Intermediate-affinity LFA-1 binds alpha-actinin-1 to control migration at the leading edge of the T cell.
T lymphocytes use LFA-1 to migrate into lymph nodes and inflammatory sites. To investigate the mechanisms regulating this migration, we utilize mAbs selective for conformational epitopes as probes for active LFA-1. Expression of the KIM127 epitope, but not the 24 epitope, defines the extended conformation of LFA-1, which has intermediate affinity for ligand ICAM-1. A key finding is that KIM127-positive LFA-1 forms new adhesions at the T lymphocyte leading edge. This LFA-1 links to the cytoskeleton through alpha-actinin-1 and disruption at the level of integrin or actin results in loss of cell spreading and migratory speed due to a failure of attachment at the leading edge. The KIM127 pattern contrasts with high-affinity LFA-1 that expresses both 24 and KIM127 epitopes, is restricted to the mid-cell focal zone and controls ICAM-1 attachment. Identification of distinctive roles for intermediate- and high-affinity LFA-1 in T lymphocyte migration provides a biological function for two active conformations of this integrin for the first time.
Stanley
Paula
P
Leukocyte Adhesion Laboratory, Cancer Research UK London Research Institute, London, UK.
Smith
Andrew
A
McDowall
Alison
A
Nicol
Alastair
A
Zicha
Daniel
D
Hogg
Nancy
N
D000185:Actinin / Q000378:metabolism*; D000595:Amino Acid Sequence; D019138:Antibodies, Blocking / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000378:metabolism; D002460:Cell Line; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006801:Humans; D016169:Lymphocyte Function-Associated Antigen-1 / Q000737:chemistry / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000276:immunology; D011487:Protein Conformation; D020033:Protein Isoforms / Q000737:chemistry / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D018984:Epitopes, T-Lymphocyte; D016169:Lymphocyte Function-Associated Antigen-1; D020033:Protein Isoforms; D000185:Actinin