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

Dorsam, Glenn; Graeler, Markus H.; Seroogy, Christine M.; Kong, Yi‐chi M.; Voice, Julia K.; Goetzl, Edward J.

doi:10.4049/jimmunol.171.7.3500

Cited by 96 publications

(123 citation statements)

References 15 publications

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“…Reduced immunostimulatory capacity of FTY720-and FTY720-P-treated DC, and cytokine production: less IL-12 p70 but more IL-10 following stimulation via CD40 ligation S1P acts as a potent suppressor of murine T cell proliferation and interferes with the cytokine production in these cells [24], and FTY720, at micromolar concentrations, is known to exert anti-proliferative effects on human T cells [2]. We asked whether these effects could be partly attributed to S1PR engagement on APC.…”

Section: Resultsmentioning

confidence: 99%

The immunomodulator FTY720 interferes with effector functions of human monocyte‐derived dendritic cells

et al. 2005

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The potent immunomodulator FTY720 elicits immunosuppression via acting on sphingosine 1-phosphate receptors (S1PR), thereby leading to an entrapment of lymphocytes in the secondary lymphoid tissue. To elucidate the potential in vitro effects of this drug on human monocyte-derived DC, we used low nanomolar therapeutic concentrations of FTY720 and phosphorylated FTY720 (FTY720-P) and investigated their influence on DC surface marker expression, protein levels of S1PR and DC effector functions: antigen uptake, chemotaxis, cytokine production, allostimulatory and Thpriming capacity. We report that both FTY720 and FTY720-P reduce chemotaxis of immature and mature DC. Mature DC generated in the presence of FTY720 or FTY720-P showed an impaired immunostimmulatory capacity and reduced IL-12 but increased IL-10 production. T cells cultured in the presence of FTY720-or FTY720-P-treated DC showed an altered cytokine production profile indicating a shift from Th1 toward Th2 differentiation. In treated immature and mature DC, expression levels for two S1PR proteins, S1P 1 and S1P 4, were reduced. We conclude that in vitro treatment with FTY720 affects DC features that are essential for serving their role as antigen-presenting cells. This might represent a new aspect of the overall immunosuppressive action of FTY720 and makes DC potential targets of further sphingolipid-derived drugs.

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Section: Resultsmentioning

confidence: 99%

The immunomodulator FTY720 interferes with effector functions of human monocyte‐derived dendritic cells

et al. 2005

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“…S1P has been shown to regulate lymphocyte homing to lymph nodes from circulation through action on the lymphocyte S1P1 receptor (12). Studies have suggested that S1P also reduces IFN-␥ production by lymphocyte cell lines (26), but studies to clearly define the role of S1P in regulating lymphocyte activation have not been performed to date.…”

Section: Cd4mentioning

confidence: 99%

“…FTY720 and SEW2871, two well-characterized S1P receptor agonists that act on the S1P1 receptor, cause dramatic lymphopenia in mice when used in vivo. Goetzl and colleagues (12,13) have shown that S1P regulates CD4 ϩ T-cell chemotaxis and proliferation through action on S1P1. Thus, S1P analogs have the potential to be important drug therapies for inflammation and immune responses in a wide range of diseases.…”

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confidence: 99%

Sphingosine-1-Phosphate Reduces CD4+ T-Cell Activation in Type 1 Diabetes Through Regulation of Hypoxia-Inducible Factor Short Isoform I.1 and CD69

et al. 2008

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OBJECTIVES-Non-obese diabetic (NOD) mice develop spontaneous type 1 diabetes. We have shown that sphingosine-1-phosphate (S1P) reduces activation of NOD diabetic endothelium via the S1P1 receptor. In the current study, we tested the hypothesis that S1P could inhibit CD4 ϩ T-cell activation, further reducing inflammatory events associated with diabetes. RESEARCH DESIGN AND METHODS-CD4ϩ T-cells were isolated from diabetic and nondiabetic NOD mouse splenocytes and treated in the absence or presence of S1P or the S1P1 receptor-specific agonist, SEW2871. Lymphocyte activation was examined using flow cytometry, cytokine bead assays, and a lymphocyte:endothelial adhesion assay.

