Critical role for IL-33 in orchestrating group 2 innate lymphoid cell and natural killer cell function in the lungs

Abstract The alarmin, IL-33, acting via ST2 receptors initiates innate immunity to inhaled allergens and environmental particulates. IL-33 belongs to the IL-1 family and is largely derived from epithelial cells, endothelial cells and fibroblasts. The cytokine plays a critical role in underpinning type 2 immunity at mucosal sites and the IL-33/ST2 axis has been implicated in bronchial asthma and virus-induced exacerbations of allergic airway disease. In this study, we found that IL-33 instillations into the airways of C57BL/6 mice, for 3 days over a 7 day period, induced a marked increase in the number of group 2 innate lymphoid cells (ILC2s) and their production of type 2 cytokines IL-13 and IL-5 and this was associated with a pronounced pulmonary eosinophilic inflammation and airway mucus production. Interestingly, IL-33 administration also resulted in an increase in the number of CD11b+CD11C+MHCII+ dendritic cells and evoked a marked expansion of Th2 cells in the lung mucosa. Concomitant with this response, there was a significant reduction in IFN-γ production by pulmonary CD3−CD19−DX5+NK1.1+ NK cells. Flow cytometry revealed that ST2 expression was predominantly expressed by pulmonary ILC2s rather than NK cells, raising the possibility that ILC2s, either directly or indirectly, regulate the NK cell response. These findings reveal that IL-33 plays critical roles in both initiating pulmonary innate and adaptive immune responses, thus providing an essential axis for rapid immune responses and tissue homeostasis in the lung as well as influencing the development of chronic airway inflammation and remodeling.