Article abstract

Nature Immunology 10, 769 - 777 (2009)
Published online: 31 May 2009 | doi:10.1038/ni.1743

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

Guangwei Liu1, Samir Burns1, Gonghua Huang1, Kelli Boyd2, Richard L Proia3, Richard A Flavell4,5 & Hongbo Chi1,5

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.

  1. Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
  2. Animal Resources Center, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
  3. Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
  4. Howard Hughes Medical Institute, New Haven, Connecticut, USA.
  5. Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.

Correspondence to: Hongbo Chi1,5 e-mail:


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