Metabolism has been shown to integrate with epigenetics and transcription to modulate cell fate and function(1-3). Beyond meeting the bioenergetic and biosynthetic demands of T-cell differentiation(4-8), whether metabolism might control T-cell fate by an epigenetic mechanism is unclear. Here, through the discovery and mechanistic characterization of a small molecule, (aminooxy) acetic acid, that reprograms the differentiation of T helper 17 (T(H)17) cells towards induced regulatory T (iT(reg)) cells, we show that increased transamination, mainly catalysed by GOT1, leads to increased levels of 2-hydroxyglutarate in differentiating T(H)17 cells. The accumulation of 2-hydroxyglutarate resulted in hypermethylation of the Foxp3 gene locus and inhibited Foxp3 transcription, which is essential for fate determination towards T(H)17 cells. Inhibition of the conversion of glutamate to a-ketoglutaric acid prevented the production of 2-hydroxyglutarate, reduced methylation of the Foxp3 gene locus, and increased Foxp3 expression. This consequently blocked the differentiation of T(H)17 cells by antagonizing the function of transcription factor ROR gamma t and promoted polarization into iT(reg) cells. Selective inhibition of GOT1 with (aminooxy) acetic acid ameliorated experimental autoimmune encephalomyelitis in a therapeutic mouse model by regulating the balance between T(H)17 and iT(reg) cells. Targeting a glutamate-dependent metabolic pathway thus represents a new strategy for developing therapeutic agents against T(H)17-mediated autoimmune diseases.