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- kappa B 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.