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

Article metrics

Abstract

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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.

References

  1. 1

    Kraal, G. Cells in the marginal zone of the spleen. Int. Rev. Cytology 132, 31–73 (1992).

  2. 2

    Schmidt, E.E., MacDonald, I.C. & Groom, A.C. Comparative aspects of splenic microcirculatory pathways in mammals: the region bordering the white pulp. Scanning Microsc. 7, 613–628 (1993).

  3. 3

    Cyster, J.G. B cells on the front line. Nat. Immunol. 1, 9–10 (2000).

  4. 4

    Martin, F. & Kearney, J.F. Marginal-zone B cells. Nat. Rev. Immunol. 2, 323–335 (2002).

  5. 5

    MacLennan, I.C.M., Gray, D., Kumararatne, D.S. & Bazin, H. The lymphocytes of splenic marginal zones: a distinct B-cell lineage. Immunol. Today 3, 305–307 (1982).

  6. 6

    Lu, T.T. & Cyster, J.G. Integrin-mediated long-term B cell retention in the splenic marginal zone. Science 297, 409–412 (2002).

  7. 7

    Guinamard, R., Okigaki, M., Schlessinger, J. & Ravetch, J.V. Absence of marginal zone B cells in Pyk-2 deficient mice define their role in the humoral response. Nat. Immunol. 1, 31–36 (2000).

  8. 8

    Chiba, K. et al. FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats. I. FTY720 selectively decreases the number of circulating mature lymphocytes by acceleration of lymphocyte homing. J. Immunol. 160, 5037–5044 (1998).

  9. 9

    Brinkmann, V. & Lynch, K. FTY720: targeting G-protein-coupled receptors for sphingosine 1-phosphate in transplantation and autoimmunity. Curr. Opin. Immunol. 14, 569–575 (2002).

  10. 10

    Rosen, H., Sanna, G. & Alfonso, C. Egress: a receptor-regulated step in lymphocyte trafficking. Immunol. Rev. 195, 160–177 (2003).

  11. 11

    Mandala, S. et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 296, 346–349 (2002).

  12. 12

    Brinkmann, V. et al. The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J. Biol. Chem. 277, 21453–21457 (2002).

  13. 13

    Matloubian, M. et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 427, 355–360 (2004).

  14. 14

    Allende, M.L., Dreier, J.L., Mandala, S. & Proia, R.L. Expression of the sphingosine-1-phosphate receptor, S1P1, on T-cells controls thymic emigration. J. Biol. Chem. 279, 15396–15401 (2004).

  15. 15

    Allende, M.L. & Proia, R.L. Sphingosine-1-phosphate receptors and the development of the vascular system. Biochim. Biophys. Acta 1582, 222–227 (2002).

  16. 16

    Spiegel, S. & Milstien, S. Sphingosine-1-phosphate: an enigmatic signalling lipid. Nat. Rev. Mol. Cell Biol. 4, 397–407 (2003).

  17. 17

    Hla, T. Signaling and biological actions of sphingosine 1-phosphate. Pharmacol. Res. 47, 401–407 (2003).

  18. 18

    Pinschewer, D.D. et al. FTY720 immunosuppression impairs effector T cell peripheral homing without affecting induction, expansion, and memory. J. Immunol. 164, 5761–5770 (2000).

  19. 19

    Liu, Y. et al. Edg-1, the G protein-coupled receptor for sphingosine-1-phosphate, is essential for vascular maturation. J. Clin. Invest. 106, 951–961 (2000).

  20. 20

    Hla, T. Sphingosine 1-phosphate receptors. Prostaglandins Other Lipid Mediat. 64, 135–142 (2001).

  21. 21

    Förster, R. et al. A putative chemokine receptor, BLR1, directs B cell migration to defined lymphoid organs and specific anatomic compartments of the spleen. Cell 87, 1037–1047 (1996).

  22. 22

    Ansel, K.M. et al. A chemokine driven positive feedback loop organizes lymphoid follicles. Nature 406, 309–314 (2000).

  23. 23

    Groeneveld, P.H., Erich, T. & Kraal, G. In vivo effects of LPS on B lymphocyte subpopulations. Migration of marginal zone-lymphocytes and IgD-blast formation in the mouse spleen. Immunobiology 170, 402–411 (1985).

  24. 24

    Graler, M.H. & Goetzl, E.J. The immunosuppressant FTY720 down-regulates sphingosine 1-phosphate G protein-coupled receptors. FASEB J. 18, 551–553 (2004).

  25. 25

    Liu, Y.-J., Oldfield, S. & MacLennan, I.C.M. Memory B cells in T cell-dependent antibody responses colonize the splenic marginal zones. Eur. J. Immunol. 18, 355–362 (1988).

  26. 26

    Sanna, M.G. et al. Sphingosine 1-phosphate (S1P) receptor subtypes S1P1 and S1P3, respectively, regulate lymphocyte recirculation and heart rate. J. Biol. Chem. 279, 13839–13848 (2004).

  27. 27

    Graeler, M. & Goetzl, E.J. Activation-regulated expression and chemotactic function of sphingosine 1-phosphate receptors in mouse splenic T cells. FASEB J. 16, 1874–1878 (2002).

  28. 28

    Graeler, M., Shankar, G. & Goetzl, E.J. Cutting edge: suppression of T cell chemotaxis by sphingosine 1-phosphate. J. Immunol. 169, 4084–4087 (2002).

  29. 29

    Dorsam, G. et al. Transduction of multiple effects of sphingosine 1-phosphate (S1P) on T cell functions by the S1P1 G protein-coupled receptor. J. Immunol. 171, 3500–3507 (2003).

  30. 30

    Steele, A.D., Szabo, I., Bednar, F. & Rogers, T.J. Interactions between opioid and chemokine receptors: heterologous desensitization. Cytokine Growth Factor Rev. 13, 209–222 (2002).

  31. 31

    Rosen, H., Alfonso, C., Surh, C.D. & McHeyzer-Williams, M.G. Rapid induction of medullary thymocyte phenotypic maturation and egress inhibition by nanomolar sphingosine 1-phosphate receptor agonist. Proc. Natl. Acad. Sci. USA 100, 10907–10912 (2003).

  32. 32

    Chu, P. et al. Systematic identification of regulatory proteins critical for T-cell activation. J. Biol. 2, 21.1–21.16 (2003).

  33. 33

    Karlsson, M.C. et al. Macrophages control the retention and trafficking of B lymphocytes in the splenic marginal zone. J. Exp. Med. 198, 333–340 (2003).

  34. 34

    Martin, F. & Kearney, J.F. B-cell subsets and the mature preimmune repertoire. Marginal zone and B1 B cells as part of a “natural immune memory”. Immunol. Rev. 175, 70–79 (2000).

  35. 35

    Reif, K. et al. Balanced responsiveness to chemoattractants from adjacent zones determines B-cell position. Nature 416, 94–99 (2002).

  36. 36

    Hargreaves, D.C. et al. A coordinated change in chemokine responsiveness guides plasma cell movements. J. Exp. Med. 194, 45–56 (2001).

  37. 37

    Forrest, M. et al. Immune cell regulation and cardiovascular effects of sphingosine 1-phosphate receptor agonists in rodents are mediated via distinct receptor subtypes. J. Pharmacol. Exp. Ther. 309, 758–768 (2004).

  38. 38

    Goodnow, C.C. et al. Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice. Nature 334, 676–682 (1988).

Download references

Acknowledgements

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.

Author information

Correspondence to Jason G Cyster.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Further reading