Targeting In Vivo Metabolic Vulnerabilities of Th2 and Th17 Cells Reduces Airway Inflammation
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ABSTRACT:
PROVIDER: PRJNA686788 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13278236_1.fastq.gz | Fastqsanger.gz | |||
| SRR13278236_2.fastq.gz | Fastqsanger.gz | |||
| SRR13278237_1.fastq.gz | Fastqsanger.gz | |||
| SRR13278237_2.fastq.gz | Fastqsanger.gz | |||
| SRR13278238_1.fastq.gz | Fastqsanger.gz |
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Project description:T cells promote inflammation in asthmatic patients and both Th2 and Th17 CD4 T cells have been implicated in severe forms of the disease. The metabolic phenotypes and dependencies of these cells, however, remain poorly understood in the regulation of airway inflammation. Here we show the bronchoalveolar lavage fluid of asthmatic patients had markers of elevated glucose and glutamine metabolism. Further, peripheral blood T cells of asthmatics had broadly elevated expression of metabolic proteins when analyzed by mass cytometry compared to healthy controls. Therefore, we hypothesized that glucose and glutamine metabolism were important in allergic airway inflammation. We tested this hypothesis in two murine models of airway inflammation. T cells from lungs of mice sensitized with Alternaria alternata extract displayed genetic signatures for elevated glucose and oxidative metabolism by single cell RNAseq. This result was most pronounced when protein levels were measured in IL17 producing cells and was recapitulated when airway inflammation was induced with House Dust Mite plus lipopolysaccharide (HDM+LPS), a model which led to abundant IL4 and IL17 producing T cells. Importantly, inhibitors of the glucose transporter 1 (Glut1) or glutaminase (GLS) in vivo attenuated HDM+LPS eosinophilia, T cell cytokine production, and airway hyperresponsiveness as well as augmented the immunosuppressive properties of dexamethasone. These data show that T cells induce markers to support metabolism in vivo in airway inflammation and that this correlates with inflammatory cytokine production. Targeting metabolic pathways may provide a new direction to protect from disease and enhance the effectiveness of steroid therapy.
2021-01-13 | GSE163572 | GEO
Project description:T effector cells promote inflammation in asthmatic patients, and both Th2 and Th17 CD4 T cells have been implicated in severe forms of the disease. The metabolic phenotypes and dependencies of these cells, however, remain poorly understood in the regulation of airway inflammation. In this study, we show the bronchoalveolar lavage fluid of asthmatic patients had markers of elevated glucose and glutamine metabolism. Further, peripheral blood T cells of asthmatics had broadly elevated expression of metabolic proteins when analyzed by mass cytometry compared with healthy controls. Therefore, we hypothesized that glucose and glutamine metabolism promote allergic airway inflammation. We tested this hypothesis in two murine models of airway inflammation. T cells from lungs of mice sensitized with Alternaria alternata extract displayed genetic signatures for elevated oxidative and glucose metabolism by single-cell RNA sequencing. This result was most pronounced when protein levels were measured in IL-17-producing cells and was recapitulated when airway inflammation was induced with house dust mite plus LPS, a model that led to abundant IL-4- and IL-17-producing T cells. Importantly, inhibitors of the glucose transporter 1 or glutaminase in vivo attenuated house dust mite + LPS eosinophilia, T cell cytokine production, and airway hyperresponsiveness as well as augmented the immunosuppressive properties of dexamethasone. These data show that T cells induce markers to support metabolism in vivo in airway inflammation and that this correlates with inflammatory cytokine production. Targeting metabolic pathways may provide a new direction to protect from disease and enhance the effectiveness of steroid therapy.
| S-EPMC7946768 | biostudies-literature
Project description:Molecular profiling studies in asthma cohorts have identified a Th2-driven asthma subtype, characterized by elevated lower airway expression of POSTN, CLCA1 and SERPINB2. To assess upper airway gene expression as a potential biomarker for lower airway Th2 inflammation, we assayed upper airway (nasal) and lower airway (bronchial) epithelial gene expression, serum total IgE, blood eosinophils and serum periostin in a cohort of 54 allergic asthmatics and 30 matched healthy controls. 23 of 51 asthmatics in our cohort were classified as âTh2 highâ based on lower airway Th2 gene signature expression. Consistent with this classification, âTh2 highâ subjects displayed elevated total IgE and blood eosinophil levels relative to âTh2 lowâ subjects. Upper airway Th2 signature expression was significantly correlated with lower airway Th2 signature expression (r=0.44), with similar strength of association as serum total IgE and blood eosinophils, known biomarkers of Th2 inflammation. In an unbiased genome-wide scan, we identified 8 upper airway genes more strongly correlated with lower airway Th2 gene signature expression (r=0.58), including Eotaxin-3 (CCL26), Galectin-10 (CLC) and Cathepsin-C (CTSC). Asthmatics classified as âTh2 highâ using this 8-gene signature show similar serum total IgE and blood eosinophil levels as âTh2 highâ asthmatics classified using lower airway Th2 gene signature expression. We have identified an 8-gene upper airway signature correlated with lower airway Th2 inflammation, which may be used as a diagnostic biomarker for Th2-driven asthma. Upper airway (nasal) and lower airway (bronchial) epithelial brushings obtained from a cohort of 54 allergic asthmatics and 30 matched healthy controls were profiled by gene expression by microarray. Subjects were assayed for gene expression, serum total IgE, blood eosinophils and serum periostin.
