Intermediate-affinity LFA-1 binds alpha-actinin-1 to control migration at the leading edge of the T cell |
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Authors: | Stanley Paula Smith Andrew McDowall Alison Nicol Alastair Zicha Daniel Hogg Nancy |
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Affiliation: | Leukocyte Adhesion Laboratory, Cancer Research UK London Research Institute, London, UK. |
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Abstract: | 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. |
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Keywords: | α-Actinin-1 integrin LFA-1 migration T lymphocyte |
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