Differential requirements for DOCK2 and phosphoinositide-3-kinase gamma during T and B lymphocyte homing.
Chemokines guide lymphocytes from blood to secondary lymphoid organs by triggering integrin-dependent firm adhesion under vascular flow and directed migration of T and B lymphocytes within lymphoid tissue. Here, we analyze the roles of DOCK2, a mammalian homolog of Caenorhabditis elegans CED-5 and Drosophila melanogaster Myoblast City, and phosphoinositide-3-kinase (PI3K) during lymphocyte recirculation. DOCK2 mediated efficient lymphocyte migration in a largely PI3K-independent manner, although a minor, PI3K-dependent pathway for migration was observed in wild-type and DOCK2-deficient lymphocytes. In T cells, this residual migration depended mainly on PI3Kgamma, whereas other PI3K isoforms were implicated in B cells. In vitro adhesion assays and intravital microscopy of lymphoid organ vasculature uncovered an unexpected defect in integrin activation in DOCK2-/- B cells, whereas lack of DOCK2 did not affect chemokine-triggered integrin activation in T cells. DOCK2 and PI3Kgamma thus play distinct roles during T and B cell integrin activation and migration.
Nombela-Arrieta
César
C
Department of Immunology and Oncology, National Center for Biotechnology, Campus Cantoblanco, 28049 Madrid, Spain.
Lacalle
Rosa Ana
RA
Montoya
María C
MC
Kunisaki
Yuya
Y
Megías
Diego
D
Marqués
Miriam
M
Carrera
Ana C
AC
Mañes
Santos
S
Fukui
Yoshinori
Y
Martínez-A
Carlos
C
Stein
Jens V
JV
D000199:Actins / Q000378:metabolism; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002448:Cell Adhesion / Q000276:immunology; D002465:Cell Movement / Q000276:immunology*; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D020690:GTPase-Activating Proteins / Q000276:immunology* / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors; D015151:Immunoblotting; D007150:Immunohistochemistry; D016023:Integrins / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008221:Lymphoid Tissue / Q000276:immunology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D000199:Actins; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D016023:Integrins; D019869:Phosphatidylinositol 3-Kinases; C471356:DOCK2 protein, mouse