Tertiary lymphoid organs (TLOs) are ectopic structures that resemble secondary lymphoid organs, but arise de novo in response to infection, inflammation, autoimmunity and cancer. TLO function is context dependent, exacerbating pathology of autoimmune and chronic inflammatory diseases, while providing immune protection following bacterial and viral infections, and in various cancers. Thus, identifying the precise signals and cells that drive beneficial TLO formation while avoiding pathogenesis is a highly significant objective that will define novel targets for developing new immune-modulating drugs. Inducible bronchus-associated lymphoid tissue (iBALT) is a type of TLO that forms in the lungs in response to infection, inflammation and pulmonary damage, where its function ranges from pathologic to protective depending on the nature and context of the disease. In the case of infection by respiratory viruses such as influenza, iBALT provides protective immunity, supporting therapeutic induction of BALT formation as a strategy to promote immunity and enhance vaccine efficacy in the lung. However, a major roadblock to pursuing this approach is the lack of identified therapeutic targets that can be exploited to promote protective BALT formation while avoiding potentially destructive inflammatory responses in lung tissue. In our ongoing studies of NF-κB signaling in immune homeostasis, we created mice lacking IKKa in lymphatic endothelial cells (LECs). These mice lack all lymph nodes, but remarkably form spontaneous BALT in the absence of inflammation, emphysema or tissue damage. Following infection with influenza virus, IKKa LEC-KO mice only transiently lost weight and all animals survived, whereas control mice lost extensive body weight and more than half died. These findings support an exciting new model in which inhibition of IKKa in LECs would drive non-pathogenic BALT, thereby providing prophylactic protection by acting as a “command center” to coordinate a rapid and enhanced local anti-viral immune response. In this proposal we will leverage these new findings to address the hypothesis that “targeting LEC-intrinsic IKKa promotes protective non-pathogenic BALT formation”. Accordingly, we will pursue the following two specific aims: (1) To determine how IKKa regulates pulmonary lymphatic vessel function; (2) To establish a new inducible in vivo model to drive non-pathogenic BALT formation. We will use this model to determine if limiting LEC-intrinsic IKKa deletion to the lungs can augment protection by increasing local protection, while leaving lymph node and lymphatic function in other tissues intact. These studies will directly impact our understanding of the signals that regulate the immune function of pulmonary lymphatics and will provide crucial insight into the feasibility of therapeutically targeting LEC-intrinsic IKKa to provide immunoprophylactic protection against respiratory pathogens. As therapeutic strategies to exploit TLOs for immuno...