PROJECT SUMMARY Millions of individuals worldwide are afflicted with inflammatory diseases of the airways such as asthma that result in difficulty breathing, increased morbidity and mortality, making them significant health concerns. Currently, no cure exists for asthma, and it is one of the most expensive diseases to treat in developed countries. A hallmark of asthma is increased airway hyperreactivity and airway inflammation facilitated by specific innate and adaptive immune cells and their soluble mediators. While therapeutics targeting inflammatory soluble mediators in asthma are currently being used clinically, a more effective treatment may exist in the manipulation of immune cells to modulate their cytokine secretion during lung inflammation. Innate lymphoid cells (ILCs) have recently been identified as important cellular contributors in asthma. In non-allergic asthma, which affects approximately 40% of all asthmatics, type 3 ILCs (ILC3s) rapidly expand and secrete cytokines that contribute to both the initiation (interleukin (IL)-17) and potentiation (IL-22) of airway hyperreactivity and inflammation. We postulate that select aryl hydrocarbon receptor (AhR) ligands can be exploited to manipulate ILC3 cytokine secretion in airway inflammation, ultimately reducing it. Therefore, this application will test the hypothesis that different classes of AhR ligands differentially regulate receptor function to control ILC3 cytokine secretion, thereby modulating airway inflammation. Our specific Aims will specifically address this hypothesis by: 1) determining the molecular mechanisms underlying the ability of AhR ligands to manipulate ILC3 cytokine secretion, and 2) investigating the therapeutic potential of AhR ligands and AhR-activated ILC3s to modulate airway inflammation. This research is highly innovative based on the potential for different classes of AhR ligands to differentially regulate AhR function and thus manipulate cytokine secretion by ILC3s during airway inflammation. Also, we propose novel approaches to study the mechanisms by which these selective AhR ligands alter the functionality of ILC3. Furthermore, we have assembled a highly experienced and collaborative team, with expertise in mucosal immunology, airway inflammation, and AhR biology. Therefore, the proposed studies are expected to lead to new therapeutic approaches to treat chronic airway inflammatory diseases, and significantly advance our understanding of how AhR signaling regulates respiratory immunity.