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Vol. 16, Issue 7, 3223-3235, July 2005

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Vav1 and Rac Control Chemokine-promoted T Lymphocyte Adhesion Mediated by the Integrin 41

David García-Bernal ^*, Natalia Wright ^*, Elena Sotillo-Mallo ^*, César Nombela-Arrieta  , Jens V. Stein  , Xosé R. Bustelo , and Joaquin Teixidó ^*

^* Department of Immunology, Centro de Investigaciones Biológicas, CSIC, 28006 Madrid, Spain; Department of Immunology and Oncology, Centro Nacional de Biotecnología, CSIC–Pfizer, 28049 Madrid, Spain; and Centro de Investigación del Cáncer, CSIC, 37007 Salamanca, Spain

Submitted December 3, 2004; Accepted April 27, 2005
Monitoring Editor: Mark Ginsberg

The chemokine CXCL12 promotes T lymphocyte adhesion mediated by the integrin 41. CXCL12 activates the GTPase Rac, as well as Vav1, a guanine-nucleotide exchange factor for Rac, concomitant with up-regulation of 41-dependent adhesion. Inhibition of CXCL12-promoted Rac and Vav1 activation by transfection of dominant negative Rac or Vav1 forms, or by transfection of their siRNA, remarkably impaired the increase in T lymphocyte attachment to 41 ligands in response to this chemokine. Importantly, inhibition of Vav1 expression by RNA interference resulted in a blockade of Rac activation in response to CXCL12. Adhesions in flow chambers and soluble binding assays using these transfectants indicated that initial ligand binding and adhesion strengthening mediated by 41 were dependent on Vav1 and Rac activation by CXCL12. Finally, CXCL12-promoted T-cell transendothelial migration involving 41-mediated adhesion was notably inhibited by expression of dominant negative Vav1 and Rac. These results indicate that activation of Vav1-Rac signaling pathway by CXCL12 represents an important inside-out event controlling efficient up-regulation of 41-dependent T lymphocyte adhesion.

Abbreviations used: VCAM-1, vascular cell adhesion molecule-1; GTPase, guanosine triphosphate-binding proteins; GEF, guanine nucleotide exchange factor.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Present address: Theodor Kocher Institute, University of Bern, Freiestrasse 1, 3012 Bern, Switzerland.

Address correspondence to: Joaquin Teixidó (joaquint{at}cib.csic.es).

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