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

Nature volume 442, pages 651–656 (2006)Cite this article

Abstract

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.

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Acknowledgements

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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  1. Irmgard Förster

    Present address: Institut für Umweltmedizinische Forschung, University of Düsseldorf, Auf'm Hennekamp 50, 40225, Düsseldorf, Germany

Authors and Affiliations

  1. III. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany

    Olaf Gross, Andreas Gewies, Katrin Finger, Christian Peschel & Jürgen Ruland

  2. Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Trogerstr. 30, 81675, Munich, Germany

    Martin Schäfer, Tim Sparwasser & Irmgard Förster

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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). https://doi.org/10.1038/nature04926

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