Non-Toll-like receptor innate immune signaling

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DESCRIPTION (provided by applicant): Innate immune receptors trigger inflammation, activate microbial killing mechanisms, and instruct the development of acquired immune responses. The Toll-like receptor (TLR) family of innate immune recognition receptors is currently the most completely described family of innate receptors. These receptors play crucial roles in recognizing a wide range of microbial products, trigger NF-(B activation and production of a host of cytokines and chemokines, and have been demonstrated to be essential for effective host defense against many pathogens. However, TLRs do not activate all innate host defenses, and additional "non-TLR" innate immune receptors trigger phagocytosis, activate antimicrobial killing mechanisms, shape the consequences of TLR signaling, and are likely equally essential for effective host defense. Currently very few of these non-TLR innate receptors have been defined. We have established the ¿-glucan receptor Dectin-1 as one model for non-TLR based innate immune recognition. This receptor triggers phagocytosis of ¿-glucan-containing particles (such as yeast) and activates production of antimicrobial reactive oxygen species. Dectin-1 signaling also collaborates with TLR signaling to orchestrate cellular cytokine and chemokine production. While TLR signaling is relatively well-understood and shares much in common with cytokine receptor signaling, we have discovered that Dectin-1 signaling shares much in common with antigen receptor signaling. Thus signaling pathways generally associated with acquired immunity including the Src/Syk and NFAT (Nuclear Factor of Activated T cells) pathways are activated in phagocytes upon exposure to zymosan or yeast. We will examine the hypothesis that innate immune activation of NFAT is an important component of inflammatory responses. In Aim 1 will define the mechanisms by which Dectin-1 and yeast activate Src family kinases and Syk in macrophages, dendritic cells, and neutrophils. In Aim 2 we will explore the mechanisms by which Dectin-1 activates NFAT and the consequences of NFAT activation on inflammatory responses in vitro. In Aim 3 we will define the effect of the role of Dectin-1 and NFAT signaling in innate and adaptive immune responses in vivo.