IL-33/ST2-independent activation of type 2 responses in allergic asthma 3589

Abstract Description Allergic asthma is a chronic inflammatory lung disease causing 1,000+ deaths per day. The innate immune response is driven by alarmins like IL-33, which signals through its cognate receptor ST2. Given its early role in the allergic cascade, IL-33 is an attractive therapeutic target for downstream asthma control. Nevertheless, ?-IL-33 treatments have shown limited clinical efficacy. In prior literature, mice lacking IL-33 (IL-33-/-) or ST2 (ST2-/-) exhibit reduced allergic responses. However, we have reproducibly found that our IL-33-/-, ST2-/-, and double-knockout mice respond to allergen similarly to wild-type controls suggesting the IL-33/ST2 axis is dispensable in our mice. To address whether this phenomenon is environmentally driven, we compared the allergic responses of our ST2-/- mice to those from another facility (Facilities A and B, respectively). Excitingly, ST2-/- mice from Facility B exhibited a reduced allergic response consistent with prior literature. In analyzing the cellular landscape in the lungs of naïve ST2-/- mice from both facilities, we found that the ILC2 compartment was expanded only in ST2-/- mice from Facility A. Thus, environment drives the generation of distinct cellular landscapes in the lung in the absence of IL-33/ST2. We are exploring alternative pathways of allergic induction and the role of the microbiome in allergic response severity to explain variability in clinical therapeutic efficacy and uncover novel therapeutic targets. Funding Sources Supported by T32AI007496-28 Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)