A Live Imaging Cell Motility Screen Identifies Prostaglandin E2 as a T Cell Stop Signal Antagonist

Abstract

The T cell migration stop signal is a central step in T cell activation and inflammation; however, its regulatory mechanisms remain largely unknown. Using a live-cell, imaging-based, high-throughput screen, we identified the PG, PGE2, as a T cell stop signal antagonist. Src kinase inhibitors, microtubule inhibitors, and PGE2 prevented the T cell stop signal, and impaired T cell–APC conjugation and T cell proliferation induced by primary human allogeneic dendritic cells. However, Src inhibition, but not PGE2 or microtubule inhibition, impaired TCR-induced ZAP-70 signaling, demonstrating that T cell stop signal antagonists can function either upstream or downstream of proximal TCR signaling. Moreover, we found that PGE2 abrogated TCR-induced activation of the small GTPase Rap1, suggesting that PGE2 may modulate T cell adhesion and stopping through Rap1. These results identify a novel role for PGs in preventing T cell stop signals and limiting T cell activation induced by dendritic cells.