Stable adhesion

(a) Transendotticâlaï migration

(3) Completion of diapedes s

ChômoattracliW gradient

Lymphocyte High endothelial cells

L-Seleclin CD34. SgpïOO. QlyCAM-1, MAdCAM-1

LFA-1 activated via PTX inhibitable palhway

MAdCANM (mucosal) 11CAM-1 orlCAM-a

HËC-dsrived stimulus that directs trarreenctothelial migration of lymphocytes

Chcmoattraclants from lymph rods

Figure 4 The sequence of events that regulate lymphocyte migration from the bloodstream across the walls of HEVs into lymphoid organs. Lymphocytes use L-selectin (and/or a4p7 integrin in mucosal tissues) to roll on the HEC surface (step 1). Rolling is rapidly converted to integrin-dependent stable adhesion within 1-3 s (step 2). This is mainly mediated by LFA-1 following its activation via a pertussis toxin (PTX)-sensitive pathway. The ligands and activating stimulus for LFA-1 on the HEC surface are not worked out. Lymphocytes migrating to mucosal lymph nodes also bind via a4p7 integrin recognition of MAdCAM-1. Transendothellal migration of bound lymphocytes (step 3) is regulated by a putative 'lymphocyte migration stimulus' expressed by HECs. The molecular basis of the final stage of migration across the basement membrane (step 4) is not understood but it is thought to be regulated by lymph node-derived chemoattractants.

inner surface of lymph node HEVs are undetermined. By analogy with the neutrophil, chemoattractant molecules operating on PTX-inhibitable G protein-linked receptors are likely candidates for this stage. Lymph node-derived chemoattractants have been proposed to direct the migration of lymphocytes across the HEV wall, although candidate molecules have not yet been identified. Since the majority of lymphocytes migrating into lymphoid organs are unactivated T and B lymphocytes, it is predicted that there are chemoattractants for these lymphocyte populations. Studies using cultured HECs suggest that transendothelial migration, the first step in dia-pedesis, can be initiated by the endothelial cells, suggesting that lymph node-derived chemoattractants may not be required for this step.

The crucial roles of L-selectin and (37 integrins in directing lymphocyte migration to peripheral and mucosal lymph nodes respectively have been confirmed in 'knockout' mice; the requirement for fuco-sylation of the functional ligand for L-selectin on HEVs is also confirmed in mice in which the enzyme fucosyltransferase VII, which generates the sialyl Lewis" modification has been deleted. This is, how ever, one of several post-translational modifications required to generate the peripheral addressin, the other being sulfation of sialyl Lewisx and, possibly, other sugars. The endothelial selectins, E- and P-sel-ectin, do not regulate lymphocyte migration via HEVs under basal conditions because they are not normally expressed by HEVs and the functional ligands for these two selectins are not expressed by naive T and B lymphocytes, which comprise the bulk of the migrating population.

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