Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA224304 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Naïve T cells respond to antigen stimulation by exiting from quiescence into clonal expansion and functional differentiation, but the control mechanism is elusive. Here we describe that Raptor/mTORC1-dependent metabolic reprogramming is a central determinant of this transitional process. Loss of Raptor abrogates T cell priming and Th2 cell differentiation, although Raptor function is less important for continuous proliferation of actively cycling cells. mTORC1 coordinates multiple metabolic programs in T cells including glycolysis, lipid synthesis and oxidative phosphorylation to mediate antigen-triggered exit from quiescence. mTORC1 further links glucose metabolism to the initiation of Th2 differentiation by orchestrating cytokine receptor expression and cytokine responsiveness. Activation of Raptor/mTORC1 integrates T cell receptor (TCR) and CD28 co-stimulatory signals in antigen-stimulated T cells. Our studies identify a Raptor/mTORC1-dependent pathway linking signal-dependent metabolic reprogramming to quiescence exit, and this in turn coordinates lymphocyte activation and fate decisions in adaptive immunity. We used microarrays to explore the gene expression profiles differentially expressed in CD4+ T-cells from wild-type (WT) and CD4(cre) x Raptor(fl/fl) mice before and after stimulation with anti CD3/CD28 antibodies.
2014-01-27 | E-GEOD-51668 | biostudies-arrayexpress
Project description:Naïve T cells respond to antigen stimulation by exiting from quiescence into clonal expansion and functional differentiation, but the control mechanism is elusive. Here we describe that Raptor/mTORC1-dependent metabolic reprogramming is a central determinant of this transitional process. Loss of Raptor abrogates T cell priming and Th2 cell differentiation, although Raptor function is less important for continuous proliferation of actively cycling cells. mTORC1 coordinates multiple metabolic programs in T cells including glycolysis, lipid synthesis and oxidative phosphorylation to mediate antigen-triggered exit from quiescence. mTORC1 further links glucose metabolism to the initiation of Th2 differentiation by orchestrating cytokine receptor expression and cytokine responsiveness. Activation of Raptor/mTORC1 integrates T cell receptor (TCR) and CD28 co-stimulatory signals in antigen-stimulated T cells. Our studies identify a Raptor/mTORC1-dependent pathway linking signal-dependent metabolic reprogramming to quiescence exit, and this in turn coordinates lymphocyte activation and fate decisions in adaptive immunity.
2014-01-27 | GSE51668 | GEO
Project description:The mechanistic target of rapamycin (mTOR) pathway integrates diverse environmental inputs, including immune signals and metabolic cues, to direct T cell fate decisions1. Activation of mTOR, comprised of mTORC1 and mTORC2 complexes, delivers an obligatory signal for proper activation and differentiation of effector CD4+ T cells2,3, whereas in the regulatory T cell (Treg) compartment, the Akt-mTOR axis is widely acknowledged as a crucial negative regulator of Treg de novo differentiation4-8 and population expansion9. However, whether mTOR signaling affects the homeostasis and function of Tregs remains largely unexplored. Here we show that mTORC1 signaling is a pivotal positive determinant of Treg function. Tregs have elevated steady-state mTORC1 activity compared to naïve T cells. Signals via T cell receptor (TCR) and IL-2 provide major inputs for mTORC1 activation, which in turn programs suppressive function of Tregs. Disruption of mTORC1 through Treg-specific deletion of the essential component Raptor leads to a profound loss of Treg suppressive activity in vivo and development of a fatal early-onset inflammatory disorder. Mechanistically, Raptor/mTORC1 signaling in Tregs promotes cholesterol/lipid metabolism, with the mevalonate pathway particularly important for coordinating Treg proliferation and upregulation of suppressive molecules CTLA-4 and ICOS to establish Treg functional competency. In contrast, mTORC1 does not directly impact the expression of Foxp3 or anti- and pro-inflammatory cytokines in Tregs, suggesting a non-conventional mechanism for Treg functional regulation. Lastly, we provide evidence that mTORC1 maintains Treg function partly through inhibiting the mTORC2 pathway. Our results demonstrate that mTORC1 acts as a fundamental ‘rheostat’ in Tregs to link immunological signals from TCR and IL-2 to lipogenic pathways and functional fitness, and highlight a central role of metabolic programming of Treg suppressive activity in immune homeostasis and tolerance. We used microarrays to explore the gene expression profiles differentially expressed in regulatory T-cells from wild-type and CD4(cre) x Raptor(fl/fl) mice
