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:

ECM1 controls TH2 cell egress from lymph nodes through re-expression of S1P1

Abstract

Type 2 helper T cells (TH2) are critically involved in allergies and asthma. Here we demonstrate that extracellular matrix protein-1 (ECM1) is highly and selectively expressed in TH2 cells. ECM1 deficiency caused impaired TH2 responses and reduced allergic airway inflammation in vivo. Functional analysis demonstrated that although the TH2 polarization of ECM1-deficient cells was unimpaired, these cells had a defect in migration and were retained in peripheral lymphoid organs. This was associated with reduced expression of KLF2 and S1P1. We also found that ECM1 could directly bind the interleukin-2 (IL-2) receptor to inhibit IL-2 signaling and activate S1P1 expression. Our data identify a previously unknown function of ECM1 in regulating TH2 cell migration through control of KLF2 and S1P1 expression.

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: ECM1 is specifically expressed by TH2 cells.
Figure 2: ECM1 expression is regulated by STAT6 and GATA-3.
Figure 3: Proliferation and lineage commitment are unaltered in T cells from ECM1-deficient mice.
Figure 4: ECM1[BM]-deficient mice show impaired TH2 function owing to defective TH2 cell migration in vivo.
Figure 5: ECM1 functions in control of TH2 cell migration.
Figure 6: ECM1 deficiency reduces expression of S1P1 in TH2 cells.
Figure 7: Secreted ECM1 functions through extracellular pathways.
Figure 8: ECM1 promotes S1P1 expression by binding to IL-2R and inhibiting IL-2 signaling.

Similar content being viewed by others

Accession codes

Accessions

Gene Expression Omnibus

References

  1. Scharton, T.M. & Scott, P. Natural killer cells are a source of interferon gamma that drives differentiation of CD4+ T cell subsets and induces early resistance to Leishmania major in mice. J. Exp. Med. 178, 567–577 (1993).

    Article  CAS  Google Scholar 

  2. Mosmann, T.R. & Coffman, R.L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu. Rev. Immunol. 7, 145–173 (1989).

    CAS  Google Scholar 

  3. Weaver, C.T., Harrington, L.E., Mangan, P.R., Gavrieli, M. & Murphy, K.M. Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 24, 677–688 (2006).

    Article  CAS  Google Scholar 

  4. Zhu, J. & Paul, W.E. CD4 T cells: fates, functions, and faults. Blood 112, 1557–1569 (2008).

    Article  CAS  Google Scholar 

  5. Dong, C. TH17 cells in development: an updated view of their molecular identity and genetic programming. Nature Rev. Immunol. 8, 337–348 (2008).

    Article  CAS  Google Scholar 

  6. Murphy, K.M. & Reiner, S.L. The lineage decisions of helper T cells. Nature Rev. Immunol. 2, 933–944 (2002).

    Article  CAS  Google Scholar 

  7. Rosen, H. et al. Modulating tone: the overture of S1P receptor immunotherapeutics. Immunol. Rev. 223, 221–235 (2008).

    Article  CAS  Google Scholar 

  8. Schwab, S.R. & Cyster, J.G. Finding a way out: lymphocyte egress from lymphoid organs. Nat. Immunol. 8, 1295–1301 (2007).

    Article  CAS  Google Scholar 

  9. Rivera, J., Proia, R.L. & Olivera, A. The alliance of sphingosine-1-phosphate and its receptors in immunity. Nature Rev. Immunol. 8, 753–763 (2008).

    Article  CAS  Google Scholar 

  10. 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  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  13. 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  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  15. Chi, H. & Flavell, R.A. Cutting edge: regulation of T cell trafficking and primary immune responses by sphingosine 1-phosphate receptor 1. J. Immunol. 174, 2485–2488 (2005).

    Article  CAS  Google Scholar 

  16. Gräler, M.H., Huang, M.C., Watson, S. & Goetzl, E.J. Immunological effects of transgenic constitutive expression of the type 1 sphingosine 1-phosphate receptor by mouse lymphocytes. J. Immunol. 174, 1997–2003 (2005).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  18. Bhalerao, J., Tylzanowski, P., Filie, J.D., Kozak, C.A. & Merregaert, J. Molecular cloning, characterization, and genetic mapping of the cDNA coding for a novel secretory protein of mouse. Demonstration of alternative splicing in skin and cartilage. J. Biol. Chem. 270, 16385–16394 (1995).

    Article  CAS  Google Scholar 

  19. Mongiat, M. et al. Perlecan protein core interacts with extracellular matrix protein 1 (ECM1), a glycoprotein involved in bone formation and angiogenesis. J. Biol. Chem. 278, 17491–17499 (2003).

    Article  CAS  Google Scholar 

  20. Hamada, T. Lipoid proteinosis. Clin. Exp. Dermatol. 27, 624–629 (2002).

    Article  CAS  Google Scholar 

  21. Han, Z. et al. Extracellular matrix protein 1 (ECM1) has angiogenic properties and is expressed by breast tumor cells. FASEB J. 15, 988–994 (2001).

    Article  CAS  Google Scholar 

  22. Wang, L. et al. Extracellular matrix protein 1 (ECM1) is over-expressed in malignant epithelial tumors. Cancer Lett. 200, 57–67 (2003).

