Mus musculus
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ABSTRACT:
PROVIDER: PRJNA201853 | ENA |
REPOSITORIES: ENA
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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 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:Regulatory T (Treg) cells respond to immune and inflammatory signals to mediate immunosuppression, but how the functional integrity of Treg cells is maintained under activating environments is unclear. Here we show that autophagy is active in Treg cells and supports their lineage stability and survival fitness. Treg cell–specific deletion of Atg7 or Atg5, both essential genes in autophagy, leads to loss of Treg cells, greater tumor resistance and development of inflammatory disorders. Atg7-deficient Treg cells show increased apoptosis and readily lose expression of the transcription factor Foxp3, especially after activation. Mechanistically, autophagy deficiency upregulates mTORC1 and c-Myc and glycolytic metabolism, which contributes to defective Treg function. Therefore, autophagy couples environmental signals and metabolic homeostasis to protect lineage and survival integrity of Treg cells in activating contexts.
2016-01-25 | GSE75218 | GEO
Project description:Effector (Teff) and regulatory (Treg) CD4 T cells undergo metabolic reprogramming to support proliferation and immune function. While Phosphatidylinositide 3-kinase (PI3K)/Akt/mTORC1 signaling induces the glucose transporter Glut1 and aerobic glycolysis for Teff proliferation and inflammatory function, mechanisms that regulate Treg metabolism and function remain unclear. We show that TLR signals that promote Treg proliferation increase Glut1, PI3K/Akt/mTORC1 signaling, and glycolysis. However, TLR-induced mTORC1 signaling also impaired Treg suppressive capacity. Conversely, FoxP3 opposed PI3K/Akt/mTOR signaling to reduce glycolysis and anabolic metabolism while increasing oxidative and catabolic metabolism. Importantly, Glut1 expression was sufficient to increase Treg numbers but reduced suppressive capacity and FoxP3 expression. Thus, inflammatory signals and FoxP3 balance mTORC1 signaling and glucose metabolism to control Treg proliferation and suppressive function.
2016-08-30 | GSE84919 | GEO
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:Project abstract: Foxp3+ T regulatory (Treg) cells have important functions in suppressing immune cell activation and establishing normal immune homeostasis. How Treg cells maintain their identity is not completely understood. Here we show that Ndfip1, a co-activator of Nedd4-family E3 ubiquitin ligases, is required for Treg cell stability and function. Ndfip1 deletion in Treg cells disrupts immune homeostasis and results in autoinflammatory disease. Ndfip1-deficient Treg cells are highly proliferative and are more likely to lose Foxp3 expression to become IL-4-producing TH2 effector cells. Proteomic analyses indicate that Ndfip1 deficiency alters the metabolic signature of Treg cells. Metabolic profiling reveals elevated glycolysis and increased mTORC1 signalling. Additional data suggest that Ndfip1 restricts Treg cell metabolic capacity and IL-4 production via distinct mechanisms. Thus, Ndfip1 preserves Treg lineage stability by preventing the expansion of highly proliferative and metabolically active cells that can cause immunopathology via secretion of IL-4.
