Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells

Nature Medicine volume 20, pages 1327–1333 (2014)Cite this article

Subjects

An Erratum to this article was published on 07 April 2015

This article has been updated

Abstract

Interleukin-17 (IL-17)-secreting T cells of the T helper 17 (TH17) lineage play a pathogenic role in multiple inflammatory and autoimmune conditions and thus represent a highly attractive target for therapeutic intervention. We report that inhibition of acetyl-CoA carboxylase 1 (ACC1) restrains the formation of human and mouse TH17 cells and promotes the development of anti-inflammatory Foxp3+ regulatory T (Treg) cells. We show that TH17 cells, but not Treg cells, depend on ACC1-mediated de novo fatty acid synthesis and the underlying glycolytic-lipogenic metabolic pathway for their development. Although TH17 cells use this pathway to produce phospholipids for cellular membranes, Treg cells readily take up exogenous fatty acids for this purpose. Notably, pharmacologic inhibition or T cell–specific deletion of ACC1 not only blocks de novo fatty acid synthesis but also interferes with the metabolic flux of glucose-derived carbon via glycolysis and the tricarboxylic acid cycle. In vivo, treatment with the ACC-specific inhibitor soraphen A or T cell–specific deletion of ACC1 in mice attenuates TH17 cell–mediated autoimmune disease. Our results indicate fundamental differences between TH17 cells and Treg cells regarding their dependency on ACC1-mediated de novo fatty acid synthesis, which might be exploited as a new strategy for metabolic immune modulation of TH17 cell–mediated inflammatory diseases.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: SorA restrains TH17 cell differentiation and promotes Treg cell development.
Figure 2: ACC1 inhibition alters the transcriptional and metabolic signature of TH17 cells and reduces their proliferative capacity.
Figure 3: ACC1 inhibition blocks the glycolytic-lipogenic pathway.
Figure 4: Inhibition of ACC1 attenuates mouse TH17 cell–mediated autoimmune disease and regulates human TH17 and Treg cell fate.

Change history

  • 31 October 2014

     In the version of this article initially published online, the number 21.45, corresponding to the percentage of cells, was missing from the bottom right quadrant of the flow cytometry plot (SorA, WT) in Figure 2a. The error has been corrected for the print, PDF and HTML versions of this article.

References

  1. Pearce, E.L., Poffenberger, M.C., Chang, C.H. & Jones, R.G. Fueling immunity: insights into metabolism and lymphocyte function. Science 342, 1242454 (2013).

    Article  Google Scholar 

  2. Wang, R. & Green, D.R. Metabolic checkpoints in activated T cells. Nat. Immunol. 13, 907–915 (2012).

    Article  CAS  Google Scholar 

  3. Chang, C.H. et al. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 153, 1239–1251 (2013).

    Article  CAS  Google Scholar 

  4. Barbi, J., Pardoll, D. & Pan, F. Metabolic control of the Treg/TH17 axis. Immunol. Rev. 252, 52–77 (2013).

    Article  Google Scholar 

  5. Waickman, A.T. & Powell, J.D. mTOR, metabolism, and the regulation of T-cell differentiation and function. Immunol. Rev. 249, 43–58 (2012).

    Article  CAS  Google Scholar 

  6. Shi, L.Z. 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).

    Article  CAS  Google Scholar 

  7. Dang, E.V. et al. Control of TH17/Treg balance by hypoxia-inducible factor 1. Cell 146, 772–784 (2011).

    Article  CAS  Google Scholar 

  8. Michalek, R.D. et al. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J. Immunol. 186, 3299–3303 (2011).

    Article  CAS  Google Scholar 

  9. Lee, J. et al. Regulator of fatty acid metabolism, acetyl coenzyme a carboxylase 1, controls T cell immunity. J. Immunol. 192, 3190–3199 (2014).

    Article  CAS  Google Scholar 

  10. Everts, B. et al. TLR-driven early glycolytic reprogramming via the kinases TBK1-IKKɛ supports the anabolic demands of dendritic cell activation. Nat. Immunol. 15, 323–332 (2014).

    Article  CAS  Google Scholar 

  11. Wakil, S.J. & Abu-Elheiga, L.A. Fatty acid metabolism: target for metabolic syndrome. J. Lipid Res. 50 (suppl.), S138–S143 (2009).

    Article  Google Scholar 

  12. Gerth, K., Bedorf, N., Irschik, H., Hofle, G. & Reichenbach, H. The soraphens: a family of novel antifungal compounds from Sorangium cellulosum (Myxobacteria). I. Soraphen A1α: fermentation, isolation, biological properties. J. Antibiot. (Tokyo) 47, 23–31 (1994).

