Abstract. The human intestine harbors an estimated 100 trillion microbes that are increasingly recognized to promote health through tonic immune stimulation. These include innocuous commensal microbes along with pathobionts - those capable of causing gut dysbiosis or invasive infection. Most of what we currently understand about host-microbe commensalism has been evaluated through the lens of bacteria. However, microbes from other taxonomic domains, including eukaryotes, also ubiquitously colonize mucosal tissues and yet our understanding of how these microbes establish commensalism and drive immunological changes remains rudimentary. This gap in knowledge is especially significant for the most common fungal pathobiont Candida albicans, which can translocate out of the gastrointestinal (GI) tract and cause life-threatening systemic infection, particularly in immunocompromised individuals. To address these fundamental gaps in knowledge, an instructive model of C. albicans intestinal colonization in mice was developed. Recombinant C. albicans cells were engineered to express defined model antigens and used to establish colonization so that T cells with surrogate C. albicans specificity could be identified. Using this model, we show that C. albicans cells colonizing the GI tract result in action at a distance - they drive the systemic accumulation of fungal-specific Th17 CD4+ T cells. These T cells work together with IL-17 and activated neutrophils to provide protection against a systemic infection by C. albicans as well as by extracellular bacterial pathogens. These results highlight the protective benefits of commensal C. albicans cells residing in the GI tract, and suggest that co-evolution with this species has led to a mutually beneficial relationship. However, important questions remain as to how C. albicans cells in the gut prime systemic immune responses, and how Th17 signals can be triggered without excessive inflammation. This line of investigation builds upon exciting preliminary data generated together by the laboratories of Dr. Way and Dr. Bennett, two investigators with complementary expertise in clinical infectious disease/cellular immunology and mycology/fungal pathogenesis, respectively. This proposal will address the molecular and cellular mechanisms by which C. albicans cells interact with mucosal host tissues to drive gut local and systemic immunity through the following specific aims: (1) Define how C. albicans morphological changes drive systemic Th17 immunity, (2) Establish the fungal ligand and host pattern recognition receptor(s) that prime systemic Th17 immunity, and (3) Investigate the role of reactive oxygen species and Duox2 (Dual Oxidase 2) for local and Th17 immunity primed by C. albicans cells. Each of these specific aims is supported by extensive published and unpublished preliminary data. Successful completion of these aims will shed light on the important symbiosis between fungal commensal and mammalian host, and t...