Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA252952 | ENA |
REPOSITORIES: ENA
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Project description:Calcineurin/NFAT/IL-2 signaling pathway is activated in dendritic cells (DC) upon encounter of β glucan, the main component of the fungal cell wall, raising the question about the role of NFAT-regulated genes in DC biology in vivo. To directly assess the function of IL-2 secreted by DC, we analyzed mice lacking of IL-2 in the DC lineage, CD4-expressing cells and with complete deletion of IL-2 in the germ line in a mouse model of pulmonary fungal infection. Here we found that specifically the loss of IL-2 in DC resulted in increased mice mortality upon the fungus Aspergillus fumigatus challenge and expansion of Th17 cells in the lung. We demonstrated that only CD103+DC were able to release IL-2 in acute phase of pulmonary Aspergillosis through the Ca2+-Calcineurin-NFAT signaling. We also found that NFAT mediates IL-23 transcription in lung DC, where IL-2 results essential in restraining the priming of a pathogenic infiltrating IL-17+Sca1+CD90+CD4+ cell with stem cell like properties. Thus, IL-2 and IL-23 secreted by DC in the lung have an antagonistic relationship on the Th17 differentiation program with IL-2 inducing T cell differentiation and IL-23 inducing a stem cell like molecular signature to Th17 cells upon Aspergillus challenge. DC-Il2-/- then confer the Th17 stemness, releasing IL-23 in response to the fungus contributing to the development of a Th17 cell effector population, particularly pathogenic in infection. D1 cells with no treatment, or treatment with different fungal types or antigens at 1, 4 and 6 hours, in triplicate, with the 3 untreated samples at 1hr also including techincal repeats
2015-12-21 | E-GEOD-58590 | biostudies-arrayexpress
Project description:Calcineurin/NFAT/IL-2 signaling pathway is activated in dendritic cells (DC) upon encounter of β glucan, the main component of the fungal cell wall, raising the question about the role of NFAT-regulated genes in DC biology in vivo. To directly assess the function of IL-2 secreted by DC, we analyzed mice lacking of IL-2 in the DC lineage, CD4-expressing cells and with complete deletion of IL-2 in the germ line in a mouse model of pulmonary fungal infection. Here we found that specifically the loss of IL-2 in DC resulted in increased mice mortality upon the fungus Aspergillus fumigatus challenge and expansion of Th17 cells in the lung. We demonstrated that only CD103+DC were able to release IL-2 in acute phase of pulmonary Aspergillosis through the Ca2+-Calcineurin-NFAT signaling. We also found that NFAT mediates IL-23 transcription in lung DC, where IL-2 results essential in restraining the priming of a pathogenic infiltrating IL-17+Sca1+CD90+CD4+ cell with stem cell like properties. Thus, IL-2 and IL-23 secreted by DC in the lung have an antagonistic relationship on the Th17 differentiation program with IL-2 inducing T cell differentiation and IL-23 inducing a stem cell like molecular signature to Th17 cells upon Aspergillus challenge. DC-Il2-/- then confer the Th17 stemness, releasing IL-23 in response to the fungus contributing to the development of a Th17 cell effector population, particularly pathogenic in infection.
2015-12-21 | GSE58590 | GEO
Project description:TGF-beta3 produced by developing Th17 cells induces highly pathogenic T cells that are functionally and molecularly distinct from TGF-beta1-induced Th17 cells. The microarray data represent a distinct molecular signature for pathogenic versus non-pathogenic Th17 cells. Total of seven groups with two to four samples per group from two independent experiments. The no cytokines group (Th0) was used as a control to normalize the data. 7 groups: B6: (IL-1beta, IL-6) B623: (IL-1beta, IL-6, IL-23) T16: (TGF-beta1, IL-6) T1623: (TGF-beta1, IL-6, IL-23) T36: (TGF-beta3, IL-6) T3623: (TGF-beta3, IL-6, IL-23) NOCYTO: no cytokines
2012-09-01 | E-GEOD-39820 | biostudies-arrayexpress
Project description:Interleukin 23 (IL-23) triggers pathogenic features in pro-inflammatory, IL-17-secreting T cells (Th17 and Tγδ17) that play a key role in the development of inflammatory diseases. However, the IL-23 signaling cascade remains largely undefined. Here we used quantitative phosphoproteomics to characterize IL-23 signaling in primary murine Th17 cells. We quantified 6,888 phosphorylation sites in Th17 cells, and found 168 phosphorylations regulated upom IL-23 stimulation. IL-23 increased the phosphorylation of the myosin regulatory light chain (RLC), an actomyosin contractibility marker, in Th17 and Tγδ cells. IL-23-induced RLC phosphorylation required JAK2 and ROCK catalytic activity, and the study of the IL-23/ROCK axis revealed an unexpected role of IL-23 in the migration of Tγδ17 and Th17 cells. Moreover, pharmacological inhibition of ROCK reduced Tγδ17 recruitment to inflamed skin upon challenge with inflammatory agent Imiquimod. This work: i) provides new insights into phosphorylation networks that control Th17 cells, ii) widely expands the current knowledge on IL-23 signaling, and iii) contributes to the increasing list of immune cells subsets characterized by global phosphoproteomic approaches.
