title: Organization of the integrin LFA-1 in nanoclusters regulates its activity.
abstract: The beta2-integrin LFA-1 facilitates extravasation of monocytes (MOs) into the underlying tissues, where MOs can differentiate into dendritic cells (DCs). Although DCs express LFA-1, unlike MOs, they cannot bind to ICAM-1. We hypothesized that an altered integrin organization on the DC plasma membrane might cause this effect and investigated the relationship between membrane organization and function of LFA-1 on MOs and DCs. High-resolution mapping of LFA-1 surface distribution revealed that on MOs LFA-1 function is associated with a distribution in well-defined nanoclusters (100-150-nm diameter). Interestingly, a fraction of these nanoclusters contains primed LFA-1 molecules expressing the specific activation-dependent L16-epitope. Live imaging of MO-T-cell conjugates showed that only these primed nanoclusters are dynamically recruited to the cellular interface forming micrometer-sized assemblies engaged in ligand binding and linked to talin. We conclude that besides affinity regulation, LFA-1 function is controlled by at least three different avidity patterns: random distributed inactive molecules, well-defined ligand-independent proactive nanoclusters, and ligand-triggered micrometer-sized macroclusters.
authors.affiliation: Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Cambi
authors.forename: Ben
authors.initials: B
authors.lastname: Joosten
authors.forename: Marjolein
authors.initials: M
authors.lastname: Koopman
authors.forename: Frank
authors.initials: F
authors.lastname: de Lange
authors.forename: Inge
authors.initials: I
authors.lastname: Beeren
authors.forename: Ruurd
authors.initials: R
authors.lastname: Torensma
authors.forename: Jack A
authors.initials: JA
authors.lastname: Fransen
authors.forename: Maria
authors.initials: M
authors.lastname: Garcia-Parajó
authors.forename: Frank N
authors.initials: FN
authors.lastname: van Leeuwen
authors.forename: Carl G
authors.initials: CG
authors.lastname: Figdor
mesh_terms: D002448:Cell Adhesion; D002449:Cell Aggregation; D002462:Cell Membrane / Q000378:metabolism*; D003713:Dendritic Cells / Q000502:physiology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism / Q000502:physiology*; D021962:Membrane Microdomains / Q000502:physiology; D008954:Models, Biological; D009000:Monocytes / Q000502:physiology*; D013601:T-Lymphocytes / Q000502:physiology
chemical_list: D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1