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

Liu G, Burns S, Huang G, Boyd K, Proia RL, Flavell RA, Chi H
Nat Immunol. 2009 10 (7): 769-77

PMID: 19483717 · PMCID: PMC2732340 · DOI:10.1038/ni.1743

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.

MeSH Terms (26)

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

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