Like the caspase recruitment domain (CARD) protein CARMA1, which acts downstream of antigen receptors in a complex with Bcl10, the structurally related CARD9 binds Bcl10--suggesting that CARD9 might modulate CARMA1-Bcl10-dependent activation of nuclear factor κB (NF-κB) signaling and thereby regulate antigen-dependent lymphocyte activation and differentiation. However, Gross et al. found that mice lacking CARD9 (Card9–/– mice) exhibited normal T cell and B cell development and normal antigen-dependent lymphocyte activation. Moreover, mice lacking CARD9 (which is also expressed in myeloid cells) responded normally to various Toll-like receptor (TLR) ligands. However, the immune response of Card9–/– mice to infection with the fungal pathogen Candida albicans was markedly impaired, as was cytokine production by bone-marrow-derived dendritic cells (BMDCs) in response to stimulation with C. albicans or with the yeast cell wall component zymosan. Zymosan is recognized by both TLR2 and the non-TLR pattern-recognition receptor Dectin-1; although TLR2 ligands elicited normal cytokine production in Card9–/– BMDCs, Dectin-1-dependent cytokine production was abolished and zymosan-induced NF-κB activation was impaired. Experiments involving overexpression (or lack of expression) of various combinations of CARD9, Bcl10, Dectin-1, and Malt1 (mucosa-associated lymphoid tissue lymphoma translocation gene 1, which can interact with Bcl10 and CARMA1 to activate NF-κB) defined a non-TLR-mediated signaling pathway through which fungal pathogens activate an innate immune response.
O. Gross, A. Gewies, K. Finger, M. Schafer, T. Sparwasser, C. Peschel, I. Forster, J. Ruland, Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity. Nature 442, 651-656 (2006). [PubMed]