CD4+ T cell activation in absence of WNK1
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA830460 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18856000.fastq.gz | Fastqsanger.gz | |||
| SRR18856001.fastq.gz | Fastqsanger.gz | |||
| SRR18856002.fastq.gz | Fastqsanger.gz | |||
| SRR18856003.fastq.gz | Fastqsanger.gz | |||
| SRR18856004.fastq.gz | Fastqsanger.gz |
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Project description:Signaling from the T cell antigen receptor (TCR) on CD4+ T cells triggers the adaptive immune response by inducing T cell activation, proliferation, and differentiation. However, TCR signaling pathways are incompletely understood. Unexpectedly, we demonstrate that WNK1, a kinase previously implicated in osmoregulation in the kidney, is required for T-dependent antibody responses. We show that WNK1-OXSR1-STK39-dependent water influx through AQP3 is required for TCR signaling in CD4+ T cells and for entry into cell cycle. Additionally, by preventing ATR activation this signaling pathway is required for T cells to progress through the G2 phase of the cell cycle. Thus, TCR signaling via WNK1, OXSR1, STK39 and AQP3 leads to water entry that is essential for CD4+ T cell proliferation and hence T cell-dependent antibody responses.
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Project description:The appropriate development of myeloid progenitors into macrophages, the body’s professional phagocyte, is essential for organismal development, especially in mammals1. This dependence is exemplified by the observation that loss-of-function mutation in colony stimulating factor 1 receptor (CSF1R) results in multiple tissue abnormalities including osteopetrosis2. Despite this importance, little is known about the molecular and cell biological regulation of macrophage development. Here, we report the surprising finding that the chloride-sensing kinase With-no-lysine 1 (WNK1) is required for embryonic development of tissue-resident macrophages (TRMs). Myeloid-specific deletion of Wnk1 caused a dramatic loss of TRMs and subsequently disrupted organ development, induced systemic neutrophilia, and resulted in mortality between 3 and 4 weeks of age. Specifically, we observed that WNK1 absence stalled macrophage differentiation at the myeloid multipotent progenitor (MPP) stage, instead skewing MPP differentiation towards granulopoiesis. Mechanistically, the cognate CSF1R cytokine, macrophage-colony stimulating factor (M-CSF), triggers macropinocytosis in myeloid progenitors, which in turn induces phosphorylation of WNK1. Importantly, macropinocytosis by myeloid progenitors increases cytosolic chloride, which is directly sensed by WNK1. Perturbing chloride flux during macropinocytosis, inhibiting WNK1 chloride-sensing, and blocking macropinocytosis each skew progenitor differentiation from macrophage lineage to granulocyte lineage. Thus, we have uncovered a novel mechanism that links a cell biological process to a molecular circuit whereby WNK1 chloride-sensing and chloride flux act downstream of M-CSF-induced macropinocytosis by multipotent progenitors to ensure macrophage lineage fidelity.
2024-02-06 | GSE196336 | GEO
Project description:Naive CD4+ T cell activation transcriptome
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Project description:Human CD4 memory T cell activation time course
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Project description:Human CD4 memory T cell activation time course
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Project description:Upon antigen-specific T Cell Receptor (TCR) engagement, human CD4+ T cells proliferate and differentiate, a process associated with rapid transcriptional changes and metabolic reprogramming utilizing aerobic glycolysis together with maintenance of oxidative phosphorylation1,2. However, the role of glycolytic-reprogramming during T-cell activation remains largely unclear3,4,5. Here, we show that maintenance of cytosolic pyruvate production is an essential requirement for remodeling of the CD4+ T cell epigenome after TCR-engagement. Furthermore, we provide evidence that the local inflammatory environment sustains metabolic reprogramming of CD4+ T-cells and impacts histone modification in a pyruvate-dependent manner. Mechanistically, we demonstrate that rapid and sustained generation of cytosolic, but not mitochondrial, pyruvate is an essential step for acetyl-coA production and subsequent H3K27ac epigenome remodeling. TCR-activation was found to induce nuclear import of pyruvate dehydrogenase (PDH) and its association with both the p300 acetyltransferase and histone H3K27ac. Disrupting PDH nuclear import impacted expression of activation-induced genes. These results reveal a direct connection between CD4+ T cell metabolic reprogramming and transcriptional regulation, with the generation of cytosolic pyruvate being an essential step in T cell activation. These data support tight integration of metabolic enzymes and histone modifying enzymes, allowing metabolic reprogramming to fuel CD4+ T cell activation.
