1. WIP and WASP play complementary roles in T cell homing and chemotaxis to SDF-1alpha.
- Author
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Gallego MD, de la Fuente MA, Anton IM, Snapper S, Fuhlbrigge R, and Geha RS
- Subjects
- Actins metabolism, Animals, Cell Adhesion, Chemokine CXCL12, Chemokines, CXC immunology, Cytoskeletal Proteins, Cytoskeleton metabolism, Female, Fibronectins physiology, Lymphoid Tissue immunology, Male, Mice, Mice, Knockout, Receptors, CXCR4 metabolism, Selectins metabolism, Signal Transduction, Wiskott-Aldrich Syndrome Protein deficiency, Carrier Proteins physiology, Chemotaxis, Leukocyte physiology, T-Lymphocytes immunology, Wiskott-Aldrich Syndrome Protein physiology
- Abstract
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-1alpha (SDF-1alpha) 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-1alpha 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-1alpha was abnormal in T cells from all knockout mice. Early biochemical events following SDF-1alpha 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.
- Published
- 2006
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