Regulatory T cell differentiation is controlled by αKG-induced alterations in mitochondrial metabolism and lipid homeostasis

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.

Automated summary

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.