Organization of the integrin LFA-1 in nanoclusters regulates its activity.
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.
Cambi
Alessandra
A
Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands.
Joosten
Ben
B
Koopman
Marjolein
M
de Lange
Frank
F
Beeren
Inge
I
Torensma
Ruurd
R
Fransen
Jack A
JA
Garcia-Parajó
Maria
M
van Leeuwen
Frank N
FN
Figdor
Carl G
CG
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
D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1