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:

Regulation of effector T cells by antigen-presenting cells via interaction of the C-type lectin MGL with CD45

Nature Immunology volume 7, pages 1200–1208 (2006)Cite this article

Abstract

Homeostatic control of T cells involves tight regulation of effector T cells to prevent excessive activation that can cause tissue damage and autoimmunity. Little is known, however, about whether antigen-presenting cells (APCs) are also involved in maintaining immune system homeostasis once effector T cells are stimulated. Here we found that immature APCs downregulated effector T cell function by a mechanism involving the C-type lectin MGL expressed by APCs. Glycosylation-dependent interactions of MGL with CD45 on effector T cells negatively regulated T cell receptor–mediated signaling and T cell–dependent cytokine responses, which in turn decreased T cell proliferation and increased T cell death. Thus, regulation of effector T cells by MGL expressed on APCs may provide a target for regulating chronic inflammatory and autoimmune diseases.

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: MGL expression in tissues and on APCs generated in vitro.
Figure 2: MGL binds CD45 on human lymphocytes.
Figure 3: Binding of MGL downregulates CD45 phosphatase activity and TCR-mediated calcium mobilization.
Figure 4: MGL induces CD45-dependent cell death.
Figure 5: MGL on dexamethasone-treated APCs provides negative regulatory signals to human Teff cells via CD45.

Similar content being viewed by others

References

  1. Janeway, C.A. & Medzhitov, R. Innate immune recognition. Annu. Rev. Immunol. 20, 197–216 (2002).

    Article  CAS  Google Scholar 

  2. Steinman, R.M., Hawiger, D. & Nussenzweig, M.C. Tolerogenic dendritic cells. Annu. Rev. Immunol. 21, 685–711 (2003).

    Article  CAS  Google Scholar 

  3. Mosser, D.M. The many faces of macrophage activation. J. Leukoc. Biol. 73, 209–212 (2003).

    Article  CAS  Google Scholar 

  4. Piemonti, L. et al. Glucocorticoids affect human dendritic cell differentiation and maturation. J. Immunol. 162, 6473–6481 (1999).

    CAS  PubMed  Google Scholar 

  5. Schebesch, C. et al. Alternatively activated macrophages actively inhibit proliferation of peripheral blood lymphocytes and CD4+ T cells in vitro. Immunology 92, 478–486 (1997).

    Article  CAS  Google Scholar 

  6. Figdor, C.G., van Kooyk, Y. & Adema, G.J. C-type lectin receptors on dendritic cells and Langerhans cells. Nat. Rev. Immunol. 2, 77–84 (2002).

    Article  CAS  Google Scholar 

  7. Geijtenbeek, T.B., van Vliet, S.J., Engering, A., 't Hart, B.A. & van Kooyk, Y. Self- and nonself-recognition by C-type lectins on dendritic cells. Annu. Rev. Immunol. 22, 33–54 (2004).

    CAS  PubMed  Google Scholar 

  8. Engering, A. et al. The dendritic cell-specific adhesion receptor DC-SIGN internalizes antigen for presentation to T cells. J. Immunol. 168, 2118–2126 (2002).

    Article  CAS  Google Scholar 

  9. Bonifaz, L. et al. Efficient targeting of protein antigen to the dendritic cell receptor DEC-205 in the steady state leads to antigen presentation on major histocompatibility complex class I products and peripheral CD8+ T cell tolerance. J. Exp. Med. 196, 1627–1638 (2002).

    Article  CAS  Google Scholar 

  10. Gantner, B.N., Simmons, R.M., Canavera, S.J., Akira, S. & Underhill, D.M. Collaborative induction of inflammatory responses by dectin-1 and Toll-like receptor 2. J. Exp. Med. 197, 1107–1117 (2003).

    Article  CAS  Google Scholar 

  11. Raes, G. et al. Macrophage galactose-type C-type lectins as novel markers for alternatively activated macrophages elicited by parasitic infections and allergic airway inflammation. J. Leukoc. Biol. 77, 321–327 (2005).

