Cutting Edge: Suppression of T Cell Chemotaxis by Sphingosine 1-Phosphate

Graeler, Markus H.; Shankar, Geetha; Goetzl, Edward J.

doi:10.4049/jimmunol.169.8.4084

Cited by 128 publications

(136 citation statements)

References 15 publications

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“…One theory proposes a loss of responsiveness towards S1P in the plasma by FTY720, resulting in inhibition of lymphocyte re-entrance into the circulation. This conception was suspected from previous findings revealing that below-plasma concentrations (<0.1 lM) of S1P apparently enhance in vitro chemotactic responses of naive T cells towards CCL21, whereas plasma concentrations (0.3-1.0 lM) inhibit chemotaxis towards CCL21 [31].…”

Section: Discussionmentioning

confidence: 93%

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: Discussionmentioning

confidence: 93%

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

et al. 2005

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“…Sphingosine 1-phosphate levels are known to be very high (0.1-1 M) in the blood relative to various tissues (33) and may directly stimulate the migration of mature thymocytes out of the thymus via a sphingosine 1-phosphate-directed chemotactic response. Indeed, sphingosine 1-phosphate, via signaling through the S1P 1 receptor, previously has been shown to be a chemotactic factor for a variety of cell types including Tlymphocytes (8,17,34). Alternatively, sphingosine 1-phosphate may regulate the responses of thymocytes to thymic chemokines important for retention or emigration.…”

Section: Discussionmentioning

confidence: 99%

“…Alternatively, sphingosine 1-phosphate may regulate the responses of thymocytes to thymic chemokines important for retention or emigration. Sphingosine 1-phosphate has been demonstrated to regulate the chemotactic responses of T-cells to chemokines in a concentration-dependent manner (17,35).…”

Section: Discussionmentioning

confidence: 99%

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

Allende

Dreier

Mandala

et al. 2004

Journal of Biological Chemistry

415

381

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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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“…Of the family of G protein-coupled receptors (GPCRs) with high specificity for S1P, the type 1 receptor (S1P 1 ) predominates in its level of expression and transduction of diverse T cell functional responses [7,8]. Signals from the S1P-S1P 1 axis inhibit T cell return from tissues to afferent lymphatics, T cell influx into lymph nodes, and marginal zone B cell entry into the T cell area of splenic follicles, in response to chemokines [6,9,10].…”

Section: Introductionmentioning

confidence: 99%

Regulation of the roles of sphingosine 1-phosphate and its type 1 G protein-coupled receptor in T cell immunity and autoimmunity

Goetzl

Liao

Huang

2008

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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The lipid mediator sphingosine 1-phosphate (S1P) and its type 1 G protein-coupled receptor (S1P 1 ) affect mammalian immunity through alterations in thymocyte emigration, differentiation of T cell subsets, lymphocyte trafficking in lymphoid organs and other tissues, T cell-dendritic cell and T cell-B cell interactions, and cytokine generation. Recent attention to effects of the S1P-S1P 1 axis on nonmigration functions of lymphocytes include delineation of a role in terminal differentiation and survival of Th17 effector cells and adaptive Treg cells of the CD4 T cell constellation, and a greater understanding of interactions of the S1P-S1P 1 axis with immune cytokines in lymphocyte survival and activities. This breadth of involvement of the S1P-S1P 1 axis in immune responses that often are altered in immunological diseases has provided many opportunities for novel therapeutic interventions. A spectrum of pharmacological and immunochemical agents is available that alter immunity by affecting either tissue and fluid concentrations of S1P or levels of expression and signaling activities of S1P 1 . Such agents have so far been beneficial in the settings of autoimmunity and rejection of transplanted organs, and are likely to become valuable constituents of combined drug programs.

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Cutting Edge: Suppression of T Cell Chemotaxis by Sphingosine 1-Phosphate

Cited by 128 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

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

Regulation of the roles of sphingosine 1-phosphate and its type 1 G protein-coupled receptor in T cell immunity and autoimmunity

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