MTHFD2 inhibition dramatically alters histone methylation landscape in Th17 cells

MTHFD2 is a mitochondrial enzyme within the folate cycle of one carbon metabolism. We found that MTHFD2 deficiency leads to impaired proliferation and induction of FoxP3 expression in Th17 cells and Treg cells differentiated in low TGFß conditions. Mechanistically, this occured through depleted purine pools, accumulation of purine synthesis intermediates, dampened mTORC1 activity, and altered DNA and histone methylation. Overall design: Treg and Th17 cells were treated with either DMSO (vehicle) or 500nM DS18561882 (MTHFD2i) for 72 hours.