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.

  • Letter
  • Published:

mTORC1 couples immune signals and metabolic programming to establish Treg-cell function

Nature volume 499, pages 485–490 (2013)Cite this article

Subjects

Abstract

The mechanistic target of rapamycin (mTOR) pathway integrates diverse environmental inputs, including immune signals and metabolic cues, to direct T-cell fate decisions1. The activation of mTOR, which is the catalytic subunit of the mTORC1 and mTORC2 complexes, delivers an obligatory signal for the proper activation and differentiation of effector CD4+ T cells2,3, whereas in the regulatory T-cell (Treg) compartment, the Akt–mTOR axis is widely acknowledged as a crucial negative regulator of Treg-cell de novo differentiation4,5,6,7,8 and population expansion9. However, whether mTOR signalling affects the homeostasis and function of Treg cells remains largely unexplored. Here we show that mTORC1 signalling is a pivotal positive determinant of Treg-cell function in mice. Treg cells have elevated steady-state mTORC1 activity compared to naive T cells. Signals through the T-cell antigen receptor (TCR) and interleukin-2 (IL-2) provide major inputs for mTORC1 activation, which in turn programs the suppressive function of Treg cells. Disruption of mTORC1 through Treg-specific deletion of the essential component raptor leads to a profound loss of Treg-cell suppressive activity in vivo and the development of a fatal early onset inflammatory disorder. Mechanistically, raptor/mTORC1 signalling in Treg cells promotes cholesterol and lipid metabolism, with the mevalonate pathway particularly important for coordinating Treg-cell proliferation and upregulation of the suppressive molecules CTLA4 and ICOS to establish Treg-cell functional competency. By contrast, mTORC1 does not directly affect the expression of Foxp3 or anti- and pro-inflammatory cytokines in Treg cells, suggesting a non-conventional mechanism for Treg-cell functional regulation. Finally, we provide evidence that mTORC1 maintains Treg-cell function partly through inhibiting the mTORC2 pathway. Our results demonstrate that mTORC1 acts as a fundamental ‘rheostat’ in Treg cells to link immunological signals from TCR and IL-2 to lipogenic pathways and functional fitness, and highlight a central role of metabolic programming of Treg-cell suppressive activity in immune homeostasis and tolerance.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: mTORC1 signalling is constitutively active in Treg cells and its disruption results in a fatal early onset inflammatory disorder.
Figure 2: Raptor deletion abrogates Treg-cell suppressive activity.
Figure 3: Raptor coordinates Treg-cell proliferation and effector molecule expression by orchestrating cholesterol/lipid biosynthetic metabolism, especially the mevalonate pathway.
Figure 4: Deletion of Rictor does not alter Treg-cell function but partially rescues inflammation in Foxp3creRptorfl/fl mice.

Similar content being viewed by others

Accession codes

Accessions

Gene Expression Omnibus

Data deposits

The microarray data have been deposited in the Gene Expression Omnibus under accession GSE46693.

References

  1. Chi, H. Regulation and function of mTOR signalling in T cell fate decisions. Nature Rev. Immunol. 12, 325–338 (2012)

    Article  CAS  Google Scholar 

  2. Delgoffe, G. M. et al. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nature Immunol. 12, 295–303 (2011)

    Article  CAS  Google Scholar 

  3. Lee, K. et al. Mammalian target of rapamycin protein complex 2 regulates differentiation of Th1 and Th2 cell subsets via distinct signaling pathways. Immunity 32, 743–753 (2010)

    Article  CAS  Google Scholar 

  4. 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 

  5. Haxhinasto, S., Mathis, D. & Benoist, C. The AKT–mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells. J. Exp. Med. 205, 565–574 (2008)

    Article  CAS  Google Scholar 

  6. Sauer, S. et al. T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc. Natl Acad. Sci. USA 105, 7797–7802 (2008)

    Article  ADS  CAS  Google Scholar 

  7. Liu, G. et al. The receptor S1P1 overrides regulatory T cell-mediated immune suppression through Akt-mTOR. Nature Immunol. 10, 769–777 (2009)

    Article  CAS  Google Scholar 

  8. Liu, G., Yang, K., Burns, S., Shrestha, S. & Chi, H. The S1P1-mTOR axis directs the reciprocal differentiation of TH1 and Treg cells. Nature Immunol. 11, 1047–1056 (2010)

    Article  CAS  Google Scholar 

  9. Battaglia, M., Stabilini, A. & Roncarolo, M. G. Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood 105, 4743–4748 (2005)

    Article  CAS  Google Scholar 

  10. Laplante, M. & Sabatini, D. M. mTOR signaling in growth control and disease. Cell 149, 274–293 (2012)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  12. Kelly, A. P. et al. Notch-induced T cell development requires phosphoinositide-dependent kinase 1. EMBO J. 26, 3441–3450 (2007)

    Article  CAS  Google Scholar 

  13. Cunningham, J. T. et al. mTOR controls mitochondrial oxidative function through a YY1–PGC-1α transcriptional complex. Nature 450, 736–740 (2007)

