Project Summary Allergic asthma is characterized by episodic airflow obstruction, airway hyper-responsiveness and airway inflammation caused by inappropriate Th2 immune responses to harmless airborne environmental antigens. The prevalence of asthma has risen sharply in the developed world over the past 3 decades, and worldwide over 300 million people suffer from asthma, with ~250,000 annual deaths attributed to this disease. As such, asthma is the most common chronic lung disease and a major public health issue. Asthma is clinically heterogeneous, and ranges from mild disease that is relatively easy to control with anti-inflammatory steroid treatment, to severe disease that is steroid resistant and prone to clinical exacerbations upon respiratory infection with viruses such as human rhinovirus (HRV) or respiratory syncytial virus (RSV) that can be life- threatening and often require hospitalization. Exactly how respiratory virus infections trigger asthma exacerbations is not well understood, but likely involve induction of inflammatory cytokines and chemokines that act to amplify the innate and adaptive immune response to allergen. In addition to facilitating gas exchange in the lungs, pulmonary epithelial cells must act as a barrier to the outside world, and are therefore are the first cells exposed to airborne allergens and are the dominant targets of respiratory virus infections. Thus, epithelial cells are poised to have a dramatic influence on pulmonary immune responses, and may be the key drivers of virus-associated asthma exacerbation. Indeed, we hypothesize that upon respiratory virus infection, epithelial cell-derived products act on local immune cells to enhance allergen-specific effector cell responses, while inhibiting the function of regulatory T cells that However, the direct impact of pulmonary epithelial cells on T cell responses in the lung is still poorly understood, largely due to the lack of tractable model systems in which the impact of the epithelial cells on T cell responses can be isolated and studied at the molecular level. In exciting preliminary data, we have developed an experimental system using air-liquid interface (ALI) cultures of pulmonary epithelial cells in which their responses to allergen and viral challenge can be characterized, and the impact of these responses on effector and regulatory T cell populations can be measured. Combined with innovative in vivo models, we will use this system to determine how epithelial cells alter T cell responses during virus-induced exacerbation of clinical asthma.