    Article  CAS  Google Scholar 

  12. Higashi, N. et al. The macrophage C-type lectin specific for galactose/N-acetylgalactosamine is an endocytic receptor expressed on monocyte-derived immature dendritic cells. J. Biol. Chem. 277, 20686–20693 (2002).

    Article  CAS  Google Scholar 

  13. van Vliet, S.J. et al. Carbohydrate profiling reveals a distinctive role for the C-type lectin MGL in the recognition of helminth parasites and tumor antigens by dendritic cells. Int. Immunol. 17, 661–669 (2005).

    Article  CAS  Google Scholar 

  14. Tsuiji, M. et al. Molecular cloning and characterization of a novel mouse macrophage C-type lectin, mMGL2, which has a distinct carbohydrate specificity from mMGL1. J. Biol. Chem. 277, 28892–28901 (2002).

    Article  CAS  Google Scholar 

  15. Hermiston, M.L., Xu, Z. & Weiss, A. CD45: a critical regulator of signaling thresholds in immune cells. Annu. Rev. Immunol. 21, 107–137 (2003).

    Article  CAS  Google Scholar 

  16. Furukawa, K. et al. Structural study of the O-linked sugar chains of human leukocyte tyrosine phosphatase CD45. Eur. J. Biochem. 251, 288–294 (1998).

    Article  CAS  Google Scholar 

  17. Zapata, J.M., Pulido, R., Acevedo, A., Sanchez-Madrid, F. & de Landazuri, M.O. Human CD45RC specificity. A novel marker for T cells at different maturation and activation stages. J. Immunol. 152, 3852–3861 (1994).

    CAS  PubMed  Google Scholar 

  18. Garcia, G.G., Berger, S.B., Sadighi Akha, A.A. & Miller, R.A. Age-associated changes in glycosylation of CD43 and CD45 on mouse CD4 T cells. Eur. J. Immunol. 35, 622–631 (2005).

    Article  CAS  Google Scholar 

  19. Daniels, M.A., Hogquist, K.A. & Jameson, S.C. Sweet 'n' sour: the impact of differential glycosylation on T cell responses. Nat. Immunol. 3, 903–910 (2002).

    Article  CAS  Google Scholar 

  20. Geijtenbeek, T.B. et al. Identification of DC-SIGN, a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses. Cell 100, 575–585 (2000).

    Article  CAS  Google Scholar 

  21. Puig-Kroger, A. et al. Regulated expression of the pathogen receptor dendritic cell-specific intercellular adhesion molecule 3 (ICAM-3)-grabbing nonintegrin in THP-1 human leukemic cells, monocytes, and macrophages. J. Biol. Chem. 279, 25680–25688 (2004).

    Article  Google Scholar 

  22. Carlsson, S.R. & Fukuda, M. Isolation and characterization of leukosialin, a major sialoglycoprotein on human leukocytes. J. Biol. Chem. 261, 12779–12786 (1986).

    CAS  PubMed  Google Scholar 

  23. Rogers, P.R., Pilapil, S., Hayakawa, K., Romain, P.L. & Parker, D.C. CD45 alternative exon expression in murine and human CD4+ T cell subsets. J. Immunol. 148, 4054–4065 (1992).

    CAS  PubMed  Google Scholar 

  24. Abraham, R.T. & Weiss, A. Jurkat T cells and development of the T-cell receptor signalling paradigm. Nat. Rev. Immunol. 4, 301–308 (2004).

    Article  CAS  Google Scholar 

  25. Xu, Z. & Weiss, A. Negative regulation of CD45 by differential homodimerization of the alternatively spliced isoforms. Nat. Immunol. 3, 764–771 (2002).

    Article  CAS  Google Scholar 

  26. Chu, D.H. et al. The Syk protein tyrosine kinase can function independently of CD45 or Lck in T cell antigen receptor signaling. EMBO J. 15, 6251–6261 (1996).

    Article  CAS  Google Scholar 

  27. Hintzen, R.Q. et al. Regulation of CD27 expression on subsets of mature T-lymphocytes. J. Immunol. 151, 2426–2435 (1993).

