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:

Interaction of the selectin ligand PSGL-1 with chemokines CCL21 and CCL19 facilitates efficient homing of T cells to secondary lymphoid organs

Nature Immunology volume 8, pages 532–539 (2007)Cite this article

Abstract

P-selectin glycoprotein ligand 1 (PSGL-1) is central to the trafficking of immune effector cells to areas of inflammation through direct interactions with P-selectin, E-selectin and L-selectin. Here we show that PSGL-1 was also required for efficient homing of resting T cells to secondary lymphoid organs but functioned independently of selectin binding. PSGL-1 mediated an enhanced chemotactic T cell response to the secondary lymphoid organ chemokines CCL21 and CCL19 but not to CXCL12 or to inflammatory chemokines. Our data show involvement of PSGL-1 in facilitating the entry of T cells into secondary lymphoid organs, thereby demonstrating the bifunctional nature of this molecule.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: PSGL-1 is required for efficient homing of lymphocytes to SLOs.
Figure 2: The effect of PSGL-1 on homing to SLOs is restricted to resting T lymphocytes.
Figure 3: The contribution of PSGL-1 in the homing to SLOs is not dependent on its interaction with selectins.
Figure 4: PSGL-1 is required for efficient chemotaxis to CCL21 and CCL19 but not to CXCL12.
Figure 5: PSGL-1 binds CCL21.
Figure 6: Chemotactic advantage of wild-type over PSGL-1-null T cells is blocked by mAb 4RA10 (to PSGL-1).
Figure 7: Core 2 O-glycan branch formation on PSGL-1 causes loss of enhanced chemotaxis on activated T cells.

Similar content being viewed by others

References

  1. von Andrian, U.H. & Mempel, T.R. Homing and cellular traffic in lymph nodes. Nat. Rev. Immunol. 3, 867–878 (2003).

    Article  CAS  Google Scholar 

  2. Rosen, S.D. Ligands for L-selectin: homing, inflammation, and beyond. Annu. Rev. Immunol. 22, 129–156 (2004).

    Article  CAS  Google Scholar 

  3. Miyasaka, M. & Tanaka, T. Lymphocyte trafficking across high endothelial venules: dogmas and enigmas. Nat. Rev. Immunol. 4, 360–370 (2004).

    Article  CAS  Google Scholar 

  4. Forster, R. et al. CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell 99, 23–33 (1999).

    Article  CAS  Google Scholar 

  5. Gunn, M.D. et al. Mice lacking expression of secondary lymphoid organ chemokine have defects in lymphocyte homing and dendritic cell localization. J. Exp. Med. 189, 451–460 (1999).

    Article  CAS  Google Scholar 

  6. Weninger, W. & von Andrian, U.H. Chemokine regulation of naive T cell traffic in health and disease. Semin. Immunol. 15, 257–270 (2003).

    Article  CAS  Google Scholar 

  7. Campbell, J.J. & Butcher, E.C. Chemokines in tissue-specific and microenvironment-specific lymphocyte homing. Curr. Opin. Immunol. 12, 336–341 (2000).

    Article  CAS  Google Scholar 

  8. Lowe, J.B. Glycan-dependent leukocyte adhesion and recruitment in inflammation. Curr. Opin. Cell Biol. 15, 531–538 (2003).

    Article  CAS  Google Scholar 

  9. Okada, T. et al. Chemokine requirements for B cell entry to lymph nodes and Peyer's patches. J. Exp. Med. 196, 65–75 (2002).

    Article  CAS  Google Scholar 

  10. Tang, M.L., Steeber, D.A., Zhang, X.Q. & Tedder, T.F. Intrinsic differences in L-selectin expression levels affect T and B lymphocyte subset-specific recirculation pathways. J. Immunol. 160, 5113–5121 (1998).

    CAS  PubMed  Google Scholar 

  11. Gauguet, J.M., Rosen, S.D., Marth, J.D. & von Andrian, U.H. Core 2 branching β1,6-N-acetylglucosaminyltransferase and high endothelial cell N-acetylglucosamine-6-sulfotransferase exert differential control over B- and T-lymphocyte homing to peripheral lymph nodes. Blood 104, 4104–4112 (2004).

    Article  CAS  Google Scholar 

  12. Sackstein, R. The lymphocyte homing receptors: gatekeepers of the multistep paradigm. Curr. Opin. Hematol. 12, 444–450 (2005).

