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:

Oral tolerance to food-induced systemic anaphylaxis mediated by the C-type lectin SIGNR1

Abstract

We propose that a C-type lectin receptor, SIGNR-1 (also called Cd209b), helps to condition dendritic cells (DCs) in the gastrointestinal lamina propria (LPDCs) for the induction of oral tolerance in a model of food-induced anaphylaxis. Oral delivery of BSA bearing 51 molecules of mannoside (Man51-BSA) substantially reduced the BSA-induced anaphylactic response. Man51-BSA selectively targeted LPDCs that expressed SIGNR1 and induced the expression of interleukin-10 (IL-10), but not IL-6 or IL-12 p70. We found the same effects in IL-10–GFP knock-in (tiger) mice treated with Man51-BSA. The Man51-BSA–SIGNR1 axis in LPDCs, both in vitro and in vivo, promoted the generation of CD4+ type 1 regulatory T (Tr1)-like cells that expressed IL-10 and interferon-γ (IFN-γ), in a SIGNR-1– and IL-10–dependent manner, but not of CD4+CD25+Foxp3+ regulatory T cells. The Tr1-like cells could transfer tolerance. These results suggest that sugar-modified antigens might be used to induce oral tolerance by targeting SIGNR1 and LPDCs.

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

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

Figure 1: Antigen-induced anaphylaxis in C3H/Hej mice.
Figure 2: Man51-BSA targets the DC subset in the lamina propria.
Figure 3: Binding analysis of neoglyco-antigens.
Figure 4: Inhibition analyses of IL-10 induction by Man51-BSA in LPDCs.
Figure 5: Analysis of cytokine expression in T cells.
Figure 6: Reversal of Man51-BSA–mediated tolerance in SIGNR1- and IL-10–deficient mice.

Similar content being viewed by others

References

  1. Coombes, J.L. & Powrie, F. Dendritic cells in intestinal immune regulation. Nat. Rev. Immunol. 8, 435–446 (2008).

    Article  CAS  Google Scholar 

  2. Chehade, M. & Mayer, L. Oral tolerance and its relation to food hypersensitivities. J. Allergy Clin. Immunol. 115, 3–12 (2005).

    Article  Google Scholar 

  3. Poulsen, L.K. In search of a new paradigm: mechanisms of sensitization and elicitation of food allergy. Allergy 60, 549–558 (2005).

    Article  CAS  Google Scholar 

  4. Finkelman, F.D. Anaphylaxis: lessons from mouse models. J. Allergy Clin. Immunol. 120, 506–515 (2007).

    Article  CAS  Google Scholar 

  5. Izcue, A., Coombes, J.L. & Powrie, F. Regulatory lymphocytes and intestinal inflammation. Annu. Rev. Immunol. 27, 313–338 (2009).

    Article  CAS  Google Scholar 

  6. Mowat, A.M. Anatomical basis of tolerance and immunity to intestinal antigens. Nat. Rev. Immunol. 3, 331–341 (2003).

    Article  CAS  Google Scholar 

  7. Chirdo, F.G., Millington, O.R., Beacock-Sharp, H. & Mowat, A.M. Immunomodulatory dendritic cells in intestinal lamina propria. Eur. J. Immunol. 35, 1831–1840 (2005).

    Article  CAS  Google Scholar 

  8. Spahn, T.W. et al. Mesenteric lymph nodes are critical for the induction of high-dose oral tolerance in the absence of Peyer's patches. Eur. J. Immunol. 32, 1109–1113 (2002).

    Article  CAS  Google Scholar 

  9. Worbs, T. et al. Oral tolerance originates in the intestinal immune system and relies on antigen carriage by dendritic cells. J. Exp. Med. 203, 519–527 (2006).

    Article  CAS  Google Scholar 

  10. Rescigno, M. et al. Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nat. Immunol. 2, 361–367 (2001).

    Article  CAS  Google Scholar 

  11. Fontenot, J.D. & Rudensky, A.Y. A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3. Nat. Immunol. 6, 331–337 (2005).

