title: WIP and WASP play complementary roles in T cell homing and chemotaxis to SDF-1alpha.
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.
authors.affiliation: Division of Immunology, Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Maria Dolores
authors.initials: MD
authors.lastname: Gallego
authors.forename: Miguel A
authors.initials: MA
authors.lastname: de la Fuente
authors.forename: Ines M
authors.initials: IM
authors.lastname: Anton
authors.forename: Scott
authors.initials: S
authors.lastname: Snapper
authors.forename: Robert
authors.initials: R
authors.lastname: Fuhlbrigge
authors.forename: Raif S
authors.initials: RS
authors.lastname: Geha
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D002448:Cell Adhesion; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D003598:Cytoskeletal Proteins; D003599:Cytoskeleton / Q000378:metabolism; D005260:Female; D005353:Fibronectins / Q000502:physiology; D008221:Lymphoid Tissue / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019718:Receptors, CXCR4 / Q000378:metabolism; D019087:Selectins / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D051316:Wiskott-Aldrich Syndrome Protein / Q000172:deficiency / Q000502:physiology*
chemical_list: D000199:Actins; D002352:Carrier Proteins; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D003598:Cytoskeletal Proteins; D005353:Fibronectins; D019718:Receptors, CXCR4; D019087:Selectins; C495768:Was protein, mouse; C491671:Waspip protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein