Submitted July 10, 2008
Accepted December 24, 2008
The Rac activator Tiam1 controls efficient T-cell trafficking and route of trans-endothelial migration
Audrey Gerard, Rob A. van der Kammen, Hans Janssen, Saskia I. Ellenbroek, and John G. Collard*
Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, Netherlands
Division of Tumor Biology, The Netherlands Cancer Institute, Amsterdam, Netherlands
* Corresponding author; email: j.collard{at}nki.nl.
Migration towards chemo-attractants is a hallmark of T-cell trafficking and is essential to produce an efficient immune response. Here, we have analysed the function of the Rac activator Tiam1 in the control of T-cell trafficking and trans-endothelial 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 trans-endothelial migration cascade revealed that PKC
/Tiam1/Rac signalling 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 trans-endothelial migration according to their polarization status and crawling capacity.