    Article  Google Scholar 

  13. Ley, K. The role of selectins in inflammation and disease. Trends Mol. Med. 9, 263–268 (2003).

    Article  CAS  Google Scholar 

  14. Rossi, F.M. et al. Recruitment of adult thymic progenitors is regulated by P-selectin and its ligand PSGL-1. Nat. Immunol. 6, 626–634 (2005).

    Article  CAS  Google Scholar 

  15. Uchimura, K. et al. A major class of L-selectin ligands is eliminated in mice deficient in two sulfotransferases expressed in high endothelial venules. Nat. Immunol. 6, 1105–1113 (2005).

    Article  CAS  Google Scholar 

  16. Kawashima, H. et al. N-acetylglucosamine-6-O-sulfotransferases 1 and 2 cooperatively control lymphocyte homing through L-selectin ligand biosynthesis in high endothelial venules. Nat. Immunol. 6, 1096–1104 (2005).

    Article  CAS  Google Scholar 

  17. Ley, K. & Kansas, G.S. Selectins in T-cell recruitment to non-lymphoid tissues and sites of inflammation. Nat. Rev. Immunol. 4, 325–335 (2004).

    Article  CAS  Google Scholar 

  18. Spertini, O., Cordey, A.S., Monai, N., Giuffre, L. & Schapira, M. P-selectin glycoprotein ligand 1 is a ligand for L-selectin on neutrophils, monocytes, and CD34+ hematopoietic progenitor cells. J. Cell Biol. 135, 523–531 (1996).

    Article  CAS  Google Scholar 

  19. Martinez, M. et al. Regulation of PSGL-1 interactions with L-selectin, P-selectin, and E-selectin: role of human fucosyltransferase-IV and -VII. J. Biol. Chem. 280, 5378–5390 (2005).

    Article  CAS  Google Scholar 

  20. Ellies, L.G. et al. Core 2 oligosaccharide biosynthesis distinguishes between selectin ligands essential for leukocyte homing and inflammation. Immunity 9, 881–890 (1998).

    Article  CAS  Google Scholar 

  21. Pilkington, K.R., Clark-Lewis, I. & McColl, S.R. Inhibition of generation of cytotoxic T lymphocyte activity by a CCL19/macrophage inflammatory protein (MIP)-3β antagonist. J. Biol. Chem. 279, 40276–40282 (2004).

    Article  CAS  Google Scholar 

  22. Hirata, T. et al. Human P-selectin glycoprotein ligand-1 (PSGL-1) interacts with the skin-associated chemokine CCL27 via sulfated tyrosines at the PSGL-1 amino terminus. J. Biol. Chem. 279, 51775–51782 (2004).

    Article  CAS  Google Scholar 

  23. Fukuda, M. Leukosialin, a major O-glycan-containing sialoglycoprotein defining leukocyte differentiation and malignancy. Glycobiology 1, 347–356 (1991).

    Article  CAS  Google Scholar 

  24. Baekkevold, E.S. et al. The CCR7 ligand elc (CCL19) is transcytosed in high endothelial venules and mediates T cell recruitment. J. Exp. Med. 193, 1105–1112 (2001).

    Article  CAS  Google Scholar 

  25. Scimone, M.L. et al. CXCL12 mediates CCR7-independent homing of central memory cells, but not naive T cells, in peripheral lymph nodes. J. Exp. Med. 199, 1113–1120 (2004).

    Article  CAS  Google Scholar 

  26. Yoshida, R. et al. Secondary lymphoid-tissue chemokine is a functional ligand for the CC chemokine receptor CCR7. J. Biol. Chem. 273, 7118–7122 (1998).

    Article  CAS  Google Scholar 

  27. Hirose, J., Kawashima, H., Yoshie, O., Tashiro, K. & Miyasaka, M. Versican interacts with chemokines and modulates cellular responses. J. Biol. Chem. 276, 5228–5234 (2001).

    Article  CAS  Google Scholar 

  28. Frenette, P.S. et al. P-Selectin glycoprotein ligand 1 (PSGL-1) is expressed on platelets and can mediate platelet-endothelial interactions in vivo. J. Exp. Med. 191, 1413–1422 (2000).

    Article  CAS  Google Scholar 

  29. Loetscher, M. et al. Chemokine receptor specific for IP10 and mig: structure, function, and expression in activated T-lymphocytes. J. Exp. Med. 184, 963–969 (1996).

    Article  CAS  Google Scholar 

  30. Willimann, K. et al. The chemokine SLC is expressed in T cell areas of lymph nodes and mucosal lymphoid tissues and attracts activated T cells via CCR7. Eur. J. Immunol. 28, 2025–2034 (1998).