2015-10-23 | E-GEOD-41861 | biostudies-arrayexpress
Project description:Molecular profiling studies in asthma cohorts have identified a Th2-driven asthma subtype, characterized by elevated lower airway expression of POSTN, CLCA1 and SERPINB2. To assess upper airway gene expression as a potential biomarker for lower airway Th2 inflammation, we assayed upper airway (nasal) and lower airway (bronchial) epithelial gene expression, serum total IgE, blood eosinophils and serum periostin in a cohort of 54 allergic asthmatics and 30 matched healthy controls. 23 of 51 asthmatics in our cohort were classified as ‘Th2 high’ based on lower airway Th2 gene signature expression. Consistent with this classification, ‘Th2 high’ subjects displayed elevated total IgE and blood eosinophil levels relative to ‘Th2 low’ subjects. Upper airway Th2 signature expression was significantly correlated with lower airway Th2 signature expression (r=0.44), with similar strength of association as serum total IgE and blood eosinophils, known biomarkers of Th2 inflammation. In an unbiased genome-wide scan, we identified 8 upper airway genes more strongly correlated with lower airway Th2 gene signature expression (r=0.58), including Eotaxin-3 (CCL26), Galectin-10 (CLC) and Cathepsin-C (CTSC). Asthmatics classified as ‘Th2 high’ using this 8-gene signature show similar serum total IgE and blood eosinophil levels as ‘Th2 high’ asthmatics classified using lower airway Th2 gene signature expression. We have identified an 8-gene upper airway signature correlated with lower airway Th2 inflammation, which may be used as a diagnostic biomarker for Th2-driven asthma.
2015-10-23 | GSE41861 | GEO
Project description:We next sought to identify the transcriptional program that differentiates IL-9+Th2 cells from “conventional” Th2 cells. To this end, we selected representative Th1, Th17, Th2, and IL-9+Th2 clones (Figure 5A) and determined their transcriptome in the resting state and at different time points after activation using RNAseq. Peripheral Blood Mononuclear Cells (PBMC) were isolated by Ficoll-Plaque Plus (GE Healthcare, UK) density gradient centrifugation. Human CD4+ T cells were isolated from PBMC by EasySep positive selection kit (Stemcell Technologies) according to manufacturer’s instruction. Positively selected CD4+ T cells were washed with PBS and stained for subsequent Th cell subset sorting. Memory Th cell subsets were sorted to over 90% purity according to their expression of chemokine receptors from CD45RA-CD25-CD8-CD3+ cells: Th1(CXCR3+CCR8-CCR6-CCR4-), Th2 (CXCR3-CCR8-CCR6-CCR4+), Th17 (CXCR3-CCR8-CCR6+CCR4+), Th9 (CXCR3-CCR8+CCR6-CCR4+). Single cell Th subset clones were directly sorted into 96well plate according to their expression of chemokine receptors (see above). Single cell clones were expanded and maintained by periodic restimulation with PHA (phytohaemaglutinine, 1 µg/ml, Sigma-Chemicals) and irradiated allogenic feeder cells (5x104/well) in culture medium. T cells were polyclonally activated using beads coated with antibodies against CD3, CD2, and CD28 (T cell/bead = 2:1, human T cell activation/expansion Kit, Miltenyi). Cell cultures were sampled before activation (time 0h) and 2, 4, 6, 9, 12, 24, and 48 hours after activation.
2017-11-10 | E-MTAB-5739 | biostudies-arrayexpress
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Project description:RORγt is the lineage-specific transcription factor for T helper 17 (Th17) cells and an attractive drug target for treating Th17-associated diseases. Though the critical role of RORγt in early Th17 cell differentiation has been well recognized, whether it maintains mature Th17 cell phenotypes remains largely unexplored. Here, we show that genetic deletion of Rorc in mature Th17 cells inhibited their pathogenic functions. Mechanistically, loss of RORγt led to a closed chromatin structure at key Th17-specific gene loci, particularly at those so called “super enhancer” regions. Furthermore, RORc deletion in effector Th17 cells resulted in a strongly Th2-biased cell phenotype at both epigenetic and transcriptional levels, in an IL-4-dependent manner. Our results thus reveal a crucial function of RORγt in effector Th17 cells in maintaining Th17 cell program and constraining Th2 cell conversion, offering new considerations in therapeutic targeting of RORγt.
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Project description:RORγt is the lineage-specific transcription factor for T helper 17 (Th17) cells and an attractive drug target for treating Th17-associated diseases. Though the critical role of RORγt in early Th17 cell differentiation has been well recognized, whether it maintains mature Th17 cell phenotypes remains largely unexplored. Here, we show that genetic deletion of Rorc in mature Th17 cells inhibited their pathogenic functions. Mechanistically, loss of RORγt led to a closed chromatin structure at key Th17-specific gene loci, particularly at those so called “super enhancer” regions. Furthermore, RORc deletion in effector Th17 cells resulted in a strongly Th2-biased cell phenotype at both epigenetic and transcriptional levels, in an IL-4-dependent manner. Our results thus reveal a crucial function of RORγt in effector Th17 cells in maintaining Th17 cell program and constraining Th2 cell conversion, offering new considerations in therapeutic targeting of RORγt.
2022-07-12 | GSE190425 | GEO
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