Lymphocyte adhesion and transendothelial migration in the central nervous system: the role of LFA-1, ICAM-1, VLA-4 and VCAM-1. off.
Lymphocyte adhesion to and migration across endothelial cell (EC) monolayers, derived from the rat blood-retinal barrier (BRB), were measured in vitro. The binding of concanavalin A (Con A)-activated peripheral lymph node lymphocytes and the migration of CD4+ T-cell lines could be significantly increased by treating the EC with interleukin-1 beta (IL-1 beta). To determine the role of various adhesion molecules during the processes of lymphocyte binding and transmonolayer migration (diapedesis), lymphocytes were treated with monoclonal antibody (mAb) specific for CD11a (alpha L subunit of leucocyte functional antigen-1; LFA-1), CD18 (beta 2 subunit of leucam family) and CD49d (alpha 4 subunit of very late activation antigen-4; VLA-4) and EC with mAb specific for CD54 (intercellular adhesion molecule-1; ICAM-1) and CD106 (vascular cell adhesion molecule-1; VCAM-1). Binding of the highly adhesive but non-migratory Con A-activated lymphocytes was inhibited by mAb to CD11a (reduced to 73% and 65% of control lymphocyte adhesion) and CD18 (42% and 54%) on non-activated and IL-1 beta-treated EC, respectively, but not by mAb to ICAM-1 or VCAM-1. Diapedesis of the highly migratory T-cell line lymphocytes was also blocked by antibodies to CD11a (reduced to 11% and 10% of control T-cell migration), CD18 (29% and 43%) but in addition was also inhibited by anti-ICAM-1 (17% and 53%) on non-activated and IL-1 beta treated EC, respectively. Both anti-VLA-4 and anti-VCAM-1 were also effective in producing a smaller reduction in migration, but only on IL-1 beta activated EC (66% and 58% of control migration, respectively). These studies indicate that lymphocyte adhesion to central nervous system (CNS) vascular EC is largely dependent on LFA-1 but not through its interaction with ICAM-1. In contrast, lymphocyte diapedesis is mostly supported through the LFA-1/ICAM-1 pairing, with a small proportion being mediated by VLA-4/VCAM-1 on IL-1 beta-activated EC. This latter pathway, however, also appears to be dependent on LFA-1 interacting with the EC.
Department of Clinical Ophthalmology, University College London, UK.
J
J
Greenwood
Y
Y
Wang
V L
VL
Calder
D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D001813:Blood-Retinal Barrier / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology; D004727:Endothelium / Q000166:cytology; D005260:Female; D005434:Flow Cytometry; D007158:Immunologic Techniques; D039041:Integrin alpha4beta1; D016023:Integrins / Q000502:physiology; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology; D008214:Lymphocytes / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D016201:Receptors, Lymphocyte Homing / Q000502:physiology; D019010:Vascular Cell Adhesion Molecule-1 / Q000502:physiology
D019138:Antibodies, Blocking; D015815:Cell Adhesion Molecules; D039041:Integrin alpha4beta1; D016023:Integrins; D016169:Lymphocyte Function-Associated Antigen-1; D016201:Receptors, Lymphocyte Homing; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1