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Differential Requirements for DOCK2 and Phosphoinositide-3-Kinase γ during T and B Lymphocyte Homing

2004; Cell Press; Volume: 21; Issue: 3 Linguagem: Inglês

10.1016/j.immuni.2004.07.012

1097-4180

César Nombela‐Arrieta, Rosa Ana Lacalle, Marı́a C. Montoya, Yuya Kunisaki, Diego Megı́as, Miriam Marqués, Ana C. Carrera, Santos Mañes, Yoshinori Fukui, Carlos Martı́nez-A, Jens V. Stein,

Phagocytosis and Immune Regulation

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 PI3Kγ, 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 PI3Kγ thus play distinct roles during T and B cell integrin activation and migration.