Targeting IKK-alpha in lymphatics to drive protective tertiary lymphoid organ formation - 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 immunotherapy are gaining traction, our findings will
have a wider impact for other diseases in which TLOs play a protective immunological role.