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)2a-encoding gene Epas1 in intestinal Th2 cells.
In addition, experimental exposure to hypoxic conditions, or selective HIF2a activation in CD4+ T cells promoted
Th2 cell differentiation both in vitro and in vivo. As such, we hypothesize that HIF2a is required for Th2 cell
terminal differentiation and promotion of inflammation in allergic asthma disease. The requirement of HIF2a in
Th2 cell terminal differentiation will be determined by deleting HIF2a in Th2 cells during house dust mite-induced
(HDM) airway inflammation in vivo and in differentiating Th2 cells in vitro. The mechanism of HIF2a-induced Th2
differentiation will be measured through evaluation of HIF2a-mediated changes in gene expression, epigenetic
remodeling, and HIF2a genomic binding sites in Th2 cells. The requirement of HIF2a in the development of
allergic asthma disease will be tested by deleting HIF2a in T cells after sensitization or challenge with HDM and
measuring the development of pathology and airway hyperresponsiveness. Finally, HIF2a will be evaluated as
a therapeutic target in treating allergic asthma through treatment of mice with a HIF2a inhibitor during HDM
sensitization or challenge. These studies will uncover the role of HIF2a 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.