High affinity very late antigen-4 subsets expressed on T cells are mandatory for spontaneous adhesion strengthening but not for rolling on VCAM-1 in shear flow

The very late Ag-4 (VLA-4) integrin supports both rolling; and firm adhesio n of leukocytes on VCAM-1 under shear flow. The molecular basis for the uni que ability of a single adhesion molecule to mediate these versatile adhesi ve processes was investigated. VLA-4 occurs in multiple activation states, with different affinities to ligand, In this study we tested how these stat es regulate VLA-4 adhesiveness under shear flow in Jurkat T cells and PBL, VLA-4 on nonstimulated Jurkat cells supported rolling and spontaneous arres t on VCAM-1, whereas a Jurkat activation mutant with reduced VLA-Q affinity failed to spontaneously arrest after tethering to or during rolling on VCA M-1, The contribution of VLA-4 affinity for ligand to rolling and spontaneo us arrests on immobilized VCAM-1 was dissected using soluble VLA-4 ligands, which selectively block high affinity states. VLA-4 saturation with ligand completely blocked spontaneous adhesion strengthening post-tethering to VC AM-1, but did not impair rolling on the endothelial ligand, High affinity V LA-4 was found to comprise a small subset of VLA-4 on resting Jurkat cells and PBL, This subset is essential for firm adhesion but not for tethering o r rolling adhesions on VCAM-1. Interestingly, low and high affinity VLA-4 s tates were found to mediate similar initial tethering to ligand, High affin ity VLA-4, constitutively expressed on circulating T cells, may control the ir early adhesion strengthening on VCAM-1-expressing endothelium before exp osure to vascular chemokines and activation of additional integrins.