2023-10-27 | PXD018132 | Pride
Project description:The kinase protein WNK1 is highly expressed and phosphorylated in the testis, suggesting possible functions in regulating male fertility. Indeed, conditional pachytene-spermatocyte Wnk1 knock-out mice generated using the novel Wnt7a-Cre failed to produce functional sperm which resulted from the primary spermatogenic arrest during mid-pachynema. Global transcriptomic approaches identified ‘translation’ as one of the impacted events in Wnk1-depleted spermatocytes.
2023-08-27 | GSE234068 | GEO
Project description:RNAseq was used to analyse transcriptional changes occuring in WNK1-expressing or WNK1-deficient DN3 thymocytes following injection of anti-CD3e
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Project description:Glucose uptake by mammalian cells is a key mechanism to maintain cell and tissue homeostasis and relies mostly on plasma membrane-localized glucose transporter proteins (GLUTs). Two main cellular mechanisms regulate GLUT proteins in the cell: first, expression of GLUT genes is under dynamic transcriptional control and is used by cancer cells to increase glucose availability. Second, GLUT proteins are regulated by membrane traffic from storage vesicles to the plasma membrane (PM). This latter process is triggered by signaling mechanisms and well-studied in case of insulin-responsive cells, which activate protein kinase AKT to phosphorylate TBC1D4, a RAB-GAP involved in membrane traffic regulation. Previously, we identified protein kinase WNK1 as another kinase able to phosphorylate TBC1D4 and regulate the surface expression of the constitutive glucose transporter GLUT1. Here we describe that downregulation of WNK1 through RNA interference in HEK293 cells led to a 2-fold decrease in PM GLUT1 expression, concomitant with a 60% decrease in glucose uptake. By mass spectrometry, we identified serine (S) 704 in TBC1D4 as a WNK1-specific phosphorylation site, and also S565 in the paralogue TBC1D1. Transfection of the respective phosphomimetic or unphosphorylatable TBC1D mutants into cells revealed that both affected the cell surface abundance of GLUT1. The results reinforce a regulatory role for WNK1 in cell metabolism and have potential impact for the understanding of cancer cell metabolism or therapeutic options in type 2 diabetes.
2021-11-03 | PXD016218 | Pride
Project description:CD4+ T cells are at the centre of the adaptive immune system and can differentiate into distinct states that maintain self-tolerance and guide specific humoral and cellular responses to infection. Perturbation of CD4+ T cell activation is associated with many human diseases, including autoimmunity, therefore characterising the transcriptional programs underlying this process is key to the development of future therapeutic interventions. To assess the gene expression on CD4+ T cells, we recruited 20 healthy volunteers from the Cambridge BioResource. Total CD4+ T cells were isolated from whole blood within 2 hours of venepuncture. To assess the transcriptional variation in response to TCR stimulation, 1 million CD4+ T cells were cultured in U-bottom 96-well plates in the presence or absence of human T activator CD3/CD28 beads. Cells were harvested at 2 , 4, 6 or 21 hours post-stimulation, or after 0, 6 or 21 hours in the absence of stimulation. Three samples from the 6 hour unstimulated timepoint were omitted from the study due to insufficient cell numbers, and a further four samples were dropped after quality control, resulting in a total of 133 samples that were included in the final analysis.
2017-02-06 | E-MTAB-4832 | biostudies-arrayexpress