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.

  • Article
  • Published:

The S1P1-mTOR axis directs the reciprocal differentiation of TH1 and Treg cells

Nature Immunology volume 11, pages 1047–1056 (2010)Cite this article

Subjects

Abstract

Naive CD4+ T cells differentiate into diverse effector and regulatory lineages to orchestrate immunity and tolerance. Here we found that the differentiation of proinflammatory T helper type 1 (TH1) cells and anti-inflammatory Foxp3+ regulatory T cells (Treg cells) was reciprocally regulated by S1P1, a receptor for the bioactive lipid sphingosine 1-phosphate (S1P). S1P1 inhibited the generation of extrathymic and natural Treg cells while driving TH1 development in a reciprocal manner and disrupted immune homeostasis. S1P1 signaled through the kinase mTOR and antagonized the function of transforming growth factor-β mainly by attenuating sustained activity of the signal transducer Smad3. S1P1 function was dependent on endogenous sphingosine kinase activity. Notably, two seemingly unrelated immunosuppressants, FTY720 and rapamycin, targeted the same S1P1 and mTOR pathway to regulate the dichotomy between TH1 cells and Treg cells. Our studies establish an S1P1-mTOR axis that controls T cell lineage specification.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: S1P1 inhibits de novo generation of Foxp3+ iTreg cells.
Figure 2: S1P1 is needed to restrain the generation and maintenance of Foxp3+ iTreg cells.
Figure 3: S1P1 drives the differentiation of TH1 cells.
Figure 4: S1P1 regulates reciprocal TH1 and iTreg differentiation and immune homeostasis in vivo.
Figure 5: S1P1 mediates iTreg and TH1 differentiation via discrete mechanisms.
Figure 6: S1P1 attenuates TGF-β-Smad3 signaling.
Figure 7: S1P1-mTOR axis targeted by FTY720 and rapamycin.
Figure 8: Sphingosine kinase activity regulates T cell differentiation.

Similar content being viewed by others

References

  1. Zhou, L., Chong, M.M. & Littman, D.R. Plasticity of CD4+ T cell lineage differentiation. Immunity 30, 646–655 (2009).

    Article  CAS  PubMed  Google Scholar 

  2. Curotto de Lafaille, M.A. & Lafaille, J.J. Natural and adaptive Foxp3+ regulatory T cells: more of the same or a division of labor? Immunity 30, 626–635 (2009).

    Article  CAS  PubMed  Google Scholar 

  3. Josefowicz, S.Z. & Rudensky, A. Control of regulatory T cell lineage commitment and maintenance. Immunity 30, 616–625 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).

    Article  CAS  PubMed  Google Scholar 

  5. Mucida, D. et al. Reciprocal Th-17 and regulatory T cell differentiation mediated by retinoic acid. Science 317, 256–260 (2007).

    Article  CAS  PubMed  Google Scholar 

  6. Sun, C.M. et al. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J. Exp. Med. 204, 1775–1785 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Coombes, J.L. et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β and retinoic acid-dependent mechanism. J. Exp. Med. 204, 1757–1764 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Veldhoen, M. et al. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453, 106–109 (2008).

    Article  CAS  PubMed  Google Scholar 

  9. Quintana, F.J. et al. Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor. Nature 453, 65–71 (2008).

    Article  CAS  PubMed  Google Scholar 

  10. Rivera, J., Proia, R.L. & Olivera, A. The alliance of sphingosine-1-phosphate and its receptors in immunity. Nat. Rev. Immunol. 8, 753–763 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kappos, L. et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N. Engl. J. Med. 362, 387–401 (2010).

