Reductive carboxylation epigenetically instructs effector T cell differentiation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA791337 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17297238.fastq.gz | Fastqsanger.gz | |||
| SRR17297239.fastq.gz | Fastqsanger.gz | |||
| SRR17297240.fastq.gz | Fastqsanger.gz | |||
| SRR17297241.fastq.gz | Fastqsanger.gz | |||
| SRR17297242.fastq.gz | Fastqsanger.gz |
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Project description:Reductive carboxylation epigenetically instructs effector T cell differentiation [RNA-Seq]
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Project description:Reductive carboxylation epigenetically instructs effector T cell differentiation [ATAC-Seq]
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Project description:The differentiation into effector and memory CD8+ T cell subsets was recently associated with specific metabolic pathways to sustain their diverse bioenergetics needs. Clonally expanding T cells rely strongly on glucose and glutamine utilization to maintain high cell proliferation and effector functions. We found that proliferating effector CD8+ T cells, in addition to oxidizing, also reductively carboxylate glutamine, to maintain rapid lipid synthesis for cell proliferation. Interfering with reductive carboxylation by genetic deletion of isocitrate dehydrogenase 2 (IDH2), the enzyme mediating this reaction in the mitochondria, surprisingly did not impair proliferation and effector function upon infection, but skewed the CD8+ T cell response towards enhanced memory differentiation. Pharmacological IDH2 inhibition during in vitro CAR T cell manufacturing also induced memory features and thus strongly enhanced their antitumor activity and persistence upon adoptive cell transfer into murine melanoma tumour models. Mechanistically, IDH2 inhibition caused a disequilibrium in metabolites regulating histone-modifying enzymes, which altered the epigenetic landscape, increasing chromatin accessibility at genes required for memory differentiation. Restoring this metabolite balance or preventing the epigenetic modifications abrogated the enhanced CD8+ T cell memory differentiation and anti-tumour activity induced by IDH2 inhibition. These findings suggest that reductive carboxylation of glutamine in activated CD8+ T cells is dispensable for their effector function, but instead primarily instructs a metabolite composition that epigenetically locks them in a terminal effector differentiation program. Blocking this metabolic route allows for increased memory formation, which can be exploited to optimize CAR T cell production for adoptive cell transfer immunotherapy against cancer.
2023-07-17 | GSE192395 | GEO
Project description:The differentiation into effector and memory CD8+ T cell subsets was recently associated with specific metabolic pathways to sustain their diverse bioenergetics needs. Clonally expanding T cells rely strongly on glucose and glutamine utilization to maintain high cell proliferation and effector functions. We found that proliferating effector CD8+ T cells, in addition to oxidizing, also reductively carboxylate glutamine, to maintain rapid lipid synthesis for cell proliferation. Interfering with reductive carboxylation by genetic deletion of isocitrate dehydrogenase 2 (IDH2), the enzyme mediating this reaction in the mitochondria, surprisingly did not impair proliferation and effector function upon infection, but skewed the CD8+ T cell response towards enhanced memory differentiation. Pharmacological IDH2 inhibition during in vitro CAR T cell manufacturing also induced memory features and thus strongly enhanced their antitumor activity and persistence upon adoptive cell transfer into murine melanoma tumour models. Mechanistically, IDH2 inhibition caused a disequilibrium in metabolites regulating histone-modifying enzymes, which altered the epigenetic landscape, increasing chromatin accessibility at genes required for memory differentiation. Restoring this metabolite balance or preventing the epigenetic modifications abrogated the enhanced CD8+ T cell memory differentiation and anti-tumour activity induced by IDH2 inhibition. These findings suggest that reductive carboxylation of glutamine in activated CD8+ T cells is dispensable for their effector function, but instead primarily instructs a metabolite composition that epigenetically locks them in a terminal effector differentiation program. Blocking this metabolic route allows for increased memory formation, which can be exploited to optimize CAR T cell production for adoptive cell transfer immunotherapy against cancer.
