PROJECT SUMMARY / ABSTRACT – Defining a type II IL-9R Cells communicate through specific cytokine-receptor binding to mediate immune responses and inflammation. Targeting these interactions has become an effective approach to patient treatment in a growing list of diseases. Among the cytokines, IL-9 is pleiotropic and is involved in allergic and autoimmune diseases and in tumor immunity. In hematopoietic cells IL-9 signals through the IL-9Rα chain and the γc chain that is shared with other cytokines including IL-2, IL-4, and IL-7. Numerous reports, including our own, demonstrate the ability of IL-9 to stimulate direct effects in non-hematopoietic cells as well. Yet, the hematopoietic-restricted expression of γc leaves a gap in our knowledge of how IL-9 delivers a signal to non-hematopoietic cells. The related cytokine IL-4 has a type II receptor that is composed of the IL-4Rα chain and the IL-13Rα1 chain to facilitate responses in non-hematopoietic cells. In this application we provide evidence of a type II IL-9R that is proposed to function in non-hematopoietic cells. We hypothesize that on airway epithelial cells IL-9Rα can combine with IL-13Rα1 to form a type II receptor and we provide preliminary data of a physical interaction between these receptor chains. We will test this hypothesis using gene-targeted mice and both in vitro and in vivo model systems to analyze IL-9 signaling and IL-9 function in airway epithelial cells. Together, these studies will expand the paradigm of cytokine receptor biology, provide detailed insight into IL-9 effector functions, and further define how targeting cytokine receptor chains impacts immunity in the patient population.