title: Role of alpha L beta 2 integrin avidity in transendothelial chemotaxis of mononuclear cells.
abstract: The leukocyte integrin alpha L beta 2 (LFA-1) is important in transendothelial migration. Since it is not fully understood how LFA-1 mediates transmigration, we studied the effects of alpha L and beta 2 cytoplasmic domain mutants that alter LFA-1 adhesiveness for intercellular adhesion molecule-1. Monocyte chemotactic protein-1 (MCP-1) induced LFA-1-dependent transendothelial migration of Jurkat and J-beta 2.7 transfectants coexpressing the MCP-1 receptor CCR2B and wild-type alpha L. No transendothelial chemotaxis was observed with truncation mutants of the alpha L cytoplasmic tail, which rendered LFA-1 constitutively active or locked LFA-1 in a low avidity state unresponsive to cellular activation. Moreover, transendothelial chemotaxis of lymphoblastoid SLA transfectants was abolished by truncation of the beta 2 cytoplasmic domain, but not by mutation of its TTT motif, which is important in phorbol ester-induced adhesion. These data indicate that transmigration may require both alpha L and beta 2 cytoplasmic domains. We further show that MCP-1-induced transendothelial chemotaxis of PBMC was inhibited by sustained activation of LFA-1 with Mn2+ or a stimulatory mAb to beta 2. Dimeric soluble intercellular adhesion molecule-1 also reduced transendothelial chemotaxis of PBMC. Taken together, our data suggest that transendothelial chemotaxis of mononuclear cells may involve dynamic changes in LFA-1 avidity.
authors.affiliation: Center for Blood Research, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: C
authors.initials: C
authors.lastname: Weber
authors.forename: C F
authors.initials: CF
authors.lastname: Lu
authors.forename: J M
authors.initials: JM
authors.lastname: Casasnovas
authors.forename: T A
authors.initials: TA
authors.lastname: Springer
mesh_terms: D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000276:immunology*; D003593:Cytoplasm / Q000276:immunology / Q000378:metabolism; D019281:Dimerization; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology; D019169:Jurkat Cells; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D009154:Mutation / Q000276:immunology; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D017434:Protein Structure, Tertiary; D012995:Solubility; D014162:Transfection / Q000276:immunology
chemical_list: D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1