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Carbohydrate-specific signaling through the DC-SIGN signalosome tailors immunity to Mycobacterium tuberculosis, HIV-1 and Helicobacter pylori

Abstract

Cooperation between different innate signaling pathways induced by pattern-recognition receptors (PRRs) on dendritic cells (DCs) is crucial for tailoring adaptive immunity to pathogens. Here we show that carbohydrate-specific signaling through the C-type lectin DC-SIGN tailored cytokine production in response to distinct pathogens. DC-SIGN was constitutively associated with a signalosome complex consisting of the scaffold proteins LSP1, KSR1 and CNK and the kinase Raf-1. Mannose-expressing Mycobacterium tuberculosis and human immunodeficiency virus type 1 (HIV-1) induced the recruitment of effector proteins to the DC-SIGN signalosome to activate Raf-1, whereas fucose-expressing pathogens such as Helicobacter pylori actively dissociated the KSR1–CNK–Raf-1 complex from the DC-SIGN signalosome. This dynamic regulation of the signalosome by mannose- and fucose-expressing pathogens led to the enhancement or suppression of proinflammatory responses, respectively. Our study reveals another level of plasticity in tailoring adaptive immunity to pathogens.

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Figure 1: Raf-1 activation is central to mannose-dependent but not fucose-dependent DC-SIGN-mediated modulation of TLR4-induced cytokine production.
Figure 2: Mannose-specific DC-SIGN signaling requires LSP1.
Figure 3: Mannose-specific DC-SIGN signaling requires a signalosome consisting of LSP1 and the KSR1–CNK–Raf-1 triad complex.
Figure 4: Mannose-specific triggering of DC-SIGN recruits LARG and RhoA to the signalosome, which is essential for Raf-1 activation via Ras.
Figure 5: Fucose-specific DC-SIGN triggering dissociates KSR1–CNK–Raf-1 but not LSP1 from the signalosome.
Figure 6: Carbohydrate-specific DC-SIGN signaling leads to pathogen-specific cytokine responses.

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References

  1. Ueno, H. et al. Dendritic cell subsets in health and disease. Immunol. Rev. 219, 118–142 (2007).

    Article  CAS  Google Scholar 

  2. Medzhitov, R. Recognition of microorganisms and activation of the immune response. Nature 449, 819–826 (2007).

    Article  CAS  Google Scholar 

  3. Wilson, C.B., Rowell, E. & Sekimata, M. Epigenetic control of T-helper-cell differentiation. Nat. Rev. Immunol. 9, 91–105 (2009).

    Article  CAS  Google Scholar 

  4. Kanneganti, T.D., Lamkanfi, M. & Núñez, G. Intracellular NOD-like receptors in host defense and disease. Immunity 27, 549–559 (2007).

    Article  CAS  Google Scholar 

  5. Meylan, E. & Tschopp, J. Toll-Like Receptors and RNA helicases: two parallel ways to trigger antiviral responses. Mol. Cell 22, 561–569 (2006).

    Article  CAS  Google Scholar 

  6. O'Neill, L.A.J. When signaling pathways collide: positive and negative regulation of Toll-like receptor signal transduction. Immunity 29, 12–20 (2008).

    Article  CAS  Google Scholar 

  7. Robinson, M.J., Sancho, D., Slack, E.C., LeibundGut-Landmann, S. & Sousa, C.R.E. Myeloid C-type lectins in innate immunity. Nat. Immunol. 7, 1258–1265 (2006).

    Article  CAS  Google Scholar 

  8. Sansonetti, P.J. The innate signaling of dangers and the dangers of innate signaling. Nat. Immunol. 7, 1237–1242 (2006).

    Article  CAS  Google Scholar 

  9. Kawai, T. & Akira, S. TLR signaling. Cell Death Differ. 13, 816–825 (2006).

    Article  CAS  Google Scholar 

  10. O'Neill, L.A.J. & Bowie, A.G. The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat. Rev. Immunol. 7, 353–364 (2007).

    Article  CAS  Google Scholar 

  11. Ouaaz, F., Arron, J., Zheng, Y., Choi, Y. & Beg, A.A. Dendritic cell development and survival require distinct NF-κB subunits. Immunity 16, 257–270 (2002).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  13. Underhill, D.M. Collaboration between the innate immune receptors dectin-1, TLRs, and Nods. Immunol. Rev. 219, 75–87 (2007).

    Article  CAS  Google Scholar 

  14. Geijtenbeek, T.B.H. & Gringhuis, S.I. Signalling through C-type lectin receptors: shaping immune responses. Nat. Rev. Immunol. 9, 465–479 (2009).

    Article  CAS  Google Scholar 

  15. Appelmelk, B.J. et al. Carbohydrate profiling identifies new pathogens that interact with dendritic cell-specific ICAM-3-grabbing nonintegrin on dendritic cells. J. Immunol. 170, 1635–1639 (2003).

