Project Summary Asthma and chronic obstructive pulmonary disease (COPD) are inflammatory diseases that affect the airways and, together, are the largest causes of disability and mortality from chronic respiratory disorders worldwide. At the heart of the pathophysiology of both diseases is altered airway epithelial cell (AEC)-immune cell interactions with aberrant activation of innate and adaptive immunity, notable for the accumulation of activated airway T cells and B cells. It is thought that pathogenic AEC-myeloid cell-CD4+ T cell circuits underlie the pathophysiology of asthma, while AEC-myeloid cell-CD8+ T cell circuits predominate in COPD, but the diversity of AECs and immune cells involved are only now receiving scrutiny. In particular, rare AEC subtypes, including tuft, hillock, microfold, and neuroendocrine cells, are known to secrete immune cell-active mediators, but their role in human disease has not been established. Additionally, airway cellular structures such as hillock islands and inducible bronchial associated lymphoid tissue (iBALT) are immunologically active in asthma and COPD, but their role in disease pathogenesis is unknown. Furthermore, studies suggest that the T cell and B cell response to specific antigens, whether host-, allergen- and/or microbe-derived, may be important in the pathophysiology of asthma and COPD, but current efforts have not deeply characterized the specificity and function of the adaptive immune cells that accumulate in airways, nor their interactions with specific AEC populations. Our overall objective is to comprehensively define the signaling and spatial relationships of common and rare AEC cell types, airway structures such as the hillock and iBALT, and specific airway immune cell populations in asthma and COPD to ultimately define therapeutic approaches that precisely target disease-specific mechanisms. Our group has established protocols and methods for safely sampling asthmatic and COPD airways from well-defined patient cohorts and for obtaining tissue from diseased lung explants and donor lungs with asthma that were rejected for transplants. Using these methods, we have characterized the cellular profiles of AEC and immune cells in healthy, asthmatic, and COPD lungs and have defined some of the critical AEC-immune cell interactions within the airways of these subjects. We hypothesize that aberrant AEC-immune cell interactions involving AEC subtypes as well as airway structural features such as hillock islands and iBALT drive chronic immune activation in the airway, which ultimately promotes activation of airway-resident memory T cells and B cells, thus establishing a persistent inflammatory state that shapes the clinical course of asthma and COPD. The specific aims are 1) to determine and compare the transcriptional and spatial profiles of AEC-immune cell interactions in asthma and COPD, and 2) to define T cell and B cell receptor repertoires in the airways of patients with asthma and COPD. A deeper understanding of AEC-immune cell interactions in asthma and COPD will help define pathogenic mechanisms of each disease and may identify disease-specific therapeutic targets.

NARRATIVE Asthma and chronic obstructive pulmonary disease (COPD) together are the largest causes of disability and death from chronic lung diseases worldwide. One of the key mechanisms causing both diseases is aberrant airway communication between the cells lining the airways in the lung (airway epithelial cells) and cells of the immune system, which leads to inflammation and remodeling of the lungs and airways. Our overall objective is to comprehensively define the signaling and spatial relationships between airway epithelial cells and airway immune cell populations in asthma and COPD to define therapeutic approaches that precisely target disease- specific mechanisms.