title: The LFA-1 integrin supports rolling adhesions on ICAM-1 under physiological shear flow in a permissive cellular environment.
abstract: The LFA-1 integrin is crucial for the firm adhesion of circulating leukocytes to ICAM-1-expressing endothelial cells. In the present study, we demonstrate that LFA-1 can arrest unstimulated PBL subsets and lymphoblastoid Jurkat cells on immobilized ICAM-1 under subphysiological shear flow and mediate firm adhesion to ICAM-1 after short static contact. However, LFA-1 expressed in K562 cells failed to support firm adhesion to ICAM-1 but instead mediated K562 cell rolling on the endothelial ligand under physiological shear stress. LFA-1-mediated rolling required an intact LFA-1 I-domain, was enhanced by Mg2+, and was sharply dependent on ICAM-1 density. This is the first indication that LFA-1 can engage in rolling adhesions with ICAM-1 under physiological shear flow. The ability of LFA-1 to support rolling correlates with decreased avidity and impaired time-dependent adhesion strengthening. A beta2 cytoplasmic domain-deletion mutant of LFA-1, with high avidity to immobilized ICAM-1, mediated firm arrests of K562 cells interacting with ICAM-1 under shear flow. Our results suggest that restrictions in LFA-1 clustering mediated by cytoskeletal attachments may lock the integrin into low-avidity states in particular cellular environments. Although low-avidity LFA-1 states fail to undergo adhesion strengthening upon contact with ICAM-1 at stasis, these states are permissive for leukocyte rolling on ICAM-1 under physiological shear flow. Rolling mediated by low-avidity LFA-1 interactions with ICAM-1 may stabilize rolling initiated by specialized vascular rolling receptors and allow the leukocyte to arrest on vascular endothelium upon exposure to stimulatory endothelial signals.
authors.affiliation: Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Sigal
authors.forename: D A
authors.initials: DA
authors.lastname: Bleijs
authors.forename: V
authors.initials: V
authors.lastname: Grabovsky
authors.forename: S J
authors.initials: SJ
authors.lastname: van Vliet
authors.forename: O
authors.initials: O
authors.lastname: Dwir
authors.forename: C G
authors.initials: CG
authors.lastname: Figdor
authors.forename: Y
authors.initials: Y
authors.lastname: van Kooyk
authors.forename: R
authors.initials: R
authors.lastname: Alon
mesh_terms: D002413:Cations, Divalent / Q000494:pharmacology; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology; D002450:Cell Communication / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism / Q000502:physiology*; D019169:Jurkat Cells; D020014:K562 Cells / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008214:Lymphocytes; D018613:Microscopy, Confocal; D008858:Microscopy, Phase-Contrast; D018715:Microscopy, Video; D011485:Protein Binding / Q000276:immunology; D012212:Rheology; D017384:Sequence Deletion / Q000276:immunology; D013314:Stress, Mechanical; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D002413:Cations, Divalent; D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1