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Blood, 15 February 2007, Vol. 109, No. 4, pp. 1381-1386. Prepublished online as a Blood First Edition Paper on October 12, 2006; DOI 10.1182/blood-2006-07-032995.
CHEMOKINES, CYTOKINES, AND INTERLEUKINS Shear flow–dependent integration of apical and subendothelial chemokines in T-cell transmigration: implications for locomotion and the multistep paradigmHarvard Skin Disease Research Center and the Departments of Dermatology and of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA
Lymphocyte extravasation requires that emigrating cells process chemoattractant signals, typically mediated by chemokines, encountered on endothelial surface (apical) and subendothelial (basal) compartments. These signals are delivered under conditions of hemodynamic shear, a fundamental feature of all physiologic leukocyte–endothelial interactions. To analyze lymphocyte responsiveness to spatially distributed chemokines and their effects on transendothelial migration (TEM) under hydrodynamic shear, we constructed a transwell-based flow assay. We observed that the inflammatory chemokine CCL5 (RANTES) induces negligible human T-cell migration across inflamed human umbilical vascular endothelial cells (HUVECs) when displayed alone in the subendothelial compartment under static or hemodynamic shear conditions or when combined with apical CXCL12 (SDF-1
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| Copyright © 2007 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
) under static conditions. However, under shear stress, T cells encountering apically presented CXCL12 were primed to undergo robust LFA-1–dependent TEM toward subendothelial CCL5. Notably, locomotive T cells arriving at endothelial junctions were retained and extended pseudopodia into and through the junctions, thereby increasing sensitivity to subendothelial CCL5. These findings provide the first evidence that lymphocytes integrate, conditional to shear forces, permissive apical chemokine deposits, and integrin engagement signals, resulting in morphologic changes and amplified chemotaxis to an otherwise weak subendothelial chemokine signal. 
