TY - JOUR
T1 - DOCK2 is required for chemokine-promoted human T lymphocyte adhesion under shear stress mediated by the integrin α4β1
AU - García-Bernal, David
AU - Sotillo-Mallo, Elena
AU - Nombela-Arrieta, César
AU - Samaniego, Rafael
AU - Fukui, Yoshinori
AU - Stein, Jens V.
AU - Teixidó, Joaquin
PY - 2006/10/15
Y1 - 2006/10/15
N2 - The α4β1 integrin is an essential adhesion molecule for recruitment of circulating lymphocytes into lymphoid organs and peripheral sites of inflammation. Chemokines stimulate α4β 1 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 α4β 1-VCAM-1 interaction, involving high affinity α 4β1 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, low 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.
AB - The α4β1 integrin is an essential adhesion molecule for recruitment of circulating lymphocytes into lymphoid organs and peripheral sites of inflammation. Chemokines stimulate α4β 1 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 α4β 1-VCAM-1 interaction, involving high affinity α 4β1 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, low 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.
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M3 - Article
C2 - 17015707
AN - SCOPUS:33749522366
VL - 177
SP - 5215
EP - 5225
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 8
ER -