Integrin-dependent induction of functional urokinase receptors in primary T lymphocytes.
In order to reach the sites of inflammation, lymphocytes leave the bloodstream and migrate into peripheral tissues, in a process involving integrin-mediated adhesion to the vascular endothelium, followed by transmigration 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 urokinase plasminogen activator (uPAR) were not expressed in resting T lymphocytes, but could be efficiently induced at the mRNA and protein level by coclustering of the antigen receptor complex and beta1 or beta2 integrins, through a signalling pathway involving both protein kinase C activation and an increase in intracellular cyclic AMP. Catalytic activation of plasminogen by uPAR-expressing T cells promoted their migration through an extracellular matrix in vitro. Plasmin-induced invasion was inhibited by plasmin-and urokinase inhibitors and by anti-uPAR antibodies. Finally, cytofluorimetric and immunohistochemical analysis of primary human tumor specimens showed the presence of uPAR positive infiltrating T cells in vivo. Collectively, these findings suggest 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 process of leukocyte transmigration.
Bianchi
E
E
Human Immunology Unit, Scientific Institute San Raffaele-DIBIT, Milano, Italy.
Ferrero
E
E
Fazioli
F
F
Mangili
F
F
Wang
J
J
Bender
J R
JR
Blasi
F
F
Pardi
R
R
D000262:Adenylyl Cyclases / Q000378:metabolism; D001943:Breast Neoplasms / Q000276:immunology; D018821:CD18 Antigens / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007152:Immunologic Capping; D019012:Integrin beta1 / Q000378:metabolism*; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000276:immunology; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D011956:Receptors, Cell Surface / Q000096:biosynthesis* / Q000235:genetics; D055293:Receptors, Urokinase Plasminogen Activator; D015290:Second Messenger Systems; D013601:T-Lymphocytes / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
D018821:CD18 Antigens; D019012:Integrin beta1; C524898:PLAUR protein, human; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D000242:Cyclic AMP; D011493:Protein Kinase C; D014568:Urokinase-Type Plasminogen Activator; D000262:Adenylyl Cyclases