    Article  CAS  PubMed  Google Scholar 

  12. Matloubian, M. et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 427, 355–360 (2004).

    Article  CAS  PubMed  Google Scholar 

  13. Chi, H. & Flavell, R.A. Cutting edge: regulation of T cell trafficking and primary immune responses by sphingosine 1-phosphate receptor 1. J. Immunol. 174, 2485–2488 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Chen, W. et al. Conversion of peripheral CD4+CD25− naive T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3. J. Exp. Med. 198, 1875–1886 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Selvaraj, R.K. & Geiger, T.L. A kinetic and dynamic analysis of Foxp3 induced in T cells by TGF-β. J. Immunol. 178, 7667–7677 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Li, M.O. & Flavell, R.A. TGF-β: a master of all T cell trades. Cell 134, 392–404 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Izcue, A., Coombes, J.L. & Powrie, F. Regulatory lymphocytes and intestinal inflammation. Annu. Rev. Immunol. 27, 313–338 (2009).

    Article  CAS  PubMed  Google Scholar 

  19. Haribhai, D. et al. A central role for induced regulatory T cells in tolerance induction in experimental colitis. J. Immunol. 182, 3461–3468 (2009).

    Article  CAS  PubMed  Google Scholar 

  20. Wei, J. et al. Antagonistic nature of T helper 1/2 developmental programs in opposing peripheral induction of Foxp3+ regulatory T cells. Proc. Natl. Acad. Sci. USA 104, 18169–18174 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wang, Z. et al. Role of IFN-γ in induction of Foxp3 and conversion of CD4+CD25−s T cells to CD4+ Tregs. J. Clin. Invest. 116, 2434–2441 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Gorelik, L. & Flavell, R.A. Abrogation of TGFβ signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity 12, 171–181 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Fahlen, L. et al. T cells that cannot respond to TGF-β escape control by CD4+CD25+ regulatory T cells. J. Exp. Med. 201, 737–746 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Li, M.O., Sanjabi, S. & Flavell, R.A. Transforming growth factor-β controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms. Immunity 25, 455–471 (2006).

    Article  CAS  PubMed  Google Scholar 

  26. Marie, J.C., Liggitt, D. & Rudensky, A.Y. Cellular mechanisms of fatal early-onset autoimmunity in mice with the T cell-specific targeting of transforming growth factor-β receptor. Immunity 25, 441–454 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. Tone, Y. et al. Smad3 and NFAT cooperate to induce Foxp3 expression through its enhancer. Nat. Immunol. 9, 194–202 (2008).

    Article  CAS  PubMed  Google Scholar 

  28. 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  PubMed  PubMed Central  Google Scholar 

  29. 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  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Thomson, A.W., Turnquist, H.R. & Raimondi, G. Immunoregulatory functions of mTOR inhibition. Nat. Rev. Immunol. 9, 324–337 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Sehrawat, S. & Rouse, B.T. Anti-inflammatory effects of FTY720 against viral-induced immunopathology: role of drug-induced conversion of T cells to become Foxp3+ regulators. J. Immunol. 180, 7636–7647 (2008).

    Article  CAS  PubMed  Google Scholar 

  33. Ouyang, W., Beckett, O., Ma, Q. & Li, M.O. Transforming growth factor-β signaling curbs thymic negative selection promoting regulatory T cell development. Immunity 32, 642–653 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Takabe, K., Paugh, S.W., Milstien, S. & Spiegel, S. 'Inside-out' signaling of sphingosine-1-phosphate: therapeutic targets. Pharmacol. Rev. 60, 181–195 (2008).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zhang, F., Meng, G. & Strober, W. Interactions among the transcription factors Runx1, RORγt and Foxp3 regulate the differentiation of interleukin 17-producing T cells. Nat. Immunol. 9, 1297–1306 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kitano, M. et al. Sphingosine 1-phosphate/sphingosine 1-phosphate receptor 1 signaling in rheumatoid synovium: regulation of synovial proliferation and inflammatory gene expression. Arthritis Rheum. 54, 742–753 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Zachariah, M.A. & Cyster, J.G. Neural crest-derived pericytes promote egress of mature thymocytes at the corticomedullary junction. Science 328, 1129–1135 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Liu, Y. et al. A critical function for TGF-β signaling in the development of natural CD4+CD25+Foxp3+ regulatory T cells. Nat. Immunol. 9, 632–640 (2008).

