International Immunology Advance Access originally published online on September 1, 2005
International Immunology 2006 18(2):221-232; doi:10.1093/intimm/dxh310
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WIP and WASP play complementary roles in T cell homing and chemotaxis to SDF-1
1 Division of Immunology, Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA
2 Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, Madrid 28049, Spain
3 Gastrointestinal Unit and the Center for the Study of Inflammatory Bowel Diseases, Massachusetts General Hospital, Boston, 02115, 4 Harvard Skin Diseases Center and Department of Pediatrics Medicine and Department of Dermatology, Harvard Medical School, Boston, MA 02115, USA
Correspondence to: R. S. Geha; E-mail: raif.geha{at}childrens.harvard.edu
Homing of lymphocytes to tissues is a biologically important multistep process that involves selectin-dependent rolling, integrin-dependent adhesion and chemokine-directed chemotaxis. The actin cytoskeleton plays a central role in lymphocyte adhesion and motility. Wiskott–Aldrich syndrome protein (WASP), the product of the gene mutated in Wiskott–Aldrich syndrome, and its partner, the Wiskott–Aldrich syndrome protein-interacting protein (WIP), play important roles in actin re-organization in T lymphocytes. We used mice with disruption of the WASP and WIP genes to examine the role of WASP and WIP in T cell homing. T cell homing to spleen and lymph nodes in vivo was deficient in WASP–/– and WIP–/– mice and severely impaired in WASP–/–WIP–/– double knockout (DKO) mice. Deficiency of WASP, WIP or both did not interfere with selectin-dependent rolling or integrin-dependent adhesion of T cells in vitro. Chemotaxis to stromal cell-derived factor-1
(SDF-1) in vitro was mildly reduced in T cells from WASP–/– mice. In contrast, it was significantly impaired in T cells from WIP–/– mice and severely reduced in T cells from DKO mice. Cellular F-actin increase following SDF-1 stimulation was normal in WASP–/– and WIP–/– T cells, but severely reduced in T cells from DKO mice. Actin re-organization and polarization in response to SDF-1 was abnormal in T cells from all knockout mice. Early biochemical events following SDF-1 stimulation that are important for chemotaxis and that included phosphorylation of Lck, cofilin, PAK1 and extracellular regulated kinase (Erk) and GTP loading of Rac-1 were examined in T cells from DKO mice and found to be normal. These results suggest that WASP and WIP are not essential for T lymphocyte rolling and adhesion, but play important and partially redundant roles in T cell chemotaxis in vitro and homing in vivo and function downstream of small GTPases.
Keywords: WASP, WIP, chemotaxis, SDF-1
* These authors contributed equally to this work.
Transmitting editor: K. Rajewsky
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