Submitted December 22, 2005
Accepted May 29, 2006
DOCK2 regulates chemokine-triggered lateral lymphocyte
motility but not transendothelial migration
Ziv Shulman, Ronit Pasvolsky, Eilon Woolf, Valentin Grabovsky, Sara W. Feigelson, Noam Erez, Yoshinori Fukui, and Ronen Alon*
Department of Immunology, Weizmann Institute of Science
Division of Immunogenetics, Department of Immunobiology and Neuroscience, Kyushu University
* Corresponding author; email: ronen.alon{at}weizmann.ac.il.
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?-activated endothelial cells in response to integrin
stimulatory chemokine signals, and their resistance to
detachment was similar to that of 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 co-immobilized with chemokines.
This is a first indication that T lymphocytes use two
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.