    Article  CAS  Google Scholar 

  12. Taams, L.S. et al. Regulatory T cells in human disease and their potential for therapeutic manipulation. Immunology 118, 1–9 (2006).

    Article  CAS  Google Scholar 

  13. Taylor, A., Verhagen, J., Blaser, K., Akdis, M. & Akdis, C.A. Mechanisms of immune suppression by interleukin-10 and transforming growth factor-β: the role of T regulatory cells. Immunology 117, 433–442 (2006).

    Article  CAS  Google Scholar 

  14. Coombes, J.L. et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β and retinoic acid–dependent mechanism. J. Exp. Med. 204, 1757–1764 (2007).

    Article  CAS  Google Scholar 

  15. Sun, C.M. et al. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 Treg cells via retinoic acid. J. Exp. Med. 204, 1775–1785 (2007).

    Article  CAS  Google Scholar 

  16. Bilsborough, J., George, T.C., Norment, A. & Viney, J.L. Mucosal CD8α+ DC, with a plasmacytoid phenotype, induce differentiation and support function of T cells with regulatory properties. Immunology 108, 481–492 (2003).

    Article  CAS  Google Scholar 

  17. Takeda, K., Kaisho, T. & Akira, S. Toll-like receptors. Annu. Rev. Immunol. 21, 335–376 (2003).

    Article  CAS  Google Scholar 

  18. van Kooyk, Y. & Rabinovich, G.A. Protein-glycan interactions in the control of innate and adaptive immune responses. Nat. Immunol. 9, 593–601 (2008).

    Article  CAS  Google Scholar 

  19. Cambi, A. & Figdor, C.G. Levels of complexity in pathogen recognition by C-type lectins. Curr. Opin. Immunol. 17, 345–351 (2005).

    Article  CAS  Google Scholar 

  20. McGreal, E.P., Miller, J.L. & Gordon, S. Ligand recognition by antigen-presenting cell C-type lectin receptors. Curr. Opin. Immunol. 17, 18–24 (2005).

    Article  CAS  Google Scholar 

  21. Koppel, E.A., van Gisbergen, K.P., Geijtenbeek, T.B. & van Kooyk, Y. Distinct functions of DC-SIGN and its homologues L-SIGN (DC-SIGNR) and mSIGNR1 in pathogen recognition and immune regulation. Cell. Microbiol. 7, 157–165 (2005).

    Article  CAS  Google Scholar 

  22. Takahara, K. et al. Functional comparison of the mouse DC-SIGN, SIGNR1, SIGNR3 and langerin, C-type lectins. Int. Immunol. 16, 819–829 (2004).

    Article  CAS  Google Scholar 

  23. Galustian, C. et al. High and low affinity carbohydrate ligands revealed for murine SIGN-R1 by carbohydrate array and cell binding approaches, and differing specificities for SIGN-R3 and langerin. Int. Immunol. 16, 853–866 (2004).

    Article  CAS  Google Scholar 

  24. Roy, K., Mao, H.Q., Huang, S.K. & Leong, K.W. Oral gene delivery with chitosan-DNA nanoparticles generates immunologic protection in a murine model of peanut allergy. Nat. Med. 5, 387–391 (1999).

    Article  CAS  Google Scholar 

  25. Lee, R.T. & Lee, Y.C. Neoglycoproteins. in Glycoproteins II (eds. Montreuil, J., Vliegenthart, J.F.G. & Schachter, H.) 601–620 (Elsevier, Amsterdam, 1997).

  26. Stowell, C.P. & Lee, Y.C. Neoglycoproteins: the preparation and application of synthetic glycoproteins. Adv. Carbohydr. Chem. Biochem. 37, 225–281 (1980).

    Article  CAS  Google Scholar 

  27. Numazaki, M. et al. Cross-linking of SIGNR1 activates JNK and induces TNF-α production in RAW264.7 cells that express SIGNR1. Biochem. Biophys. Res. Commun. 386, 202–206 (2009).

    Article  CAS  Google Scholar 

  28. Kamanaka, M. et al. Expression of interleukin-10 in intestinal lymphocytes detected by an interleukin-10 reporter knockin tiger mouse. Immunity 25, 941–952 (2006).

