Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Natural killer cell trafficking in vivo requires a dedicated sphingosine 1-phosphate receptor

Abstract

Consistent with their function in immune surveillance, natural killer (NK) cells are distributed throughout lymphoid and nonlymphoid tissues. However, the mechanisms governing the steady-state trafficking of NK cells remain unknown. The lysophospholipid sphingosine 1-phosphate (S1P), by binding to its receptor S1P1, regulates the recirculation of T and B lymphocytes. In contrast, S1P5 is detected in the brain and regulates oligodendrocyte migration and survival in vitro. Here we show that S1P5 was also expressed in NK cells in mice and humans and that S1P5-deficient mice had aberrant NK cell homing during steady-state conditions. In addition, we found that S1P5 was required for the mobilization of NK cells to inflamed organs. Our data emphasize distinct mechanisms regulating the circulation of various lymphocyte subsets and raise the possibility that NK cell trafficking may be manipulated by therapies specifically targeting S1P5.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Expression of genes encoding S1P receptors in mouse lymphocytes.
Figure 2: Steady-state tissue distribution of NK cells wild-type and S1P5-deficient mice.
Figure 3: Tissue distribution of NK cells in wild-type and S1P5-deficient mice treated with IL-15.
Figure 4: NK cell–intrinsic function for S1P5 in NK cell tissue distribution.
Figure 5: Effect of S1P5 deficiency on the tissue distribution of NK cell subsets.
Figure 6: Defective in vivo and in vitro migration of S1P5-deficient NK cells.
Figure 7: Pharmacological modulation of NK cell trafficking.

Similar content being viewed by others

References

  1. Bottino, C., Moretta, L. & Moretta, A. NK cell activating receptors and tumor recognition in humans. Curr. Top. Microbiol. Immunol. 298, 175–182 (2006).

    CAS  PubMed  Google Scholar 

  2. Newman, K.C. & Riley, E.M. Whatever turns you on: accessory-cell-dependent activation of NK cells by pathogens. Nat. Rev. Immunol. 7, 279–291 (2007).

    Article  CAS  PubMed  Google Scholar 

  3. Lodoen, M.B. & Lanier, L.L. Natural killer cells as an initial defense against pathogens. Curr. Opin. Immunol. 18, 391–398 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Huntington, N.D., Vosshenrich, C.A. & Di Santo, J.P. Developmental pathways that generate natural-killer-cell diversity in mice and humans. Nat. Rev. Immunol. 7, 703–714 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Stewart, C.A. et al. Germ-line and rearranged Tcrd transcription distinguish bona fide NK cells and NK-like γδ T cells. Eur. J. Immunol. 37, 1442–1452 (2007).

    Article  CAS  PubMed  Google Scholar 

  6. Gregoire, C. et al. The trafficking of natural killer cells. Immunol. Rev. (in the press).

  7. Hokeness, K.L., Kuziel, W.A., Biron, C.A. & Salazar-Mather, T.P. Monocyte chemoattractant protein-1 and CCR2 interactions are required for IFN-α/β-induced inflammatory responses and antiviral defense in liver. J. Immunol. 174, 1549–1556 (2005).

    Article  CAS  PubMed  Google Scholar 

  8. Thapa, M., Kuziel, W.A. & Carr, D.J. Susceptibility of CCR5-deficient mice to genital herpes simplex virus type 2 is linked to NK cell mobilization. J. Virol. 81, 3704–3713 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ajuebor, M.N. et al. CCR5 deficiency drives enhanced natural killer cell trafficking to and activation within the liver in murine T cell-mediated hepatitis. Am. J. Pathol. 170, 1975–1988 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Khan, I.A. et al. CCR5 is essential for NK cell trafficking and host survival following Toxoplasma gondii infection. PLoS Pathog 2, e49 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Martin-Fontecha, A. et al. Induced recruitment of NK cells to lymph nodes provides IFN-γ for TH1 priming. Nat. Immunol. 5, 1260–1265 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. Jiang, D. et al. Regulation of pulmonary fibrosis by chemokine receptor CXCR3. J. Clin. Invest. 114, 291–299 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Huang, D. et al. The neuronal chemokine CX3CL1/fractalkine selectively recruits NK cells that modify experimental autoimmune encephalomyelitis within the central nervous system. FASEB J. 20, 896–905 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Yu, Y.R. et al. Defective antitumor responses in CX3CR1-deficient mice. Int. J. Cancer 121, 316–322 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Lavergne, E. et al. Fractalkine mediates natural killer-dependent antitumor responses in vivo. Cancer Res. 63, 7468–7474 (2003).

