IL-17 is the signature cytokine of a relatively new CD4+ T helper subset, known as ?Th17? cells. IL-17 is an essential mediator of immunity to extracellular microbes, especially fungi such as Candida albicans. Humans lacking Th17 cells, IL-17 signaling or where IL-17 is neutralized are susceptible to mucosal C. albicans infections, particularly oropharyngeal candidiasis (OPC, thrush). Although considerable research effort has focused on how Th17 cells are generated and regulated, the mechanisms by which IL- 17 and its receptor mediate specific downstream signals in relevant disease processes such as candidiasis have received far less attention. Our studies of OPC in mice identified an IL-17-dependent novel RNA binding protein that promotes IL-17-dependent signaling. Here we propose to create a mouse with a conditional deletion in the gene encoding this RBP and simultaneously knock-in an epitope tag order to define its mechanistic role in immunity to C. albicans. We will also perform parallel analyses in human oral epithelial cells to determine the relevance of this RBP in the human immune system.
Sarah L. Gaffen, Ph.D. Project Narrative The immune system maintains a careful balance between protecting the body from infectious pathogens and the collateral damage that may arise as a result of too much inflammation. Interleukin (IL)-17 is an important mediator of immune inflammation and protects against fungal pathogens, but an overabundance of IL- 17 signaling contributes to the pathogenesis of autoimmunity. Although we know quite a bit about which cells make IL-17, the molecular process of IL-17 signaling through its receptor is poorly defined. This proposal focuses on the role of IL-17- driven mRNA expression and how these processes control IL-17 antifungal activity.