Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA354447 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5043180_1.fastq.gz | Fastqsanger.gz | |||
| SRR5043180_2.fastq.gz | Fastqsanger.gz | |||
| SRR5043177_1.fastq.gz | Fastqsanger.gz | |||
| SRR5043177_2.fastq.gz | Fastqsanger.gz | |||
| SRR5043178_1.fastq.gz | Fastqsanger.gz |
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Project description:The tumor suppressor menin prevents effector CD8 T cell dysfunction by targeting mTORC1-dependent metabolic activation [Agilent]
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Project description:While menin plays an important role in preventing T-cell dysfunction, such as senescence and exhaustion, the regulatory mechanisms remain unclear. We found that menin prevents the induction of dysfunction in activated CD8 T cells by restricting the cellular metabolism. mTOR complex 1 (mTORC1) signaling, glycolysis, and glutaminolysis are augmented by menin deficiency. Rapamycin treatment prevents CD8 T-cell dysfunction in menin-deficient CD8 T cells. Limited glutamine availability also prevents CD8 T-cell dysfunction induced by menin deficiency, and its inhibitory effect is antagonized by α-ketoglutarate (α-KG), an intermediate metabolite of glutaminolysis. α-KG-dependent histone H3K27 demethylation seems to be involved in the dysfunction in menin-deficient CD8 T cells. We also found that α-KG activates mTORC1-dependent central carbon metabolism. These findings suggest that menin maintains the T-cell functions by limiting mTORC 1 activity and subsequent cellular metabolism.
2018-08-30 | GSE90163 | GEO
Project description:While menin plays an important role in preventing T-cell dysfunction, such as senescence and exhaustion, the regulatory mechanisms remain unclear. We found that menin prevents the induction of dysfunction in activated CD8 T cells by restricting the cellular metabolism. mTOR complex 1 (mTORC1) signaling, glycolysis, and glutaminolysis are augmented by menin deficiency. Rapamycin treatment prevents CD8 T-cell dysfunction in menin-deficient CD8 T cells. Limited glutamine availability also prevents CD8 T-cell dysfunction induced by menin deficiency, and its inhibitory effect is antagonized by α-ketoglutarate (α-KG), an intermediate metabolite of glutaminolysis. α-KG-dependent histone H3K27 demethylation seems to be involved in the dysfunction in menin-deficient CD8 T cells. We also found that α-KG activates mTORC1-dependent central carbon metabolism. These findings suggest that menin maintains the T-cell functions by limiting mTORC 1 activity and subsequent cellular metabolism.
2018-08-30 | GSE90106 | GEO
Project description:High-resolution quantitative mass-spectrometry reveals similarities and disparities in how murine naïve CD4 and CD8 T cells respond to immune activation and re-structure proteomes as they differentiate to effector cells. The data map core transcriptional, metabolic and protein synthesis machinery, nutrient transporters and environment sensing molecules and reveal differences in the biosynthetic capacity of CD4 and CD8 T cells. One key nutrient sensing kinase is mammalian target of rapamycin complex1 (mTORC1). The current study identifies common and distinct mTORC1 regulated processes and divergent outcomes of mTORC1 inhibition in naïve versus effector CD4 and CD8 T cell populations. The data provide a resource that maps how immune activation and mTORC1 reshape CD4 and CD8 T cell proteomes and highlights that a deep understanding of T cell phenotype requires modelling of the impact of immune regulators on protein copy number, cellular protein concentrations and the subunit stoichiometry of key protein complexes.
2019-03-28 | PXD012058 | Pride
Project description:High resolution mass spectrometry maps the CD8 cytotoxic cell (CTL) proteome and the impact of mammalian target of rapamycin complex 1 (mTORC1) on CTL. We show mTORC1 selectively represses and promotes expression of a subset (10%) of CTL proteins including key CTL effector and adhesion molecules and adaptor proteins. mTORC1 also controls flux through a selective subset of metabolic pathways but is not an on/off switch for CTL metabolism. Proteomic data highlighted the potential for mTORC1 negative control of phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P3) production in CTL. Further work revealed that mTORC1 represses PI(3,4,5)P3 production and controls the mTORC2 requirement for activation of the serine/threonine kinase AKT. Unbiased proteomic analysis thus provides a comprehensive understanding of CTL identity and mTORC1 control of CTL function.
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Project description:Activated T cells differentiate into functional subsets which require distinct metabolic programs. Glutaminase (GLS) converts glutamine to glutamate to provide substrate for the tricarboxylic acid cycle and epigenetic reactions and here we identify a key role for GLS in T cell activation and specification. Though GLS-deficiency diminished T cell activation, proliferation and impaired differentiation of Th17 cells, loss of GLS also increased Tbet and Interferon-γ expression and CD4 Th1 and CD8 CTL effector cell differentiation. These changes were mediated by differentially altered gene expression and chromatin accessibility, leading to increased sensitivity of Th1 cells to IL-2 mediated mTORC1 signaling. In vivo, GLS-null T cells failed to drive a Th17 mediated Graft-vs-Host Disease model. Transient inhibition of GLS, however, increased Th1 and CTL T cell numbers in viral and chimeric antigen receptor models. Glutamine metabolism thus has distinct roles to promote Th17 but constrain Th1 and CTL effector cell differentiation.
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Project description:T cell dysfunctionality prevents clearance of chronic infections and cancer. Furthermore, epigenetic programming in dysfunctional CD8+ T cells limits durable responses to T cell-based immunotherapies, including immune checkpoint blockade (ICB). However, major gaps concern how upstream signals drive acquisition of dysfunctional epigenetic programs, and whether therapeutically targeting these signals can remodel terminally dysfunctional T cells to an ICB-responsive state. Here, we use an in vitro model of human T cell dysfunction and complementary in vivo mouse chronic virus infection and tumor models. We show that post-effector TGFβ1 signaling establishes terminal dysfunction in human CD8+ T cells through stable epigenetic changes. Importantly, we demonstrate that promoting BMP signaling while blocking TGFβ1 restored effector and memory programs in dysfunctional human CD8+ T cells, induced superior anti-tumor activity, and boosted ICB responses during mouse chronic virus infection. Thus, rebalancing TGFβ1/BMP-signals in dysfunctional CD8+ T cells provides an exciting new approach to enhance T cell immunotherapies.
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