Letter | Published:

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

Nature volume 548, pages 228233 (10 August 2017) | Download Citation

Abstract

Metabolism has been shown to integrate with epigenetics and transcription to modulate cell fate and function1,2,3. Beyond meeting the bioenergetic and biosynthetic demands of T-cell differentiation4,5,6,7,8, 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 (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.

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References

  1. 1.

    & A two-way street: reciprocal regulation of metabolism and signalling. Nat. Rev. Mol. Cell Biol. 13, 270–276 (2012)

  2. 2.

    & Metabolic regulation of epigenetics. Cell Metab. 16, 9–17 (2012)

  3. 3.

    & Influence of metabolism on epigenetics and disease. Cell 153, 56–69 (2013)

  4. 4.

    , , & Fueling immunity: insights into metabolism and lymphocyte function. Science 342, 1242454 (2013)

  5. 5.

    & Metabolic pathways in immune cell activation and quiescence. Immunity 38, 633–643 (2013)

  6. 6.

    & Metabolic checkpoints in activated T cells. Nat. Immunol. 13, 907–915 (2012)

  7. 7.

    et al. HIF1α-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J. Exp. Med. 208, 1367–1376 (2011)

  8. 8.

    et al. De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat. Med. 20, 1327–1333 (2014)

  9. 9.

    et al. Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity 29, 44–56 (2008)

  10. 10.

    et al. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc. Natl Acad. Sci. USA 104, 19345–19350 (2007)

  11. 11.

    et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 496, 101–105 (2013)

  12. 12.

    et al. Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of α-ketoglutarate to citrate to support cell growth and viability. Proc. Natl Acad. Sci. USA 108, 19611–19616 (2011)

  13. 13.

    et al. MYC-driven accumulation of 2-hydroxyglutarate is associated with breast cancer prognosis. J. Clin. Invest. 124, 398–412 (2014)

  14. 14.

    et al. TGF-β-induced Foxp3 inhibits TH17 cell differentiation by antagonizing RORγt function. Nature 453, 236–240 (2008)

  15. 15.

    et al. Hydrogen sulfide promotes Tet1- and Tet2-mediated Foxp3 demethylation to drive regulatory T cell differentiation and maintain immune homeostasis. Immunity 43, 251–263 (2015)

  16. 16.

    et al. Control of Foxp3 stability through modulation of TET activity. J. Exp. Med. 213, 377–397 (2016)

  17. 17.

    & CREB/ATF-dependent T cell receptor-induced FoxP3 gene expression: a role for DNA methylation. J. Exp. Med. 204, 1543–1551 (2007)

  18. 18.

    et al. Ursolic acid suppresses interleukin-17 (IL-17) production by selectively antagonizing the function of RORγt protein. J. Biol. Chem. 286, 22707–22710 (2011)

  19. 19.

    et al. Myelin oligodendrocyte glycoprotein-specific T cell receptor transgenic mice develop spontaneous autoimmune optic neuritis. J. Exp. Med. 197, 1073–1081 (2003)

  20. 20.

    et al. Systems-level metabolic flux profiling identifies fatty acid synthesis as a target for antiviral therapy. Nat. Biotechnol. 26, 1179–1186 (2008)

  21. 21.

    et al. IDH2 mutation-induced histone and DNA hypermethylation is progressively reversed by small-molecule inhibition. Blood 125, 296–303 (2015)

  22. 22.

    , , & Ultrahigh performance liquid chromatography–tandem mass spectrometry method for fast and robust quantification of anionic and aromatic metabolites. Anal. Chem. 82, 4403–4412 (2010)

  23. 23.

    et al. The methylcytosine dioxygenase Tet2 promotes DNA demethylation and activation of cytokine gene expression in T cells. Immunity 42, 613–626 (2015)

  24. 24.

    et al. Active demethylation of the Foxp3 locus leads to the generation of stable regulatory T cells within the thymus. J. Immunol. 190, 3180–3188 (2013)

  25. 25.

    et al. Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells. Nature 445, 936–940 (2007)

  26. 26.

    Model-based analysis of ChIP–seq (MACS). Genome Biol. 9, R137 (2008)

  27. 27.

    , , & Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 10, R25 (2009)

  28. 28.

    & BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26, 841–842 (2010)

Download references

Acknowledgements

S.D. is supported by funding from the Gladstone Institutes and Tsinghua University. X.W. is supported by a grant from NFSC (31570884). A Race to Erase MS Young Investigator Award, and American Heart Association Scientist Development Grant were awarded to J.K.R. and NIH/NINDS R35 NS097976 was awarded to K.A. We thank G. Howard for help with editing the manuscript, and H. W. Lim for discussion.

Author information

Author notes

    • Edward M. Driggers

    Present address: General Metabolics, LLC, 3 Huntington Road, Arlington, Massachusetts 02474, USA.

    • Tao Xu
    • , Kelly M. Stewart
    •  & Xiaohu Wang

    These authors contributed equally to this work.

    • Chen Dong
    • , Edward M. Driggers
    •  & Sheng Ding

    These authors jointly supervised this work.

Affiliations

  1. The J. David Gladstone Institutes, 1650 Owens Street, San Francisco, California 94158, USA

    • Tao Xu
    • , Kai Liu
    • , Min Xie
    • , Jae Kyu Ryu
    • , Ke Li
    • , Tianhua Ma
    • , Haixia Wang
    • , Saiyong Zhu
    • , Nan Cao
    • , Yu Zhang
    • , Katerina Akassoglou
    •  & Sheng Ding
  2. Agios Pharmaceuticals, 38 Sidney Street, Cambridge, Massachusetts 02139, USA

    • Kelly M. Stewart
    • , Dongwei Zhu
    •  & Edward M. Driggers
  3. Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China

    • Xiaohu Wang
    • , Lu Ni
    •  & Chen Dong
  4. School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China

    • Tianhua Ma
    •  & Sheng Ding
  5. Department of Neurology, University of California, San Francisco, San Francisco, California 94143, USA

    • Katerina Akassoglou

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Contributions

T.X. and S.D. conceived the project; T.X., K.M.S., X.W., C.D., E.M.D. and S.D. designed the experiments. T.X., K. Li, T.M., H.W., S.Z., N.C. and Y.Z. performed the in vitro experiments; T.X. prepared the samples for metabolic analysis; K.M.S. conducted all metabolomics and flux analysis; D.Z. helped to analyse 2-HG levels. X.W. and L.N. performed active EAE experiments; T.X. and J.K.R. performed transfer EAE experiment (T.X. prepared cells and injected cells into mice, and J.K.R. scored the mice, and T.X. and J.K.R. analysed T cells infiltrated into the central nervous system). M.X. prepared chemicals. K. Liu analysed the data from (h)MeDIP–seq. K.A. designed experiments and analysed data. T.X., K.M.S., X.W., C.D., E.M.D. and S.D. wrote the manuscript; K.A., C.D., E.M.D. and S.D. edited the manuscript. All authors read and approved the final manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Chen Dong or Edward M. Driggers or Sheng Ding.

Reviewer Information Nature thanks L. O’Neill and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains the uncropped blots from Extended Data Figures 1 and 5 and general information for characterization of (R)-dimethyl 2-hydroxyglutarate

  2. 2.

    Supplementary Data 1

    Supplementary Data 1 contains the list of primer for qRT-PCR.

  3. 3.

    Supplementary Data 2

    Supplementary Data 1 contains the list of genes.

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DOI

https://doi.org/10.1038/nature23475

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