Abstract
Sphingosine 1-phosphate (S1P) in blood, lymph, and immune tissues stimulates and regulates T cell migration through their S1P(1) (endothelial differentiation gene encoded receptor-1) G protein-coupled receptors. We show now that S1P(1)Rs also mediate suppression of T cell proliferation and cytokine production. Uptake of [(3)H]thymidine by mouse CD4 T cells stimulated with anti-CD3 mAbs plus either anti-CD28 or IL-7 was inhibited up to 50% by 10(-9)-10(-6) M S1P. Suppression by S1P required Ca(2+) signaling and was reduced by intracellular cAMP. S1P decreased CD4 T cell generation of IFN-gamma and IL-4, without affecting IL-2. A Th1 line from D011.10 TCR transgenic mice without detectable S1P(1) was refractory to S1P until introduction of S1P(1) by retroviral transduction. S1P then evoked chemotaxis, inhibited chemotaxis to CCL-5 and CCL-21, and suppressed Ag-stimulated proliferation and IFN-gamma production. Thus, S1P(1) signals multiple immune functions of T cells as well as migration and tissue distribution.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adjuvants, Immunologic / genetics
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Adjuvants, Immunologic / pharmacology
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Adjuvants, Immunologic / physiology
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Animals
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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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Cell Division / genetics
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Cell Division / immunology
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Cell Line
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Cell Line, Tumor
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Cell Movement / genetics
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Cell Movement / immunology
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Female
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Growth Inhibitors / pharmacology
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Humans
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Interferon-gamma / antagonists & inhibitors
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Interferon-gamma / metabolism
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Interleukin-2 / biosynthesis
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Interleukin-4 / antagonists & inhibitors
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Interleukin-4 / metabolism
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Lymphocyte Activation / genetics
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Lysophospholipids*
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Transgenic
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Rats
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Receptors, Antigen, T-Cell / physiology
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Receptors, G-Protein-Coupled / genetics
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Receptors, G-Protein-Coupled / physiology*
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Receptors, Lysophospholipid
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Signal Transduction / genetics*
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Signal Transduction / immunology*
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Sphingosine / analogs & derivatives*
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Sphingosine / genetics
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Sphingosine / metabolism
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Sphingosine / pharmacology
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Sphingosine / physiology*
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T-Lymphocyte Subsets / cytology
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T-Lymphocyte Subsets / immunology*
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T-Lymphocyte Subsets / metabolism*
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Transduction, Genetic / methods
Substances
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Adjuvants, Immunologic
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Growth Inhibitors
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Interleukin-2
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Lysophospholipids
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Receptors, Antigen, T-Cell
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Receptors, G-Protein-Coupled
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Receptors, Lysophospholipid
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Interleukin-4
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sphingosine 1-phosphate
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Interferon-gamma
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Sphingosine