The lung is a natural tolerogenic organ. Lung mucosal tolerance must be exquisitely controlled by the lung immune system to avoid the development of chronic inflammatory lung diseases. Our knowledge of lung tolerance is, however, inadequate. This is evident in asthma treatments. Current asthma therapies are limited to blunting the progression of the disease. Patients relapse once the treatments are stopped because the treatments do not repair the underlying, dysregulated lung mucosal tolerance. Lung dendritic cells (DCs) orchestrate lung immune responses. We recently reported a lung epithelial cells IFN?-TNFR2+ cDC2 (R2D2) - Tregs axis in control of lung tolerance. We further showed that lung R2D2 cells are plastic, which makes them an ideal target for therapeutic intervention. The essential role of lung Tregs in maintaining tolerance has been firmly established. In this proposal, we focus on i) uncovering the molecular and cellular mechanisms of the lung epithelial cells IFN?-R2D2 control of lung mucosal tolerance; ii) developing an IFN?-based regimen to restore lung tolerance in chronic inflammatory lung diseases. We showed, in this proposal, that lung alveolar type II cells (AT-II) are the IFN?+ cells, and STING is essential for basal IFN? production in the lung.
In Aim1, we will determine the in vivo mechanism by which lung AT-II cells sustain lung IFN? level and maintain lung tolerance at the steady-state.
In Aim2, we will determine the tolerogenic IFN? program in mouse and human lung R2D2 cells.
In Aim3, we will develop an IFN?-based regimen to enhance, restore lung tolerance, and prevent, treat inflammatory lung diseases in mice. Chronic inflammatory lung diseases are the 4th leading cause of death in the U.S. Understanding the fundamental mechanism for lung tolerance and develop a new innovative regimen to restore lung mucosal tolerance in chronic lung diseases are highly significant.
Loss of lung tolerance causes chronic lung diseases, including asthma and COPD. This study aims to uncover the mechanism of lung tolerance and further develop therapeutics for chronic lung diseases. The knowledge obtained will improve healthcare for lung disease patients.
