THE ROLES OF ADHESION MOLECULES AND PROTEINASES IN LYMPHOCYTE TRANSENDOTHELIAL MIGRATION

T cell extravasation into perivascular tissue during inflammation invo lves transmigration through the endothelial cell (EC) layer and baseme nt membrane. We have demonstrated that matrix metalloproteinase-2 (MMP -2) is induced in T cells upon adhesion to endothelial cells and that the induction of MMP-2 is mediated by binding of T cell VLA-4 to VCAM- 1. Cloned murine Th1 cells antigenic to myelin basic protein, either e xpressing VLA-4 on their cell surface and causing experimental autoimm une encephalomyelitis (EAE) or not expressing VLA-4 and not causing EA E, were used. VLA-4 positive (+)T cells that adhered to VCAM-1 positiv e (+) endothelial cells exhibited an induction in MMP-2 mRNA, protein, and activity, whereas MMP-2 was not induced in the T cells that adher ed to the VCAM-1 negative (-) endothelial cells or VLA-4 negative (-) T cells that adhered to VCAM-1+ endothelial cells. Incubating T cells with rVCAM-1-coated dishes showed that VLA-4+ T cells adhered to the m olecule and that adhesion to rVCAM-1 was sufficient to induce MMP-2. V LA-4+ T cells that had transmigrated through a VCAM-1+ endothelial cel l monolayer exhibited MMP-2 activity. TIMP-2 was shown to reduce T cel l transmigration in vitro. Transmigrated T cells exhibited downregulat ion of VLA-4 and LFA-1 integrin surface expression and decreased bindi ng to rVCAM-1 and rICAM-1 and increased binding to collagens I and IV, fibronectin, and laminin. Brain sections of mice demonstrated that as T cells migrated farther into the tissue, VLA-4 expression was lost, although CD4 expression remained unchanged. These results demonstrate that binding to VCAM-1 on endothelial cells induces MMP-2 in T cells, which, in turn, may facilitate T cell migration into perivascular tiss ue. The significance of these findings in the modulation of the inflam matory response is discussed.