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The regulatory role of PGAM was dependent on the contribution of 3-phosphoglycerate (3 PG), the PGAM substrate, to de novo serine synthesis. Blocking de novo serine synthesis from 3 PG reversed the effect of PGAM inhibition on Treg polarization, while exogenous serine directly inhibited Treg polarization. Additionally, altering serine levels in vivo with a serine\/glycine-free diet increased peripheral Tregs and attenuated autoimmunity in a murine model of multiple sclerosis. Mechanistically, we found that serine limits Treg polarization by contributing to one-carbon metabolism and methylation of Treg-associated genes. Inhibiting one-carbon metabolism increased Treg polarization and suppressive function both in vitro and in vivo in a murine model of autoimmune colitis. 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