Sphingosine 1-phosphate receptor 1 promotes B cell localization in the splenic marginal zone

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The factors directing marginal zone B cells to the splenic marginal zone are not well understood. Here we report that FTY720, a drug that targets sphingosine 1-phosphate (S1P) receptors, induced marginal zone B cell migration into follicles. Marginal zone B cells expressed S1P receptors 1 and 3 (S1P1 and S1P3, respectively). Using gene-targeted mice, we show that S1P1 but not S1P3 was required for localization in the marginal zone. In mice lacking the chemokine CXCL13, S1P1-deficient marginal zone B cells reacquired a marginal zone distribution. Exposure to lipopolysaccharide or antigen caused marginal zone B cells to downregulate S1P1 and S1P3 and to migrate into the splenic white pulp. These data suggest that marginal zone B cell localization to the marginal zone depends on responsiveness to the blood lysophospholipid S1P, with S1P1 signaling overcoming the recruiting activity of CXCL13.

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Figure 1: FTY720 treatment causes rapid and reversible marginal zone B cell relocalization into lymphoid follicles.
Figure 2: Marginal zone B cells have higher expression of S1P1 and S1P3 than do follicular B cells and show robust chemotactic responsiveness to S1P.
Figure 3: S1P1-deficient fetal liver chimeras have normal numbers of marginal zone B cells, but these cells fail to lodge in the marginal zone.
Figure 4: S1P chemotactic responsiveness of S1P1- and S1P3-deficient marginal zone B cells and marginal zone B cell distribution in S1P3-deficient mice.
Figure 5: In CXCL13-deficient mice, FTY720 fails to cause marginal zone B cell displacement and S1P1-deficient marginal zone B cells localize in the marginal zone.
Figure 6: LPS and antigen exposure cause downregulation of S1P1 and S1P3 and reduced S1P responsiveness.


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We thank V. Brinkmann for providing FTY720 (Novartis Institutes for Biomedical Research, Basel, Switzerland); D. Hargreaves for contributions to the early part of this project; M. Graeler for help with initial PCR analysis; and C. Lo for comments on the manuscript. Supported by Howard Hughes Medical Institute (G.C. and J.G.C.) and National Institutes of Health.

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Correspondence to Jason G Cyster.

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Cinamon, G., Matloubian, M., Lesneski, M. et al. Sphingosine 1-phosphate receptor 1 promotes B cell localization in the splenic marginal zone. Nat Immunol 5, 713–720 (2004) doi:10.1038/ni1083

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