PROJECT SUMMARY The skin serves as a primary barrier to the external world and is thus often injured. As such, rapid repair of tissue damage is vital for organismal survival. Failure to repair wounds results in the formation of chronic or non-healing wounds, which affect over 2% of the western population and cost an estimated 25 billion dollars to manage annually. Immunosuppression is one major predisposing factor to chronic wound formation, indicating that signals derived from immune cells are necessary for optimal repair. Yet, there is a significant gap in our understanding of exactly how immune cells are activated and precisely how they crosstalk with the epithelium to direct repair. Normal skin comprises a myriad of “homeostatic” immune cell types that actively patrol the tissue in health and we find are rapidly activated and recruited to the site of injury. These include type 17 immune cell subsets that have only been uncovered in the last 10 years and whole function in repair has not been studied in immunocompetent animals. We systematically ablated each type 17 cell type to determine their role in activating the wound edge epithelium and found that in type17-γδ T cells, but not other subsets are absolutely necessary for wound -re-epithelialization. This crosstalk is mediated by the prototypic cytokines IL-17A/F signaling directly into the epithelium via their receptor IL-17RC. Surprisingly, we uncovered that IL17RC signaling activates HIF1a protein, and that this signaling axis is required for optimal HIF1a activation at the wound edge even in the pres- ence of hypoxia. Loss of epithelial HIF1a profoundly disrupts wound re-epithelization indicating that this tran- scription factor is a master regulator of epithelial activation at the wounds edge. While type17-γδ T cells have been studied in pathogen responses, how they are recruited and activated in wounds is poorly understood. Additionally, exactly how IL17 signaling induces HIF1a is unclear and the molecular targets of HIF1a that drive repair require elucidation. We will address these fundamental questions in two independent aims: (1) How are type17-γδ T cells recruited to and activated at the wound’s re-epithelizing front? ; (2) How does inflammatory HIF1a control re- epithelialization programs downstream of IL-17? Decoding the molecular interactions between wound-associ- ated lymphocytes and would edge epithelium, as we propose here, is an essential first step in finding immune- based therapies for chronic non-healing wounds. Moreover, many inflammatory conditions and cancers, driven by type 17 immunity, co-opt features wound repair. Thus, our studies will not only unearth fundamental mecha- nisms of immune-epithelial crosstalk in repair, but may also provide novel therapeutic targets for a range of type17 immunity-mediated epithelial pathologies.