    Article  CAS  Google Scholar 

  13. Shen, Y., Volrath, S.L., Weatherly, S.C., Elich, T.D. & Tong, L. A mechanism for the potent inhibition of eukaryotic acetyl-coenzyme A carboxylase by soraphen A, a macrocyclic polyketide natural product. Mol. Cell 16, 881–891 (2004).

    Article  CAS  Google Scholar 

  14. Vahlensieck, H.F., Pridzun, L., Reichenbach, H. & Hinnen, A. Identification of the yeast ACC1 gene product (acetyl-CoA carboxylase) as the target of the polyketide fungicide soraphen A. Curr. Genet. 25, 95–100 (1994).

    Article  CAS  Google Scholar 

  15. Cho, Y.S. et al. Molecular mechanism for the regulation of human ACC2 through phosphorylation by AMPK. Biochem. Biophys. Res. Commun. 391, 187–192 (2010).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  17. McGeachy, M.J. et al. The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17–producing effector T helper cells in vivo. Nat. Immunol. 10, 314–324 (2009).

    Article  CAS  Google Scholar 

  18. Abu-Elheiga, L., Matzuk, M.M., Abo-Hashema, K.A. & Wakil, S.J. Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2. Science 291, 2613–2616 (2001).

    Article  CAS  Google Scholar 

  19. Mao, J. et al. Liver-specific deletion of acetyl-CoA carboxylase 1 reduces hepatic triglyceride accumulation without affecting glucose homeostasis. Proc. Natl. Acad. Sci. USA 103, 8552–8557 (2006).

    Article  CAS  Google Scholar 

  20. Abu-Elheiga, L. et al. Mutant mice lacking acetyl-CoA carboxylase 1 are embryonically lethal. Proc. Natl. Acad. Sci. USA 102, 12011–12016 (2005).

    Article  CAS  Google Scholar 

  21. Delgoffe, G.M. et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30, 832–844 (2009).

    Article  CAS  Google Scholar 

  22. Wang, R. et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35, 871–882 (2011).

    Article  CAS  Google Scholar 

  23. Dufort, F.J. et al. Glucose-dependent de novo lipogenesis in B lymphocytes: a requirement for ATP-citrate lyase in LPS-induced differentiation. J. Biol. Chem. 289, 7011–7024 (2014).

    Article  CAS  Google Scholar 

  24. Menendez, J.A. & Lupu, R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat. Rev. Cancer 7, 763–777 (2007).

    Article  CAS  Google Scholar 

  25. Saggerson, D. Malonyl-CoA, a key signaling molecule in mammalian cells. Annu. Rev. Nutr. 28, 253–272 (2008).

    Article  CAS  Google Scholar 

  26. Glatz, J.F., Luiken, J.J. & Bonen, A. Membrane fatty acid transporters as regulators of lipid metabolism: implications for metabolic disease. Physiol. Rev. 90, 367–417 (2010).

    Article  CAS  Google Scholar 

  27. Martin, B.R. & Cravatt, B.F. Large-scale profiling of protein palmitoylation in mammalian cells. Nat. Methods 6, 135–138 (2009).

    Article  CAS  Google Scholar 

  28. Ueda, A., Zhou, L. & Stein, P.L. Fyn promotes Th17 differentiation by regulating the kinetics of RORγt and Foxp3 expression. J. Immunol. 188, 5247–5256 (2012).

    Article  CAS  Google Scholar 

  29. Shriver, L.P. & Manchester, M. Inhibition of fatty acid metabolism ameliorates disease activity in an animal model of multiple sclerosis. Sci. Rep. 1, 79 (2011).

    Article  Google Scholar 

  30. Lee, P.P. et al. A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival. Immunity 15, 763–774 (2001).

    Article  CAS  Google Scholar 

  31. Berod, L. et al. PI3Kγ deficiency delays the onset of experimental autoimmune encephalomyelitis and ameliorates its clinical outcome. Eur. J. Immunol. 41, 833–844 (2011).

    Article  CAS  Google Scholar 

  32. Abraham, W.R., Hesse, C. & Pelz, O. Ratios of carbon isotopes in microbial lipids as an indicator of substrate usage. Appl. Environ. Microbiol. 64, 4202–4209 (1998).

    Article  CAS  Google Scholar 

  33. Abrajano, J.T.A., Murphy, D.E., Fang, J., Comet, P. & Brooks, J.M. 13C/12C ratios in individual fatty acids of marine mytilids with and without bacterial symbionts. Org. Geochem. 21, 611–617 (1994).

