Sphingosine 1-phosphate (S1P) from platelets and macrophages stimulates migration and enhances survival of T cells. Mouse spleen CD4 and CD8 T cells are shown to express predominantly S1P1 (Edg-1) and S1P4 (Edg-6) G-protein-coupled receptors with only minimal representation of S1P2, S1P3, and S1P5. At and below plasma concentrations of healthy mammals (1 nM-1 microM), S1P evokes trans-Matrigel chemotaxis of mouse CD4 and CD8 T cells and recruits T cells into subcutaneous air pouches. T cell receptor-mediated activation of CD4 T cells suppresses expression of S1P1 and S1P4 receptors and eliminates their chemotactic responses to S1P. The immunoregulator FTY720, a structural homologue of S1P, lacks T cell chemotactic activity and competitively inhibits T cell chemotactic responses to S1P in vitro and in vivo. S1P may be a distinctive contributor to compartmental immunity by attracting naïve and memory T cells preferentially over activated effector T cells.

Murine CD4 and CD8 T cells express predominantly types 1 and 4 sphingosine 1-phosphate (S1P) G protein-coupled receptors (designated S1P1 and S1P4 or previously endothelial differentiation gene-encoded 1 and 6) for S1P, which has a normal plasma concentration of 0.1–1 μM. S1P now is shown to enhance chemotaxis of CD4 T cells to CCL-21 and CCL-5 by up to 2.5-fold at 10 nM to 0.1 μM, whereas 0.3–3 μM S1P inhibits this chemotaxis by up to 70%. Chemotaxis of S1P1, but not S1P4, transfectants to CXCL1 and CXCL4 was similarly affected by S1P. Activation of CD4 T cells, which decreases S1P receptor expression, suppressed effects of S1P on chemotaxis. Pretreatment of labeled CD4 T cells with S1P before reintroduction into mice inhibited by a maximum of 75% their migration into chemokine-challenged s.c. air pouches. The S1P-S1P1 receptor axis thus controls recruitment of naive T cells by maintaining their response threshold to diverse lymphotactic factors.

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.

Sphingosine 1-phosphate (S1P) has diverse effects on T cells that are mediated by the predominant S1P1 and S1P4 G protein-coupled receptors (GPCRs). S1P4 is expressed principally by leukocytes, but little is known of its T cell effects in immunity. Two approaches were used to investigate S1P4 signals in T cells. First, S1P4 was introduced into D10G4.1 mouse Th2 cells and EL4.IL-2 mouse T cells lacking endogenous S1P GPCRs. Second, mouse splenic CD4 T cells were treated with FTY720 to suppress S1P1 and leave S1P4 GPCRs as the only functionally relevant S1P receptor. Unlike S1P1, S1P4 failed to transduce chemotactic responses of any of the S1P4-only T cells to S1P or the phyto-S1P ligand selective for S1P4, or to suppress their chemotactic responses to chemokines. The S1P-S1P4 axis significantly inhibited T cell proliferation in each of the S1P4-only T cells activated by anti-CD3 and anti-CD28 MoAbs. Secretion of IL-4 by S1P4-D10G4.1 cells, IL-2 by S1P4-EL4.IL-2, and IFN-gamma by FTY720-treated CD4 T cells were significantly inhibited by S1P. In contrast, S1P enhanced secretion of IL-10 by stimulated S1P4-D10G4.1 T cells. Thus, S1P4 mediates immunosuppressive effects of S1P by inhibiting proliferation and secretion of effector cytokines, while enhancing secretion of the suppressive cytokine IL-10.

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