    CAS  PubMed  Google Scholar 

  28. Xia, C.Q., Peng, R., Beato, F. & Clare-Salzler, M.J. Dexamethasone induces IL-10-producing monocyte-derived dendritic cells with durable immaturity. Scand. J. Immunol. 62, 45–54 (2005).

    Article  CAS  Google Scholar 

  29. Ju, T. & Cummings, R.D. A unique molecular chaperone Cosmc required for activity of the mammalian core 1 β3-galactosyltransferase. Proc. Natl. Acad. Sci. USA 99, 16613–16618 (2002).

    Article  CAS  Google Scholar 

  30. Ohta, T., Kitamura, K., Maizel, A.L. & Takeda, A. Alterations in CD45 glycosylation pattern accompanying different cell proliferation states. Biochem. Biophys. Res. Commun. 200, 1283–1289 (1994).

    Article  CAS  Google Scholar 

  31. Stamenkovic, I., Sgroi, D., Aruffo, A., Sy, M.S. & Anderson, T. The B lymphocyte adhesion molecule CD22 interacts with leukocyte common antigen CD45RO on T cells and α2–6 sialyltransferase, CD75, on B cells. Cell 66, 1133–1144 (1991).

    Article  CAS  Google Scholar 

  32. Walzel, H., Schulz, U., Neels, P. & Brock, J. Galectin-1, a natural ligand for the receptor-type protein tyrosine phosphatase CD45. Immunol. Lett. 67, 193–202 (1999).

    Article  CAS  Google Scholar 

  33. London, C.A., Lodge, M.P. & Abbas, A.K. Functional responses and costimulator dependence of memory CD4+ T cells. J. Immunol. 164, 265–272 (2000).

    Article  CAS  Google Scholar 

  34. Penninger, J.M., Irie-Sasaki, J., Sasaki, T. & Oliveira-dos-Santos, A.J. CD45: new jobs for an old acquaintance. Nat. Immunol. 2, 389–396 (2001).

    Article  CAS  Google Scholar 

  35. Majeti, R., Bilwes, A.M., Noel, J.P., Hunter, T. & Weiss, A. Dimerization-induced inhibition of receptor protein tyrosine phosphatase function through an inhibitory wedge. Science 279, 88–91 (1998).

    Article  CAS  Google Scholar 

  36. Nam, H.J., Poy, F., Saito, H. & Frederick, C.A. Structural basis for the function and regulation of the receptor protein tyrosine phosphatase CD45. J. Exp. Med. 201, 441–452 (2005).

    Article  CAS  Google Scholar 

  37. Tchilian, E.Z. & Beverley, P.C. Altered CD45 expression and disease. Trends Immunol. 27, 146–153 (2006).

    Article  CAS  Google Scholar 

  38. Irie-Sasaki, J. et al. CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling. Nature 409, 349–354 (2001).

    Article  CAS  Google Scholar 

  39. Klaus, S.J., Sidorenko, S.P. & Clark, E.A. CD45 ligation induces programmed cell death in T and B lymphocytes. J. Immunol. 156, 2743–2753 (1996).

    CAS  PubMed  Google Scholar 

  40. Fortin, M. et al. Apoptosis mediated through CD45 is independent of its phosphatase activity and association with leukocyte phosphatase-associated phosphoprotein. J. Immunol. 168, 6084–6089 (2002).

    Article  CAS  Google Scholar 

  41. Lesage, S. et al. CD4+ CD8+ thymocytes are preferentially induced to die following CD45 cross-linking, through a novel apoptotic pathway. J. Immunol. 159, 4762–4771 (1997).

    CAS  PubMed  Google Scholar 

  42. Liu, Z., Dawes, R., Petrova, S., Beverley, P.C. & Tchilian, E.Z. CD45 regulates apoptosis in peripheral T lymphocytes. Int. Immunol. 18, 959–966 (2006).

    Article  CAS  Google Scholar 

  43. Latinis, K.M. et al. Regulation of CD95 (Fas) ligand expression by TCR-mediated signaling events. J. Immunol. 158, 4602–4611 (1997).

