The C-type lectin dectin-1 binds to yeast and signals through the kinase Syk and the adaptor CARD9 to induce production of interleukin 10 (IL-10) and IL-2 in dendritic cells (DCs). However, whether this pathway promotes full DC activation remains unclear. Here we show that dectin-1-Syk-CARD9 signaling induced DC maturation and the secretion of proinflammatory cytokines, including IL-6, tumor necrosis factor and IL-23, but little IL-12. Dectin-1-activated DCs 'instructed' the differentiation of CD4+ IL-17-producing effector T cells (T(H)-17 cells) in vitro, and a dectin-1 agonist acted as an adjuvant promoting the differentiation of T(H)-17 and T helper type 1 cells in vivo. Infection with Candida albicans induced CARD9-dependent T(H)-17 responses to the organism. Our data indicate that signaling through Syk and CARD9 can couple innate to adaptive immunity independently of Toll-like receptor signals and that CARD9 is required for the development of T(H)-17 responses to some pathogens.

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.

IntroductionThe development, maintenance, and progression of malignant lymphomas depend mechanistically on a deregulation of cellular pathways that control differentiation, proliferation, or apoptosis in lymphocytes. One essential and tightly regulated signaling cascade that mediates development, activation, and survival of normal lymphocytes for regulated immune responses is the nuclear factor-B (NF-B) pathway. In recent years it is becoming clear that aberrant deregulated NF-B activation is a hallmark of several lymphoid malignancies and is directly linked to advanced disease. Several lymphoma types depend on NF-B activity for cell cycling and survival, indicating that an inhibition of this pathway could be a therapeutic option. Here, we review the central components and the molecular regulation of NF-B signaling as well as summarize mechanisms and consequences of aberrant NF-B activation in distinct lymphoma entities, together with experimental data that validate the NF-B pathway as a therapeutic target in lymphoma. Physiology of NF-B signaling Mechanisms of NF-B activationNF-B is not a single protein, but a small family of inducible transcription factors that operates in virtually all mammalian cells. 1 It plays a particular important role in the activation and survival of immune cells. 2 The 5 mammalian NF-B/Rel members are RelA (p65), RelB, c-Rel, NF-B1 (p50 and its precursor p105), and NF-B2 (p52 and its precursor p100) ( Figure 1A). These proteins form various homodimers and heterodimers and are kept inactive by cytoplasmic association with inhibitory proteins, which consist of IB␣, IB␤, IB⑀, as well as the p105 and p100 precursors of p50 and p52, respectively ( Figure 1B). Physiologic activation of NF-B occurs mainly through either the canonical or the alternative pathway ( Figure 2). 2 Both pathways are based on inducible phosphorylation of IB proteins by the multiprotein IB-kinase (IKK) that contains 2 catalytic subunits, IKK␣ (IKK1) and IKK␤ (IKK2), as well as the regulatory subunit IKK␥ (or NEMO for NF-B essential modifier) ( Figure 1C).The canonical pathway of NF-B activation can be engaged by a large series of stimuli, including proinflammatory cytokines, pathogen-associated molecular patterns that bind to innate immune receptors, T-cell receptor (TCR) and B-cell receptor (BCR) signaling, as well as ligation of lymphocyte coreceptors. 1-3 Activated IKK phosphorylates IB proteins, thereby inducing IB polyubiquitinylation and subsequent proteolytic degradation by the proteasome. Following IB degradation, NF-B dimers are released and are then able to translocate into the nucleus, activating gene transcription ( Figure 2A).The alternative pathway of NF-B activation represents an additional specialized signaling cascade that is particularly important in mature B cells. This pathway is engaged by a restricted set of cell-surface receptors that belong to the TNF receptor superfamily, including CD40, the lymphotoxin ␤ receptor, and BAFF receptor. 2 This pathway culminates in the activation of IKK␣ that di...