Sphingosine 1-phosphate regulates peritoneal B-cell trafficking for subsequent intestinal IgA production

Abstract

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...

Enhanced trafficking to the pancreatic lymph nodes and auto-antigen presentation capacity distinguishes peritoneal B lymphocytes in non-obese diabetic mice

“…S1P has received considerable attention in recent years as a regulator of lymphocyte trafficking [16]. For peritoneal B lymphocytes, S1P signalling is required for retention of B-lymphocytes within the peritoneum [11]. In agreement with a previous study [12], a moderate but significant migratory response of BALB/c peritoneal B cells towards S1P was observed (Fig.…”

“…Antigen presentation assay NOD and BALB/c mice were immunised subcutaneously on the hind flank with 50 μg insulin peptide (Insulin B [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]; Anaspec, San Jose, CA, USA). After 10 days, spleens were collected from these animals and splenic CD4 + T cells purified using CD4 MicroBeads (Miltenyi Biotec, Bergisch Gladbach, Germany).…”

“…In the peritoneum, S1P helps retain B lymphocytes within the peritoneal cavity [11]. B cell unresponsiveness to chemotactic signals from S1P thus facilitates the emigration of peritoneal lymphocytes.…”

Anti-Inflammatory Effects of Sphingosine Kinase Modulation in Inflammatory Arthritis

“…Interestingly, B cell lines derived from RA patients are uniquely resistant to Fas-mediated apoptosis, in part due to overactivity of SphK1 and overproduction of S1P, which can inhibit apoptosis and regulate lymphoid migratory pathways (26). Additionally, FTY720-phosphate, which binds to S1P receptors, caused the rapid disappearance of peritoneal B cells by inhibiting their emigration from parathymic lymph nodes, as well as reducing peritoneal B cell-derived intestinal secretory IgA production (46). This suggests that S1P may play an important role in regulating B cell survival, trafficking, and Ab production.…”

CD19+CD5+ B Cells in Primary IgA Nephropathy

“…CD19 ϩ CD5 ϩ B cells in the peritoneal cavity and the gut lamina propria serve as an important source of IgA-producing plasma cells in response to various stimuli, contributing significantly to the response against enteric pathogens. 13,14 In both mice and humans, CD19 ϩ…”