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* Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada;
Department of Immunology, Roswell Park Cancer Institute, Buffalo NY 14263;
Departments of Microbiology and Immunology and Medicine, Dalhousie University, Halifax, Nova Scotia, Canada; and
Institute for Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria
Dendritic cells (DCs) are the most potent APCs for activating naive T cells, a process facilitated by the ability of immature DCs to mature and home to lymph nodes after encountering an inflammatory stimulus. Proteins involved in cytoskeletal rearrangement play an important role in regulating the adherence and motility of DCs. Vav1, a guanine nucleotide exchange factor for Rho family GTPases, mediates cytoskeletal rearrangement in hematopoietic cells following integrin ligation. We show that Vav1 is not required for the normal maturation of DCs in vitro; however, it is critical for DC binding to fibronectin and regulates the distribution but not the formation of podosomes. We also found that DC Vav1 was an important component of a signaling pathway involving focal adhesion kinase, phospholipase C-
2, and ERK1/2 following integrin ligation. Surprisingly, Vav1–/– DCs had increased rates of migration in vivo compared with wild-type control DCs. In vitro findings show that the presence of adhesive substrates such as fibronectin resulted in inhibition of migration. However, there was less inhibition in the absence of Vav1. These findings suggest that DC migration is negatively regulated by adhesion and integrin-mediated signaling and that Vav1 has a central role in this process.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants to K.A.W. from the Kidney Foundation of Canada and the Canadian Institutes of Health Research (MOP 62205) as well as by National Institutes of Health grants AI54666 (to J.L.C.), CA16056 (Roswell Park Cancer Center Support Grant), and an Arthritis Foundation Investigator Award (to J.L.C.).
2 D.R.S., N.A.L., and D.C.M. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Kenneth A. West, Department of Medicine, Dalhousie University, Suite 5087, Dickson Building, 5820 University Avenue, Halifax, Nova Scotia B3H 2Y9, Canada. E-mail address: kawest{at}dal.ca or Dr. James L. Clements, Kinex Pharmaceuticals, New York State Center of Excellence in Bioinformatics and Life Sciences, 701 Ellicott Street, Buffalo, NY 14203. E-mail address: jclements{at}kinexpharma.com
4 Abbreviations used in this paper: DC, dendritic cell; FAK, focal adhesion kinase; GEF, guanine exchange factor; LC, Langerhans cell; LN, lymph node; PLC, phospholipase C; PLL, poly-L-lysine; PTK, protein tyrosine kinase; RGDS, Arg-Gly-Asp-Ser; SLP-76, Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa; WASP, Wiskott-Aldrich syndrome protein; WT, wild type.
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