Journal
CELL REPORTS
Volume 37, Issue 5, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2021.109911
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Funding
- French National Research Agency [ANR-10-INBS-04]
- French Ministry of Health
- ARC
- Australian Postgraduate Award
- Cancer Therapeutics Australia
- Cancer Research UK [C596/A17196, A23982]
- NIH Intramural Research Program of NIAID
- NCI
- ANR [CHIC-20-CE14-0049]
- FRM
- Sidaction
- ANRS
- French laboratory consortium EpiGenMed
- French laboratory consortium GR-Ex
- ERICAN program of MSD Avenir
- [MetaboHUB-ANR-11-INBS-0010]
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It is demonstrated that aKG alters DNA methylation profile of CD4 T cells, inhibits Treg differentiation, and promotes inflammatory cytokine expression, leading to enhanced tumor infiltration. aKG shifts cellular energy state towards mitochondrial metabolism and directly participates in fatty acid synthesis.
Suppressive regulatory T cell (Treg) differentiation is controlled by diverse immunometabolic signaling pathways and intracellular metabolites. Here we show that cell-permeable a-ketoglutarate (aKG) alters the DNA methylation profile of naive CD4 T cells activated under Treg polarizing conditions, markedly attenuating FoxP3+ Treg differentiation and increasing inflammatory cytokines. Adoptive transfer of these T cells into tumor-bearing mice results in enhanced tumor infiltration, decreased FoxP3 expression, and delayed tumor growth. Mechanistically, aKG leads to an energetic state that is reprogrammed toward a mitochondrial metabolism, with increased oxidative phosphorylation and expression of mitochondrial complex enzymes. Furthermore, carbons from ectopic aKG are directly utilized in the generation of fatty acids, associated with lipidome remodeling and increased triacylglyceride stores. Notably, inhibition of either mitochondrial complex II or DGAT2-mediated triacylglyceride synthesis restores Treg differentiation and decreases the aKG-induced inflammatory phenotype. Thus, we identify a crosstalk between aKG, mitochondrial metabolism and triacylglyceride synthesis that controls Treg fate.
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