Transduction of Multiple Effects of Sphingosine 1-Phosphate (S1P) on T Cell Functions by the S1P1 G Protein-Coupled Receptor

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Abstract
Sphingosine 1-phosphate (S1P) in blood, lymph, and immune tissues stimulates and regulates T cell migration through their S1P1 (endothelial differentiation gene encoded receptor-1) G protein-coupled receptors. We show now that S1P1Rs also mediate suppression of T cell proliferation and cytokine production. Uptake of [3H]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 Ca2+ signaling and was reduced by intracellular cAMP. S1P decreased CD4 T cell generation of IFN-γ and IL-4, without affecting IL-2. A Th1 line from D011.10 TCR transgenic mice without detectable S1P1 was refractory to S1P until introduction of S1P1 by retroviral transduction. S1P then evoked chemotaxis, inhibited chemotaxis to CCL-5 and CCL-21, and suppressed Ag-stimulated proliferation and IFN-γ production. Thus, S1P1 signals multiple immune functions of T cells as well as migration and tissue distribution.