Suppression of alveolar stem cells by tissue-resident lymphocytes in emphysema

Project Summary/Abstract Acute exacerbations in chronic obstructive lung disease (COPD) are often triggered by respiratory viral infections that leads to irreversible decline in lung function. Mechanistic insight into the pathophysiologic link between viral triggers and loss of lung structural cells could uncover therapeutic modalities to attenuate the frequent exacerbations in COPD patients that leads to significant morbidity and mortality. This proposal will interrogate how tissue factors in the lung alters the inflammatory niche associated with viral infections to suppress alveolar type 2 (AT2) stem cell in emphysema, a subtype of COPD characterized by the loss of alveolar epithelium. Our preliminary data demonstrate that fibroblast-specific deletion of Hhip, an emphysema susceptibility gene, promotes the accumulation of T cells with tissue residency features (tissue resident lymphocytes, or TRLs) in the alveoli and subsequent loss of AT2s after viral infections, suggesting that host factors in the lung can alter the inflammatory cascade after viral infections to suppress a lung stem cell reservoir. We go on to demonstrate that TRLs can directly suppress the self-renewal capacity of AT2s, which is in part mediated by the secretion of the antiviral cytokine, interferon gamma (IFNγ). Finally, we show that a highly clonogenic human AT2 subset characterized by basal interferon gene expression is lost in the lungs of emphysema patients concurrent with accumulation of TRLs. Utilizing a combination of novel genetic tools to trace and delete Hhip+ stromal cells, genetic model of IFNγ activation, human organoid platform, 3D high-content tissue imaging, single cell analysis of human lung stem cell subsets, and a novel pharmacologic reagent made in our lab to target TRL accumulation, this proposal will determine the mechanism by which stromal factors in the lung modifies TRL accumulation in response to viral infections and tobacco smoke, and how TRLs suppress AT2s in both mouse and human models. Furthermore, we will determine whether host factors that modify TRLs can be leveraged as pharmacologic therapy to attenuate the inflammation and stem cell loss associated with acute exacerbation in emphysema.