Signaling through integrin LFA-1 leads to filamentous actin polymerization and remodeling, resulting in enhanced T cell adhesion.
The integrins can activate signaling pathways, but the final downstream outcome of these pathways is often unclear. This study analyzes the consequences of signaling events initiated by the interaction of the leukocyte integrin LFA-1 with its ligand, dimeric ICAM-1. We show that the active form of LFA-1 regulates its own function on primary human T cells by directing the remodeling of the F-actin cytoskeleton to strengthen T cell adhesion to ICAM-1. Confocal microscopy revealed that both F-actin bundling and overall levels of F-actin are increased in the ICAM-1-adhering T cells. This increase in F-actin levels and change in F-actin distribution was quantitated for large numbers of T cells using the technique of laser scanning cytometry and was found to be significant. The study went on to show that clustering of conformationally altered LFA-1 is essential for the changes in F-actin, and a model is proposed in which clustered, high-avidity T cell LFA-1, interacting with multivalent ICAM-1, causes LFA-1 signaling, which results in F-actin polymerization and higher-order F-actin bundling. The findings demonstrate that LFA-1 acts not only as an adhesion receptor but also as a signaling receptor by actively initiating the F-actin reorganization that is essential for many T cell-dependent processes.
Porter
Joanna C
JC
Leukocyte Adhesion Laboratory, Cancer Research U.K. London Research Institute, London, United Kingdom.
Bracke
Madelon
M
Smith
Andrew
A
Davies
Derek
D
Hogg
Nancy
N
D008841:Actin Cytoskeleton / Q000378:metabolism*; D000199:Actins / Q000378:metabolism*; D000276:Adjuvants, Immunologic / Q000502:physiology*; D002413:Cations, Divalent / Q000494:pharmacology; D002448:Cell Adhesion / Q000276:immunology; D003599:Cytoskeleton / Q000378:metabolism; D019281:Dimerization; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism / Q000502:physiology*; D046911:Macromolecular Substances; D008274:Magnesium / Q000494:pharmacology; D018613:Microscopy, Confocal; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000378:metabolism / Q000502:physiology*
D000199:Actins; D000276:Adjuvants, Immunologic; D002413:Cations, Divalent; D007141:Immunoglobulin Fc Fragments; D008024:Ligands; D016169:Lymphocyte Function-Associated Antigen-1; D046911:Macromolecular Substances; D011993:Recombinant Fusion Proteins; D018799:Intercellular Adhesion Molecule-1; D008274:Magnesium