SUMMARY/ABSTRACT Dectin-1 is an innate immune receptor expressed by myeloid phagocytes such as macrophages and dendritic cells that is essential for effective host defense against fungal infections. Dectin-1 recognizes the β-1,3-glucan polysaccharide that makes up as much as half the dry weight of fungal cell walls, and activation of the receptor triggers phagocytosis, production of microbicidal reactive oxygen species, and production of a host of pro- inflammatory cytokines. Dectin-1 is one of only a few receptors so far shown to be sufficient for triggering phagocytosis, and it has thus become an important model for understanding how such receptors work. This renewal project focuses on further understanding the mechanisms of Dectin-1 signaling. Previous studies have documented that Dectin-1 signaling in response to common yeast such as Candida albicans promotes IL-23 production by dendritic cells that, together with other inflammatory mediators, supports a good Th1/Th17 T cell response. This response is essential for mucosal immunity to fungal infections. In contrast, we now observe that C. albicans hyphae activate dendritic cells to drive a response better characterized as Th2/Th9 and that Dectin- 1 is also critical for this response. Further, we note that colonization with certain fungi including Candida spp. and Wallemia spp. exacerbate Th2/9-driven mouse models of allergic airway disease. In this project, we will investigate the mechanisms by which the Dectin-1 signaling pathway promotes Th2 and Th9 type immune responses in vitro and in vivo. We will further develop novel strategies for pharmacologically manipulating this signaling pathway.