Michelle Cully

"Targeting Lymphatic Endothelial Cell IKKα Drives Formation of Bronchus Associated Lymphoid Tissue"

Michelle Cully and Michael May

The non-canonical NF-κB pathway is required for secondary lymphoid organ development and recent evidence suggests that activation of this pathway in lymphatic endothelial cells (LECs) drives lymphoid organogenesis. To study this in detail, we generated mice lacking LEC-intrinsic IKKα, a central kinase in the non-canonical NF-κB pathway. These mice failed to develop lymph nodes and strikingly, we found peri-bronchiolar and perivascular aggregates of immune cells in their lungs that were otherwise healthy and undamaged. Further assessment of these immune cell accumulations revealed them to be lung-associated tertiary lymphoid organs (TLOs) that we named spontaneous bronchus-associated lymphoid tissue (sBALT). Tertiary lymphoid organs (TLOs) are ectopic accumulations of immune cells that arise in a range of inflammatory diseases and cancers, but the mechanisms that control their formation and function remain incompletely understood. We determined that sBALT is highly organized, containing a B cell follicle adjacent to a T cell zone, as well as dendritic cells at the T-B interface and CXCL13 expressing stroma underlying the B cell follicle. Importantly, when we infected the mice with influenza virus, they displayed remarkably improved morbidity and mortality compared with littermate controls. From these findings, we hypothesize that targeting IKKα in LECs impairs immune cell egress from the lung leading to the formation of sBALT that can protect against respiratory infection. We speculate that targeting IKK in LECs to drive TLO formation may be a valuable treatment opportunity against emerging respiratory pathogens.