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Blood, 1 October 2006, Vol. 108, No. 7, pp. 2150-2158. Prepublished online as a Blood First Edition Paper on June 13, 2006; DOI 10.1182/blood-2006-04-017608.
CHEMOKINES, CYTOKINES, AND INTERLEUKINS DOCK2 regulates chemokine-triggered lateral lymphocyte motility but not transendothelial migrationFrom the Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel; Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan; and Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, Saitoma, Japan.
Rac GTPases are key regulators of leukocyte motility. In lymphocytes, chemokine-mediated Rac activation depends on the CDM adaptor DOCK2. The present studies addressed the role of DOCK2 in chemokine-triggered lymphocyte adhesion and motility. Rapid chemokine-triggered activation of both LFA-1 and VLA-4 integrins took place normally in DOCK2–/– T lymphocytes under various shear flow conditions. Consequently, DOCK2–/– T cells arrested normally on TNF
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| Copyright © 2006 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||||
-activated endothelial cells in response to integrin stimulatory chemokine signals, and their resistance to detachment was similar to that of wild-type (wt) T lymphocytes. Nevertheless, DOCK2–/– T lymphocytes exhibited reduced microvillar collapse and lamellipodium extension in response to chemokine signals, ruling out a role for these events in integrin-mediated adhesion strengthening. Strikingly, arrested DOCK2–/– lymphocytes transmigrated through a CCL21-presenting endothelial barrier with similar efficiency and rate as wt lymphocytes but, unlike wt lymphocytes, could not locomote away from the transmigration site of the basal endothelial side. DOCK2–/– lymphocytes also failed to laterally migrate over multiple integrin ligands coimmobilized with chemokines. This is a first indication that T lymphocytes use 2 different chemokine-triggered actin remodeling programs: the first, DOCK2 dependent, to locomote laterally along apical and basal endothelial surfaces; the second, DOCK2 independent, to cross through a chemokine-bearing endothelial barrier. 
