The Sphingosine-1-Phosphate (S1P) Lysophospholipid Receptor S1P3 Regulates MAdCAM-1+ Endothelial Cells in Splenic Marginal Sinus Organization

Abstract

Marginal zones (MZs) are microdomains in the spleen that contain various types of immune cells, including MZ B cells, MOMA1 ϩ metallophilic macrophages, and mucosal addressin cell adhesion molecule 1 (MAdCAM-1) ϩ endothelial cells. MAdCAM-1 ϩ and MOMA1 ϩ cells line the sinus, that separates MZs from splenic follicles. Here we show that a receptor for the lysophospholipid sphingosine-1-phosphate (S1P), S1P 3 , is required for normal numbers of splenic immature and MZ B cells, and for S1P-induced chemotaxis of MZ B cells. S1P 3 is also essential for proper alignment of MOMA1 ϩ macrophages and MAdCAM-1 ϩ endothelial cells along the marginal sinus. The lack of cohesion of the marginal sinus in S1P 3 Ϫ / Ϫ mice affects MZ B cell functions, as wild-type (WT) MZ B cells migrate more into S1P 3 Ϫ / Ϫ follicles than into WT follicles after treatment with lipopolysaccharide. Additionally, short-term homing experiments demonstrate that WT MZ B cells home to the S1P 3 Ϫ / Ϫ spleen in increased numbers, suggesting a role for the marginal sinus in regulating MZ B cells numbers. Moreover, S1P 3 Ϫ / Ϫ mice are defective in mounting immune responses to thymus-independent antigen type 2 due to defects in radiation-resistant cells in the spleen. These data identify lysophospholipids and the S1P 3 receptor as essential regulators of the MZ sinus and its role as a barrier to the follicle.

The Sphingosine 1-Phosphate Receptor Agonist FTY720 Differentially Affects the Sequestration of CD4+/CD25+ T-Regulatory Cells and Enhances Their Functional Activity

“…In contrast, no significant differences were found in the CD4 ϩ / CD25 ϩ T cell subset, indicating that CD4 ϩ /CD25 ϩ T cells might be less responsive to S1P-induced chemotaxis. In contrast, in some lymphoid organs, B cells were shown to express higher levels of S1P 3 than T cells, and this receptor seems to be required for the migration of B cells in the spleen (37,38). A similar role for S1P 3 might exist in T-regulatory cells because the S1P 3 mRNA levels were significantly higher in T-regulatory cells without changes after FTY720 treatment.…”

Ageing adversely affects the migration and function of marginal zone B cells

“…The MZ B cells play important roles in the rapid induction of TI responses to blood‐borne polysaccharide antigen,22, 25, 26 but whether this ability was affected by ageing was not known. Therefore we first determined whether ageing affected the ability of MZ B cells to acquire TNP‐Ficoll, a TI‐type 2 model antigen 27.…”

“…Continual S1P stimulation is required to retain MZ B cells in the MZ and it is the desensitization of S1P receptors on MZ B cells that enables them to overcome their attraction towards S1P in the blood30 and migrate into the follicles. Stromal cells, including FDC, within the B‐cell follicles express CXCL13,31 which stimulates the attraction of CXCR5‐expressing B cells towards the follicles 2, 3, 25, 32. Once within the follicles, the cells up‐regulate their expression of S1P 1 and S1P 3 and are attracted in an S1P‐dependent manner back to the MZ.…”

“…This implies that the effects of ageing on the MAdCAM‐1 + stromal cell layer were, at least in part, responsible for the effects observed on the distribution of MZ B cells and CD169 + macrophages within this region. The distribution of MAdCAM‐1 + stromal cells and CD169 + MZ metallophilic macrophages is disturbed in the spleens of S1P 3 −/− mice, indicating an important role for S1P–S1P 3 signalling in the organization of the marginal sinus 25. Whether the effects of ageing on the MZ microarchitecture were similarly a consequence of reduced S1P 3 receptor expression by splenic stromal cells remains to be determined.…”

CD69 down‐modulation and inhibition of thymic egress by short‐ and long‐term selective chemical agonism of sphingosine 1‐phosphate receptors

“…Recently, deletion of the S1P 1 receptor in lymphocytes results in developmental changes in surface phenotype (elevated CD69 expression in both in both T cells and B cells) as well as retention in lymphoid organs [19,20]. Transgenic expression of S1P 1 within lymphocytes also alters cell trafficking in vivo [21][22][23], and both S1P 1 and S1P 3 have been reported to play a role in the organization of the splenic marginal sinus [24,25]. S1P 4 is largely expressed within lymphoid tissue [26,27], but as with S1P 2 and S1P 5 , scant evidence exists for receptor function in vivo.…”