    Article  CAS  Google Scholar 

  29. Jang, M.H. et al. CCR7 is critically important for migration of dendritic cells in intestinal lamina propria to mesenteric lymph nodes. J. Immunol. 176, 803–810 (2006).

    Article  CAS  Google Scholar 

  30. Awasthi, A. et al. A dominant function for interleukin 27 in generating interleukin 10–producing anti-inflammatory T cells. Nat. Immunol. 8, 1380–1389 (2007).

    Article  CAS  Google Scholar 

  31. Dillon, S. et al. Yeast zymosan, a stimulus for TLR2 and dectin-1, induces regulatory antigen-presenting cells and immunological tolerance. J. Clin. Invest. 116, 916–928 (2006).

    Article  CAS  Google Scholar 

  32. 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 

  33. Geijtenbeek, T.B. et al. Mycobacteria target DC-SIGN to suppress dendritic cell function. J. Exp. Med. 197, 7–17 (2003).

    Article  CAS  Google Scholar 

  34. Ilarregui, J.M. et al. Tolerogenic signals delivered by dendritic cells to T cells through a galectin-1–driven immunoregulatory circuit involving interleukin 27 and interleukin 10. Nat. Immunol. 10, 981–991 (2009).

    Article  CAS  Google Scholar 

  35. Fujikado, N. et al. Dcir deficiency causes development of autoimmune diseases in mice due to excess expansion of dendritic cells. Nat. Med. 14, 176–180 (2008).

    Article  CAS  Google Scholar 

  36. Mine, Y. & Yang, M. Recent advances in the understanding of egg allergens: basic, industrial and clinical perspectives. J. Agric. Food Chem. 56, 4874–4900 (2008).

    Article  CAS  Google Scholar 

  37. Arslanoglu, S. et al. Early dietary intervention with a mixture of prebiotic oligosaccharides reduces the incidence of allergic manifestations and infections during the first two years of life. J. Nutr. 138, 1091–1095 (2008).

    Article  CAS  Google Scholar 

  38. Bashir, M.E., Andersen, P., Fuss, I.J., Shi, H.N. & Nagler-Anderson, C. An enteric helminth infection protects against an allergic response to dietary antigen. J. Immunol. 169, 3284–3292 (2002).

    Article  CAS  Google Scholar 

  39. Hsu, S.C. et al. Functional interaction of common allergens and a C-type lectin receptor, DC-specific ICAM3-grabbing non-integrin (DC-SIGN), on human dendritic cells. J. Biol. Chem. 285, 7903–7910 (2010).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank A. Myers and H. Rohde for technical assistance; K. Takahara (Kyoto University) for SIGNR1-transfectant cells; and the Consortium for Functional Glycomics for SIGNR1-deficient mice. This work was supported, in part, by US National Institutes of Health grants (AI052468 and AI073610).

Author information

Authors and Affiliations

Authors

Contributions

Y.Z. conducted experiments involving characterizing mucosal DC subsets and their regulatory role, analyzed data and wrote the manuscript; H.K. performed in vivo experiments on antigen-induced anaphylactic responses, analyzed data and wrote the manuscript; S.-C.H. conducted experiments involving binding analyses of neoglyco-antigens; R.T.L. synthesized neoglyco-antigens and wrote the manuscript; X.Y. conducted in vitro experiments characterizing T cell responses; B.P. performed flow cytometric experiments and edited the manuscript; J.F. conducted in vivo cell transfer experiments; K.Y. contributed to the design and preparation of neoglyco-antigens; Y.C.L. designed and prepared neoglyco-antigens and supervised their synthesis; S.-K.H. planned, designed, supervised and coordinated the overall research efforts.

Corresponding author

Correspondence to Shau-Ku Huang.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6 and Supplementary Methods (PDF 599 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhou, Y., Kawasaki, H., Hsu, SC. et al. Oral tolerance to food-induced systemic anaphylaxis mediated by the C-type lectin SIGNR1. Nat Med 16, 1128–1133 (2010). https://doi.org/10.1038/nm.2201

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.2201

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