    CAS  PubMed  Google Scholar 

  16. Wald, O. et al. IFN-γ acts on T cells to induce NK cell mobilization and accumulation in target organs. J. Immunol. 176, 4716–4729 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Inngjerdingen, M., Damaj, B. & Maghazachi, A.A. Expression and regulation of chemokine receptors in human natural killer cells. Blood 97, 367–375 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Geissmann, F. et al. Intravascular immune surveillance by CXCR6+ NKT cells patrolling liver sinusoids. PLoS Biol. 3, e113 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Cyster, J.G. Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs. Annu. Rev. Immunol. 23, 127–159 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Rosen, H. & Goetzl, E.J. Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network. Nat. Rev. Immunol. 5, 560–570 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. Rosen, H., Sanna, M.G., Cahalan, S.M. & Gonzalez-Cabrera, P.J. Tipping the gatekeeper: S1P regulation of endothelial barrier function. Trends Immunol. 28, 102–107 (2007).

    Article  CAS  PubMed  Google Scholar 

  22. Brinkmann, V. Sphingosine 1-phosphate receptors in health and disease: Mechanistic insights from gene deletion studies and reverse pharmacology. Pharmacol. Ther. 115, 84–105 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Schwab, S.R. et al. Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients. Science 309, 1735–1739 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  25. Wei, S.H. et al. Sphingosine 1-phosphate type 1 receptor agonism inhibits transendothelial migration of medullary T cells to lymphatic sinuses. Nat. Immunol. 6, 1228–1235 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Terai, K. et al. Edg-8 receptors are preferentially expressed in oligodendrocyte lineage cells of the rat CNS. Neuroscience 116, 1053–1062 (2003).

    Article  CAS  PubMed  Google Scholar 

  27. Im, D.S. et al. Characterization of a novel sphingosine 1-phosphate receptor, Edg-8. J. Biol. Chem. 275, 14281–14286 (2000).

    Article  CAS  PubMed  Google Scholar 

  28. Jaillard, C. et al. Edg8/S1P5: an oligodendroglial receptor with dual function on process retraction and cell survival. J. Neurosci. 25, 1459–1469 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Walzer, T. et al. Identification, activation, and selective in vivo ablation of mouse NK cells via NKp46. Proc. Natl. Acad. Sci. USA 104, 3384–3389 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Walzer, T., Jaeger, S., Chaix, J. & Vivier, E. Natural killer cells: from CD3NKp46+ to post-genomics meta-analyses. Curr. Opin. Immunol. 19, 365–372 (2007).

    Article  CAS  PubMed  Google Scholar 

  31. Goetzl, E.J. & Rosen, H. Regulation of immunity by lysosphingolipids and their G protein-coupled receptors. J. Clin. Invest. 114, 1531–1537 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lucas, M., Schachterle, W., Oberle, K., Aichele, P. & Diefenbach, A. Dendritic cells prime natural killer cells by trans-presenting interleukin 15. Immunity 26, 503–517 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Mortier, E. et al. Soluble interleukin-15 receptor α (IL-15R α)-sushi as a selective and potent agonist of IL-15 action through IL-15Rβ/γ. Hyperagonist IL-15 x IL-15Rα fusion proteins. J. Biol. Chem. 281, 1612–1619 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Hayakawa, Y. & Smyth, M.J. CD27 dissects mature NK cells into two subsets with distinct responsiveness and migratory capacity. J. Immunol. 176, 1517–1524 (2006).

    Article  CAS  PubMed  Google Scholar 

  35. Goetzl, E.J., Kong, Y. & Mei, B. Lysophosphatidic acid and sphingosine 1-phosphate protection of T cells from apoptosis in association with suppression of Bax. J. Immunol. 162, 2049–2056 (1999).

    CAS  PubMed  Google Scholar 

  36. Wang, W., Graeler, M.H. & Goetzl, E.J. Physiological sphingosine 1-phosphate requirement for optimal activity of mouse CD4+ regulatory T Cells. FASEB J. 18, 1043–1045 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. 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 

  38. Kveberg, L., Bryceson, Y., Inngjerdingen, M., Rolstad, B. & Maghazachi, A.A. Sphingosine 1 phosphate induces the chemotaxis of human natural killer cells. Role for heterotrimeric G proteins and phosphoinositide 3 kinases. Eur. J. Immunol. 32, 1856–1864 (2002).

