Targeting the stromal niche for tissue-resident lymphocytes in asthma

Project Summary/Abstract The current paradigm of asthma attributes epithelial cells in recruiting immune cells that promote pathologies seen in asthmatic airways, including infiltration of immune cells and mucous metaplasia. What is less clear is how stromal cells surrounding the airway alter the inflammatory response to allergic challenge, and whether targeting these cells represents a viable strategy for asthma therapeutics. This proposal aims to characterize a targetable stromal factor that alters immune cell accumulation in the lung and define the downstream effects of these immune cells on airway epithelial cells. Our preliminary data demonstrate that fibroblast-specific deletion of Hhip promotes the accumulation of T cells with tissue residency features (tissue resident lymphocytes, or TRLs) within the adventitial space surrounding the airways, suggesting that host factors in the lung can alter the inflammatory response after allergen challenge. Utilizing a combination of novel genetic tools to trace and delete Hhip+ fibroblasts, human organoid platform, 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 allergen challenge. Furthermore, we will determine whether host factors that modify TRLs can be leveraged as pharmacologic therapy to attenuate the inflammation and airway metaplasia seen in asthmatic airways. Finally, we will develop an ex vivo organoid model of human asthmatic airways that preserves the stromal-epithelial-immune architecture for drug screening. Successful completion of this proposal will highlight an unrecognized axis whereby a dysregulated lung stromal niche can drive the maladaptive expansion of TRLs that promote mucous metaplasia in asthmatic airways, and provide preclinical studies of novel therapeutic agents to target the stroma in asthma.