IL-33 and TSLP in chitin-induced lung inflammation

In humans, allergic disease bears striking resemblance to the host response to helminth infection. Thus, we studied N. brasiliensis infection in mice to identify factors that initiate host immunity and identified three that bind the environmental polysaccharide chitin. We further demonstrated that purified chitin acutely induces lung inflammation in mice, similar to that observed in human allergic disease, dependent on resident group 2 innate lymphoid cells (ILC2s). Given their number, distribution and function, lung ILC2s likely coordinate responses with resident epithelial cells that monitor barrier interactions with the environment. In this thesis, we demonstrate that alveolar type II (ATII) cells are the main source of interleukin (IL)-33 and thymic stromal lymphopoietin (TSLP) generated in response to chitin or N. brasiliensis challenge. IL-33 and TSLP synergistically activate ILC2s to produce IL-5, IL-13 and IL-9, and autocrine IL-9 promotes an ILC2 transcriptional program associated with rapid and robust cytokine production necessary to optimize epithelial gene responses in the conducting airways. Thus, ILC2s link a specialized, distal, epithelial population involved in alveolar function with more proximal epithelia that regulate airway flow, revealing a key role for ILC2s in tissue homeostasis that might underlie similar organizational hierarchies for innate lymphoid cells in other organs.