    Article  CAS  PubMed  Google Scholar 

  39. Wang, J., Xu, J.W., Zhang, W.C., Wei, H.M. & Tian, Z.G. TLR3 ligand-induced accumulation of activated splenic natural killer cells into liver. Cell. Mol. Immunol. 2, 449–453 (2005).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  41. Chen, S., Kawashima, H., Lowe, J.B., Lanier, L.L. & Fukuda, M. Suppression of tumor formation in lymph nodes by L-selectin-mediated natural killer cell recruitment. J. Exp. Med. 202, 1679–1689 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Bajenoff, M. et al. Natural killer cell behavior in lymph nodes revealed by static and real-time imaging. J. Exp. Med. 203, 619–631 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kelly, P., Casey, P.J. & Meigs, T.E. Biologic functions of the G12 subfamily of heterotrimeric G proteins: growth, migration, and metastasis. Biochemistry 46, 6677–6687 (2007).

    Article  CAS  PubMed  Google Scholar 

  44. Novgorodov, A.S., El-Alwani, M., Bielawski, J., Obeid, L.M. & Gudz, T.I. Activation of sphingosine-1-phosphate receptor S1P5 inhibits oligodendrocyte progenitor migration. FASEB J. 21, 1503–1514 (2007).

    Article  CAS  PubMed  Google Scholar 

  45. Hanessian, S., Charron, G., Billich, A. & Guerini, D. Constrained azacyclic analogues of the immunomodulatory agent FTY720 as molecular probes for sphingosine 1-phosphate receptors. Bioorg. Med. Chem. Lett. 17, 491–494 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. Freud, A.G. & Caligiuri, M.A. Human natural killer cell development. Immunol. Rev. 214, 56–72 (2006).

    Article  CAS  PubMed  Google Scholar 

  47. Ferlazzo, G. et al. The abundant NK cells in human secondary lymphoid tissues require activation to express killer cell Ig-like receptors and become cytolytic. J. Immunol. 172, 1455–1462 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Vaessen, L.M., van Besouw, N.M., Mol, W.M., Ijzermans, J.N. & Weimar, W. FTY720 treatment of kidney transplant patients: a differential effect on B cells, naive T cells, memory T cells and NK cells. Transpl. Immunol. 15, 281–288 (2006).

    Article  CAS  PubMed  Google Scholar 

  49. Ljunggren, H.G. & Malmberg, K.J. Prospects for the use of NK cells in immunotherapy of human cancer. Nat. Rev. Immunol. 7, 329–339 (2007).

    Article  CAS  PubMed  Google Scholar 

  50. Chiesa, S. et al. Multiplicity and plasticity of natural killer cell signaling pathways. Blood 107, 2364–2372 (2005).

    Article  PubMed  Google Scholar 

  51. Walzer, T., Arpin, C., Beloeil, L. & Marvel, J. Differential in vivo persistence of two subsets of memory phenotype CD8 T cells defined by CD44 and CD122 expression levels. J. Immunol. 168, 2704–2711 (2002).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank L. Chasson and the mouse functional genomics platform of the Marseille-Nice Genopole for immunohistochemistry; B. Malissen, J. Ewbank, C. Luci and S. Ugolini for discussions; and N. Fuseri (Innate-Pharma, Marseille) for mouse housing. FTY720 was provided by V. Brinkmann (Novartis). Supported by European Union Sixth Framework Programme, LSHB-CT-2004-503319-Allostem, Ligue Nationale contre le Cancer ('Equipe labellisée La Ligue'), Agence Nationale de la Recherche ('Réseau Innovation Biotechnologies' and 'Microbiologie Immunologie–Maladies Emergentes'”), Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique and Ministère de l'Enseignement Supérieur et de la Recherche.

Author information

Authors and Affiliations

Authors

Contributions

T.W. and E.V. designed the experiments and wrote the paper; T.W. did experiments for Figures 2, 3, 4, 5, 6, 7; L.C. did experiments for Figures 2 and 6 and Supplementary Figure 3; J.C. did experiments for Figures 1 and 5; A.C. provided S1P5-deficient mice, Y.J. and L.G.-A. provided RLI; E.T. did experiments for Supplementary Figure 2; M.B. contributed to analysis of the results; and C.C. did experiments not shown and contributed to analysis of the results.

Corresponding authors

Correspondence to Thierry Walzer or Eric Vivier.

Ethics declarations

Competing interests

A.C. is an employee of Glaxo-SmithKline; E.V. is a c-founder and shareholder of Innate-Pharma.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3 and Table 1 (PDF 1734 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Walzer, T., Chiossone, L., Chaix, J. et al. Natural killer cell trafficking in vivo requires a dedicated sphingosine 1-phosphate receptor. Nat Immunol 8, 1337–1344 (2007). https://doi.org/10.1038/ni1523

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni1523

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing