Integrin cross talk: activation of lymphocyte function-associated antigen-1 on human T cells alters alpha4beta1- and alpha5beta1-mediated function.
A regulated order of adhesion events directs leukocytes from the vascular compartment into injured tissues in response to inflammatory stimuli. We show that on human T cells, the interaction of the beta2 integrin leucocyte function-associated antigen-1 (LFA-1) with its ligand intercellular adhesion molecule-1 (ICAM-1) will decrease adhesion mediated by alpha4beta1 and, to a lesser extent, alpha5beta1. Similar inhibition is also seen when T cells are exposed to mAb 24, which stabilizes LFA-1 in an active state after triggering integrin function through divalent cation Mg2+, PdBu, or T cell receptor/ CD3 complex (TCR/CD3) cross-linking. Such cross talk decreases alpha4beta1 integrin-mediated binding of T cells to fibronectin and vascular cell adhesion molecule-1 (VCAM-1). In contrast, ligand occupancy or prolonged activation of beta1 integrin has no effect on LFA-1 adhesion to ICAM-1. We also show that T cell migration across fibronectin, unlike adhesion, is mediated solely by alpha5beta1, and is increased when the alpha4beta1-mediated component of fibronectin adhesion is decreased either by cross talk or the use of alpha4-blocking mAb. The ability of mAb 24 Fab' fragments to induce cross talk without cross-linking LFA-1 suggests signal transduction through the active integrin. These data provide the first direct evidence for cross talk between LFA-1 and beta1 integrins on T cells. Together, these findings imply that activation of LFA-1 on the extravasating T cell will decrease the binding to VCAM-1 while enhancing the subsequent migration on fibronectin. This sequence of events provides a further level of complexity to the coordination of T cell integrins, whose sequential but overlapping roles are essential for transmigration.
Porter
J C
JC
Leukocyte Adhesion Laboratory, Imperial Cancer Research Fund, Lincoln's Inn Fields, London WC2A 3PX, United Kingdom. porterj@europa.lif.icnet.uk
Hogg
N
N
D018926:Anti-Allergic Agents / Q000276:immunology / Q000378:metabolism*; D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D002448:Cell Adhesion / Q000276:immunology; D015536:Down-Regulation / Q000502:physiology; D005353:Fibronectins / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D039041:Integrin alpha4beta1; D016023:Integrins / Q000276:immunology / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D008863:Microspheres; D017469:Receptors, Fibronectin / Q000276:immunology / Q000378:metabolism*; D016201:Receptors, Lymphocyte Homing / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000737:chemistry* / Q000166:cytology / Q000276:immunology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism / Q000494:pharmacology
D018926:Anti-Allergic Agents; D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D005353:Fibronectins; D039041:Integrin alpha4beta1; D016023:Integrins; D016169:Lymphocyte Function-Associated Antigen-1; D017469:Receptors, Fibronectin; D016201:Receptors, Lymphocyte Homing; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1