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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.

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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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