|
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)
|
|
This SubSeries is part of SuperSeries: |
GSE192396 |
Reductive carboxylation epigenetically instructs effector T cell differentiation |
|
Relations |
BioProject |
PRJNA791336 |
SRA |
SRP351950 |