Protease-Dependent T Cell Activation: Ligation of Effector Cell Protease Receptor-1 (EPR-1) Stimulates Lymphocyte Proliferation

Blood proteases regulate cellular growth through the recognition and signaling properties of specialized membrane receptors. Previous studies have identified a novel lymphocyte activation-dependent antigen, denominated effector cell protease receptor-1 (EPR-1), which binds the coagulation protease factor Xa on various leukocyte subsets. Here we show that occupancy of EPR-1 with physiologic concentrations of factor Xa (15-75 nM), or with "surrogate" monoclonal antibody ligands, stimulates proliferation of both T and B lymphocyte subsets and augments CD3-dependent lymphocyte proliferation. At suboptimal responder cell concentrations, ligation of EPR-1 costimulates lymphocyte proliferation in the presence of accessory signals, i.e., phorbol ester, IL-2. At higher responder cell concentrations, occupancy of EPR-1 per se is sufficient to initiate lymphocyte proliferation. EPR-1-dependent T cell activation is associated with early surface expression of IL-2 receptor on target cells, thus increasing by five- to eightfold their mitogenic responsiveness to very low doses of IL-2 (0.2 U/ml). Consistent with a postulated role in transmembrane signal transduction, cross-linking of EPR-1 transiently increases cytosolic free [Ca2+]i in single adherent T cells. These findings suggest that proteases ubiquitously generated in vivo might contribute a regulatory mechanism of cytokine- or antigen receptor-dependent T cell activation and identify EPR-1 as a novel signal-transducing molecule of lymphocyte stimulation.