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Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1


Adaptive immunity depends on T-cell exit from the thymus and T and B cells travelling between secondary lymphoid organs to survey for antigens. After activation in lymphoid organs, T cells must again return to circulation to reach sites of infection; however, the mechanisms regulating lymphoid organ exit are unknown. An immunosuppressant drug, FTY720, inhibits lymphocyte emigration from lymphoid organs, and phosphorylated FTY720 binds and activates four of the five known sphingosine-1-phosphate (S1P) receptors1,2,3,4. However, the role of S1P receptors in normal immune cell trafficking is unclear. Here we show that in mice whose haematopoietic cells lack a single S1P receptor (S1P1; also known as Edg1) there are no T cells in the periphery because mature T cells are unable to exit the thymus. Although B cells are present in peripheral lymphoid organs, they are severely deficient in blood and lymph. Adoptive cell transfer experiments establish an intrinsic requirement for S1P1 in T and B cells for lymphoid organ egress. Furthermore, S1P1-dependent chemotactic responsiveness is strongly upregulated in T-cell development before exit from the thymus, whereas S1P1 is downregulated during peripheral lymphocyte activation, and this is associated with retention in lymphoid organs. We find that FTY720 treatment downregulates S1P1, creating a temporary pharmacological S1P1-null state in lymphocytes, providing an explanation for the mechanism of FTY720-induced lymphocyte sequestration. These findings establish that S1P1 is essential for lymphocyte recirculation and that it regulates egress from both thymus and peripheral lymphoid organs.

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Figure 1: Defective emigration of S1P1-/- mature thymocytes and recirculation of S1P1-/- B cells.
Figure 2: Transferred S1P1-/- T and B cells accumulate in secondary lymphoid organs and fail to exit.
Figure 3: Mature single-positive (SP) thymocytes upregulate S1P1 and respond to S1P in an S1P1-dependent manner.
Figure 4: In vivo T-cell activation is associated with loss and subsequent reacquisition of S1P1 and S1P responsiveness.
Figure 5: FTY720 treatment uncouples S1P1 from the chemotactic machinery and downmodulates S1P1 surface expression.

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  1. 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)

    CAS  PubMed  Google Scholar 

  2. Yagi, H. et al. Immunosuppressant FTY720 inhibits thymocyte emigration. Eur. J. Immunol. 30, 1435–1444 (2000)

    Article  CAS  PubMed  Google Scholar 

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

    Article  ADS  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  6. Kohama, T. et al. Molecular cloning and functional characterization of murine sphingosine kinase. J. Biol. Chem. 273, 23722–23728 (1998)

    Article  CAS  PubMed  Google Scholar 

  7. 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)

    Article  CAS  PubMed  Google Scholar 

  8. 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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Chaffin, K. E. & Perlmutter, R. M. A pertussis toxin sensitive process controls thymocyte emigration. Eur. J. Immunol. 21, 2565–2573 (1991)

    Article  CAS  PubMed  Google Scholar 

  10. 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)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lucas, B., Vasseur, F. & Penit, C. Production, selection, and maturation of thymocytes with high surface density of TCR. J. Immunol. 153, 53–62 (1994)

    CAS  PubMed  Google Scholar 

  12. Gabor, M. J., Godfrey, D. I. & Scollay, R. Recent thymic emigrants are distinct from most medullary thymocytes. Eur. J. Immunol. 27, 2010–2015 (1997)

    Article  CAS  PubMed  Google Scholar 

  13. Chu, P. et al. Systematic identification of regulatory proteins critical for T-cell activation. J. Biol. 2, 211–2116 (2003)

    Article  Google Scholar 

  14. Parrot, D. M. V. & de Sousa, M. Thymus-dependent and thymus-independent populations: origin, migratory patterns and lifespan. Clin. Exp. Immunol. 8, 663–673 (1971)

    Google Scholar 

  15. Hall, J. G. & Morris, B. The immediate effect of antigens on the cell output of a lymph node. Br. J. Exp. Pathol. 46, 450–454 (1965)

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Sprent, J., Miller, J. F. A. P. & Mitchell, G. F. Antigen-induced selective recruitment of circulating lymphocytes. Cell. Immunol. 2, 171–181 (1971)

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  18. Edsall, L. C. & Spiegel, S. Enzymatic measurement of sphingosine 1-phosphate. Anal. Biochem. 272, 80–86 (1999)

    Article  CAS  PubMed  Google Scholar 

  19. Murata, N. et al. Interaction of sphingosine 1-phosphate with plasma components, including lipoproteins, regulates the lipid receptor-mediated actions. Biochem. J. 352, 809–815 (2000)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Caligan, T. B. et al. A high-performance liquid chromatographic method to measure sphingosine 1-phosphate and related compounds from sphingosine kinase assays and other biological samples. Anal. Biochem. 281, 36–44 (2000)

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  22. Idzko, M. et al. Sphingosine 1-phosphate induces chemotaxis of immature and modulates cytokine-release in mature human dendritic cells for emergence of Th2 immune responses. FASEB J. 16, 625–627 (2002)

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  ADS  PubMed  Google Scholar 

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We are grateful to C. Low for technical assistance; C. McArthur and S. Jiang for cell sorting; R. Albert at Novartis Institutes for BioMedical Research for synthesis of FTY720-P; and T. Okada, C. Allen and S. Watson for helpful discussions. M.M. is supported by the Pfizer Postdoctoral Fellowship in Immunology and Rheumatology and the Rosalind Russell Medical Research Center for Arthritis at University of California, San Francisco; J.G.C. is a Packard fellow and an HHMI assistant investigator. This work was supported in part by grants from the National Institutes of Health.

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Correspondence to Jason G. Cyster.

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

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