INTEGRIN-DEPENDENT INDUCTION OF FUNCTIONAL UROKINASE RECEPTORS IN PRIMARY T-LYMPHOCYTES

In order to reach the sites of inflammation, lymphocytes leave the blo odstream and migrate into peripheral tissues, in a process involving i ntegrin-mediated adhesion to the vascular endothelium, followed by tra nsmigration across the endothelial barrier and through the underlying interstitial matrix. We have investigated the role of the plasminogen activator/plasmin system in normal T cell migration. Receptors for uro kinase plasminogen activator (uPAR) were not expressed in resting T ly mphocytes, but could be efficiently induced at the mRNA and protein le vel by co-clustering of the antigen receptor complex and beta 1 or bet a 2 integrins, through a signalling pathway involving both protein kin ase C activation and an increase in intracellular cyclic AMP. Catalyti c activation of plasminogen by uPAR-expressing T cells promoted their migration through an extracellular matrix in vitro. Plasmin-induced in vasion was inhibited by plasmin-and urokinase inhibitors and by anti-u PAR antibodies. Finally, cytofluorimetric and immunohistochemical anal ysis of primary human tumor specimens showed the presence of uPAR posi tive infiltrating T cells in vivo. Collectively, these findings sugges t that plasminogen activation may play a role in lymphocyte migration in vivo, and that integrin-dependent expression of membrane-associated endopeptidases could represent an additional step in the regulated pr ocess of leukocyte transmigration.