingly, intratumoral Treg cells were uniquely sensitive to Foxp3 loss, leading to impaired suppressive function and enhanced tumor rejection. These findings uncover a differential, context-dependent requirement for Foxp3 across Treg cell ontogeny, highlighting a distinct, largely indirect mechanism by which Foxp3 establishes — and to a more limited extent maintains — Treg identity and function.
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