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 Blood, 11 June 2009, Vol. 113, No. 24, pp. 6138-6147.
Prepublished online as a Blood First Edition Paper on January 12, 2009; DOI 10.1182/blood-2008-07-167668.

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IMMUNOBIOLOGY

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

Audrey Gérard1, Rob A. van der Kammen1, Hans Janssen2, Saskia I. Ellenbroek1, and John G. Collard1

Divisions of 1 Cell Biology and 2 Tumor Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

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 PKC{zeta}/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.


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