    Article  CAS  Google Scholar 

  16. van Kooyk, Y. & Geijtenbeek, T.B.H. DC-SIGN: escape mechanism for pathogens. Nat. Rev. Immunol. 3, 697–709 (2003).

    Article  CAS  Google Scholar 

  17. Feinberg, H., Mitchell, D.A., Drickamer, K. & Weis, W.I. Structural basis for selective recognition of oligosaccharides by DC-SIGN and DC-SIGNR. Science 294, 2163–2166 (2001).

    Article  CAS  Google Scholar 

  18. Bergman, M.P. et al. Helicobacter pylori modulates the T helper cell 1/T helper cell 2 balance through phase-variable interaction between lipopolysaccharide and DC-SIGN. J. Exp. Med. 200, 979–990 (2004).

    Article  CAS  Google Scholar 

  19. Smits, H.H. et al. Selective probiotic bacteria induce IL-10-producing regulatory T cells in vitro by modulating dendritic cell function through dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin. J. Allergy Clin. Immunol. 115, 1260–1267 (2005).

    Article  CAS  Google Scholar 

  20. Steeghs, L. et al. Neisseria meningitidis expressing lgtB lipopolysaccharide targets DC-SIGN and modulates dendritic cell function. Cell. Microbiol. 8, 316–325 (2006).

    Article  CAS  Google Scholar 

  21. van Liempt, E. et al. Schistosoma mansoni soluble egg antigens are internalized by human dendritic cells through multiple C-type lectins and suppress TLR-induced dendritic cell activation. Mol. Immunol. 44, 2605–2615 (2007).

    Article  CAS  Google Scholar 

  22. Gringhuis, S.I. et al. C-type lectin DC-SIGN modulates toll-like receptor signaling via Raf-1 kinase-dependent acetylation of transcription factor NF-κB. Immunity 26, 605–616 (2007).

    Article  CAS  Google Scholar 

  23. Wellbrock, C., Karasarides, M. & Marais, R. The Raf proteins take centre stage. Nat. Rev. Mol. Cell Biol. 5, 875–885 (2004).

    Article  CAS  Google Scholar 

  24. Geijtenbeek, T.B.H. et al. DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell 100, 587–597 (2000).

    Article  CAS  Google Scholar 

  25. Hong, P.W.P. et al. Human immunodeficiency virus envelope (gp120) binding to DC-SIGN and primary dendritic cells is carbohydrate dependent but does not involve 2G12 or cyanovirin binding sites: implications for structural analyses of gp120-DC-SIGN binding. J. Virol. 76, 12855–12865 (2002).

    Article  CAS  Google Scholar 

  26. 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 

  27. van Gisbergen, K.P.J.M., Sanchez-Hernandez, M., Geijtenbeek, T.B.H. & van Kooyk, Y. Neutrophils mediate immune modulation of dendritic cells through glycosylation-dependent interactions between Mac-1 and DC-SIGN. J. Exp. Med. 201, 1281–1292 (2005).

    Article  CAS  Google Scholar 

  28. Smith, A.L. et al. Leukocyte-specific protein 1 interacts with DC-SIGN and mediates transport of HIV to the proteasome in dendritic cells. J. Exp. Med. 204, 421–430 (2007).

    Article  CAS  Google Scholar 

  29. Harrison, R.E., Sikorski, B.A. & Jongstra, J. Leukocyte-specific protein 1 targets the ERK/MAP kinase scaffold protein KSR and MEK1 and ERK2 to the actin cytoskeleton. J. Cell Sci. 117, 2151–2157 (2004).

    Article  CAS  Google Scholar 

  30. Douziech, M., Sahmi, M., Laberge, G. & Therrien, M.A. KSR/CNK complex mediated by HYP, a novel SAM domain-containing protein, regulates RAS-dependent RAF activation in Drosophila. Genes Dev. 20, 807–819 (2006).

    Article  CAS  Google Scholar 

  31. Hodges, A. et al. Activation of the lectin DC-SIGN induces an immature dendritic cell phenotype triggering Rho-GTPase activity required for HIV-1 replication. Nat. Immunol. 8, 569–577 (2007).

    Article  CAS  Google Scholar 

  32. Dhillon, A.S., von, K.A., Grindlay, J. & Kolch, W. Phosphatase and feedback regulation of Raf-1 signaling. Cell Cycle 6, 3–7 (2007).

    Article  CAS  Google Scholar 

  33. Yadav, M. & Schorey, J.S. The β-glucan receptor dectin-1 functions together with TLR2 to mediate macrophage activation by mycobacteria. Blood 108, 3168–3175 (2006).

    Article  CAS  Google Scholar 

  34. Appelmelk, B.J. et al. The mannose cap of mycobacterial lipoarabinomannan does not dominate the Mycobacterium-host interaction. Cell. Microbiol. 10, 930–944 (2008).

