UROKINASE RECEPTOR - AN ACTIVATION ANTIGEN IN HUMAN T-LYMPHOCYTES

The ability of activated T lymphocytes to extravasate and reach inflam matory and malignant foci in the tissues is a basic function of cellul ar immunity. Recent evidence strongly suggests that the urokinase rece ptor (uPAR) holds a central position in the development of human two-c hain urokinase-mediated pericellular proteolysis and matrix degradatio n, an important element in cell migration. In this report we establish uPAR as a pan T cell activation Ag. As determined by FACS analysis, C D3+ lymphocytes from healthy donors exhibited no significant uPAR expr ession. In contrast, patients (e.g., HIV-positive donors) showed disti nct uPAR expression, confined to HLA-DR+ cells, in up to 80% of all T cells. In vitro activation by PMA caused a rapid up-regulation of memb rane uPAR in all healthy donor T cells and was accompanied by enhanced receptor synthesis and elevated uPAR mRNA levels. A similar induction resulted from activation via the TCR/CD3 complex using mitogens (PHA, and Con A), anti-CD3 antibodies, and alloantigen. Receptor expression at single cell level was also modulated by a number of cytokines. IL- 2, IL-4 and IL-7 increased uPAR presentation on 20 to 50% of the T cel l population, and combined stimulation of bulk cultures demonstrated a n additive effect of IL-2 and IL-7, whereas the response to each of th e two was inhibited by IL-4. In addition, TGF-beta1 substantially redu ced the uPAR expression in T cell cultures responding to PHA, IL-2, an d IL-7. Irrespective of the activating reagent, the T cells appeared t o produce the same molecular uPAR species, but the affinity of uPAR ex pressed in PMA blasts was decreased, presumably because of a different ial location at the cell surface. All activated cultures showed co-exp ression of uPAR and CD25. The finding that the urokinase receptor is a n activation Ag may suggest that cell-associated plasminogen activatio n is involved in extravasation and migration of activated T cells.