title: The Rac activator Tiam1 controls efficient T-cell trafficking and route of transendothelial migration.
abstract: 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.
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Audrey
authors.initials: A
authors.lastname: Gérard
authors.forename: Rob A
authors.initials: RA
authors.lastname: van der Kammen
authors.forename: Hans
authors.initials: H
authors.lastname: Janssen
authors.forename: Saskia I
authors.initials: SI
authors.lastname: Ellenbroek
authors.forename: John G
authors.initials: JG
authors.lastname: Collard
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002448:Cell Adhesion; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D005434:Flow Cytometry; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology*; D015151:Immunoblotting; D008246:Lysophospholipids / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects; D051745:Protein Kinase C-delta / Q000378:metabolism; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D013601:T-Lymphocytes / Q000166:cytology*; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D008246:Lysophospholipids; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C513260:Tiam1 protein, mouse; C060506:sphingosine 1-phosphate; D051745:Protein Kinase C-delta; D020744:rac GTP-Binding Proteins; D013110:Sphingosine