2017-04-19 | PXD006251 | Pride
Project description:Regulatory T (Treg) cells derived from the thymus (tTreg) and periphery (pTreg) play central and distinct roles in immunosuppression, but mechanisms governing the generation and activation of Treg subsets in vivo remain uncertain. Here, we report that mechanistic target of rapamycin (mTOR) unexpectedly supports the homeostasis and functional activation of tTreg and pTreg cells. Further, mTOR signaling is crucial for programming activated Treg cell effector function to protect immune tolerance and tissue homeostasis. Treg-specific deletion of mTOR drives spontaneous TH2 responses and altered barrier tissue homeostasis, associated with reductions in both thymic derived effector Treg (eTreg) and pTreg cells. Mechanistically, mTOR acts downstream of antigenic signals to drive IRF4 expression and mitochondrial metabolism, and accordingly, disruption of mitochondrial metabolism severely impairs Treg cell suppressive function and their homeostasis in tissues. Collectively, our results demonstrate that mTOR coordinates transcriptional and metabolic programs in activated Treg subsets to mediate tissue homeostasis
2019-09-12 | GSE104130 | GEO
Project description:Lymphocyte activation gene 3 (Lag3) has emerged as the next-generation immune checkpoint molecule due to its ability to inhibit effector T cell activity. Foxp3+ regulatory T (Treg) cells, a master regulator of immunity and tolerance, also highly express Lag3. While Lag3 is thought to be necessary for Treg cell-mediated regulation of immunity, the precise roles and underlying mechanisms remain largely elusive. In this study, we report that Lag3 is indispensable for Treg cells to control autoimmune inflammation. Utilizing a newly generated Treg cell specific Lag3 mutant mouse model, we found that these animals are highly susceptible to autoimmune diseases, suggesting defective Treg cell function. Genome wide transcriptome analysis further uncovered that Lag3 mutant Treg cells upregulated genes involved in metabolic processes. Mechanistically, we found that Lag3 limits Treg cell expression of Myc, a key regulator of aerobic glycolysis. We further found that Lag3-dependent Myc expression determines Treg cells’ metabolic programming as well as the in vivo function to suppress autoimmune inflammation. Taken together, our results uncovered a novel function of Lag3 in supporting Treg cell suppressive function by regulating Myc-dependent metabolic programming.
2024-08-30 | GSE226083 | GEO
Project description:Obesity and type-2 diabetes are associated with tissue-inflammation and metabolic defects in fat depots. Foxp3+regulatory T(Treg) cells mediate T-cell tolerance, thereby controlling tissue inflammation. However, the molecular underpinnings how environmental stimuli interlink T-cell tolerance with adipose tissue function remain largely unknown. Here, we report that cold exposure or beta3-adrenergic receptor (ADRB3) stimulation induces T-cell tolerance in vitro and in murine and humanized models. Tolerance induction was verified by CD4+T-cell-proteomes revealing higher protein expression of Foxp3 regulatory networks. Specifically, Ragulator-interacting protein C17orf59, which limits mTORC1 activity, was upregulated by either ADRB3-stimulation or cold-exposure, and therefore might enhance Treg induction. By loss and gain-of-function studies, including Treg depletion and transfers in vivo, we demonstrated that a T-cell-specific Stat6/Pten axis links cold-exposure or ADRB3 stimulation with Foxp3+Treg induction and adipose tissue function. Our findings open new avenues in understanding tissue-specific T-cell tolerance and the design of precision concepts toward personalized immune-metabolic health.
2017-09-11 | PXD004671 | Pride
Project description:The mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth that stimulates macromolecule synthesis via insulin, growth factors, and oncogenic signals. mTORC1 activates anabolic pathways by inducing posttranslational modifications of metabolic enzymes, and by regulating expression through transcription and mRNA processing. However, mechanisms of how mTORC1 orchestrates these tightly connected processes remain unclear. Here, we identify FAM120A as a transcriptional co-activator that couples transcription and splicing of lipid synthesis enzymes downstream of mTORC1-SRPK2 signaling. Mechanistically, the mTORC1-activated SRPK2 phosphorylates a splicing factor SRSF1, enhancing its binding to FAM120A. FAM120A directly interacts with a lipogenic transcription factor SREBP1 at active promoters, thereby bridging newly transcribed lipogenic genes to the RNA splicing machinery. This multi-protein complex regulated by mTORC1 promotes efficient splicing and stability of lipogenic transcripts, resulting in fatty acid synthesis and cancer cell proliferation. These results elucidate FAM120A as a critical transcription co-factor that connects mTORC1-dependent gene regulation programs for anabolic cell growth.
2023-09-01 | GSE229657 | GEO