Metabolic control of TH17 and induced Treg cell balance by an epigenetic mechanism
Open accessAbstract
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 (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 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 T H 17 cells by antagonizing the function of transcription factor RORγt 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.
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- Authors
- Xu, T., Stewart, K. M., Wang, X., Liu, K., Xie, M., Ryu, J. K., Li, K., Ma, T., Wang, H., Ni, L., Zhu, S., Cao, N., Zhu, D., Zhang, Y., Akassoglou, K., Dong, C., Driggers, E. M., & Ding, S.
- Affiliations
- Gladstone Institutes (US)
- Agios Pharmaceuticals (United States) (US)
- Tsinghua University (CN)
- Corresponding author
- Dong, Chen
- Driggers, Edward M.
- Ding, Sheng
- ORCID
- Venue
- Nature
- Published
- 2017-08-02
- Volume
- 548
- Issue
- 7666
- Pages
- 228-233
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6701955
- OpenAlex
- W2741802290
- Cited by
- 395
- References
- 30
- Citations by year
- 2026: 38 · 2025: 55 · 2024: 53 · 2023: 36 · 2022: 43 · 2021: 59 · 2020: 41 · 2019: 36 · 2018: 23 · 2017: 9 · 2014: 2
- FWCI
- 13.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R35NS097976)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- Th17 cells, induced regulatory T cells, T cell metabolism, epigenetic regulation, DNA methylation, Foxp3, 2-hydroxyglutarate, GOT1, transamination, glutamate metabolism, RORγt, experimental autoimmune encephalomyelitis, autoimmune disease therapy, T cell fate determination
- MeSH terms
- Aminooxyacetic Acid, Transaminases, Animals, Cell Differentiation, Encephalomyelitis, Autoimmune, Experimental, Female, Glutarates, Ketoglutaric Acids, Male, Aspartate Aminotransferase, Cytoplasmic, Epigenesis, Genetic, T-Lymphocytes, Regulatory, Mice, Forkhead Transcription Factors, Nuclear Receptor Subfamily 1, Group F, Member 3, Th17 Cells
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