2013-06-24 | E-GEOD-46693 | biostudies-arrayexpress
Project description:The interaction between extrinsic factors and intrinsic signal strength governs thymocyte development, but mechanisms linking them remain elusive. We report that mTORC1 couples microenvironmental cues with metabolic programs in orchestrating reciprocal development of two fundamentally distinct lineages, αβ and γδ T cells. Loss of mTORC1 impairs αβ but promotes γδ T cell development, and disrupts metabolic remodeling of oxidative and glycolytic metabolism. Mechanistically, reactive oxygen species (ROS) controlled by mTORC1 serves as a key metabolic signal, and perturbation of redox homeostasis impinges upon fate decisions. Furthermore, singlecell RNA sequencing and genetic dissection reveal that mTORC1 links developmental signals from T cell receptors and NOTCH to coordinate metabolic activity and signal strength. Our results establish mTORC1-driven metabolic signaling as a fundamental mechanism underlying thymocyte lineage choices. We used microarrays to compare the global transcription profiles of WT and Raptor-null cell populations in DN3a developing thymocytes, immaturesingle-positive (ISP) T-cells, and γδ T-cells
2018-07-06 | GSE86495 | GEO
Project description:The mechanistic target of rapamycin (mTOR) pathway integrates diverse environmental inputs, including immune signals and metabolic cues, to direct T cell fate decisions1. Activation of mTOR, comprised of mTORC1 and mTORC2 complexes, delivers an obligatory signal for proper activation and differentiation of effector CD4+ T cells2,3, whereas in the regulatory T cell (Treg) compartment, the Akt-mTOR axis is widely acknowledged as a crucial negative regulator of Treg de novo differentiation4-8 and population expansion9. However, whether mTOR signaling affects the homeostasis and function of Tregs remains largely unexplored. Here we show that mTORC1 signaling is a pivotal positive determinant of Treg function. Tregs have elevated steady-state mTORC1 activity compared to naïve T cells. Signals via T cell receptor (TCR) and IL-2 provide major inputs for mTORC1 activation, which in turn programs suppressive function of Tregs. Disruption of mTORC1 through Treg-specific deletion of the essential component Raptor leads to a profound loss of Treg suppressive activity in vivo and development of a fatal early-onset inflammatory disorder. Mechanistically, Raptor/mTORC1 signaling in Tregs promotes cholesterol/lipid metabolism, with the mevalonate pathway particularly important for coordinating Treg proliferation and upregulation of suppressive molecules CTLA-4 and ICOS to establish Treg functional competency. In contrast, mTORC1 does not directly impact the expression of Foxp3 or anti- and pro-inflammatory cytokines in Tregs, suggesting a non-conventional mechanism for Treg functional regulation. Lastly, we provide evidence that mTORC1 maintains Treg function partly through inhibiting the mTORC2 pathway. Our results demonstrate that mTORC1 acts as a fundamental ‘rheostat’ in Tregs to link immunological signals from TCR and IL-2 to lipogenic pathways and functional fitness, and highlight a central role of metabolic programming of Treg suppressive activity in immune homeostasis and tolerance.
2013-06-24 | GSE46693 | GEO
Project description:Multinucleated giant cells (MGCs) are implicated in many diseases including schistosomiasis, sarcoidosis and arthritis. Formation of MGCs is energy intensive to enforce membrane fusion and cytoplasmic expansion. Here we used receptor activator of nuclear factor kappa-Β ligand (RANKL) induced osteoclastogenesis to model MGC formation. We found amino acid (AA) scarcity controls MGC formation and reveal specific requirements for extracellular arginine in RANKL cellular programming. Indeed, systemic arginine restriction improved outcome in multiple murine arthritis models, by inducing preosteoclast metabolic quiescence, associated with a dysregulated tricarboxylic acid (TCA) cycle, and diverted metabolic fluxes from central metabolic pathways independent of mTORC1 activity or global transcriptional and translational inhibition. A conserved metabolic mechanism occurred in IL-4 induced MGCs. Strikingly, we demonstrate that restriction of multiple AAs triggered metabolic adaptation and blocked MGC formation and each was rescued by their downstream metabolites. These data establish how environmental nutrients control the metabolic fate of polykaryons and suggest metabolic ways to manipulate MGC-associated pathologies and bone remodeling.
