Article

CARD9 controls a non-TLR signaling 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: 41.46). 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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    • "CARD9 is an important part of the pathway engaged by the pattern recognition receptor Dectin-1, which is responsible for initiating many innate immune responses to fungal elements, including, ultimately, the development of Th17 cells as discussed previously.17 Consistent with its essential role as a “danger signal” capable of recognizing Candida-derived fungal elements AR mutations in Dectin-1 and CARD9 have also been associated with the CMC phenotype. "
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    • "Previous studies suggest that -glucans from C. albicans activate Dectin-1–mediated NF-B activation through a CARD9- dependent pathway (Gross et al., 2006). To further investigate the role of CARD9 in Dectin-1–induced signaling pathways in response to fungal infection, BM-derived macrophages (BMDMs) or BM-derived DCs (BMDCs) from WT (Card9 +/+ ) or CARD9-deficient (Card9 / ) mice were stimulated with WT or mnn5 strain of C. albicans yeast. "
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