2020-03-25 | PXD016633 | Pride
Project description:CD4+ T helper 17 (Th17) cells encompass a spectrum of cell states including homeostatic cells that maintain physiological functions such as barrier integrity and pathogenic cells that drive autoimmune tissue inflammation. Identifying the regulators that determine these cell states will provide means to control tissue inflammation without compromising the physiological functions of Th17 cells. Here, we identified TCF1 as the key regulator that determines Th17 cell state. IL-23, a cytokine critical for inducing pathogenic Th17 cells, decreased TCF1 expression. Consistent with this observation, conditional deletion of Tcf7/TCF1 in mature myelin-specific T cells conferred pathogenicity to homeostatic Th17 cells independent of IL-23. Conversely, sustained TCF1 expression impaired acquisition of pathogenicity. Integration of transcriptional and chromatin accessibility data showed that TCF1 maintained homeostatic state through a regulatory network involving ETS family transcription factors, EGR1, and FOXO1 and by binding to and interfering with RORt activity. Our findings provide mechanistic insight into how the homeostatic and pathogenic Th17 cell states are determined and into the association of genetic variants in TCF7 with susceptibility to autoimmunity.
2024-11-03 | GSE233907 | GEO
Project description:CD4+ T helper 17 (Th17) cells encompass a spectrum of cell states including homeostatic cells that maintain physiological functions such as barrier integrity and pathogenic cells that drive autoimmune tissue inflammation. Identifying the regulators that determine these cell states will provide means to control tissue inflammation without compromising the physiological functions of Th17 cells. Here, we identified TCF1 as the key regulator that determines Th17 cell state. IL-23, a cytokine critical for inducing pathogenic Th17 cells, decreased TCF1 expression. Consistent with this observation, conditional deletion of Tcf7/TCF1 in mature myelin-specific T cells conferred pathogenicity to homeostatic Th17 cells independent of IL-23. Conversely, sustained TCF1 expression impaired acquisition of pathogenicity. Integration of transcriptional and chromatin accessibility data showed that TCF1 maintained homeostatic state through a regulatory network involving ETS family transcription factors, EGR1, and FOXO1 and by binding to and interfering with RORt activity. Our findings provide mechanistic insight into how the homeostatic and pathogenic Th17 cell states are determined and into the association of genetic variants in TCF7 with susceptibility to autoimmunity.
2024-11-03 | GSE233905 | GEO
Project description:Th17 cells are highly proinflammatory cells that are critical for clearing extracellular pathogens like fungal infections and for induction of multiple autoimmune diseases1. IL-23 plays a critical role in stabilizing and endowing Th17 cells with pathogenic effector functions2. Previous studies have shown that IL-23 signaling reinforces the Th17 phenotype by increasing expression of IL-23 receptor (IL-23R)3. However, the precise molecular mechanism by which IL-23 sustains the Th17 response and induces pathogenic effector functions has not been elucidated. Here, we used unbiased transcriptional profiling of developing Th17 cells to construct a model of their signaling network and identify major nodes that regulate Th17 development. We identified serum glucocorticoid kinase-1 (SGK1), as an essential node downstream of IL-23 signaling, critical for regulating IL-23R expression and for stabilizing the Th17 cell phenotype by deactivation of Foxo1, a direct repressor of IL-23R expression. A serine-threonine kinase homologous to AKT4, SGK1 has been associated with cell cycle and apoptosis, and has been shown to govern Na+ transport and homeostasis5, 6 7, 8. We here show that a modest increase in salt (NaCl) concentration induces SGK1 expression, promotes IL-23R expression and enhances Th17 cell differentiation in vitro and in vivo, ultimately accelerating the development of autoimmunity. The loss of SGK1 resulted in abrogation of Na+-mediated Th17 differentiation in an IL-23-dependent manner. These data indicate that SGK1 is a critical regulator for the induction of pathogenic Th17 cells and provides a molecular insight by which an environmental factor such as a high salt diet could trigger Th17 development and promote tissue inflammation. Th17 cells; comparing Sgk1-/- to WT
2013-03-07 | E-GEOD-43956 | biostudies-arrayexpress
