The origin and maturity of dendritic cells determine the pattern of sphingosine 1-phosphate receptors expressed and required for efficient migration.

Dendritic cells (DCs) represent the most potent inducers of adaptive immune responses. Depending on their activation phenotype, DCs drive naive T cells into distinct differentiation pathways. To achieve this, DCs are present in virtually all tissues where they sample Ag and migrate to the T cell areas of lymph nodes (LNs) and spleen. Ample evidence exists demonstrating that sphingosine 1-phosphate (S1P) is an important modulator of these processes, exerting its effects by binding to the S1P receptor S1P(1) and/or S1P(3). However, published data are contradictory, in part. We show in this study that the expression pattern, as well as the regulation of the S1P receptors, differs among in vitro-generated DCs experiencing different kinds and duration of stimuli. Moreover, the influence of S1P(1) and S1P(3) on the in vivo migration of maturing DCs depends on the origin of these cells. Thus, in vitro-generated DCs require S1P(1) and S1P(3) to accomplish this, whereas skin-derived DCs migrate unhindered in the absence of S1P(3) but not when S1P(1) signaling is blocked. Migration of lamina propria DCs to the mesenteric LNs depends on S1P(1) and S1P(3). In contrast, relocation of maturing spleen-resident DCs to the T cell zone is independent of S1P(1) and S1P(3). However, intrasplenic positioning of immature DCs to the bridging channels depends on S1P(1) activity, with no noticeable contribution of S1P(3). These observations reveal a tissue-dependent contribution of S1P(3) to DC migration and suggest a fundamental role for S1P(1) for maturing DCs migrating from periphery to draining LNs.