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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.
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Submitted July 6, 2006
Accepted September 25, 2006
Shear flow-dependent integration of apical and subendothelial chemokines in T cell transmigration: implications for locomotion and the "multi-step paradigm"
Taylor Schreiber, Vera Shinder, Derek Cain, Ronen Alon, and Robert Sackstein*
Brigham and Women's Hospital
Dana-Farber Cancer Institute
* Corresponding author; email: rsackstein{at}rics.bwh.harvard.edu.
Lymphocyte extravasation requires that emigrating cells process chemoattractant signals, typically mediated by chemokines, encountered on both endothelial surface (apical) and subendothelial (basal) compartments. Natively, these signals are delivered in the setting of hemodynamic shear, a fundamental feature of all physiologic leukocyte-endothelial interactions. To analyze lymphocyte responsiveness to spatially distributed chemokines and their effects on trans-endothelial 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 (HUVEC) when displayed alone in the subendothelial compartment under static or hemodynamic shear conditions, or when combined with apical CXCL12 (SDF-1 ) 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, locomoting 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 first evidence that lymphocytes integrate, conditional to shear forces, apical chemokine and integrin engagement signals resulting in morphologic changes and amplified chemotaxis to an otherwise weak subendothelial chemokine signal.
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