The CD81 tetraspanin facilitates instantaneous leukocyte VLA-4 adhesion strengthening to vascular cell adhesion molecule 1 (VCAM-1) under shear flow.
Leukocyte integrins must rapidly strengthen their binding to target endothelial sites to arrest rolling adhesions under physiological shear flow. We demonstrate that the integrin-associated tetraspanin, CD81, regulates VLA-4 and VLA-5 adhesion strengthening in monocytes and primary murine B cells. CD81 strengthens multivalent VLA-4 contacts within subsecond integrin occupancy without altering intrinsic adhesive properties to low density ligand. CD81 facilitates both VLA-4-mediated leukocyte rolling and arrest on VCAM-1 under shear flow as well as VLA-5-dependent adhesion to fibronectin during short stationary contacts. CD81 also augments VLA-4 avidity enhancement induced by either chemokine-stimulated Gi proteins or by protein kinase C activation, although it is not required for Gi protein or protein kinase C signaling activities. In contrast to other proadhesive integrin-associated proteins, CD81-promoted integrin adhesiveness does not require its own ligand occupancy or ligation. These results provide the first demonstration of an integrin-associated transmembranal protein that facilitates instantaneous multivalent integrin occupancy events that promote leukocyte adhesion to an endothelial ligand under shear flow.
Feigelson
Sara W
SW
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel 76100.
Grabovsky
Valentin
V
Shamri
Revital
R
Levy
Shoshana
S
Alon
Ronen
R
D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D001402:B-Lymphocytes / Q000378:metabolism / Q000502:physiology; D002448:Cell Adhesion; D002478:Cells, Cultured; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D039041:Integrin alpha4beta1 / Q000378:metabolism*; D036904:Leukocyte Rolling; D007962:Leukocytes / Q000378:metabolism / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D009000:Monocytes / Q000378:metabolism / Q000502:physiology; D011485:Protein Binding; D012212:Rheology; D060225:Tetraspanin 28; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*
D015703:Antigens, CD; C554798:CD81 protein, human; C554799:Cd81 protein, mouse; D005353:Fibronectins; D039041:Integrin alpha4beta1; D008565:Membrane Proteins; D060225:Tetraspanin 28; D019010:Vascular Cell Adhesion Molecule-1