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.
Altieri
D C
DC
Department of Immunology, Scripps Research Institute, La Jolla, California 92037.
Stamnes
S J
SJ
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002118:Calcium / Q000032:analysis; D002478:Cells, Cultured; D003432:Cross-Linking Reagents; D003600:Cytosol / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D015951:Factor Xa / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D007376:Interleukin-2 / Q000494:pharmacology; D008213:Lymphocyte Activation; D010641:Phenotype; D011956:Receptors, Cell Surface / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism*; D015398:Signal Transduction; D000077022:Survivin; D013601:T-Lymphocytes / Q000276:immunology*
D000911:Antibodies, Monoclonal; C107489:BIRC5 protein, human; D003432:Cross-Linking Reagents; D051034:Inhibitor of Apoptosis Proteins; D007376:Interleukin-2; D011956:Receptors, Cell Surface; D000077022:Survivin; D012697:Serine Endopeptidases; D015951:Factor Xa; D002118:Calcium