Direct observations of the kinetics of migrating T-cells suggest active retention by endothelial cells with continual bidirectional migration

Introduction

Lymphocytes of all classes must migrate through endothelium in order to home to lymph
nodes or to enter inflamed or infected tissue. In the context of inflammation, flowing cells are
captured by specialised, fast-acting adhesion receptors (such as vascular cell adhesion molecule-
1, VCAM-1, and E- or P-selectin) presented by venular endothelial cells (EC) responding to
cytokines such as tumour necrosis factor-α (TNF), interleukin-1β (IL-1) or interferon-γ (IFN)
[1]. Initial capture is followed by activation of the lymphocytes by surface-presented
chemokine(s). Chemokines induce integrin activation and stabilisation of adhesion, followed by
migration over and through the endothelial monolayer. In vitro, flow-based assays have shown
that, depending on the stimulus applied to the EC, T-cell capture is possible through VCAM-1, E-
selectin or P-selectin (although efficiency for each may depend on the T-cell subset), and that
stable adhesion is mediated through binding of activated α4β1-integrin to VCAM-1 and αLβ2-
integrin to inter-cellular adhesion molecule-1 (ICAM-1) [2-4]. Transendothelial migration of T-
cells has been observed within minutes of adhesion in such flow systems, for TNF-treated EC
(where blockade of β2-integrins was inhibitory) [3], for EC stimulated with TNF plus IFN [5] and
for EC that had been stimulated with TNF and had stromal-derived factor-1α (SDF, CXCL12) or
CCL19 (ELC) added to their surface [6]. In the last study, little migration was seen without an
added chemokine (CXCL12 or CCL9), and even then, migration was much more effective in the
presence of flow than if flow was stopped.

In contrast, most studies on the regulation of lymphocyte migration through endothelium,
have used static assays in which EC have been grown on porous filters. These necessarily tests
migration away from the sub-endothelial space as well as through the endothelial cells, and

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