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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 PKCzeta/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.

Original publication

DOI

10.1182/blood-2008-07-167668

Type

Journal article

Journal

Blood

Publication Date

06/2009

Volume

113

Pages

6138 - 6147

Addresses

Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Keywords

Endothelium, Vascular, Brain, T-Lymphocytes, Animals, Mice, Knockout, Mice, Sphingosine, rac GTP-Binding Proteins, Lysophospholipids, Guanine Nucleotide Exchange Factors, Immunoblotting, Flow Cytometry, Cell Adhesion, Signal Transduction, Chemotaxis, Leukocyte, Phosphorylation, Protein Kinase C-delta