    Article  CAS  Google Scholar 

  31. Xia, L. et al. N-terminal residues in murine P-selectin glycoprotein ligand-1 required for binding to murine P-selectin. Blood 101, 552–559 (2003).

    Article  CAS  Google Scholar 

  32. Li, F. et al. Visualization of P-selectin glycoprotein ligand-1 as a highly extended molecule and mapping of protein epitopes for monoclonal antibodies. J. Biol. Chem. 271, 6342–6348 (1996).

    Article  CAS  Google Scholar 

  33. Moore, K.L. et al. P-selectin glycoprotein ligand-1 mediates rolling of human neutrophils on P-selectin. J. Cell Biol. 128, 661–671 (1995).

    Article  CAS  Google Scholar 

  34. Hidari, K.I., Weyrich, A.S., Zimmerman, G.A. & McEver, R.P. Engagement of P-selectin glycoprotein ligand-1 enhances tyrosine phosphorylation and activates mitogen-activated protein kinases in human neutrophils. J. Biol. Chem. 272, 28750–28756 (1997).

    Article  CAS  Google Scholar 

  35. Ba, X., Chen, C., Gao, Y. & Zeng, X. Signaling function of PSGL-1 in neutrophil: tyrosine-phosphorylation-dependent and c-Abl-involved alteration in the F-actin-based cytoskeleton. J. Cell. Biochem. 94, 365–373 (2005).

    Article  CAS  Google Scholar 

  36. Galkina, E. et al. L-selectin shedding does not regulate constitutive T cell trafficking but controls the migration pathways of antigen-activated T lymphocytes. J. Exp. Med. 198, 1323–1335 (2003).

    Article  CAS  Google Scholar 

  37. Rivera-Nieves, J. et al. Critical role of endothelial P-selectin glycoprotein ligand 1 in chronic murine ileitis. J. Exp. Med. 203, 907–917 (2006).

    Article  CAS  Google Scholar 

  38. Hicks, A.E., Nolan, S.L., Ridger, V.C., Hellewell, P.G. & Norman, K.E. Recombinant P-selectin glycoprotein ligand-1 directly inhibits leukocyte rolling by all 3 selectins in vivo: complete inhibition of rolling is not required for anti-inflammatory effect. Blood 101, 3249–3256 (2003).

    Article  CAS  Google Scholar 

  39. Sumariwalla, P.F., Malfait, A.M. & Feldmann, M. P-selectin glycoprotein ligand 1 therapy ameliorates established collagen-induced arthritis in DBA/1 mice partly through the suppression of tumour necrosis factor. Clin. Exp. Immunol. 136, 67–75 (2004).

    Article  CAS  Google Scholar 

  40. Clark-Lewis, I., Mattioli, I., Gong, J.H. & Loetscher, P. Structure-function relationship between the human chemokine receptor CXCR3 and its ligands. J. Biol. Chem. 278, 289–295 (2003).

    Article  CAS  Google Scholar 

  41. Carlow, D.A., Corbel, S.Y. & Ziltener, H.J. Absence of CD43 fails to alter T cell development and responsiveness. J. Immunol. 166, 256–261 (2001).

    Article  CAS  Google Scholar 

  42. Bullard, D.C. et al. Infectious susceptibility and severe deficiency of leukocyte rolling and recruitment in E-selectin and P-selectin double mutant mice. J. Exp. Med. 183, 2329–2336 (1996).

    Article  CAS  Google Scholar 

  43. Corbel, S.Y. et al. Contribution of hematopoietic stem cells to skeletal muscle. Nat. Med. 9, 1528–1532 (2003).

    Article  CAS  Google Scholar 

  44. Merzaban, J.S., Zuccolo, J., Corbel, S.Y., Williams, M.J. & Ziltener, H.J. An alternate core 2 β1,6-N-acetylglucosaminyltransferase selectively contributes to P-selectin ligand formation in activated CD8 T cells. J. Immunol. 174, 4051–4059 (2005).

    Article  CAS  Google Scholar 

  45. McLean, G.R., Nakouzi, A., Casadevall, A. & Green, N.S. Human and murine immunoglobulin expression vector cassettes. Mol. Immunol. 37, 837–845 (2000).

