Membrane receptors for blood proteases govern the clotting and fibrinolytic cascades, regulate signal transduction and control the growth of mesenchymal cells. Despite their importance in the development of vascular injury, it is unclear whether these mechanisms participate in the generation of an immune response. Here we report that targeting a factor Xa receptor, designated effector cell protease receptor-1 (EPR-1), with antisense oligonucleotide or with a monoclonal antibody (mAB 2E1) inhibited CD3/T-cell receptor-dependent lymphocyte proliferation. Immunosuppression was mediated by abolishing cytokine production and down-modulating membrane expression of the interleukin (IL)-2 receptor. In vivo administration of mAb 2E1 to severe-combined-immunodeficient mice injected with human peripheral blood leukocytes suppressed production of human immunoglobulin, abolished graft-versus-host disease, and protected these xenochimaeric mice from Epstein-Barr-virus-induced human lymphoproliferative disease. These observations indicate a new role for protease receptors in the regulation of the immune response, and identify a potential target for therapeutic immunosuppression in humans.