Prostaglandin I₂ signaling restrains Treg cell ST2 expression by repressing β-catenin in allergic airway inflammation

T regulatory (Treg) cells dampen immune activation. Treg cells downregulate the type 2 response to innocuous environmental antigens that produce allergic airway inflammation; however, ST2-positive Treg cells promote allergic airway inflammation. Prostaglandin I₂ (PGI₂), which signals through the G protein-coupled receptor IP, promotes Treg cell function in an ovalbumin-based model of allergic airway inflammation, suggesting a role for PGI₂ signaling through the IP receptor augmenting β-catenin activity in Treg cells.

We sought to define the mechanisms responsible for PGI₂'s promotion of Treg cell function in the context of an environmental allergen.

Treg cell-specific IP-deficient mice, Treg cell fate-tracking IP-deficient mice, and Treg cell-specific IP- and β-catenin-deficient mice were exposed to an Alternaria alternata extract sensitization and challenge model. Bronchoalveolar lavage fluid was evaluated for cell number, cell differential, and cytokines by ELISA. Lungs were evaluated by flow cytometry and histopathology.

Utilizing Treg cell-specific IP-deficient mice, we found that loss of PGI₂ signaling impaired Treg cell-suppressive function in response to A alternata; specifically, we found enhanced type 2 cytokine production, eosinophil infiltration, vascular remodeling, and numbers of ST2-positive Treg cells compared to controls. We found that dual IP and β-catenin deficiency in Treg cells prevented the enhanced type 2 response and the further increase in ST2-positive Treg cells via prevention of an increase in GATA3 expression in response to A alternata.

Together, these data further support the importance of PGI₂ signaling within Treg cells to their support functionality and demonstrate that PGI₂ prevents Treg cell dysfunction through downregulation of β-catenin.