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Series GSE192394 Query DataSets for GSE192394
Status Public on Jul 17, 2023
Title Reductive carboxylation epigenetically instructs effector T cell differentiation [ATAC-Seq]
Organism Mus musculus
Experiment type Genome binding/occupancy profiling by high throughput sequencing
Summary 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.
 
Overall design Chromatin accessibility analysis by ATAC sequencing was performed on activated CD8+ T cells that were conditioned for 7 days with DMSO or AG-221 5µM (an IDH2 inhibitor).
 
Contributor(s) Jaccard A, Wyss T, Romero P, Wenes M
Citation(s) 37730993
Submission date Dec 21, 2021
Last update date Oct 13, 2023
Contact name Tania Wyss
Organization name SIB Swiss Institute of Bioinformatics
Street address Rue du Bugnon 25A
City Lausanne
ZIP/Postal code 1015
Country Switzerland
 
Platforms (1)
GPL19057 Illumina NextSeq 500 (Mus musculus)
Samples (4)
GSM5746313 DMSO-treated replicate 1.
GSM5746314 DMSO-treated replicate 2.
GSM5746315 AG-221-treated replicate 1.
This SubSeries is part of SuperSeries:
GSE192396 Reductive carboxylation epigenetically instructs effector T cell differentiation
Relations
BioProject PRJNA791336
SRA SRP351950

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Supplementary file Size Download File type/resource
GSE192394_AG221_shift_bampe_peaks.txt.gz 1.0 Mb (ftp)(http) TXT
GSE192394_DMSO_shift_bampe_peaks.txt.gz 1.0 Mb (ftp)(http) TXT
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Raw data are available in SRA
Processed data are available on Series record

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