    Article  CAS  Google Scholar 

  35. Shaw, A.S. & Filbert, E.L. Scaffold proteins and immune-cell signalling. Nat. Rev. Immunol. 9, 47–56 (2009).

    Article  CAS  Google Scholar 

  36. Dhanasekaran, D.N., Kashef, K., Lee, C.M., Xu, H. & Reddy, E.P. Scaffold proteins of MAP-kinase modules. Oncogene 26, 3185–3202 (2007).

    Article  CAS  Google Scholar 

  37. Taya, S. et al. Direct interaction of insulin-like growth factor-1 receptor with leukemia-associated RhoGEF. J. Cell Biol. 155, 809–820 (2001).

    Article  CAS  Google Scholar 

  38. Jaffe, A.B., Aspenstrom, P. & Hall, A. Human CNK1 acts as a scaffold protein, linking Rho and Ras signal transduction pathways. Mol. Cell. Biol. 24, 1736–1746 (2004).

    Article  CAS  Google Scholar 

  39. Ziogas, A., Moelling, K. & Radziwill, G. CNK1 is a scaffold protein that regulates Src-mediated Raf-1 activation. J. Biol. Chem. 280, 24205–24211 (2005).

    Article  CAS  Google Scholar 

  40. Kolch, W. Coordinating ERK/MAPK signalling through scaffolds and inhibitors. Nat. Rev. Mol. Cell Biol. 6, 827–837 (2005).

    Article  CAS  Google Scholar 

  41. Matheny, S.A. et al. Ras regulates assembly of mitogenic signalling complexes through the effector protein IMP. Nature 427, 256–260 (2004).

    Article  CAS  Google Scholar 

  42. Guo, Y. et al. Structural basis for distinct ligand-binding and targeting properties of the receptors DC-SIGN and DC-SIGNR. Nat. Struct. Mol. Biol. 11, 591–598 (2004).

    Article  CAS  Google Scholar 

  43. Madura Larsen, J. et al. BCG stimulated dendritic cells induce an interleukin-10 producing T-cell population with no T helper 1 or T helper 2 bias in vitro. Immunology 121, 276–282 (2007).

    Article  Google Scholar 

  44. van Die, I. et al. The dendritic cell-specific C-type lectin DC-SIGN is a receptor for Schistosoma mansoni egg antigens and recognizes the glycan antigen Lewis x. Glycobiology 13, 471–478 (2003).

    Article  CAS  Google Scholar 

  45. Uematsu, S. & Akira, S. Toll-Like receptors (TLRs) and their ligands. Handb. Exp. Pharmacol. 183, 1–20 (2008).

    Article  CAS  Google Scholar 

  46. Hanke, J.H. et al. Discovery of a novel, potent, and Src family-selective tyrosine kinase inhibitor. Study of Lck- and FynT-dependent T cell activation. J. Biol. Chem. 271, 695–701 (1996).

    Article  CAS  Google Scholar 

  47. Gringhuis, S.I. et al. Dectin-1 directs T helper cell differentiation by controlling noncanonical NF-κB activation through Raf-1 and Syk. Nat. Immunol. 10, 203–213 (2009).

    Article  CAS  Google Scholar 

  48. Remans, P.H.J. et al. Rap1 signaling is required for suppression of Ras-generated reactive oxygen species and protection against oxidative stress in T lymphocytes. J. Immunol. 173, 920–931 (2004).

    Article  CAS  Google Scholar 

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Acknowledgements

ManLAM and M. tuberculosis were gifts from J. Belisle (Colorado State University; as part of the National Institute of Allergy and Infectious Diseases, US National Institutes of Health contract HHSN266200400091C, “Tuberculosis Vaccine Testing and Research Materials”); H. pylori strains were gifts from B. Appelmelk (Vrije University Medical Center); and ICAM-3–Fc was a gift from D. Simmons (University of Oxford). Supported by the Dutch Scientific Research Program (NWO 912-04-025 to J.d.D.), the AIDS Foundation (2007036 to M.d.v.V.) and the Dutch Asthma Foundation (3.2.03.39 to S.I.G.).

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S.I.G. designed, did and interpreted most experiments and prepared the manuscript; J.d.D. and M.L. participated in RNAi, flow cytometry and immunoblot experiments; M.v.d.V. assisted with flow cytometry and Ras-precipitation experiments; and T.B.H.G. participated in flow cytometry and enzyme-linked immunosorbent assays (ELISAs) and supervised all aspects of this study.

Corresponding authors

Correspondence to Sonja I Gringhuis or Teunis B H Geijtenbeek.

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Gringhuis, S., den Dunnen, J., Litjens, M. et al. Carbohydrate-specific signaling through the DC-SIGN signalosome tailors immunity to Mycobacterium tuberculosis, HIV-1 and Helicobacter pylori. Nat Immunol 10, 1081–1088 (2009). https://doi.org/10.1038/ni.1778

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