    Article  CAS  PubMed  Google Scholar 

  40. Martinez, G.J. et al. Smad3 differentially regulates the induction of regulatory and inflammatory T cell differentiation. J. Biol. Chem. 284, 35283–35286 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wang, W., Huang, M.C. & Goetzl, E.J. Type 1 sphingosine 1-phosphate G protein-coupled receptor (S1P1) mediation of enhanced IL-4 generation by CD4 T cells from S1P1 transgenic mice. J. Immunol. 178, 4885–4890 (2007).

    Article  CAS  PubMed  Google Scholar 

  42. Huang, M.C., Watson, S.R., Liao, J.J. & Goetzl, E.J. Th17 augmentation in OTII TCR plus T cell-selective type 1 sphingosine 1-phosphate receptor double transgenic mice. J. Immunol. 178, 6806–6813 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. 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  PubMed  PubMed Central  Google Scholar 

  44. Merkenschlager, M. & von Boehmer, H. PI3 kinase signalling blocks Foxp3 expression by sequestering Foxo factors. J. Exp. Med. 207, 1347–1350 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Song, K., Wang, H., Krebs, T.L. & Danielpour, D. Novel roles of Akt and mTOR in suppressing TGF-β/ALK5-mediated Smad3 activation. EMBO J. 25, 58–69 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Seoane, J., Le, H.V., Shen, L., Anderson, S.A. & Massague, J. Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation. Cell 117, 211–223 (2004).

    Article  CAS  PubMed  Google Scholar 

  47. Pappu, R. et al. Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate. Science 316, 295–298 (2007).

    Article  CAS  PubMed  Google Scholar 

  48. Liu, X. et al. Transforming growth factor β-induced phosphorylation of Smad3 is required for growth inhibition and transcriptional induction in epithelial cells. Proc. Natl. Acad. Sci. USA 94, 10669–10674 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Yang, K. et al. Hsp90 regulates activation of interferon regulatory factor 3 and TBK-1 stabilization in Sendai virus-infected cells. Mol. Biol. Cell 17, 1461–1471 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank R. Proia (US National Institutes of Health) for S1pr1flox/flox mice; A. Rudensky (Memorial Sloan-Kettering Institute) for Foxp3gfp knock-in mice; T. Ludwig (Columbia University) for Rosa26-Cre-ERT2 mice; D. Littman (New York University) for Foxp3-expressing retroviral constructs; D. Green (St. Jude Children's Research Hospital) for Bcl-2-transgenic mice and discussions; and R. Cross, G. Lennon and S. Morgan for cell sorting. Supported by US National Institutes of Health (K01 AR053573 and administrative supplement, R01 NS064599, and Cancer Center Support Grant CA021765), the Arthritis Foundation, the Lupus Research Institute and the American Lebanese Syrian Associated Charities (H.C.).

Author information

Author notes

  1. Guangwei Liu and Kai Yang: These authors contributed equally to this work.

Authors and Affiliations

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

    Guangwei Liu, Kai Yang, Samir Burns, Sharad Shrestha & Hongbo Chi

Authors
  1. Guangwei Liu
    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. Samir Burns
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sharad Shrestha
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hongbo Chi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

G.L. designed and did in vivo and cellular experiments and contributed to the writing of the manuscript; K.Y. designed and did biochemical analyses and cellular and molecular experiments; S.B. did in vivo and cellular experiments and gene-expression analysis; S.S. contributed to cell isolation and gene expression analysis and managed the mouse colony; and H.C. designed experiments, wrote 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 Text and Figures

Supplementary Figures 1–13 (PDF 992 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu, G., Yang, K., Burns, S. et al. The S1P1-mTOR axis directs the reciprocal differentiation of TH1 and Treg cells. Nat Immunol 11, 1047–1056 (2010). https://doi.org/10.1038/ni.1939

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.1939

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