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“…S1P 1 and S1P 4 receptors have been detected in T-lymphocytes (15)(16)(17). Stimulation of receptor signaling has been found to mediate and regulate cell migration and suppress proliferation and cytokine production (17,18). Recently, S1P 1 receptors have also been implicated in lymphocyte trafficking and homing as the result of studies using FTY720, a potent immunosuppressive agent.…”

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confidence: 95%

Expression of the Sphingosine 1-Phosphate Receptor, S1P1, on T-cells Controls Thymic Emigration

Allende

Dreier

Mandala

et al. 2004

Journal of Biological Chemistry

409

384

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S1P 1 is a widely distributed G protein-coupled receptor whose ligand, sphingosine 1-phosphate, is present in high concentrations in the blood. The sphingosine 1-phosphate receptor-signaling pathway is believed to have potent effects on cell trafficking in the immune system. To determine the precise role of the S1P 1 receptor on T-cells, we established a T-cell-specific S1P 1 knock-out mouse. The mutant mice showed a block in the egress of mature T-cells into the periphery. The expression of the S1P 1 receptor was up-regulated in mature thymocytes, and its deletion altered the chemotactic responses of thymocytes to sphingosine 1-phosphate. The results indicated that the expression of the S1P 1 receptor on T-cells controls their exit from the thymus and entry into the blood and, thus, has a central role in regulating the numbers of peripheral T-cells.Sphingolipids are important signaling molecules in a variety of biologic contexts (1-3). Sphingosine 1-phosphate, in one paradigm, binds to members of a family of G protein-coupled receptors (S1P 1-15 ) triggering diverse effects including proliferation, survival, migration, morphogenesis, adhesion molecule expression, and cytoskeletal changes (4 -8).S1P 1 /Edg 1 , the first of these receptors described (9, 10), couples to a G i pathway. During embryonic development, the S1P 1 receptor is highly expressed in the vascular system. Gene disruption in mice has demonstrated an essential function of the S1P 1 receptor in endothelial cells for the formation of a stable vascular network (11,12).The S1P 1 receptor is widely expressed in the adult, in particular in endothelial cells, the brain, and the heart, and also in the cells of the immune system (13, 14). S1P 1 and S1P 4 receptors have been detected in T-lymphocytes (15-17). Stimulation of receptor signaling has been found to mediate and regulate cell migration and suppress proliferation and cytokine production (17, 18). Recently, S1P 1 receptors have also been implicated in lymphocyte trafficking and homing as the result of studies using FTY720, a potent immunosuppressive agent. FTY720, a sphingosine analogue, is phosphorylated by sphingosine kinase type I and more efficiently by sphingosine kinase type II (19 -21) and functions as an agonist ligand for S1P 1 , S1P 3 , S1P 4 , and S1P 5 receptors (19,22). FTY720 causes lymphopenia through sequestration of circulating lymphocytes within lymph nodes and Peyer's patches (19,(22)(23)(24) and also blocks the egress of T-cells from the thymus (25, 26). However, it is not known at which S1P receptor and cell type FTY720 exerts its effects.To begin to address the physiologic function of the S1P 1 receptor and sphingosine 1-phosphate signaling in T-cells, we have generated a T-cell-specific mouse knock-out of the S1P 1 receptor using the Cre/loxP system. Our results with these mice reveal a crucial role for the S1P 1 receptor in the egress of mature T-cells from the thymus into the circulation. EXPERIMENTAL PROCEDURESGeneration of the S1P 1 loxP/loxP Lck-Cre Mice-We previously g...

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

Cited by 96 publications

References 15 publications

The immunomodulator FTY720 interferes with effector functions of human monocyte‐derived dendritic cells

The immunomodulator FTY720 interferes with effector functions of human monocyte‐derived dendritic cells

Sphingosine-1-Phosphate Reduces CD4+ T-Cell Activation in Type 1 Diabetes Through Regulation of Hypoxia-Inducible Factor Short Isoform I.1 and CD69

Expression of the Sphingosine 1-Phosphate Receptor, S1P1, on T-cells Controls Thymic Emigration

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