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

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

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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.

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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.

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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.).

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

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

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

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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.

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Correspondence to Hongbo Chi.

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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

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