    CAS  PubMed  Google Scholar 

  44. Powrie, F. et al. Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells. Immunity 1, 553–562 (1994).

    Article  CAS  Google Scholar 

  45. Fowell, D. & Mason, D. Evidence that the T cell repertoire of normal rats contains cells with the potential to cause diabetes. Characterization of the CD4+ T cell subset that inhibits this autoimmune potential. J. Exp. Med. 177, 627–636 (1993).

    Article  CAS  Google Scholar 

  46. Luke, P.P., O'Brien, C.A., Jevnikar, A.M. & Zhong, R. Anti-CD45RB monoclonal antibody-mediated transplantation tolerance. Curr. Mol. Med. 1, 533–543 (2001).

    Article  CAS  Google Scholar 

  47. Gregori, S. et al. An anti-CD45RO/RB monoclonal antibody modulates T cell responses via induction of apoptosis and generation of regulatory T cells. J. Exp. Med. 201, 1293–1305 (2005).

    Article  CAS  Google Scholar 

  48. Barrat, F.J. et al. In vitro generation of interleukin 10-producing regulatory CD4+ T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)- and Th2-inducing cytokines. J. Exp. Med. 195, 603–616 (2002).

    Article  CAS  Google Scholar 

  49. Kumamoto, Y. et al. Identification of sialoadhesin as a dominant lymph node counter-receptor for mouse macrophage galactose-type C-type lectin 1. J. Biol. Chem. 279, 49274–49280 (2004).

    Article  CAS  Google Scholar 

  50. van Kooyk, Y., van de Wiel-van Kemenade, P., Weder, P., Kuijpers, T.W. & Figdor, C.G. Enhancement of LFA-1-mediated cell adhesion by triggering through CD2 or CD3 on T lymphocytes. Nature 342, 811–813 (1989).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank R. van Lier and A. Weiss for discussions; F. Sánchez-Madrid for reagents; R. Mebius for critical review of the manuscript; E. van Liempt for assistance; and T. van der Pouw Kraan and T. Timmer for rheumatoid arthritis tissues. Supported by the Netherlands Organization for Health Research and Development (900-02-002 to S.J.v.V. and Y.v.K.) and Dutch Asthma Foundation 3.2.03.39 (T.B.H.G. and S.I.G.).

Author information

Authors and Affiliations

  1. Department of Molecular Cell Biology & Immunology, Vrije University Medical Center, Amsterdam, The Netherlands

    Sandra J van Vliet, Sonja I Gringhuis, Teunis B H Geijtenbeek & Yvette van Kooyk

Authors
  1. Sandra J van Vliet
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sonja I Gringhuis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Teunis B H Geijtenbeek
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yvette van Kooyk
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.J.v.V. designed and did all the experiments and prepared the manuscript; S.I.G. designed experiments; T.B.H.G. and Y.v.K. provided overall supervision, designed experiments and prepared the manuscript.

Corresponding author

Correspondence to Yvette van Kooyk.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

CD45 is a counterreceptor for MGL on lymphocytes. (PDF 178 kb)

Supplementary Fig. 2

MGL binding reduces TNF production by CD4+ and CD8+ T cells. (PDF 176 kb)

Supplementary Fig. 3

Model of MGL mediated control of effector T cell homeostasis. (PDF 251 kb)

Supplementary Table 1

MGL expression on cultured APCs. (PDF 93 kb)

Supplementary Table 2

Characterization of MGLpos APCs in skin and lymph node. (PDF 88 kb)

Supplementary Table 3

MGL-Fc recognition of hematopoietic cell lines. (PDF 54 kb)

Supplementary Table 4

Expression of co-stimulatory molecules on cultured APCs. (PDF 60 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

van Vliet, S., Gringhuis, S., Geijtenbeek, T. et al. Regulation of effector T cells by antigen-presenting cells via interaction of the C-type lectin MGL with CD45. Nat Immunol 7, 1200–1208 (2006). https://doi.org/10.1038/ni1390

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni1390

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