    Article  CAS  Google Scholar 

  46. Drew, E., Merzaban, J.S., Seo, W., Ziltener, H.J. & McNagny, K.M. CD34 and CD43 inhibit mast cell adhesion and are required for optimal mast cell reconstitution. Immunity 22, 43–57 (2005).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank R. Beavis for discussions; K.M. McNagny for critically reading the manuscript; P.D. Ziltener and M.J. Ford for technical assistance; J. Marth (University of California at San Diego) for C2GlcNAcT-1-deficient mice; D.C. Bullard (University of Alabama) for E-selectin-deficient mice; I. Weissman (Stanford University) for mice expressing GFP; G. McLean (University of Texas Health Sciences Center at Houston) for the vector encoding for human IgG1; and F. Melchers (Basel Institute of Immunology) for myeloma X.653 cells transfected with cDNA encoding mouse IL-2. Supported by the National Institutes of Health (R01GM57411 and R01GM23547 to S.D.R.), the Canadian Institutes for Health Research (J.S.M.; MOP-64267 and MOP-77552 to H.J.Z.) and Deutsche Forschungsgemeinschaft (S.N.)

Author information

Author notes

  1. Kenji Uchimura & Jasmeen S Merzaban

    Present address: Present addresses: National Institute for Longevity Sciences, 36-3 Gengo, Morioka, Obu, Aichi 474-8511, Japan (K.U.), and Harvard Institutes of Medicine, Boston, Massachusetts 02115, USA (J.S.M.).,

  2. Krystle M Veerman and Michael J Williams: These authors contributed equally to this work.

Authors and Affiliations

  1. The Biomedical Research Centre, University of British Columbia, Vancouver, V6T 1Z3, British Columbia, Canada

    Krystle M Veerman, Michael J Williams, Jasmeen S Merzaban, Silvia Naus, Douglas A Carlow, Philip Owen & Hermann J Ziltener

  2. Department of Anatomy and Program in Immunology, University of California, San Francisco, San Francisco, 94143-0452, California, USA

    Kenji Uchimura, Mark S Singer & Steven D Rosen

  3. Digestive Health Center of Excellence, University of Virginia Health Sciences Center, Charlottesville, 22908, Virginia, USA

    Jesús Rivera-Nieves

  4. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, V6T 1Z3, British Columbia, Canada

    Hermann J Ziltener

Authors
  1. Krystle M Veerman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael J Williams
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kenji Uchimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mark S Singer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jasmeen S Merzaban
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Silvia Naus
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Douglas A Carlow
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Philip Owen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jesús Rivera-Nieves
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Steven D Rosen
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hermann J Ziltener
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.S.M., H.J.Z. and K.U., S.D.R. independently discovered the PSGL-1 requirement for T cell homing; K.M.V. did the competitive homing assays; K.U. and M.S.S. did the mAb inhibition homing assays; M.J.W. designed and did the chemotaxis and CCL21 binding assays; S.N. contributed to the CCL21 binding studies; D.A.C. contributed to the experimental design of the competitive in vivo and in vitro studies; P.O. produced all chemokines; J.R.-N. provided anti-PSGL-1 and helped with the inhibition studies; H.J.Z. and S.D.R. supervised research and coordinated ongoing work; K.M.V. and H.J.Z. wrote the first draft of the manuscript; and all authors contributed to discussions and preparation of the manuscript.

Corresponding author

Correspondence to Hermann J Ziltener.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

SLO homing and chemotactic migration rates are not influenced by fluorescent labeling of lymphocytes. (PDF 11 kb)

Supplementary Fig. 2

The PSGL-1 influence on homing of lymphocytes to SLO is independent of C2GlcNAcT-I. (PDF 12 kb)

Supplementary Fig. 3

CD4+ and CD8+ T cells express more PSGL-1 than B220+ B cells. (PDF 24 kb)

Supplementary Fig. 4

Sodium azide blocks CCL21 internalization but diminishes the degree of PSGL-1 dependent CCL21 binding. (PDF 18 kb)

Supplementary Table 1

Raw data collected and used to calculate the differences in homing between anti-PSGL-1 mAb treated and IgG1 control treated lymphocytes. (PDF 8 kb)

Supplementary Table 2

Raw data collected and used to calculate the differences in homing between PSGL-1 knockout and WT lymphocytes. (PDF 12 kb)

Supplementary Table 3

Raw data collected and used to calculate the differences in homing between PSGL-1 knockout and WT lymphocytes. (PDF 9 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Veerman, K., Williams, M., Uchimura, K. et al. Interaction of the selectin ligand PSGL-1 with chemokines CCL21 and CCL19 facilitates efficient homing of T cells to secondary lymphoid organs. Nat Immunol 8, 532–539 (2007). https://doi.org/10.1038/ni1456

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni1456

This article is cited by

Search

Advanced 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