Sphingosine 1-phosphate (S1P) is known to play a pivotal role in the regulation of lymphocyte emigration from organized lymphoid tissues such as the peripheral lymph nodes and thymus, but its immunologic role in unorganized and diffused tissues remains to be elucidated. Here we show that the trafficking of peritoneal B cells is principally regulated by S1P. All peritoneal B cells including B1a, B1b, and B2 B cells express comparable levels of the type 1 S1P receptor. Thus, treatment with FTY720, an S1P receptor modulator, caused the rapid disappearance of peritoneal B cells by inhibiting both their emigration from parathymic lymph nodes and their recirculation from the blood into the peritoneal cavity without affecting their progenitor populations. These changes did not affect natural plasma antibody production or phosphorylcholine (PC)-specific antibody production in serum after peritoneal immunization with heatkilled Streptococcal pneumoniae (R36A). However, FTY720 dramatically reduced peritoneal B cell-derived natural intestinal secretory IgA production without affecting the expression of J-chain and polyimmunoglobulin receptors. Additionally, FTY720 impaired the generation of PC-specific fecal IgA responses after oral immunization with R36A. These findings point to a pivotal role for S1P in connect IntroductionSphingosine 1-phosphate (S1P) has been identified as an important molecule in the regulation of lymphocyte egress from the organized lymphoid structures including the thymus and secondary lymphoid organs. 1,2 At present, 5 kinds of S1P receptors have been identified, each sharing S1P as its ligand but associating with a different type of G protein, resulting in a distinct signal transduction. 3 Accumulating evidence has demonstrated that type 1 S1P receptor (S1P1) is preferentially expressed on lymphocytes, and their expression is closely regulated by lymphocyte activation or development, which determines lymphocyte emigration from secondary lymph organs as well as the thymus. 4,5 FTY720, 2-amino-2-[2-(4-octylphenyl)-ethyl] propane-1,3-diol hydrochloride, acts as an agonist for S1P receptors, except the type 2 S1P receptor (S1P2). 6-8 FTY720 blocks S1P-mediated signaling by inducing internalization of receptors. 4,9 Therefore, treatment with FTY720 decreased the number of circulating lymphocytes in both blood and lymph, by inhibiting their emigration from the secondary lymphoid organs and thymus and by modulating integrin-dependent lymphocyte homing into peripheral lymph nodes. [10][11][12] Several lines of evidence have revealed that S1P also regulates B-cell distribution in the spleen, suggesting that FTY720 can impair plasma antibody production, especially against T-dependent (TD) antigen due to the abolishment of germinal center formation. [13][14][15] In addition, a recent study revealed that S1P plays an important role in the determination of plasma cell tropism to bone marrow. 16 Despite the substantial evidence pointing to the role of S1P in the regulation of lymphocyte trafficking at the syst...

It is well established that Peyer’s patches (PPs) are sites for the differentiation of IgA plasma cell precursors, but molecular and cellular mechanisms in their trafficking remain to be elucidated. In this study, we show that alterations in type 1 sphingosine 1-phosphate (S1P) receptor expression during B cell differentiation in the PPs control the emigration of IgA plasma cell precursors. Type 1 S1P receptor expression decreased during the differentiation of IgM+B220+ B cells to IgA+B220+ B cells, but recovered on IgA+B220− plasmablasts for their emigration from the PPs. Thus, IgA+B220− plasmablasts migrated in response to S1P in vitro. Additionally, IgA+ plasmablasts selectively accumulated in lymphatic regions of PPs when S1P-mediated signaling was disrupted by FTY720 treatment. This accumulation of IgA+ plasmablasts in the PPs led to their reduction in the intestinal lamina propria and simultaneous impairment of Ag-specific intestinal IgA production against orally administered Ag. These findings suggest that S1P regulates the retention and emigration of PP B cells and plays key roles in the induction of intestinal IgA production.

It is well established that intraepithelial T lymphocytes (IELs) are derived from conventional single-positive (SP) thymocytes, as well as unconventional double-negative (DN) thymocytes and CD103+CD8αβ recent thymic emigrants (RTEs). We show that IELs can be divided into two groups according to their dependency on sphingosine 1-phosphate (S1P) for trafficking into the intestines. CD4 or CD8αβ naive lymphocytes originating from SP thymocytes express high levels of type 1 S1P receptor (S1P1), and their preferential migration into the large intestine is regulated by S1P. In contrast, RTEs migrate exclusively into the small intestine, whereas DN thymic IEL precursors expressing either TCRαβ or TCRγδ migrate into both the small and large intestines. S1P does not play a role in the migration pathways of these unconventional thymic IEL precursors. Thus, down-regulation of S1P1 expression or disruption of the S1P gradient halted conventional CD4 or CD8αβ IEL trafficking into the intestines, but did not affect the trafficking of unconventional thymic IEL precursors. These data are the first to demonstrate that a lipid-mediated system discriminates IELs originating from conventional and unconventional thymic precursors.