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DOCK2 is Required for Chemokine-Promoted Human T Lymphocyte Adhesion Under Shear Stress Mediated by the Integrin {alpha}4beta1

AuthorsGarcía-Bernal, David ; Sotillo-Mallo, Elena; Nombela, César; Samaniego, Rafael ; Fukui, Yoshinori; Stein, Jens V.; Teixidó, Joaquín
Issue Date15-Oct-2006
PublisherAmerican Association of Immunologists
CitationJournal of Immunology 177(8):5215-5225(2006)
AbstractThe α4β1 integrin is an essential adhesion molecule for recruitment of circulating lymphocytes into lymphoid organs and peripheral sites of inflammation. Chemokines stimulate α4β1 adhesive activity allowing lymphocyte arrest on endothelium and subsequent diapedesis. Activation of the GTPase Rac by the guanine-nucleotide exchange factor Vav1 promoted by CXCL12 controls T lymphocyte adhesion mediated by α4β1. In this study, we investigated the role of DOCK2, a lymphocyte guanine-nucleotide exchange factor also involved in Rac activation, in CXCL12-stimulated human T lymphocyte adhesion mediated by α4β1. Using T cells transfected with DOCK2 mutant forms defective in Rac activation or with DOCK2 small interfering RNA, we demonstrate that DOCK2 is needed for efficient chemokine-stimulated lymphocyte attachment to VCAM-1 under shear stress. Flow chamber, soluble binding, and cell spreading assays identified the strengthening of α4β1-VCAM-1 interaction, involving high affinity α4β1 conformations, as the adhesion step mainly controlled by DOCK2 activity. The comparison of DOCK2 and Vav1 involvement in CXCL12-promoted Rac activation and α4β1-dependent human T cell adhesion indicated a more prominent role of Vav1 than DOCK2. These results suggest that DOCK2-mediated signaling regulates chemokine-stimulated human T lymphocyte α4β1 adhesive activity, and that cooperation with Vav1 might be required to induce sufficient Rac activation for efficient adhesion. In contrast, flow chamber experiments using lymph node and spleen T cells from DOCK2−/− mice revealed no significant alterations in CXCL12-promoted adhesion mediated by α4β1, indicating that DOCK2 activity is dispensable for triggering of this adhesion in mouse T cells, and suggesting that Rac activation plays minor roles in this process
Description11 páginas, 6 figuras -- PAGS nros. 5215-5225
Appears in Collections:(CIB) Artículos
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