The Rac activator Tiam1 controls efficient T-cell trafficking and route of transendothelial migration

• Published in: Blood Vol. 113; no. 24; pp. 6138 - 6147
• Main Authors: Gérard, Audrey, van der Kammen, Rob A., Janssen, Hans, Ellenbroek, Saskia I., Collard, John G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.06.2009
• Subjects: Animals; Brain - cytology; Brain - drug effects; Brain - metabolism; Cell Adhesion; Chemotaxis, Leukocyte - physiology; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Flow Cytometry; Guanine Nucleotide Exchange Factors - physiology; Immunoblotting; Lysophospholipids - pharmacology; Mice; Mice, Knockout; Phosphorylation - drug effects; Protein Kinase C-delta - metabolism; rac GTP-Binding Proteins - genetics; rac GTP-Binding Proteins - metabolism; Signal Transduction; Sphingosine - analogs & derivatives; Sphingosine - pharmacology; T-Lymphocytes - cytology; T-Lymphoma Invasion and Metastasis-inducing Protein 1
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2008-07-167668

Migration toward chemoattractants is a hallmark of T-cell trafficking and is essential to produce an efficient immune response. Here, we have analyzed the function of the Rac activator Tiam1 in the control of T-cell trafficking and transendothelial migration. We found that Tiam1 is required for chemokine- and S1P-induced Rac activation and subsequent cell migration. As a result, Tiam1-deficient T cells show reduced chemotaxis in vitro, and impaired homing, egress, and contact hypersensitivity in vivo. Analysis of the T-cell transendothelial migration cascade revealed that PKCζ/Tiam1/Rac signaling is dispensable for T-cell arrest but is essential for the stabilization of polarization and efficient crawling of T cells on endothelial cells. T cells that lack Tiam1 predominantly transmigrate through individual endothelial cells (transcellular migration) rather than at endothelial junctions (paracellular migration), suggesting that T cells are able to change their route of transendothelial migration according to their polarization status and crawling capacity.