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
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adoptive Transfer
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Animals
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Animals, Newborn
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CD4-Positive T-Lymphocytes / cytology
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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Carrier Proteins / metabolism*
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Cell Differentiation / immunology
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Colon / immunology
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Colon / metabolism
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Colon / pathology
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Female
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Flow Cytometry
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / metabolism
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Homeostasis / immunology
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Immune Tolerance / immunology
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Interleukin-2 Receptor alpha Subunit / immunology
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Leukocyte Common Antigens / immunology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Phosphotransferases (Alcohol Group Acceptor) / metabolism*
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Proto-Oncogene Proteins c-akt / metabolism*
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Receptors, Lysosphingolipid / genetics
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Receptors, Lysosphingolipid / metabolism*
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Signal Transduction / immunology
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T-Lymphocytes, Regulatory / immunology*
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T-Lymphocytes, Regulatory / metabolism
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T-Lymphocytes, Regulatory / transplantation
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TOR Serine-Threonine Kinases
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Thymus Gland / cytology
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Thymus Gland / immunology
Substances
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Carrier Proteins
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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Interleukin-2 Receptor alpha Subunit
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Receptors, Lysosphingolipid
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Phosphotransferases (Alcohol Group Acceptor)
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mTOR protein, mouse
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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Leukocyte Common Antigens