Mitochondrial Metabolism Drives Triacylglycerol Synthesis to Control Regulatory T Cell Differentiation

Suppressive regulatory T cell (Treg) differentiation is controlled by diverse immunometabolic signaling pathways. However, the impact of intracellular metabolites on Treg fate has not been well explored. Here we show that the α-ketoglutarate (αKG) tricarboxylic acid (TCA) cycle metabolite increases oxidative phosphorylation (OXPHOS) in naive CD4 T cells activated under Treg polarizing conditions, markedly attenuating Foxp3+ Treg differentiation and increasing inflammatory cytokine expression. Adoptive transfer of these T cells into tumor-bearing mice results in enhanced tumor infiltration and decreased Foxp3 expression. Mechanistically, αKG-induced OXPHOS is associated with lipidome remodelling, characterized by augmented mitochondrial lipids and triacylglyceride (TAG) stores. Inhibiting succinate dehydrogenase, the bridging enzyme between the TCA cycle and the ETC, enforces Treg differentiation. Strikingly, TAG storage directly promotes an inflammatory phenotype –– Treg differentiation is restored by inhibiting DGAT2-mediated TAG synthesis. Thus, we identify a novel crosstalk between αKG, mitochondrial metabolism and DGAT2-mediated TAG synthesis in controlling Treg fate.