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The receptor S1P1 overrides regulatory T cell–mediated immune suppression through Akt-mTOR

Nature Immunology volume 10, pages 769–777 (2009)Cite this article

Abstract

Regulatory T cells (Treg cells) are critically involved in maintaining immunological tolerance, but this potent suppression must be 'quenched' to allow the generation of adaptive immune responses. Here we report that sphingosine 1-phosphate (S1P) receptor type 1 (S1P1) delivers an intrinsic negative signal to restrain the thymic generation, peripheral maintenance and suppressive activity of Treg cells. Combining loss- and gain-of-function genetic approaches, we found that S1P1 blocked the differentiation of thymic Treg precursors and function of mature Treg cells and affected Treg cell–mediated immune tolerance. S1P1 induced selective activation of the Akt-mTOR kinase pathway to impede the development and function of Treg cells. Dynamic regulation of S1P1 contributed to lymphocyte priming and immune homeostasis. Thus, by antagonizing Treg cell–mediated immune suppression, the lipid-activated S1P1-Akt-mTOR pathway orchestrates adaptive immune responses.

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Figure 1: S1P1 negatively regulates the thymic Foxp3+ Treg population.
Figure 2: S1P1 blocks the thymic differentiation of Treg cells.
Figure 3: Enhanced peripheral population and suppressive activity of S1P1-knockout Treg cells.
Figure 4: Diminished suppressive activity of S1P1-Tg Treg cells in vitro and in vivo.
Figure 5: S1P1-Tg mice show disrupted immune homeostasis and develop age-related autoimmunity due to defects in the Treg cell compartment.
Figure 6: S1P1 induces activation of Akt-mTOR to inhibit the development and function of Treg cells.
Figure 7: S1P1 is necessary for Akt activation in Treg cells.
Figure 8: Different regulation of S1P1 expression in Treg cells and Tconv cells.

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Acknowledgements

We thank A. Rudensky (University of Washington) for Foxp3gfp 'knock-in' mice; D. Hildeman (University of Cincinnati) for dominant negative and constitutively active Akt retroviral constructs; S. Shrestha for help with genotyping; M. McGargill for help with the FTOC procedure; R. Cross and G. Lennon for cell sorting; and D. Green and D. Vignali for scientific discussions and reagents. Supported by the US National Institutes of Health (H.C.), the Arthritis Foundation (H.C.), the Arthritis National Research Foundation (H.C.), the American Lebanese Syrian Associated Charities (H.C.) and the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (R.L.P.).

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Authors and Affiliations

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

    Guangwei Liu, Samir Burns, Gonghua Huang & Hongbo Chi

  2. Animal Resources Center, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

    Kelli Boyd

  3. Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA

    Richard L Proia

  4. Howard Hughes Medical Institute, New Haven, Connecticut, USA

    Richard A Flavell

  5. Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA

    Richard A Flavell & Hongbo Chi

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  1. Guangwei Liu
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Contributions

G.L. designed and did the experiments with cells and mice, analyzed data and contributed to writing the manuscript; S.B. did retroviral transduction of bone marrow cells and reconstitution and managed the mouse colony; G.H. and S.B. contributed to real-time PCR analysis; K.B. analyzed and assigned scores to histology data; R.L.P. and R.A.F. provided animal models; and H.C. designed experiments, analyzed data, wrote the manuscript and provided overall direction.

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Correspondence to Hongbo Chi.

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Liu, G., Burns, S., Huang, G. et al. The receptor S1P1 overrides regulatory T cell–mediated immune suppression through Akt-mTOR. Nat Immunol 10, 769–777 (2009). https://doi.org/10.1038/ni.1743

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