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¹ Department of Physiological Chemistry, ² Department of Gastroenterology and Endocrinology, and ³ Department of Immmunology, University of Ulm, D-89069 Ulm, Germany
⁴ Department of Molecular Biology, Helen L. Dorris Institute for Neurological and Psychiatric Disorders, The Scripps Research Institute, La Jolla, CA 92037

Address correspondence to Klaus-Dieter Fischer, Dept. of Physiological Chemistry, University of Ulm, Albert-Einstein-Allee 11, D-89069 Ulm, Germany. Phone: 49-731-502-3269; Fax: 49-731-503-1126; email: klaus.fischer{at}medizin.uni-ulm.de

Marginal zones (MZs) are microdomains in the spleen that contain various types of immune cells, including MZ B cells, MOMA1⁺ metallophilic macrophages, and mucosal addressin cell adhesion molecule 1 (MAdCAM-1)⁺ endothelial cells. MAdCAM-1⁺ and MOMA1⁺ cells line the sinus, that separates MZs from splenic follicles. Here we show that a receptor for the lysophospholipid sphingosine-1-phosphate (S1P), S1P₃, is required for normal numbers of splenic immature and MZ B cells, and for S1P-induced chemotaxis of MZ B cells. S1P₃ is also essential for proper alignment of MOMA1⁺ macrophages and MAdCAM-1⁺ endothelial cells along the marginal sinus. The lack of cohesion of the marginal sinus in S1P₃^–/– mice affects MZ B cell functions, as wild-type (WT) MZ B cells migrate more into S1P₃^–/– follicles than into WT follicles after treatment with lipopolysaccharide. Additionally, short-term homing experiments demonstrate that WT MZ B cells home to the S1P₃^–/– spleen in increased numbers, suggesting a role for the marginal sinus in regulating MZ B cells numbers. Moreover, S1P₃^–/– 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 S1P₃ receptor as essential regulators of the MZ sinus and its role as a barrier to the follicle.

Key Words: marginal zone • B cells • lipopolysaccharide • endothelium • MOMA1⁺ metallophilic macrophages

I. Girkontaite's present address is Fermentas UAB, Graiciuno 8, LT 2028 Vilnius, Lithuania.

Abbreviations used in this paper: CFSE, carboxyfluorescein diacetate succinimidyl ester; FO, follicular; IM, immature; MAdCAM-1, mucosal addressin cell adhesion molecule 1; MZ, marginal zone; S1P, sphingosine-1-phosphate; TI, thymus-independent.

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