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Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity


Fungal infections are increasing worldwide due to the marked rise in immunodeficiencies including AIDS; however, immune responses to fungi are poorly understood. Dectin-1 is the major mammalian pattern recognition receptor for the fungal component zymosan. Dectin-1 represents the prototype of innate non-Toll-like receptors (TLRs) containing immunoreceptor tyrosine-based activation motifs (ITAMs) related to those of adaptive antigen receptors. Here we identify Card9 as a key transducer of Dectin-1 signalling. Although being dispensable for TLR/MyD88-induced responses, Card9 controls Dectin-1-mediated myeloid cell activation, cytokine production and innate anti-fungal immunity. Card9 couples to Bcl10 and regulates Bcl10–Malt1-mediated NF-κB activation induced by zymosan. Yet, Card9 is dispensable for antigen receptor signalling that uses Carma1 as a link to Bcl10–Malt1. Thus, our results define a novel innate immune pathway and indicate that evolutionarily distinct ITAM receptors in innate and adaptive immune cells use diverse adaptor proteins to engage selectively the conserved Bcl10–Malt1 module.

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Figure 1: Regular adaptive immunity in Card9-deficient mice.
Figure 2: Impaired zymosan-induced cytokine production in Card9 -/- BMDCs.
Figure 3: Impaired immune responses to Candida albicans.
Figure 4: Impaired Dectin-1/Syk signalling in Card9 -/- cells.
Figure 5: Card9 signals via Bcl10 and Malt1.


  1. Akira, S. & Takeda, K. Toll-like receptor signalling. Nature Rev. Immunol. 4, 499–511 (2004)

    Article  CAS  Google Scholar 

  2. Gordon, S. Pattern recognition receptors: doubling up for the innate immune response. Cell 111, 927–930 (2002)

    Article  CAS  Google Scholar 

  3. Inohara, N. & Nunez, G. NODs: intracellular proteins involved in inflammation and apoptosis. Nature Rev. Immunol. 3, 371–382 (2003)

    Article  CAS  Google Scholar 

  4. Lin, X. & Wang, D. The roles of CARMA1, Bcl10, and MALT1 in antigen receptor signaling. Semin. Immunol. 16, 429–435 (2004)

    Article  CAS  Google Scholar 

  5. Bonizzi, G. & Karin, M. The two NF-κB activation pathways and their role in innate and adaptive immunity. Trends Immunol. 25, 280–288 (2004)

    Article  CAS  Google Scholar 

  6. Thome, M. CARMA1, BCL-10 and MALT1 in lymphocyte development and activation. Nature Rev. Immunol. 4, 348–359 (2004)

    Article  CAS  Google Scholar 

  7. Bertin, J. et al. CARD9 is a novel caspase recruitment domain-containing protein that interacts with BCL10/CLAP and activates NF-κB. J. Biol. Chem. 275, 41082–41086 (2000)

    Article  CAS  Google Scholar 

  8. Matsumoto, R. et al. Phosphorylation of CARMA1 plays a critical role in T Cell receptor-mediated NF-κB activation. Immunity 23, 575–585 (2005)

    Article  CAS  Google Scholar 

  9. Sommer, K. et al. Phosphorylation of the CARMA1 linker controls NF-κB activation. Immunity 23, 561–574 (2005)

    Article  CAS  Google Scholar 

  10. Thome, M. & Tschopp, J. TCR-induced NF-κB activation: a crucial role for Carma1, Bcl10 and MALT1. Trends Immunol. 24, 419–424 (2003)

    Article  CAS  Google Scholar 

  11. Di Carlo, F. J. & Fiore, J. V. On the composition of zymosan. Science 127, 756–757 (1958)

    Article  ADS  CAS  Google Scholar 

  12. Brown, G. D. & Gordon, S. Immune recognition. A new receptor for β-glucans. Nature 413, 36–37 (2001)

    Article  ADS  CAS  Google Scholar 

  13. Underhill, D. M. et al. The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens. Nature 401, 811–815 (1999)

    Article  ADS  CAS  Google Scholar 

  14. Brown, G. D. & Gordon, S. Fungal β-glucans and mammalian immunity. Immunity 19, 311–315 (2003)

    Article  CAS  Google Scholar 

  15. Villamon, E. et al. Toll-like receptor-2 is essential in murine defenses against Candida albicans infections. Microbes Infect. 6, 1–7 (2004)