    Article  ADS  CAS  Google Scholar 

  14. van der Windt, G. J. et al. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity 36, 68–78 (2012)

    Article  CAS  Google Scholar 

  15. Gurumurthy, S. et al. The Lkb1 metabolic sensor maintains haematopoietic stem cell survival. Nature 468, 659–663 (2010)

    Article  ADS  CAS  Google Scholar 

  16. Takahashi, T. et al. Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state. Int. Immunol. 10, 1969–1980 (1998)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  18. Gavin, M. A., Clarke, S. R., Negrou, E., Gallegos, A. & Rudensky, A. Homeostasis and anergy of CD4+CD25+ suppressor T cells in vivo. Nature Immunol. 3, 33–41 (2002)

    Article  CAS  Google Scholar 

  19. Thornton, A. M., Donovan, E. E., Piccirillo, C. A. & Shevach, E. M. Cutting edge: IL-2 is critically required for the in vitro activation of CD4+CD25+ T cell suppressor function. J. Immunol. 172, 6519–6523 (2004)

    Article  CAS  Google Scholar 

  20. Herman, A. E., Freeman, G. J., Mathis, D. & Benoist, C. CD4+CD25+ T regulatory cells dependent on ICOS promote regulation of effector cells in the prediabetic lesion. J. Exp. Med. 199, 1479–1489 (2004)

    Article  CAS  Google Scholar 

  21. Wing, K. et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science 322, 271–275 (2008)

    Article  ADS  CAS  Google Scholar 

  22. Rubtsov, Y. P. et al. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 28, 546–558 (2008)

    Article  CAS  Google Scholar 

  23. Kanangat, S. et al. Disease in the scurfy (sf) mouse is associated with overexpression of cytokine genes. Eur. J. Immunol. 26, 161–165 (1996)

    Article  CAS  Google Scholar 

  24. Chaudhry, A. et al. Interleukin-10 signaling in regulatory T cells is required for suppression of Th17 cell-mediated inflammation. Immunity 34, 566–578 (2011)

    Article  CAS  Google Scholar 

  25. Josefowicz, S. Z., Lu, L. F. & Rudensky, A. Y. Regulatory T cells: mechanisms of differentiation and function. Annu. Rev. Immunol. 30, 531–564 (2012)

    Article  CAS  Google Scholar 

  26. Ouyang, W. et al. Novel Foxo1-dependent transcriptional programs control Treg cell function. Nature 491, 554–559 (2012)

    Article  ADS  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  28. Tai, X. et al. Basis of CTLA-4 function in regulatory and conventional CD4+ T cells. Blood 119, 5155–5163 (2012)

    Article  CAS  Google Scholar 

  29. Corse, E. & Allison, J. P. Cutting edge: CTLA-4 on effector T cells inhibits in trans. J. Immunol. 189, 1123–1127 (2012)

    Article  CAS  Google Scholar 

  30. Sadlack, B. et al. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 75, 253–261 (1993)

    Article  CAS  Google Scholar 

  31. Yang, K., Neale, G., Green, D. R., He, W. & Chi, H. The tumor suppressor Tsc1 enforces quiescence of naive T cells to promote immune homeostasis and function. Nature Immunol. 12, 888–897 (2011)

    Article  CAS  Google Scholar 

  32. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005)

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

We thank A. Rudensky for Foxp3YFP-Cre mice, D. Green for help with metabolic assays, N. Brydon for animal colony management, Y. Wang for editing of the manuscript, and the St Jude Immunology FACS core facility for cell sorting. This work was supported by the US National Institutes of Health (K01 AR053573, R21 AI094089, R01 AI101407 and R01 NS064599), the Lupus Research Institute, and the American Lebanese Syrian Associated Charities (all to H.C.).

Author information

Authors and Affiliations

  1. Department of Immunology, St Jude Children’s Research Hospital, Memphis, 38105, Tennessee, USA

    Hu Zeng, Kai Yang, Caryn Cloer & Hongbo Chi

  2. Hartwell Center for Bioinformatics and Biotechnology, St Jude Children’s Research Hospital, Memphis, 38105, Tennessee, USA

    Geoffrey Neale

  3. Department of Pathology, St Jude Children’s Research Hospital, Memphis, 38105, Tennessee, USA

    Peter Vogel

Authors
  1. Hu Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kai Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Caryn Cloer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Geoffrey Neale
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Peter Vogel
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hongbo Chi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

H.Z. designed and performed experiments, and wrote the manuscript; K.Y. contributed to cellular experiments; C.C. contributed to survival curves and technical support; G.N. performed bioinformatic analyses; P.V. performed histological analysis; H.C. designed experiments, contributed to writing the manuscript, and provided overall direction.

Corresponding author

Correspondence to Hongbo Chi.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-17. (PDF 1314 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zeng, H., Yang, K., Cloer, C. et al. mTORC1 couples immune signals and metabolic programming to establish Treg-cell function. Nature 499, 485–490 (2013). https://doi.org/10.1038/nature12297

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature12297

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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