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The direction of migration of T-lymphocytes under flow depends upon which adhesion receptors are engaged.

ABSTRACT: T-lymphocyte migration is important for homing, cell trafficking, and immune surveillance. T-lymphocytes express lymphocyte function-associated antigen-1 (LFA-1; ?L?2) and very late antigen-4 (VLA-4; ?4?1), which bind to their cognate ligands, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). These adhesive interactions provide T-lymphocytes with the ability to withstand hemodynamic shear forces to facilitate adhesion and migration along the blood endothelium. Recently, it has been shown that T-lymphocytes will crawl upstream against the direction of flow on surfaces functionalized with ICAM-1. Here, we have investigated whether the identity of the receptor and the magnitude of its engagement affects the direction of T-lymphocyte migration under flow. We used microcontact printed ICAM-1 and VCAM-1 PDMS surfaces on which density and type of adhesion molecule can be tightly controlled and non-specific adhesion adequately blocked. Using a laminar flow chamber, we demonstrate that T-lymphocytes migrate either upstream or downstream dependent upon ligand type, ligand concentration and shear rate. T-lymphocytes were found to migrate upstream on ICAM-1 but downstream on VCAM-1 surfaces - a behavior unique to T-lymphocytes. By varying concentrations of ICAM-1 and VCAM-1, directed migration under flow was observed to be dependent upon the type and concentration of ligand. As shear rates increase, T-lymphocytes favor upstream migration when any ICAM-1 is present, even in the presence of substantial amounts of VCAM-1. Furthermore, a loss of cytoskeletal polarity was observed upon introduction of fluid flow with reorganization that is dependent upon ligand presentation. These results indicate that T-lymphocytes exhibit two different modes of motility - upstream or downstream - under fluid flow that depends on ligand composition and the shear rate.

SUBMITTER: Dominguez GA

PROVIDER: S-EPMC4746477 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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The direction of migration of T-lymphocytes under flow depends upon which adhesion receptors are engaged.

Dominguez George A GA Anderson Nicholas R NR Hammer Daniel A DA

Integrative biology : quantitative biosciences from nano to macro 20150212 3

T-lymphocyte migration is important for homing, cell trafficking, and immune surveillance. T-lymphocytes express lymphocyte function-associated antigen-1 (LFA-1; αLβ2) and very late antigen-4 (VLA-4; α4β1), which bind to their cognate ligands, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). These adhesive interactions provide T-lymphocytes with the ability to withstand hemodynamic shear forces to facilitate adhesion and migration along the blood endothe ...[more]

PMID: 25674729

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Project description:In order to perform critical immune functions at sites of inflammation, circulatory T lymphocytes must be able to arrest, adhere, migrate and transmigrate on the endothelial surface. This progression of steps is coordinated by cellular adhesion molecules (CAMs), chemokines, and selectins presented on the endothelium. Two important interactions are between Lymphocyte Function-associated Antigen-1 (LFA-1) and Intracellular Adhesion Molecule-1 (ICAM-1) and also between Very Late Antigen-4 (VLA-4) and Vascular Cell Adhesion Molecule-1 (VCAM-1). Recent studies have shown that T lymphocytes and other cell types can migrate upstream (against the direction) of flow through the binding of LFA-1 to ICAM-1. Since upstream migration of T cells depends on a specific adhesive pathway, we hypothesized that mechanotransduction is critical to migration, and that signals might allow T-cells to remember their direction of migration after the flow is terminated. Cells on ICAM-1 surfaces migrate against the shear flow, but the upstream migration reverts to random migration after the flow is stopped. Cells on VCAM-1 migrate with the direction of flow. However, on surfaces that combine ICAM-1 and VCAM-1, cells crawl upstream at a shear rate of 800 s-1 and continue migrating in the upstream direction for at least 30 minutes after the flow is terminated-we call this 'migrational memory'. Post-flow upstream migration on VCAM-1/ICAM-1 surfaces is reversed upon the inhibition of PI3K, but conserved with cdc42 and Arp2/3 inhibitors. Using an antibody against VLA-4, we can block migrational memory on VCAM-1/ICAM-1 surfaces. Using a soluble ligand for VLA-4 (sVCAM-1), we can promote migrational memory on ICAM-1 surfaces. These results indicate that, while upstream migration under flow requires LFA-1 binding to immobilized ICAM-1, signaling from VLA-4 and PI3K activity is required for the migrational memory of CD4+ T cells. These results indicate that crosstalk between integrins potentiates the signal of upstream migration.

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The direction of migration of T-lymphocytes under flow depends upon which adhesion receptors are engaged.

Publications

The direction of migration of T-lymphocytes under flow depends upon which adhesion receptors are engaged.

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