DOCK2 is required for chemokine-promoted human T lymphocyte adhesion under shear stress mediated by the integrin α4β1

David García-Bernal, Elena Sotillo-Mallo, César Nombela-Arrieta, Rafael Samaniego, Yoshinori Fukui, Jens V. Stein, Joaquin Teixidó

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Abstract

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.

Original languageEnglish
Pages (from-to)5215-5225
Number of pages11
JournalJournal of Immunology
Volume177
Issue number8
Publication statusPublished - Oct 15 2006

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All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

García-Bernal, D., Sotillo-Mallo, E., Nombela-Arrieta, C., Samaniego, R., Fukui, Y., Stein, J. V., & Teixidó, J. (2006). DOCK2 is required for chemokine-promoted human T lymphocyte adhesion under shear stress mediated by the integrin α4β1. Journal of Immunology, 177(8), 5215-5225.