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Reductive carboxylation epigenetically instructs effector T cell differentiation [ATAC-Seq]

ABSTRACT: Reductive carboxylation epigenetically instructs effector T cell differentiation [ATAC-Seq]

PROVIDER: PRJNA791336 | ENA |

REPOSITORIES: ENA

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Reductive carboxylation epigenetically instructs effector T cell differentiation

Project description:Reductive carboxylation epigenetically instructs effector T cell differentiation

| PRJNA791337 | ENA

Reductive carboxylation epigenetically instructs effector T cell differentiation [ATAC-Seq]

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 | GSE192394 | GEO

Reductive carboxylation epigenetically instructs effector T cell differentiation [RNA-Seq]

Project description:Reductive carboxylation epigenetically instructs effector T cell differentiation [RNA-Seq]

| PRJNA791335 | ENA

Reductive carboxylation epigenetically instructs effector T cell differentiation [RNA-Seq]

2023-07-17 | GSE192395 | GEO

Reductive carboxylation epigenetically instructs effector T cell differentiation

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-07-17 | GSE192396 | GEO

Renin Regulatory Pathway Inhibition Epigenetically Silences *Ren1* (ATAC-Seq)

Project description:Renin Regulatory Pathway Inhibition Epigenetically Silences *Ren1* (ATAC-Seq)

| PRJNA1072670 | ENA

ATAC-seq analyses with knockout eHAP cells for effector genes

Project description:A genome-wide screening identified effector genes of chromatin accessibility. To investigate the functional consequences of the loss of each effector gene, we conducted ATAC-seq analysis with eHAP cells knocked out for each effector gene.

2022-05-01 | GSE144448 | GEO

Immunoediting instructs tumor metabolic reprogramming to support immune evasion [ATAC-seq]

Project description:Immunoediting sculpts immunogenicity and thwarts host anti-tumor responses in tumor cells during tumorigenesis; however, it remains unknown whether metabolic programming of tumor cells can be guided by immunosurveillance. Here, we report that T cell-mediated immunosurveillance in early staged tumorigenesis instructs c-Myc upregulation and metabolic reprogramming in tumor cells. This previously unexplored tumor-immune interaction is controlled by a non-canonical IFNg-STAT3 signaling and supports tumor immune evasion. Our findings uncover that immunoediting instructs deregulated bioenergetic programs in tumor cells for empowering them to disarm the T cell-mediated immunosurveillance by imposing metabolic tug-of-war between tumor and infiltrating T cells and forming the suppressive tumor microenvironment.

2022-11-15 | GSE217475 | GEO

Immunoediting instructs tumor metabolic reprogramming to support immune evasion [ATAC-seq]

Project description:Immunoediting instructs tumor metabolic reprogramming to support immune evasion [ATAC-seq]

| PRJNA899081 | ENA

Exercise instructs hematopoietic progenitor cells and reduces chronic leukocytosis [ATAC-seq]

Project description:Exercise instructs hematopoietic progenitor cells and reduces chronic leukocytosis [ATAC-seq]

| PRJNA434141 | ENA