A major goal of this PPG is to define the cellular and molecular basis for structure, function, and remodeling of the lung epithelium. In that context, we have focused on the development of mucous cell metaplasia. In the previous cycle, we provided proof for the hypothesis that acute viral infections can permanently reprogram the immune response to drive airway epithelial cells towards chronic mucous cell metaplasia. For this renewal, we will focus on how the immune system becomes capable of regulating this type of airway epithelial cell behavior. In that regard, we have recently discovered two novel mechanisms for immune cells to persistently produce IL-13 and thereby cause chronic mucous cell metaplasia. The first mechanism is based on the capacity of acute viral infection to activate CDId-dependent invariant NKT cells that in turn drive the generation of IL-13-producing macrophages in the lung. The second mechanism depends on the capacity of viral infection to drive interferon (IFN)-dependent expression of the high-affinity IgE receptor (FcsRI) on conventional dendritic cells (cDCs) that in turn recruit IL-13-producing CD4* T helper type 2 (Th2) cells to the lung. Thus, IL-13 production and consequent mucous cell metaplasia derives from the combined contributions of persistently activated macrophages and Th2 cells. Each of these pathways appears active in patients with mucous cell metaplasia due to asthma or COPD as well. In addition to these two new pathways, we have recently discovered that a third type of immune cell population also contributes significantly to IL-13 production and consequent mucous cell metaplasia after viral infection in mice. This cell population exhibits a distinct non-B non-T (NBNT) cell lineage with high levels of MHC Class II expression. The closest known counterpart for these IL-13+MHC-H+ NBNT cells appears to be an IL-25- dependent cell population found in mouse gut after helminth infection. Others report an IL-25 requirement for the response to inhaled allergen in mice and a marked increased IL-25 and IL-25 receptor (IL-25R) expression in allergic asthma patients. Taken together, we propose a new role for the lung population of IL- 13+MHC-ir NBNT cells in chronic airway disease. The present project will determine whether this NBNT cell population found after viral infection is also driven by IL-25 and/or other factors, and how this distinct immune cell population contributes to the development of chronic airway disease in this mouse model and in patients with chronic mucous cell metaplasia due to asthma or COPD. Together, the findings should provide a comprehensive scheme for the immune pathways leading to mucous cell metaplasia in the remodeling of airway epithelium. The findings should also provide new targets for therapeutic intervention in patients with mucus obstruction.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Washington University
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