    Article  CAS  Google Scholar 

  23. Liu, Z. et al. Dec2 promotes Th2 cell differentiation by enhancing IL-2R signaling. J. Immunol. 183, 6320–6329 (2009).

    Article  CAS  Google Scholar 

  24. Luger, D. et al. Either a Th17 or a Th1 effector response can drive autoimmunity: conditions of disease induction affect dominant effector category. J. Exp. Med. 205, 799–810 (2008).

    Article  CAS  Google Scholar 

  25. Carlson, C.M. et al. Kruppel-like factor 2 regulates thymocyte and T-cell migration. Nature 442, 299–302 (2006).

    Article  CAS  Google Scholar 

  26. Kerdiles, Y.M. et al. Foxo1 links homing and survival of naive T cells by regulating L-selectin, CCR7 and interleukin 7 receptor. Nat. Immunol. 10, 176–184 (2009).

    Article  CAS  Google Scholar 

  27. Sinclair, L.V. et al. Phosphatidylinositol-3-OH kinase and nutrient-sensing mTOR pathways control T lymphocyte trafficking. Nat. Immunol. 9, 513–521 (2008).

    Article  CAS  Google Scholar 

  28. Leonard, W.J. & O′Shea, J.J. Jaks and STATs: biological implications. Annu. Rev. Immunol. 16, 293–322 (1998).

    Article  CAS  Google Scholar 

  29. Miller, J.D., Stevens, E.T., Smith, D.R., Wight, T.N. & Wrenshall, L.E. Perlecan: a major IL-2-binding proteoglycan in murine spleen. Immunol. Cell Biol. 86, 192–199 (2008).

    Article  CAS  Google Scholar 

  30. Kuznetsova, S.A. & Roberts, D.D. Functional regulation of T lymphocytes by modulatory extracellular matrix proteins. Int. J. Biochem. Cell Biol. 36, 1126–1134 (2004).

    Article  CAS  Google Scholar 

  31. Medoff, B.D., Thomas, S.Y. & Luster, A.D. T cell trafficking in allergic asthma: the ins and outs. Annu. Rev. Immunol. 26, 205–232 (2008).

    Article  CAS  Google Scholar 

  32. Dang, X., Raffler, N.A. & Ley, K. Transcriptional regulation of mouse L-selectin. Biochim. Biophys. Acta 1789, 146–152 (2009).

    Article  CAS  Google Scholar 

  33. Le Gros, G., Ben-Sasson, S.Z., Seder, R., Finkelman, F.D. & Paul, W.E. Generation of interleukin 4 (IL-4)-producing cells in vivo and in vitro: IL-2 and IL-4 are required for in vitro generation of IL-4-producing cells. J. Exp. Med. 172, 921–929 (1990).

    Article  CAS  Google Scholar 

  34. Hou, W. et al. Pertussis toxin enhances Th1 responses by stimulation of dendritic cells. J. Immunol. 170, 1728–1736 (2003).

    Article  CAS  Google Scholar 

  35. Wang, Y. et al. Trichosanthin functions as Th2-type adjuvant in induction of allergic airway inflammation. Cell Res. 19, 962–972 (2009).

    Article  CAS  Google Scholar 

  36. Wu, X. et al. Novel function of IFN-gamma: negative regulation of dendritic cell migration and T cell priming. J. Immunol. 177, 934–943 (2006).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank R. Caspi, Y. He, Y. Zhuang, H. Gu, W. Zhang, Y. Liu and D. Li for helpful comments about this paper, S. Skinner for reviewing the manuscript, and X. Zhu for help with the experiments. This work was supported by grants from the National Natural Science Foundation of China (30623003, 31030029, 30721065, 30801011, 90713044, 30870126, 30950002), a Chinese Academy of Sciences project (KSCX2-YW-R-161, KSCX2-YW-R-169), the Technology Commission of Shanghai Municipality (08DZ2291703, 088014199, 08431903004), the National 973 key project (2007CB512404), the National 863 project (2006AA02A247), an EU project (SP5B-CT-2006-044161), a China National Science and Technology Major Project (2008ZX10002-014, 2008ZX10004-002, 2009ZX10004-105, 2009ZX10004-016), the China National Ministry of Science and Technology (20072714), the Shanghai Pasteur Health Research Foundation (SPHRF2008001, SPHRF2009001), the E-institutes of the Shanghai Universities Immunology Division and the Li Kha Shing Foundation.

Author information

Authors and Affiliations

Authors

Contributions

Z. Li designed (with help from Z. Liu) and performed mouse experiments and in vitro cell culture experiments, analyzed data and wrote the manuscript; Y. Zhang did all western blotting and real-time PCR experiments and helped in mouse experiments and analyzing data; X.W., K.M. and Y. Zheng helped in mouse experiments; Z.T. bred mice and confirmed the Ecm1−/− genotype; J.W. helped with immunoprecipitation experiments; G.L., L.T. and Y.J. made two ECM1 antibodies; M.Q. supplied reagents; S.S. performed flow cytometry; X.Z. helped design experiments and edit the manuscript; and B.S. conceived of the research, directed the study and edited the manuscript.

Corresponding author

Correspondence to Bing Sun.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–10 (PDF 631 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, Z., Zhang, Y., Liu, Z. et al. ECM1 controls TH2 cell egress from lymph nodes through re-expression of S1P1. Nat Immunol 12, 178–185 (2011). https://doi.org/10.1038/ni.1983

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.1983

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