Regulation of adhesion of CD4⁺ T lymphocytes to intact or heparinase- treated subendothelial extracellular matrix by diffusible or anchored RANTES and MIP-1β

Chemokines, a superfamily of 8- to 11-kDa mediators of inflammation, affect the attachment of immune cells to vascular endothelia by binding to cell surface glycosaminoglycans. We analyzed whether chemokines are also involved in interactions between CD4⁺ T lymphocytes and the subendothelial extracellular matrix (ECM). Soluble mediators, such as MIP-1β and RANTES, induced the binding of resting human CD4⁺ T cells to ECM in an integrin- dependent manner. Both MIP-1β and RANTES bound to intact ECM and retained their adhesive properties, and moreover, ECM-bound RANTES and MIP-1β prolonged the time course of interactions between the CD4⁺ T cells and the ECM. Because the adhesive effect of these chemokines was restricted by an inhibitor of GTP-binding proteins, the adhesive effect of ECM-bound RANTES and MIP-1β, which requires an intact cytoskeleton, seems to involve activation of a G protein-linked receptor. MIP-1β and RANTES exert their pro-adhesive effects through interactions with glycosaminoglycans, because heparinase-treated ECM did not bound chemokines and because the chemokines ability to induce T cell adhesion was abrogated if: 1) either of the chemokines is pretreated with heparin or heparan-sulfate (HS), 2) HS is removed from intact ECM by heparinase, an HS-specific endoglycosidase, or 3) the ECM-bound chemokines are released by pretreatment with heparinase. Hence, the adhesive effects of immobilized chemokines is not restricted to T cells interacting with endothelial cells, but also affects the migration of immune cells which reside and function in the context of ECM.