Abstract

CD4+ effector T cells (Teff cells) and regulatory T cells (Treg cells) undergo metabolic reprogramming to support proliferation and immunological function. Although signaling via the lipid kinase PI(3)K (phosphatidylinositol-3-OH kinase), the serine-threonine kinase Akt and the metabolic checkpoint kinase complex mTORC1 induces both expression of the glucose transporter Glut1 and aerobic glycolysis for Teff cell proliferation and inflammatory function, the mechanisms that regulate Treg cell metabolism and function remain unclear. We found that Toll-like receptor (TLR) signals that promote Treg cell proliferation increased PI(3)K-Akt-mTORC1 signaling, glycolysis and expression of Glut1. However, TLR-induced mTORC1 signaling also impaired Treg cell suppressive capacity. Conversely, the transcription factor Foxp3 opposed PI(3)K-Akt-mTORC1 signaling to diminish glycolysis and anabolic metabolism while increasing oxidative and catabolic metabolism. Notably, Glut1 expression was sufficient to increase the number of Treg cells, but it reduced their suppressive capacity and Foxp3 expression. Thus, inflammatory signals and Foxp3 balance mTORC1 signaling and glucose metabolism to control the proliferation and suppressive function of Treg cells.

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References

  1. 1.

    , & T cell metabolism drives immunity. J. Exp. Med. 212, 1345–1360 (2015).

  2. 2.

    & Fundamentals of cancer metabolism. Sci. Adv. 2, e1600200 (2016).

  3. 3.

    et al. Post-transcriptional control of T cell effector function by aerobic glycolysis. Cell 153, 1239–1251 (2013).

  4. 4.

    et al. The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab. 20, 61–72 (2014).

  5. 5.

    et al. Essential role of mitochondrial energy metabolism in Foxp3+ T-regulatory cell function and allograft survival. FASEB J. 29, 2315–2326 (2015).

  6. 6.

    et al. Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation. J. Clin. Invest. 125, 194–207 (2015).

  7. 7.

    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).

  8. 8.

    et al. HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J. Exp. Med. 208, 1367–1376 (2011).

  9. 9.

    , , & Regulatory T-cell homeostasis: steady-state maintenance and modulation during inflammation. Immunol. Rev. 259, 40–59 (2014).

  10. 10.

    & Metabolic control of regulatory T cell development and function. Trends Immunol. 36, 3–12 (2015).

  11. 11.

    et al. Production of IL-10 by CD4+ regulatory T cells during the resolution of infection promotes the maturation of memory CD8(+) T cells. Nat. Immunol. 16, 871–879 (2015).

  12. 12.

    et al. Cutting edge: regulatory T cells facilitate cutaneous wound healing. J. Immunol. 196, 2010–2014 (2016).

  13. 13.

    et al. A distinct function of regulatory T cells in tissue protection. Cell 162, 1078–1089 (2015).

  14. 14.

    et al. Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell 146, 772–784 (2011).

  15. 15.

    et al. Bcl-6 directly represses the gene program of the glycolysis pathway. Nat. Immunol. 15, 957–964 (2014).

  16. 16.

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

  17. 17.

    et al. An oscillatory switch in mTOR kinase activity sets regulatory T cell responsiveness. Immunity 33, 929–941 (2010).

  18. 18.

    et al. mTORC1 couples immune signals and metabolic programming to establish T(reg)-cell function. Nature 499, 485–490 (2013).

  19. 19.

    et al. Control of PI(3) kinase in Treg cells maintains homeostasis and lineage stability. Nat. Immunol. 16, 188–196 (2015).

  20. 20.

    et al. Treg cells require the phosphatase PTEN to restrain TH1 and TFH cell responses. Nat. Immunol. 16, 178–187 (2015).

  21. 21.

    et al. TSC1 regulates the balance between effector and regulatory T cells. J. Clin. Invest. 123, 5165–5178 (2013).

  22. 22.

    & The Immunological Genome Project: networks of gene expression in immune cells. Nat. Immunol. 9, 1091–1094 (2008).

  23. 23.

    et al. Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function. Science 309, 1380–1384 (2005).

  24. 24.

    et al. Toll-like receptor 2 controls expansion and function of regulatory T cells. J. Clin. Invest. 116, 485–494 (2006).

  25. 25.

    et al. Targeting of TLRs inhibits CD4+ regulatory T cell function and activates lymphocytes in human peripheral blood mononuclear cells. J. Immunol. 193, 627–634 (2014).

  26. 26.

    et al. TLR2 stimulation drives human naive and effector regulatory T cells into a Th17-like phenotype with reduced suppressive function. J. Immunol. 187, 2278–2290 (2011).

  27. 27.

    et al. Tissue adaptation of regulatory and intraepithelial CD4+ T cells controls gut inflammation. Science 352, 1581–1586 (2016).

  28. 28.

    et al. MyD88 adaptor-dependent microbial sensing by regulatory T cells promotes mucosal tolerance and enforces commensalism. Immunity 43, 289–303 (2015).

  29. 29.

    et al. A wave of regulatory T cells into neonatal skin mediates tolerance to commensal microbes. Immunity 43, 1011–1021 (2015).

  30. 30.

    et al. Rab8a interacts directly with PI(3)Kγ to modulate TLR4-driven PI(3)K and mTOR signalling. Nat. Commun. 5, 4407 (2014).

