COX-2-Derived PGE₂ Modulates IL-17 Production by γδ T Cells During Allergic Lung Inflammation

Cyclooxygenase-2 (COX-2)-derived prostaglandins (PGs) regulate differentiation of αβ T helper cells to Th2, Th9, and Th17 cell subsets during allergic lung inflammation. IL-17, the signature cytokine of Th17 cells, is a critical regulator of allergic immunopathology. Most studies on IL-17 have focused on Th17 cells, though $\mathrm{\gamma \delta }$ T cells are the primary IL-17-producing lymphocyte subset. Unlike conventional αβ T cells, $\mathrm{\gamma \delta }$ T cells preferentially colonize non-lymphoid tissues, such as intestine and airway epithelia/mucosa. It remains unknown if COX-2-derived PGs regulate $\mathrm{\gamma \delta }$ T cells during allergic lung inflammation. Herein, we examined how COX-2-derived PGs regulate $\mathrm{\gamma \delta }$ T cells using in vivo and in vitro assays with COX-2^+/+ and COX-2^-/- mice and isolated $\mathrm{\gamma \delta }$ T cells. COX-2 disruption reduced bronchoalveolar lavage fluid (BALF) IL-17A production during ovalbumin (OVA)-induced allergic lung inflammation in vivo without altering the number of IL-17A-producing $\mathrm{\gamma \delta }$ T cells. Isolated $\mathrm{\gamma \delta }$ T cells produced IL-17A upon restimulation with IL-1β + IL-23 ex vivo; however, $\mathrm{\gamma \delta }$ T cells from COX-2^-/- mice produced less IL-17A than $\mathrm{\gamma \delta }$ T cells from COX-2^+/+ mice. Of multiple PGs tested, only PGE₂ significantly promoted IL-1β + IL-23-induced IL-17A production by $\mathrm{\gamma \delta }$ T cells. Single cell RNA sequencing (scRNA-seq) identified, and qPCR confirmed, that $\mathrm{\gamma \delta }$ T cells express only two PGE₂ receptors (EP2 and EP4). Both EP2 and EP4 antagonists attenuated the PGE₂-mediated increases in IL-17A formation by $\mathrm{\gamma \delta }$ T cells. Taken together, these data suggest that COX-2-derived PGE₂ enhances IL-17A production in $\mathrm{\gamma \delta }$ T cells in an EP2/EP4 dependent manner during allergic lung inflammation.