ABSTRACT 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 T cells are the primary IL‐17‐producing lymphocyte subset. Unlike conventional αβ T cells, T cells preferentially colonize non‐lymphoid tissues, such as intestine and airway epithelia/mucosa. It remains unknown if COX‐2‐derived PGs regulate T cells during allergic lung inflammation. Herein, we examined how COX‐2‐derived PGs regulate T cells using in vivo and in vitro assays with COX‐2 +/+ and COX‐2 −/− mice and isolated 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 T cells. Isolated T cells produced IL‐17A upon restimulation with IL‐1β + IL‐23 ex vivo; however, T cells from COX‐2 −/− mice produced less IL‐17A than T cells from COX‐2 +/+ mice. Of multiple PGs tested, only PGE 2 significantly promoted IL‐1β + IL‐23‐induced IL‐17A production by T cells. Single cell RNA sequencing (scRNA‐seq) identified, and qPCR confirmed, that T cells express only two PGE 2 receptors (EP2 and EP4). Both EP2 and EP4 antagonists attenuated the PGE 2 ‐mediated increases in IL‐17A formation by T cells. Taken together, these data suggest that COX‐2‐derived PGE 2 enhances IL‐17A production in T cells in an EP2/EP4 dependent manner during allergic lung inflammation.
Feng et al. (2026) studied this question.