TNF-α Associated with Extracellular Matrix Fibronectin Provides a Stop Signal for Chemotactically Migrating T Cells

Abstract

The migration of T cells into extravascular sites of inflammation is regulated by information derived from the molecular structure of the invaded tissue and from chemokine and cytokine gradients in the context of the extracellular matrix (ECM). Although recent studies have highlighted the role of particular chemoattractants in leukocyte migration, to date little is known about how specific combinations of contextual signals control the migration of leukocytes and their localization at sites of inflammation. Here we studied the interplay between a pleiotropic cytokine, TNF-α, and two prototypic chemoattractants, RANTES and stromal cell-derived factor-1α (SDF-1α), on human CD45RO+ T cells migrating within an ECM-like context. For this purpose, we used a newly constructed three-dimensional gel system designed to follow, in real time, the migration of individual leukocytes along chemotactic gradients in vitro. We found that TNF-α, which binds the ECM protein fibronectin and lacks adhesion- and migration-promoting effects of its own, can act as a proadhesive cytokine on T cells exposed to RANTES and SDF-1α. Furthermore, fibronectin-complexed TNF-α provided anchorage signals to the T cells as they moved directionally along chemoattractive gradients. This effect of TNF-α required an intact TNF-α receptor II subtype on the migrating T cells. The anchoring effect of TNF-α 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-α present in the ECM at sites of inflammation may function to anchor T cells recruited to these sites by chemotactic signals.