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Nature. 2017 Aug 10;548(7666):228-233. doi: 10.1038/nature23475. Epub 2017 Aug 2.

Metabolic control of TH17 and induced Treg cell balance by an epigenetic mechanism.

Author information

1
The J. David Gladstone Institutes, 1650 Owens Street, San Francisco, California 94158, USA.
2
Agios Pharmaceuticals, 38 Sidney Street, Cambridge, Massachusetts 02139, USA.
3
Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China.
4
School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China.
5
Department of Neurology, University of California, San Francisco, San Francisco, California 94143, USA.

Abstract

Metabolism has been shown to integrate with epigenetics and transcription to modulate cell fate and function. Beyond meeting the bioenergetic and biosynthetic demands of T-cell differentiation, 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 (TH17) cells towards induced regulatory T (iTreg) cells, we show that increased transamination, mainly catalysed by GOT1, leads to increased levels of 2-hydroxyglutarate in differentiating TH17 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 TH17 cells. Inhibition of the conversion of glutamate to α-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 TH17 cells by antagonizing the function of transcription factor RORγt and promoted polarization into iTreg cells. Selective inhibition of GOT1 with (aminooxy)acetic acid ameliorated experimental autoimmune encephalomyelitis in a therapeutic mouse model by regulating the balance between TH17 and iTreg cells. Targeting a glutamate-dependent metabolic pathway thus represents a new strategy for developing therapeutic agents against TH17-mediated autoimmune diseases.

PMID:
28783731
DOI:
10.1038/nature23475
[Indexed for MEDLINE]

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