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Migration of CD4 T Cells and Dendritic Cells toward Sphingosine 1-Phosphate (S1P) Is Mediated by Different Receptor Subtypes: S1P Regulates the Functions of Murine Mature Dendritic Cells via S1P Receptor Type 3

Research Laboratory III (Immunology), Pharmaceuticals Research Division, Mitsubishi Pharma Corporation Yokohama, Japan

Dendritic cells (DCs) and lymphocytes are known to show a migratory response to the phospholipid mediator, sphingosine 1-phosphate (S1P). However, it is unclear whether the same S1P receptor subtype mediates the migration of lymphocytes and DCs toward S1P. In this study, we investigated the involvement of S1P receptor subtypes in S1P-induced migration of CD4 T cells and bone marrow-derived DCs in mice. A potent S1P receptor agonist, the (S)-enantiomer of FTY720-phosphate [(S)-FTY720-P], at 0.1 nM or higher and a selective S1P receptor type 1 (S1P₁) agonist, SEW2871, at 0.1 µM or higher induced a dose-dependent down-regulation of S1P₁. The pretreatment with these compounds resulted in a significant inhibition of mouse CD4 T cell migration toward S1P. Thus, it is revealed that CD4 T cell migration toward S1P is highly dependent on S1P₁. Mature DCs, when compared with CD4 T cells or immature DCs, expressed a relatively higher level of S1P₃ mRNA. S1P at 10–1000 nM induced a marked migration and significantly enhanced the endocytosis of FITC-dextran in mature but not immature DCs. Pretreatment with (S)-FTY720-P at 0.1 µM or higher resulted in a significant inhibition of S1P-induced migration and endocytosis in mature DCs, whereas SEW2871 up to 100 µM did not show any clear effect. Moreover, we found that S1P-induced migration and endocytosis were at an extremely low level in mature DCs prepared from S1P₃-knockout mice. These results indicate that S1P regulates migration and endocytosis of murine mature DCs via S1P₃ but not S1P₁.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Kenji Chiba, Research Laboratory III (Immunology), Pharmaceuticals Research Division, Mitsubishi Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama, Japan. E-mail address: Chiba.Kenji{at}mk.m-pharma.co.jp

² Abbreviations used in this paper: DC, dendritic cell; CHO, Chinese hamster ovary; FITC-Dx, FITC-dextran; HA, hemagglutinin; hS1P₁-CHO cell, CHO cells stably expressing human S1P₁; mS1P₁-CHO cell, CHO cells stably expressing mouse S1P₁; rm, recombinant mouse; (S)-FTY720-P, the (S)-enantiomer of FTY720-phosphate; S1P, sphingosine 1-phosphate; S1P₁, S1P receptor type 1; SPHK, sphingosine kinase.

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