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Published online before print May 17, 2007

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(Journal of Leukocyte Biology. 2007;82:380-391.)
© 2007 by Society for Leukocyte Biology

Intracellular signaling required for CCL25-stimulated T cell adhesion mediated by the integrin 4β1

Marisa Parmo-Cabañas^*,1, David García-Bernal^*,1, Rosa García-Verdugo^*, Leonor Kremer, Gabriel Márquez^,2 and Joaquin Teixidó^*,3

^* Department of Molecular and Cellular Physiopathology, Centro de Investigaciones Biológicas (CSIC), Madrid, Spain; and
Protein Tools Unit and
Department of Immunology and Oncology, Centro Nacional de Biotecnología (CSIC), Madrid, Spain

³ Correspondence: Centro de Investigaciones Biológicas, Department of Physiopathology, Ramiro de Maeztu 9, 28040 Madrid, Spain. E-mail: joaquint{at}cib.csic.es

The 4β1 integrin is expressed on thymocytes and mediates cell attachment to its ligands CS-1/fibronectin (CS-1/FN) and VCAM-1 in the thymus. The chemokine CCL25 is highly expressed in the thymus, where it binds to its receptor CCR9 on thymocytes promoting migration and activation. We show here that 4β1 and CCR9 are coexpressed mainly on double- and single-positive thymocytes and that CCL25 strongly stimulates CD4⁺CD8⁺ and CD4⁺CD8^– adhesion to CS-1/FN and VCAM-1. CCL25 rapidly activated the GTPases Rac and Rap1 on thymocytes, and this activation was required for stimulation of adhesion, as detected using the CCR9⁺/4β1⁺ human T cell line Molt-4. To study the role on CCL25-stimulated adhesion of the Rac downstream effector Wiskott-Aldrich syndrome protein family verproline-homologous protein 2 (WAVE2) as well as of Rap1-GTP-interacting proteins, regulator of adhesion and cell polarization enriched in lymphoid tissues (RAPL) and Rap1-GTP-interacting adapter molecule (RIAM), we knocked down their expression and tested transfectant attachment to 4β1 ligands. We found that WAVE2 and RAPL but not RIAM were required for efficient triggering by CCL25 of T cell adhesion to CS-1/FN and VCAM-1. Although Rac and Rap1 activation was required during early steps of T cell adhesion stimulated by CCL25, WAVE2 was needed for the development of actin-dependent T cell spreading subsequent to adhesion strengthening but not during initial 4β1-ligand interactions. These results suggest that regulation by CCL25 of adhesion of thymocyte subpopulations mediated by 4β1 could contribute to control their trafficking in the thymus during maturation, and identify Rac-WAVE2 and Rap1-RAPL as pathways whose activation is required in inside-out signaling, leading to stimulated adhesion.

Key Words: chemokine • fibronectin

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