TNF-alpha associated with extracellular matrix fibronectin provides a stopsignal for chemotactically migrating T cells

The migration of T cells into extravascular sites of inflammation is regula ted by information derived from the molecular structure of the invaded tiss ue and from chemokine and cytokine gradients in the context of the extracel lular matrix (ECM). Although recent studies have highlighted the role of pa rticular chemoattractants in leukocyte migration, to date little Is known a bout how specific combinations of contextual signals control the migration of leukocytes and their localization at sites of inflammation. Here me stud ied the interplay between a pleiotropic cytokine, TNF-alpha, and two protot ypic chemoattractants, RANTES and stromal cell-derived factor-1 alpha (SDF- 1 alpha), on human CD45RO(+) T cells migrating within an ECM-like contest, For this purpose, we used a newly constructed three-dimensional gel system designed to follow, in real time, the migration of individual leukocytes al ong chemotactic gradients in vitro. We found that TNF-alpha, which binds th e ECM protein fibronectin and lacks adhesion- and migration-promoting effec ts of its own, can act as a proadhesive cytokine on T cells exposed to RANT ES and SDF-1 alpha, Furthermore, fibronectin-complexed TNF-alpha provided a nchorage signals to the T cells as they moved directionally along chemoattr active gradients. This effect of TNF-alpha required an intact TNF-alpha rec eptor II subtype on the migrating T cells. The anchoring effect of TNF-alph a appears to be specific; IL-2, an integrin-activating proadhesive cytokine , does not transmit stoppage signals to T cell migration induced by RANTES, Thus, TNF-alpha present in the ECM at sites of inflammation may function t o anchor T cells recruited to these sites by chemotactic signals.