The affinity of integrin alpha(4)beta(1) governs lymphocyte migration.
The interaction of integrin alpha(4)beta(1) with endothelial VCAM-1 controls the trafficking of lymphocytes from blood into peripheral tissues. Cells actively regulate the affinity of alpha(4)beta(1) for VCAM-1 (activation). To investigate the biological function of alpha(4)beta(1) activation, we isolated Jurkat T cell lines with defective alpha(4)beta(1) activation. Using these cells, we found that alpha(4)beta(1)-stimulated alpha(L)beta(2)-dependent cell migration was dramatically reduced in cells with defects in alpha(4)beta(1) activation. These cells required 20 times more VCAM-1 to promote alpha(L)beta(2)-dependent cell migration. This defect was at the level of alpha(4)beta(1) affinity as an activating alpha(4)beta(1) Ab rescued alpha(4)beta(1)-stimulated alpha(L)beta(2)-dependent migration. In contrast, migration of alpha(4)beta(1) activation-defective cells on VCAM-1 alone was enhanced at higher VCAM-1 densities. Thus, alpha(4)beta(1) activation determines a set point or threshold at which VCAM-1 can regulate alpha(L)beta(2)-dependent as well as alpha(4)beta(1)-dependent cell migration. Changes in this set point may specify preferred anatomical sites of integrin-dependent leukocyte emigration from the bloodstream.
Rose
D M
DM
Department of Vascular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Grabovsky
V
V
Alon
R
R
Ginsberg
M H
MH
D002448:Cell Adhesion / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology; D006801:Humans; D039041:Integrin alpha4beta1; D016023:Integrins / Q000235:genetics / Q000378:metabolism*; D019169:Jurkat Cells; D008024:Ligands; D008214:Lymphocytes / Q000276:immunology*; D009154:Mutation; D016201:Receptors, Lymphocyte Homing / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D039041:Integrin alpha4beta1; D016023:Integrins; D008024:Ligands; D016201:Receptors, Lymphocyte Homing; D011993:Recombinant Fusion Proteins; D019010:Vascular Cell Adhesion Molecule-1