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

Nat Immunol. 2009 Jul;10(7):769-77. doi: 10.1038/ni.1743. Epub 2009 May 31.

Abstract

Regulatory T cells (T(reg) 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 T(reg) cells. Combining loss- and gain-of-function genetic approaches, we found that S1P1 blocked the differentiation of thymic T(reg) precursors and function of mature T(reg) cells and affected T(reg) cell-mediated immune tolerance. S1P1 induced selective activation of the Akt-mTOR kinase pathway to impede the development and function of T(reg) cells. Dynamic regulation of S1P1 contributed to lymphocyte priming and immune homeostasis. Thus, by antagonizing T(reg) cell-mediated immune suppression, the lipid-activated S1P1-Akt-mTOR pathway orchestrates adaptive immune responses.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Animals, Newborn
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • Carrier Proteins / metabolism*
  • Cell Differentiation / immunology
  • Colon / immunology
  • Colon / metabolism
  • Colon / pathology
  • Female
  • Flow Cytometry
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Homeostasis / immunology
  • Immune Tolerance / immunology
  • Interleukin-2 Receptor alpha Subunit / immunology
  • Leukocyte Common Antigens / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Receptors, Lysosphingolipid / genetics
  • Receptors, Lysosphingolipid / metabolism*
  • Signal Transduction / immunology
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism
  • T-Lymphocytes, Regulatory / transplantation
  • TOR Serine-Threonine Kinases
  • Thymus Gland / cytology
  • Thymus Gland / immunology

Substances

  • Carrier Proteins
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Interleukin-2 Receptor alpha Subunit
  • Receptors, Lysosphingolipid
  • Phosphotransferases (Alcohol Group Acceptor)
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Leukocyte Common Antigens