Article

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

III. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675 Munich, Germany.
Nature (Impact Factor: 42.35). 09/2006; 442(7103):651-6. DOI: 10.1038/nature04926
Source: PubMed

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-kappaB 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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    • ", deletion of Syk had no effect on the synthesis of IFN-b by BMDCs stimulated by LPS as expected, but completely blocked its production by Curdlan-stimulated BMDCs, confirming the involvement of Syk in Dectin-1-mediated IFN-b production. Because Card9 is involved in NF-kB activation resulting from Dectin-1 engagement (Gross et al., 2006) and NF-kB is required for the transcriptional activation of the Ifnb gene (Panne et al., 2007), we hypothesized that Card9 could also control IFN-b production in response to Curdlan. To address this issue, we analyzed BMDCs from Card9 À/À mice for their ability to produce IFN-b after stimulation with Curdlan or LPS. "
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