Journal Article

Regulation of integrin affinity on cell surfaces

Springer, Timothy A, Schürpf, Thomas

2011

Overview

Lymphocyte activation triggers adhesiveness of lymphocyte function‐associated antigen‐1 (LFA‐1; integrin α L β 2 ) for intercellular adhesion molecules (ICAMs) on endothelia or antigen‐presenting cells. Whether the activation signal, after transmission through multiple domains to the ligand‐binding αI domain, results in affinity changes for ligand has been hotly debated. Here, we present the first comprehensive measurements of LFA‐1 affinities on T lymphocytes for ICAM‐1 under a broad array of activating conditions. Only a modest increase in affinity for soluble ligand was detected after activation by chemokine or T‐cell receptor ligation, conditions that primed LFA‐1 and robustly induced lymphocyte adhesion to ICAM‐1 substrates. By stabilizing well‐defined LFA‐1 conformations by Fab, we demonstrate the absolute requirement of the open LFA‐1 headpiece for adhesiveness and high affinity. Interaction of primed LFA‐1 with immobilized but not soluble ICAM‐1 triggers energy‐dependent affinity maturation of LFA‐1 to an adhesive, high affinity state. Our results lend support to the traction or translational motion dependence of integrin activation. It has been proposed that integrin activation involves the generation of traction by binding to immobilized extracellular matrix and coupling to the actin cytoskeleton. Direct evidence, however, is lacking. Here, comparison of integrin affinity for soluble versus immobilized ligands supports this traction model.

• Publisher: John Wiley & Sons, Ltd,Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
• Subject: Adhesion / Antigens / CD11a/CD18 / Cell adhesion & migration / Cell Adhesion - physiology / Chemokine CXCL12 - metabolism / EMBO05 / HEK293 Cells / Humans / ICAM-1 / Intercellular Adhesion Molecule-1 - immunology / Intercellular Adhesion Molecule-1 - metabolism / K562 Cells / lymphocyte function-associated antigen-1 (LFA-1) / Lymphocyte Function-Associated Antigen-1 - immunology / Lymphocyte Function-Associated Antigen-1 - metabolism / Lymphocyte receptors / Lymphocytes / metal ion-dependent adhesion site (MIDAS) / Models, Biological / Protein Binding - physiology / Protein Conformation / stromal cell-derived factor (SDF) / T-Lymphocytes - immunology / T-Lymphocytes - metabolism / Tetradecanoylphorbol Acetate - analogs & derivatives / Tetradecanoylphorbol Acetate - metabolism / Traction