Requirement of HIF2a signaling in Th2 cell differentiation and allergic asthma - PROJECT SUMMARY Asthma affects over 300 million people globally, yet there a few therapies available for patients with severe asthma. Th2 cells and their cytokines, primarily IL-4 and IL-13, are responsible for airway inflammation and hyperresponsiveness in allergic asthma. Lymph node Th2 cells primarily express IL-4 while tissue Th2 cells express IL-13. However, it is currently unclear how Th2 cells sense and rapidly adapt to the inflammatory tissue milieu, altering their cytokine expression and promoting lung tissue pathology. Hypoxia Inducible Factor expression associated with increased inflammation in allergic asthma and may represent a key tissue-derived signal capable of licensing Th2 cells. Supporting this, during intestinal helminth infection, we identified selective transcriptional upregulation of the Hypoxia Inducible Factor (HIF)2α-encoding gene Epas1 in intestinal Th2 cells. In addition, experimental exposure to hypoxic conditions, or selective HIF2α activation in CD4+ T cells promoted Th2 cell differentiation both in vitro and in vivo. As such, we hypothesize that HIF2α is required for Th2 cell terminal differentiation and promotion of inflammation in allergic asthma disease. The requirement of HIF2α in Th2 cell terminal differentiation will be determined by deleting HIF2α in Th2 cells during house dust mite-induced (HDM) airway inflammation in vivo and in differentiating Th2 cells in vitro. The mechanism of HIF2α-induced Th2 differentiation will be measured through evaluation of HIF2α-mediated changes in gene expression, epigenetic remodeling, and HIF2α genomic binding sites in Th2 cells. The requirement of HIF2α in the development of allergic asthma disease will be tested by deleting HIF2α in T cells after sensitization or challenge with HDM and measuring the development of pathology and airway hyperresponsiveness. Finally, HIF2α will be evaluated as a therapeutic target in treating allergic asthma through treatment of mice with a HIF2α inhibitor during HDM sensitization or challenge. These studies will uncover the role of HIF2α in Th2 cell differentiation and the development of allergic asthma. Our findings will advance our understanding of the signals shaping Th2 cell responses in inflamed tissues and identify a novel therapeutic target for suppressing Th2 cell responses in allergic asthma and Th2 cell-induced airway inflammation.