  31. 31.

    et al. Metabolic reprogramming is required for antibody production that is suppressed in anergic but exaggerated in chronically BAFF-exposed B cells. J. Immunol. 192, 3626–3636 (2014).

  32. 32.

    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).

  33. 33.

    et al. Glucose uptake is limiting in T cell activation and requires CD28-mediated Akt-dependent and independent pathways. J. Immunol. 180, 4476–4486 (2008).

  34. 34.

    et al. Continuous activation of autoreactive CD4+ CD25+ regulatory T cells in the steady state. J. Exp. Med. 198, 737–746 (2003).

  35. 35.

    & Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nat. Immunol. 8, 277–284 (2007).

  36. 36.

    , & Foxp3-mediated inhibition of Akt inhibits Glut1 (glucose transporter 1) expression in human T regulatory cells. J. Leukoc. Biol. 97, 279–283 (2015).

  37. 37.

    et al. Inflammation-induced repression of chromatin bound by the transcription factor Foxp3 in regulatory T cells. Nat. Immunol. 15, 580–587 (2014).

  38. 38.

    et al. FOXO1 couples metabolic activity and growth state in the vascular endothelium. Nature 529, 216–220 (2016).

  39. 39.

    , & Tissue Tregs. Annu. Rev. Immunol. 34, 609–633 (2016).

  40. 40.

    , & Differentiation and function of Foxp3+ effector regulatory T cells. Trends Immunol. 34, 74–80 (2013).

  41. 41.

    et al. The role of low-level lactate production in airway inflammation in asthma. Am. J. Physiol. Lung Cell. Mol. Physiol. 302, L300–L307 (2012).

  42. 42.

    & Molecular mechanisms of regulation of Toll-like receptor signaling. J. Leukoc. Biol. (published online 24 June 2016).

  43. 43.

    et al. IkappaB kinase epsilon and TANK-binding kinase 1 activate AKT by direct phosphorylation. Proc. Natl. Acad. Sci. USA 108, 6474–6479 (2011).

  44. 44.

    & Regulatory T cells in systemic lupus erythematosus. Eur. J. Immunol. 45, 344–355 (2015).

  45. 45.

    & The impact of biological therapy on regulatory T cells in rheumatoid arthritis. Rheumatology (Oxford) 54, 768–775 (2015).

  46. 46.

    , , & Activated Akt promotes increased resting T cell size, CD28-independent T cell growth, and development of autoimmunity and lymphoma. Eur. J. Immunol. 33, 2223–2232 (2003).

  47. 47.

    , , , & Inducible reprogramming of human T cells into Treg cells by a conditionally active form of FOXP3. Eur. J. Immunol. 38, 3282–3289 (2008).

  48. 48.

    , & Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc. 4, 44–57 (2009).

  49. 49.

    et al. PANTHER: a library of protein families and subfamilies indexed by function. Genome Res. 13, 2129–2141 (2003).

  50. 50.

    , , , & Transcriptional regulation by Foxp3 is associated with direct promoter occupancy and modulation of histone acetylation. J. Biol. Chem. 281, 36828–36834 (2006).

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Acknowledgements

We thank members of the Rathmell and Wells laboratories for discussions, and the Immunological Genome Project. Supported by the Crohn's and Colitis Foundation of America (Senior Research Grant to J.C.R.), the Alliance for Lupus Research (J.C.R.), the US National Institutes of Health (R01HL 108006 and R01105550DK to J.C.R.; P01HL018646 to L.A.T. and J.C.R.; F31CA183529 to R.J.K.; R00CA168997 to J.W.L.; and R01AI070807 and P01AI073489 to A.D.W.), and the German Research Foundation (Deutsche Forschungsgemeinschaft; P.J.S.).

Author information

Author notes

    • Valerie A Gerriets
    •  & Rigel J Kishton

    These authors contributed equally to this work.

Affiliations

  1. Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, USA.

    • Valerie A Gerriets
    • , Rigel J Kishton
    • , Marc O Johnson
    • , Sivan Cohen
    • , Amanda G Nichols
    •  & Jason W Locasale
  2. Department of Pathology, Microbiology, and Immunology, Vanderbilt Center for Immunobiology, Vanderbilt University, Nashville, Tennessee, USA.

    • Marc O Johnson
    • , Peter J Siska
    •  & Jeffrey C Rathmell
  3. Center for Environmental and Systems Biochemistry, Department of Toxicology and Cancer Biology and Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA.

    • Marc O Warmoes
  4. Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

    • Aguirre A de Cubas
  5. Division of Pediatric Endocrinology and Diabetes, Duke University, Durham, North Carolina, USA.

    • Nancie J MacIver
  6. Massachusetts General Hospital, Center for Transplantation Sciences, Boston, Massachusetts, USA.

    • Laurence A Turka
  7. Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Andrew D Wells

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Contributions

V.A.G., R.J.K., A.D.W. and J.C.R. designed the study, interpreted data and wrote the manuscript. V.A.G. and R.J.K. performed most of the experiments. M.O.J., S.C. and P.J.S. performed experiments to analyze Foxp3 regulation of metabolism. A.G.N. assisted V.A.G. and R.J.K. and maintained animals that were essential for the study. M.O.W. performed mass spectrometry. A.A.d.C. analyzed RNAseq data. J.W.L. assisted in metabolomics analysis. N.J.M. and L.A.T. assisted with data analysis and interpretation. A.D.W. performed microarray analysis.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jeffrey C Rathmell.

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DOI

https://doi.org/10.1038/ni.3577

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