DOCK2 regulates chemokine-triggered lateral lymphocyte motility but not transendothelial migration.
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 TNFalpha-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.
Shulman
Ziv
Z
Department of Immunology, The Weizmann Institute of Science, Rehovot, 76100, Israel.
Pasvolsky
Ronit
R
Woolf
Eilon
E
Grabovsky
Valentin
V
Feigelson
Sara W
SW
Erez
Noam
N
Fukui
Yoshinori
Y
Alon
Ronen
R
D000199:Actins / Q000378:metabolism; D000818:Animals; D002465:Cell Movement; D054421:Chemokine CCL21; D018925:Chemokines / Q000378:metabolism*; D019742:Chemokines, CC; D042783:Endothelial Cells / Q000166:cytology*; D005109:Extracellular Matrix / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000235:genetics* / Q000502:physiology*; D020662:Guanine Nucleotide Exchange Factors; D008024:Ligands; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000166:cytology
D000199:Actins; C515479:Ccl21c protein, mouse; D054421:Chemokine CCL21; D018925:Chemokines; D019742:Chemokines, CC; C471356:DOCK2 protein, mouse; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D008024:Ligands