Project description:Th17 cells are highly proinflammatory cells that are critical for clearing extracellular pathogens like fungal infections and for induction of multiple autoimmune diseases1. IL-23 plays a critical role in stabilizing and endowing Th17 cells with pathogenic effector functions2. Previous studies have shown that IL-23 signaling reinforces the Th17 phenotype by increasing expression of IL-23 receptor (IL-23R)3. However, the precise molecular mechanism by which IL-23 sustains the Th17 response and induces pathogenic effector functions has not been elucidated. Here, we used unbiased transcriptional profiling of developing Th17 cells to construct a model of their signaling network and identify major nodes that regulate Th17 development. We identified serum glucocorticoid kinase-1 (SGK1), as an essential node downstream of IL-23 signaling, critical for regulating IL-23R expression and for stabilizing the Th17 cell phenotype by deactivation of Foxo1, a direct repressor of IL-23R expression. A serine-threonine kinase homologous to AKT4, SGK1 has been associated with cell cycle and apoptosis, and has been shown to govern Na+ transport and homeostasis5, 6 7, 8. We here show that a modest increase in salt (NaCl) concentration induces SGK1 expression, promotes IL-23R expression and enhances Th17 cell differentiation in vitro and in vivo, ultimately accelerating the development of autoimmunity. The loss of SGK1 resulted in abrogation of Na+-mediated Th17 differentiation in an IL-23-dependent manner. These data indicate that SGK1 is a critical regulator for the induction of pathogenic Th17 cells and provides a molecular insight by which an environmental factor such as a high salt diet could trigger Th17 development and promote tissue inflammation. Effects of NaCl on Th17 differentiation
2013-03-07 | E-GEOD-43957 | biostudies-arrayexpress
Project description:IL-23 induces ptgs2 encoding cyclooxygenase 2 in Th17 cells and produces PGE2, which acts back on PGE2 receptors EP2 and EP4 in these cells and enhances IL-23-induced expression of an IL-23 receptor subunit gene, Il23r, by activating STAT3, CREB1 and NF-κB through cAMP-protein kinase A signaling. This PGE2 signaling also induces expression of various inflammation-related genes, which possibly function in Th17 cell-mediated pathology. Combined deletion of EP2 and EP4 selectively in T cells suppressed accumulation of IL-17A+ and IL-17A+IFN-γ+ pathogenic Th17 cells and abolished skin inflammation in IL-23-induced psoriasis mouse model. Analysis of human psoriatic skin biopsies shows positive correlation between PGE2 signaling and the IL-23/Th17 pathway.
2021-02-23 | GSE167248 | GEO
Project description:Th17 cells are highly proinflammatory cells that are critical for clearing extracellular pathogens like fungal infections and for induction of multiple autoimmune diseases1. IL-23 plays a critical role in stabilizing and endowing Th17 cells with pathogenic effector functions2. Previous studies have shown that IL-23 signaling reinforces the Th17 phenotype by increasing expression of IL-23 receptor (IL-23R)3. However, the precise molecular mechanism by which IL-23 sustains the Th17 response and induces pathogenic effector functions has not been elucidated. Here, we used unbiased transcriptional profiling of developing Th17 cells to construct a model of their signaling network and identify major nodes that regulate Th17 development. We identified serum glucocorticoid kinase-1 (SGK1), as an essential node downstream of IL-23 signaling, critical for regulating IL-23R expression and for stabilizing the Th17 cell phenotype by deactivation of Foxo1, a direct repressor of IL-23R expression. A serine-threonine kinase homologous to AKT4, SGK1 has been associated with cell cycle and apoptosis, and has been shown to govern Na+ transport and homeostasis5, 6 7, 8. We here show that a modest increase in salt (NaCl) concentration induces SGK1 expression, promotes IL-23R expression and enhances Th17 cell differentiation in vitro and in vivo, ultimately accelerating the development of autoimmunity. The loss of SGK1 resulted in abrogation of Na+-mediated Th17 differentiation in an IL-23-dependent manner. These data indicate that SGK1 is a critical regulator for the induction of pathogenic Th17 cells and provides a molecular insight by which an environmental factor such as a high salt diet could trigger Th17 development and promote tissue inflammation.
2013-03-07 | GSE43956 | GEO