The LFA-1 integrin supports rolling adhesions on ICAM-1 under physiological sheer flow in a permissive cellular environment

The LFA-1 integrin is crucial for the firm adhesion of circulating leukocyt es to ICAM-1-expressing endothelial cells, In the present study, we demonst rate that LFA-1 can arrest unstimulated PBL subsets and lymphoblastoid Jurk at cells on immobilized ICAM-1 under subphysiological shear flow and mediat e firm adhesion to ICAM-1 after short static contact. However, LFA-1 expres sed in K562 cells failed to support firm adhesion to ICAM-1 but instead med iated K562 cell rolling on the endothelial ligand under physiological shear stress. LFA-1-mediated rolling required an intact LFA-1 I-domain, was enha nced by Mg2+, and was sharply dependent on ICAM-1 density. This is the firs t indication that LFA-1 can engage in rolling adhesions with ICAM-1 under p hysiological shear flow. The ability of LFA-1 to support rolling correlates with decreased avidity and impaired time-dependent adhesion strengthening. A beta(2) cytoplasmic domain-deletion mutant of LFA-1, with high avidity t o immobilized ICAM-1, mediated firm arrests of K562 cells interacting with ICAM-1 under shear how, Our results suggest that restrictions in LFA-1 clus tering mediated by cytoskeletal attachments may lock the integrin into low- avidity states in particular cellular environments. Although low-avidity LF A-1 states fail to undergo adhesion strengthening upon contact with ICAM-1 at stasis, these states are permissive for leukocyte rolling on ICAM-1 unde r physiological shear flow. Rolling mediated by low-avidity LFA-1 interacti ons with ICAM-1 may stabilize rolling initiated by specialized vascular rol ling receptors and allow the leukocyte to arrest on vascular endothelium up on exposure to stimulatory endothelial signals.