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

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REGULATORY T CELLS Article 13 April 2021 RETINOIC ACID SIGNALING ACTS AS A RHEOSTAT TO BALANCE TREG FUNCTION Article 17 May 2022 LYMPHOTOXIN LIMITS FOXP3+ REGULATORY T CELL DEVELOPMENT FROM

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(2007). Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS We thank A. Rudensky (University of Washington) for _Foxp3_gfp '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.). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Immunology, St. Jude Children's Research Hospital, Memphis,

Tennessee, USA Guangwei Liu, Samir Burns, Gonghua Huang & Hongbo Chi * Animal Resources Center, St. Jude Children's Research Hospital, Memphis, Tennessee, USA Kelli Boyd * 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 * Howard Hughes

Medical Institute, New Haven, Connecticut, USA Richard A Flavell * Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA Richard A Flavell & Hongbo

Chi Authors * Guangwei Liu View author publications You can also search for this author inPubMed Google Scholar * Samir Burns View author publications You can also search for this author

inPubMed Google Scholar * Gonghua Huang View author publications You can also search for this author inPubMed Google Scholar * Kelli Boyd View author publications You can also search for

this author inPubMed Google Scholar * Richard L Proia View author publications You can also search for this author inPubMed Google Scholar * Richard A Flavell View author publications You

can also search for this author inPubMed Google Scholar * Hongbo Chi View author publications You can also search for this author inPubMed Google Scholar 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. CORRESPONDING AUTHOR Correspondence to Hongbo Chi. SUPPLEMENTARY INFORMATION SUPPLEMENTARY TEXT AND FIGURES Supplementary

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T cell–mediated immune suppression through Akt-mTOR. _Nat Immunol_ 10, 769–777 (2009). https://doi.org/10.1038/ni.1743 Download citation * Received: 23 December 2008 * Accepted: 21 April

2009 * Published: 31 May 2009 * Issue Date: July 2009 * DOI: https://doi.org/10.1038/ni.1743 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content:

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