Reader TTS

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.

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.).

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

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

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

Howard Hughes Medical Institute, New Haven, Connecticut, USA

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

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.

Anyone you share the following link with will be able to read this content: