Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Cell Biology, REDUCTIVE GLUTAMINE-METABOLISM, DIACYLGLYCEROL ACYLTRANSFERASE, SUCCINATE-DEHYDROGENASE, KETOGLUTARATE, ACTIVATION, GLUCOSE, FATE, INHIBITION, EXPRESSION, MTORC1, CAR T cells, DNA methylation, T cell differentiation, TCA cycle, Th1, Treg, lipidome, mitochondrial metabolism, triacylglyceride synthesis, α-ketoglutarate, Animals, Cell Differentiation, Cells, Cultured, Cytokines, Diacylglycerol O-Acyltransferase, Energy Metabolism, Fibrosarcoma, Forkhead Transcription Factors, Homeostasis, Humans, Immunotherapy, Adoptive, Ketoglutaric Acids, Lipid Metabolism, Mice, Inbred C57BL, Mice, Knockout, Mitochondria, Phenotype, Receptors, Chimeric Antigen, Signal Transduction, T-Lymphocytes, Regulatory, Th1 Cells, Mice, 0601 Biochemistry and Cell Biology, 1116 Medical Physiology, 31 Biological sciences

Abstract:

Suppressive regulatory T cell (Treg) differentiation is controlled by diverse immunometabolic signaling pathways and intracellular metabolites. Here we show that cell-permeable α-ketoglutarate (αKG) 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, αKG 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 αKG 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 αKG-induced inflammatory phenotype. Thus, we identify a crosstalk between αKG, mitochondrial metabolism and triacylglyceride synthesis that controls Treg fate.