Efficient T‐cell priming and activation requires signaling through prostaglandin E2 (EP) receptors

Understanding the regulation of T‐cell responses during inflammation and auto‐immunity is fundamental for designing efficient therapeutic strategies against immune diseases. In this regard, prostaglandin E 2 (PGE 2 ) is mostly considered a myeloid‐derived immunosuppressive molecule. We describe for the first time that T cells secrete PGE 2 during T‐cell receptor stimulation. In addition, we show that autocrine PGE 2 signaling through EP receptors is essential for optimal CD4 + T‐cell activation in vitro and in vivo, and for T helper 1 (Th1) and regulatory T cell differentiation. PGE 2 was found to provide additive co‐stimulatory signaling through AKT activation. Intravital multiphoton microscopy showed that triggering EP receptors in T cells is also essential for the stability of T cell–dendritic cell (DC) interactions and Th‐cell accumulation in draining lymph nodes (LNs) during inflammation. We further demonstrated that blocking EP receptors in T cells during the initial phase of collagen‐induced arthritis in mice resulted in a reduction of clinical arthritis. This could be attributable to defective T‐cell activation, accompanied by a decline in activated and interferon‐γ‐producing CD4 + Th1 cells in draining LNs. In conclusion, we prove that T lymphocytes secret picomolar concentrations of PGE 2 , which in turn provide additive co‐stimulatory signaling, enabling T cells to attain a favorable activation threshold. PGE 2 signaling in T cells is also required for maintaining long and stable interactions with DCs within LNs. Blockade of EP receptors in vivo impairs T‐cell activation and development of T cell‐mediated inflammatory responses. This may have implications in various pathophysiological settings.