    Article  CAS  Google Scholar 

  16. 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  PubMed Central  Google Scholar 

  17. Rogers, N. C. et al. Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins. Immunity 22, 507–517 (2005)

    Article  CAS  Google Scholar 

  18. Brown, G. D. et al. Dectin-1 mediates the biological effects of β-glucans. J. Exp. Med. 197, 1119–1124 (2003)

    Article  CAS  PubMed Central  Google Scholar 

  19. Brown, G. D. Dectin-1: a signalling non-TLR pattern-recognition receptor. Nature Rev. Immunol. 6, 33–43 (2005)

    Article  Google Scholar 

  20. Takeuchi, O. et al. Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components. Immunity 11, 443–451 (1999)

    Article  CAS  Google Scholar 

  21. Aliprantis, A. O. et al. Cell activation and apoptosis by bacterial lipoproteins through toll-like receptor-2. Science 285, 736–739 (1999)

    Article  CAS  Google Scholar 

  22. Takeuchi, O., Hoshino, K. & Akira, S. Cutting edge: TLR2-deficient and MyD88-deficient mice are highly susceptible to Staphylococcus aureus infection. J. Immunol. 165, 5392–5396 (2000)

    Article  CAS  Google Scholar 

  23. Kawai, T., Adachi, O., Ogawa, T., Takeda, K. & Akira, S. Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 11, 115–122 (1999)

    Article  CAS  PubMed Central  Google Scholar 

  24. Ruland, J. et al. Bcl10 is a positive regulator of antigen receptor-induced activation of NF-κB and neural tube closure. Cell 104, 33–42 (2001)

    Article  CAS  Google Scholar 

  25. McAllister-Lucas, L. M. et al. Bimp1, a MAGUK family member linking protein kinase C activation to Bcl10-mediated NF-κB induction. J. Biol. Chem. 276, 30589–30597 (2001)

    Article  CAS  Google Scholar 

  26. Eliopoulos, A. G., Das, S. & Tsichlis, P. N. The tyrosine kinase Syk regulates TPL2 activation signals. J. Biol. Chem. 281, 1371–1380 (2006)

    Article  CAS  Google Scholar 

  27. Ruland, J., Duncan, G. S., Wakeham, A. & Mak, T. W. Differential requirement for Malt1 in T and B cell antigen receptor signaling. Immunity 19, 749–758 (2003)

    Article  CAS  Google Scholar 

  28. Klemm, S. et al. The Bcl10-Malt1 complex segregates FcɛRI-mediated nuclear factor κB activation and cytokine production from mast cell degranulation. J. Exp. Med. 203, 337–347 (2006)

    Article  PubMed Central  Google Scholar 

  29. Hammer, M. et al. Control of dual-specificity phosphatase-1 expression in activated macrophages by IL-10. Eur. J. Immunol. 35, 2991–3001 (2005)

    Article  CAS  Google Scholar 

  30. Sparwasser, T. et al. Bacterial DNA and immunostimulatory CpG oligonucleotides trigger maturation and activation of murine dendritic cells. Eur. J. Immunol. 28, 2045–2054 (1998)

    Article  CAS  Google Scholar 

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We thank H. Wagner, R. Lang, R. Rupec and M. Thome for discussions; S. Bauer and K. Pechloff for critically reading the manuscript; B. Holzmann for providing Myd88-/- bone marrow; A. Walch for access to a confocal microscope; M. Neuenhahn for help with intravenous injections; and S. Weiss, S. Leeder and K. Meiners for technical assistance. This work was supported by SFB grants from Deutsche Forschungsgemeinschaft to I.F. and J.R. and by a Max-Eder-Program grant from Deutsche Krebshilfe to J.R.

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Correspondence to Jürgen Ruland.

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Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1–3. Supplementary Figure 1 details generation of Card9 deficient mice. Supplementary Figure 2 details FACS analysis of lymphocyte development. Supplementary Figure 3 details Bcl10 and Malt1 control Candida albicans induced cytokine production and zymosan induced NF-κB activation. (PDF 5461 kb)

Supplementary Methods

This file contains a more detailed description of the methods used in this study. (PDF 111 kb)

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Gross, O., Gewies, A., Finger, K. et al. Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity. Nature 442, 651–656 (2006).

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