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2023-07-17 | GSE192396 | GEO
Project description:Understanding the mechanisms underlying the acquisition and maintenance of effector function during T cell differentiation is important to unraveling how these processes can be dysregulated in the context of disease and manipulated for therapeutic intervention. Herein, we report the identification of a novel regulator of murine T cell differentiation through the evaluation of a previously unreported activity of the kinase inhibitor, BioE-1197. Specifically, we demonstrate liver kinase B1 (LKB1) mediated activation of salt-inducible kinases (SIKs) epigenetically regulates cytokine recall potential in effector CD8+ and Th1 cells. Evaluation of this phenotype revealed SIK mediated phosphorylation dependent stabilization of histone deacetylase 7 (HDAC7) occurred during late-stage effector differentiation. HDAC7 stabilization increased nuclear HDAC7 levels which correlated with both global and cytokine loci specific reductions in the activating transcription mark, histone 3 lysine 27 acetylation (H3K27Ac). Accordingly, HDAC7 stabilization diminished transcriptional induction of cytokine upon re-stimulation. Inhibition of this pathway during differentiation produced effector T cells epigenetically poised for enhanced cytokine recall. This work identifies a novel target for enhancing effector T cell functionality.
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Project description:Metazoan organisms rely on conserved stress response pathways to detect and alleviate adverse conditions and preserve their cellular integrity. Stress responses are particularly important in stem cells that provide lifetime support for tissue formation and repair, yet how these protective systems are integrated into developmental programs is poorly understood. Here, we have used myoblast differentiation to identify the E3 ligase CUL2FEM1B and its substrate FNIP1 as core components of the reductive stress response. Reductive stress, as caused by prolonged antioxidant signaling or mitochondrial inactivity, reverts the oxidation of invariant Cys residues in FNIP1 and thereby allows CUL2FEM1B to recognize its target. The ensuing proteasomal degradation of FNIP1 restores mitochondrial activity to preserve both redox homeostasis and stem cell integrity. The reductive stress response is therefore built around a ubiquitin-dependent rheostat that tunes mitochondrial activity to cellular redox needs and implicates metabolic control in the coordination of stress and developmental signaling.
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Project description:The molecular mechanisms responsible for the high immunosuppressive capacity of CD4+ Tregs in tumors are not well known. High-dimensional single-cell profiling of T cells from chemotherapy-naive individuals with non-small-cell lung cancer identified the transcription factor IRF4 as specifically expressed by a subset of intratumoral CD4+ effector Tregs with superior suppressive activity. In contrast to the IRF4- counterparts, IRF4+ Tregs expressed a vast array of suppressive molecules, and their presence correlated with multiple exhausted subpopulations of T cells. Integration of transcriptomic and epigenomic data revealed that IRF4, either alone or in combination with its partner BATF, directly controlled a molecular program responsible for immunosuppression in tumors. Accordingly, deletion of Irf4 exclusively in Tregs resulted in delayed tumor growth in mice while the abundance of IRF4+ Tregs correlated with poor prognosis in patients with multiple human cancers. Thus, a common mechanism underlies immunosuppression in the tumor microenvironment irrespective of the tumor type.
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Project description:Notch signaling plays a role in specifying a cardiac fate but the downstream effectors remain unknown. In this study we implicate the Notch downstream effector HES5 in cardiogenesis. We show transient Hes5 expression in early mesoderm of gastrulating embryos and demonstrate, by loss and gain-of-function experiments in mouse embryonic stem cells, that HES5 favors cardiac over primitive erythroid fate. Hes5 overexpression promotes upregulation of the cardiac gene Isl1, while the hematopoietic regulator Scl is downregulated. Moreover, whereas a pulse of Hes5 instructs cardiac commitment, sustained expression after lineage specification impairs progression of differentiation to contracting cardiomyocytes. These findings establish a role for HES5 in cardiogenesis and provide insights into the early cardiac molecular network.
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Project description:Epigenetically regulated transcription factor network of intestinal M cell differentiation
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