title: Alpha 4 beta 1 integrin/VCAM-1 interaction activates alpha L beta 2 integrin-mediated adhesion to ICAM-1 in human T cells.
abstract: Modulation of integrin affinity and/or avidity provides a regulatory mechanism by which leukocyte adhesion to endothelium is strengthened or weakened at different stages of emigration. In this study, we demonstrate that binding of high-affinity alpha 4 beta 1 integrins to VCAM-1 strengthens alpha L beta 2 integrin-mediated adhesion. The strength of adhesion of Jurkat cells, a human leukemia T cell line, or MnCl2-treated peripheral blood T cells to immobilized chimeric human VCAM-1/Fc, ICAM-1/Fc, or both was quantified using parallel plate flow chamber leukocyte detachment assays in which shear stress was increased incrementally (0.5-30 dynes/cm2). The strength of adhesion to VCAM-1 plus ICAM-1, or to a 40-kDa fragment of fibronectin containing the CS-1 exon plus ICAM-1, was greater than the sum of adhesion to each molecule alone. Treatment of Jurkat or blood T cells with soluble cross-linked VCAM-1/Fc or HP2/1, a mAb to alpha 4, significantly increased adhesion to ICAM-1. These treatments induced clustering of alpha L beta 2 integrins, but not the high-affinity beta 2 integrin epitope recognized by mAb 24. Up-regulated adhesion to ICAM-1 was abolished by cytochalasin D, an inhibitor of cytoskeletal rearrangement. Taken together, our data suggest that the binding of VCAM-1 or fibronectin to alpha 4 beta 1 integrins initiates a signaling pathway that increases beta 2 integrin avidity but not affinity. A role for the cytoskeleton is implicated in this process.
authors.affiliation: Department of Laboratory Medicine, University of Toronto, Toronto General Hospital Research Institute, Toronto, Canada.
authors.forename: J R
authors.initials: JR
authors.lastname: Chan
authors.forename: S J
authors.initials: SJ
authors.lastname: Hyduk
authors.forename: M I
authors.initials: MI
authors.lastname: Cybulsky
mesh_terms: D002448:Cell Adhesion / Q000276:immunology; D004357:Drug Synergism; D005353:Fibronectins / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000378:metabolism; D039041:Integrin alpha4beta1; D016023:Integrins / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D019169:Jurkat Cells; D016169:Lymphocyte Function-Associated Antigen-1 / Q000097:blood / Q000378:metabolism / Q000502:physiology*; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D016201:Receptors, Lymphocyte Homing / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism / Q000502:physiology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood / Q000378:metabolism* / Q000502:physiology
chemical_list: D005353:Fibronectins; D007141:Immunoglobulin Fc Fragments; D039041:Integrin alpha4beta1; D016023:Integrins; D016169:Lymphocyte Function-Associated Antigen-1; D010446:Peptide Fragments; D016201:Receptors, Lymphocyte Homing; D011993:Recombinant Fusion Proteins; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1