    Article  CAS  Google Scholar 

  34. Abraham, W.R. & Hesse, C. Isotope fractionations in the biosynthesis of cell components by different fungi: a basis for environmental carbon flux studies. FEMS Microbiol. Ecol. 46, 121–128 (2003).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank S.J. Wakil (Baylor College of Medicine) for providing ACC1lox and ACC2-knockout mice, M. Swallow for critical reading of the manuscript and all members of the Institute of Infection Immunology at TWINCORE for discussion and support. We would like to acknowledge the assistance of the Cell Sorting Core Facility of the Hannover Medical School supported in part by the Braukmann-Wittenberg-Herz-Stiftung and the Deutsche Forschungsgemeinschaft. We thank E. Surges for excellent technical help, B. Beckmann for support using the Seahorse XF Analyzer, F. Sasse (Helmholtz Centre for Infection Research) for providing SorA and M. Haidukiewicz (Hannover Medical School) for providing human cord blood. This work was supported by grants from the Deutsche Forschungsgemeinschaft (LO1415/2-1, KFO250 and SFB900 to T.S. and M.L. and PO732 to E.P.) and the Novartis Research Foundation to M.L.; A.N. was supported by the German academic exchange service and C.T.M. by the German National Academic Foundation.

Author information

Author notes

  1. Luciana Berod, Christin Friedrich, Amrita Nandan, Matthias Lochner and Tim Sparwasser: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research,

    Luciana Berod, Christin Friedrich, Amrita Nandan, Jenny Freitag, Stefanie Hagemann, Aline Sandouk, Christina Hesse, Carla N Castro, Melanie Gohmert, Christian T Mayer, Matthias Lochner & Tim Sparwasser

  2. a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany

    Luciana Berod, Christin Friedrich, Amrita Nandan, Jenny Freitag, Stefanie Hagemann, Aline Sandouk, Christina Hesse, Carla N Castro, Melanie Gohmert, Christian T Mayer, Matthias Lochner & Tim Sparwasser

  3. Helmholtz Centre for Infection Research and Department of Pharmaceutical Biotechnology, Helmholtz Institute for Pharmaceutical Research, Saarland University, Saarbrücken, Germany

    Kirsten Harmrolfs & Rolf Müller

  4. Institute of Pharmacology, Hannover Medical School, Hannover, Germany

    Heike Bähre & Sarah K Tschirner

  5. Research Core Unit Metabolomics, Hannover Medical School, Hannover, Germany

    Heike Bähre

  6. Institute of Cellular Neurophysiology, Hannover Medical School, Hannover, Germany

    Nataliya Gorinski & Evgeni Ponimaskin

  7. Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany

    Jochen Huehn

  8. Department of Chemical Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany

    Wolf-Rainer Abraham

Authors
  1. Luciana Berod
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christin Friedrich
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Amrita Nandan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jenny Freitag
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Stefanie Hagemann
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kirsten Harmrolfs
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Aline Sandouk
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Christina Hesse
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Carla N Castro
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Heike Bähre
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Sarah K Tschirner
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Nataliya Gorinski
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Melanie Gohmert
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Christian T Mayer
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Jochen Huehn
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Evgeni Ponimaskin
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Wolf-Rainer Abraham
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Rolf Müller
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Matthias Lochner
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Tim Sparwasser
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

L.B., C.F., A.N., J.F., S.H., M.G., C.H. and C.N.C. performed the experiments, interpreted the data and assisted with the paper. K.H. and R.M. provided essential materials and generated the SorA derivatives. W.-R.A. performed the 13C incorporation analysis. N.G. and E.P. performed the palmitoylation assay. A.S., H.B. and S.K.T. performed the metabolic analysis using HPLC–mass spectrometry or mass spectrometry. C.T.M and J.H. supported the work with key suggestions and helped with interpretation of the data. M.L. and T.S. designed the research, interpreted the data and wrote the paper.

Corresponding authors

Correspondence to Matthias Lochner or Tim Sparwasser.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–14 and Supplementary Tables 1 and 2. (PDF 3852 kb)

Supplementary Table 3

Real-time PCR analysis of metabolic genes in wild-type and ACC1-deficient CD4+ T cells cultured under TH17 (DMSO/SorA/TACC1) or Treg inducing conditions (XLS 38 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Berod, L., Friedrich, C., Nandan, A. et al. De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat Med 20, 1327–1333 (2014). https://doi.org/10.1038/nm.3704

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.3704

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing