Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA354613 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:The tumor suppressor menin prevents effector CD8 T cell dysfunction by targeting mTORC1-dependent metabolic activation
| PRJNA354609 | ENA
Project description:The tumor suppressor menin prevents effector CD8 T cell dysfunction by targeting mTORC1-dependent metabolic activation [RNA-seq]
| PRJNA354447 | ENA
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:The transcription factor BATF is required for Th17 and TFH differentiation. Here, we show that BATF also has a fundamental role in regulating effector CD8+ T cell differentiation. BATF-deficient CD8+ T cells show profound defects in effector expansion and undergo proliferative and metabolic catastrophe early after antigen encounter. BATF, together with IRF4 and Jun proteins, binds to and promotes early expression of genes encoding lineage-specific transcription-factors (T-bet and Blimp-1) and cytokine receptors, while paradoxically repressing genes encoding effector molecules (IFNg and granzyme B). Thus, BATF amplifies TCR-dependent transcription factor expression and augments inflammatory signal propagation but restrains effector gene expression. This checkpoint prevents irreversible commitment to an effector fate until a critical threshold of downstream transcriptional activity has been achieved. P14 TCR transgenic CD8+ T cells from wild-type or BATF-/- mice were examined either as naïve cells or after 3 days of in vitro stimulation with antibodies to CD3 and CD28 in the presence of IL-2
2014-03-02 | E-GEOD-54215 | biostudies-arrayexpress
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.
2022-11-03 | GSE217087 | GEO
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.
2022-11-03 | GSE217072 | GEO
Project description:The transcription factor BATF is required for Th17 and TFH differentiation. Here, we show that BATF also has a fundamental role in regulating effector CD8+ T cell differentiation. BATF-deficient CD8+ T cells show profound defects in effector expansion and undergo proliferative and metabolic catastrophe early after antigen encounter. BATF, together with IRF4 and Jun proteins, binds to and promotes early expression of genes encoding lineage-specific transcription-factors (T-bet and Blimp-1) and cytokine receptors, while paradoxically repressing genes encoding effector molecules (IFNg and granzyme B). Thus, BATF amplifies TCR-dependent transcription factor expression and augments inflammatory signal propagation but restrains effector gene expression. This checkpoint prevents irreversible commitment to an effector fate until a critical threshold of downstream transcriptional activity has been achieved. This is an examination of 5 different transcription factors (TFs) with 5 different histone modifications in effector CD8+ T cells. Two of the TFs (BATF and IRF4) and the histone modifications were replicated. Appropriate control sequence files for ChIP input, IgG ChIP, and Total H3 are also included.
2014-03-02 | E-GEOD-54191 | biostudies-arrayexpress
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.
2015-10-13 | PXD002928 | Pride