Targeting the EP2 receptor ameliorates inflammatory bowel disease in mice by enhancing the immunosuppressive activity of T cells.

Inflammatory bowel diseases (IBDs) are characterized by unrestrained innate and adaptive immune responses and compromised intestinal epithelial barrier integrity. Regulatory T (T) cells are crucial for maintaining self-tolerance and immune homeostasis in intestinal tissues. Prostaglandin E (PGE), a bioactive lipid compound derived from arachidonic acid, can modulate T cell functions in a receptor subtype-specific manner. However, whether PGE regulates T cell function and contributes to IBD pathogenesis remains unclear. Here, we found that the PGE receptor subtype 2 (EP2) is highly expressed in T cells. T cell-specific deletion of EP2 resulted in increased T cell numbers, and enhanced granzyme B(GzmB) expression and immunosuppressive capacity of T cells in mice. Adoptive transfer of EP2-deficient T cells attenuated naïve CD4 T cell transfer-induced colitis in Rag1 mice. Mice with EP2-deficient T cells were protected from 2,4,6-trinitrobenzene sulfonic acid (TNBS)- and dextran sodium sulfate (DSS)-induced colitis. Pharmacological blockage of EP2 with PF-04418948 markedly alleviated DSS-induced colitis in mice in a T-dependent manner. Mechanistically, activation of EP2 suppressed T cell function, at least in part, through reduction of GzmB expression via PKA-mediated inhibition of NF-κB signaling. Thus, we identified the PGE/EP2 axis as a key negative modulator of T cell function, suggesting EP2 inhibition as a potential therapeutic strategy for IBD treatment.