Migration of CD4 T cells and dendritic cells toward sphingosine 1-phosphate (SIP) is mediated by different receptor subtypes: S1P regulates the functions of murine mature dendritic cells via S1P receptor type 3

Dendritic cells (DCs) and lymphocytes are known to show a migratory response to the phospholipid mediator, sphingosine 1-phosphate (SIP). However, it is unclear whether the same SIP receptor subtype mediates the migration of lymphocytes and DCs toward S1P. In this study, we investigated the involvement of SIP 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 SIP receptor type 1 (S1P(1)) agonist, SEW2871, at 0.1 mu M or higher induced a dose-dependent down-regulation of SIP,. The pretreatment with these compounds resulted in a significant inhibition of mouse CD4 T cell migration toward SIP. Thus, it is revealed that CD4 T cell migration toward SIP is highly dependent on SIP,. Mature DCs, when compared with CD4 T cells or immature DCs, expressed a relatively higher level of SIP, mRNA. SIP 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 mu M or higher resulted in a significant inhibition of SIP-induced migration and endocytosis in mature DCs, whereas SEW2871 up to 100 mu M did not show any clear effect. Moreover, we found that SIP-induced migration and endocytosis were at an extremely low level in mature DCs prepared from S1P(3)-knockout mice. These results indicate that SIP regulates migration and endocytosis of murine mature DCs via S1P(3) but not S1P(1).