2019-12-17 | PXD012405 | Pride
Project description:Regulation of chromatin accessibility is critical for cell fate decisions. Chromatin architecture responds to extrinsic environments rapidly. The traditional adult stem cell isolation approach requires tissue dissociation, and adult stem cells respond to the stimulation and adapt a different chromatin conformation. Here, we characterized the DNA regulatory landscape and transcriptomic profile of muscle stem cell quiescence exit and self-renewal by time-course profiling of the in situ fixed SCs upon injury-induced activation and during aging. Detailed analysis of the chromatin accessibility profiles leads to the identification of enhancer elements for SC quiescence. Constant activation of the enhancer elements promotes stemness and prevents SCs from differentiation, whereas loss of them causes cell-cycle arrest and essentially leads to defects in SC activation. Interestingly, we also showed that aged SCs display a more open chromatin environment than young SCs. Our compre hensive characterization of the chromatin accessibility and transcriptomic landscapes during SC quiescence exit and self-renewal broadens our understanding of this process and identifies functional distal regulatory elements for SC function.
2022-08-12 | GSE189046 | GEO
Project description:Regulation of chromatin accessibility is critical for cell fate decisions. Chromatin architecture responds to extrinsic environments rapidly. The traditional adult stem cell isolation approach requires tissue dissociation, and adult stem cells respond to the stimulation and adapt a different chromatin conformation. Here, we characterized the DNA regulatory landscape and transcriptomic profile of muscle stem cell quiescence exit and self-renewal by time-course profiling of the in situ fixed SCs upon injury-induced activation and during aging. Detailed analysis of the chromatin accessibility profiles leads to the identification of enhancer elements for SC quiescence. Constant activation of the enhancer elements promotes stemness and prevents SCs from differentiation, whereas loss of them causes cell-cycle arrest and essentially leads to defects in SC activation. Interestingly, we also showed that aged SCs display a more open chromatin environment than young SCs. Our compre hensive characterization of the chromatin accessibility and transcriptomic landscapes during SC quiescence exit and self-renewal broadens our understanding of this process and identifies functional distal regulatory elements for SC function.
2022-08-12 | GSE189044 | GEO
Project description:Regulation of chromatin accessibility is critical for cell fate decisions. Chromatin architecture responds to extrinsic environments rapidly. The traditional adult stem cell isolation approach requires tissue dissociation, and adult stem cells respond to the stimulation and adapt a different chromatin conformation. Here, we characterized the DNA regulatory landscape and transcriptomic profile of muscle stem cell quiescence exit and self-renewal by time-course profiling of the in situ fixed SCs upon injury-induced activation and during aging. Detailed analysis of the chromatin accessibility profiles leads to the identification of enhancer elements for SC quiescence. Constant activation of the enhancer elements promotes stemness and prevents SCs from differentiation, whereas loss of them causes cell-cycle arrest and essentially leads to defects in SC activation. Interestingly, we also showed that aged SCs display a more open chromatin environment than young SCs. Our compre hensive characterization of the chromatin accessibility and transcriptomic landscapes during SC quiescence exit and self-renewal broadens our understanding of this process and identifies functional distal regulatory elements for SC function.
2022-08-12 | GSE189073 | GEO
Project description:The mechanistic target of rapamycin mTORC1 is a key regulator of cell metabolism and autophagy. Despite widespread clinical use of mTOR inhibitors, the role of mTORC1 in renal tubular function and kidney homeostasis remains elusive. By utilizing constitutive and inducible deletion of conditional Raptor alleles in renal tubular epithelial cells, we discovered that mTORC1 deficiency caused a marked concentrating defect, loss of tubular cells and slowly progressive renal fibrosis. Transcriptional profiling revealed that mTORC1 maintains renal tubular homeostasis by controlling mitochondrial metabolism and biogenesis as well as transcellular transport processes involved in counter-current multiplication and urine concentration. Although mTORC2 partially compensated the loss of mTORC1, exposure to ischemia and reperfusion injury exaggerated the tubular damage in mTORC1-deficient mice, and caused pronounced apoptosis, diminished proliferation rates and delayed recovery. These findings identify mTORC1 as an essential regulator of tubular energy metabolism and as a crucial component of ischemic stress responses. Pharmacological inhibition of mTORC1 likely affects tubular homeostasis, and may be particularly deleterious if the kidney is exposed to acute injury. Furthermore, the combined inhibition of mTORC1 and mTORC2 may increase the susceptibility to renal damage. Raptor fl/fl*KspCre and Raptor fl/fl animals were sacrificed at P14 before the development of an overt functional phenotype. Kidneys were split in half and immediately snap frozen in liquid nitrogen.
2014-06-09 | E-GEOD-54417 | biostudies-arrayexpress