PROJECT SUMMARY/ABSTRACT Seasonal influenza A virus epidemics are an obstinate global health issue and cause severe illness and death in high-risk populations. As with other respiratory viral infections, recovery from illness requires pathogen clearance, resolution of the anti-viral inflammatory response, and repair of damaged lung tissue. Restoring the pulmonary epithelial barrier is of profound importance to organ physiology and necessary to minimize susceptibility to secondary bacterial infections1, 2. While many studies have focused on the stages of viral elimination by innate and adaptive immune responses3, a comprehensive understanding of how tissue repair is coordinated, and the role of leukocytes in this process, is poorly defined. Recent studies have demonstrated a role for leukocyte-derived epidermal growth factor receptor (EGFR) ligand, amphiregulin, in promoting tissue protection in the intestine and muscle4, 5, and following influenza virus?induced damage in the lung6, 7. The applicant recently illustrated that genetic ablation of amphiregulin in murine regulatory T (Treg) cells results in impaired lung function and markedly reduced airway epithelial repair after challenge with influenza virus in vivo6. Transcriptional profiling and flow cytometric analyses of murine lung Treg cells isolated at 5 days post-infection indicated that these cells express receptors for two hallmark tissue damage cytokines, IL-18 and IL-33, and in vitro treatment of purified nave Treg cells with either of these cytokines was sufficient to induce amphiregulin production. These findings uncovered an important and previously unknown role for Treg cell?derived amphiregulin in maintaining epithelial barrier integrity during the immune response to a respiratory pathogen. This K22 proposal builds on the applicant's prior study and examines (1) the mechanism by which Treg cell?derived amphiregulin contributes to tissue repair and (2) the role of other amphiregulin-producing leukocytes and tissue-protective mediators in coordinating repair processes throughout the course of influenza infection. Characterizing the molecular and cellular pathways that protect against infectious damage and prevent associated immunopathology will broaden our knowledge of immunological responses and aid in the development of novel therapeutics for treating infectious, allergic, and autoimmune diseases.