Sreeramkumar, VinathaHons, MiroslavPunzón, CarmenStein, Jens V.Sancho, DavidFresno, ManuelCuesta Rubio, Natalia2019-10-092019-10-092016Sreeramkumar, V., Hons, M., Punzón, C., Stein, J. V., Sancho, D., Fresno, M., & Cuesta, N. (2016). Efficient T‐cell priming and activation requires signaling through prostaglandin E2 (EP) receptors. Immunology and Cell Biology, 94(1), 39-51. https://doi.org/10.1038/icb.2015.620818-96411440-1711http://hdl.handle.net/11268/8316Understanding 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 E2 (PGE2) is mostly considered a myeloid-derived immunosuppressive molecule. We describe for the first time that T cells secrete PGE2 during T-cell receptor stimulation. In addition, we show that autocrine PGE2 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. PGE2 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 PGE2, which in turn provide additive co-stimulatory signaling, enabling T cells to attain a favorable activation threshold. PGE2 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.engjournal article10.1038/icb.2015.62restricted accessLinfocitos TProstaglandinasBiología celularLucha contra las enfermedades