title: Binding of WIP to actin is essential for T cell actin cytoskeleton integrity and tissue homing.
abstract: The Wiskott-Aldrich syndrome protein (WASp) is important for actin polymerization in T cells and for their migration. WASp-interacting protein (WIP) binds to and stabilizes WASp and also interacts with actin. Cytoskeletal and functional defects are more severe in WIP(-/-) T cells, which lack WASp, than in WASp(-/-) T cells, suggesting that WIP interaction with actin may be important for T cell cytoskeletal integrity and function. We constructed mice that lack the actin-binding domain of WIP (WIPΔABD mice). WIPΔABD associated normally with WASp but not F-actin. T cells from WIPΔABD mice had normal WASp levels but decreased cellular F-actin content, a disorganized actin cytoskeleton, impaired chemotaxis, and defective homing to lymph nodes. WIPΔABD mice exhibited a T cell intrinsic defect in contact hypersensitivity and impaired responses to cutaneous challenge with protein antigen. Adoptively transferred antigen-specific CD4(+) T cells from WIPΔABD mice had decreased homing to antigen-challenged skin of wild-type recipients. These findings show that WIP binding to actin, independently of its binding to WASp, is critical for the integrity of the actin cytoskeleton in T cells and for their migration into tissues. Disruption of WIP binding to actin could be of therapeutic value in T cell-driven inflammatory diseases.
authors.affiliation: Division of Immunology, Children's Hospital, and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Michel J
authors.initials: MJ
authors.lastname: Massaad
authors.affiliation: Division of Immunology, Children's Hospital, and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Michiko K
authors.initials: MK
authors.lastname: Oyoshi
authors.affiliation: Division of Immunology, Children's Hospital, and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kane
authors.affiliation: Division of Immunology, Children's Hospital, and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Suresh
authors.initials: S
authors.lastname: Koduru
authors.affiliation: Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Pilar
authors.initials: P
authors.lastname: Alcaide
authors.affiliation: Division of Translational Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Nakamura
authors.affiliation: Division of Immunology, Children's Hospital, and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Narayanaswamy
authors.initials: N
authors.lastname: Ramesh
authors.affiliation: Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Francis W
authors.initials: FW
authors.lastname: Luscinskas
authors.affiliation: Division of Translational Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: John
authors.initials: J
authors.lastname: Hartwig
authors.affiliation: Division of Immunology, Children's Hospital, and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA raif.geha@childrens.harvard.edu.
authors.forename: Raif S
authors.initials: RS
authors.lastname: Geha
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D000199:Actins / Q000378:metabolism*; D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000637:transplantation; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000276:immunology; D054415:Chemokine CCL19 / Q000276:immunology; D054377:Chemokine CXCL12 / Q000276:immunology; D003598:Cytoskeletal Proteins; D003877:Dermatitis, Contact / Q000235:genetics / Q000276:immunology; D055879:Gene Knock-In Techniques; D006433:Hemocyanins / Q000276:immunology; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D058105:Polymerization; D017434:Protein Structure, Tertiary / Q000235:genetics; D054400:Receptors, CCR7 / Q000276:immunology; D019718:Receptors, CXCR4 / Q000276:immunology; D051316:Wiskott-Aldrich Syndrome Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D000199:Actins; C514936:CXCR4 protein, mouse; D002352:Carrier Proteins; C515461:Ccl19 protein, mouse; C515371:Ccr7 protein, mouse; D054415:Chemokine CCL19; D054377:Chemokine CXCL12; D003598:Cytoskeletal Proteins; D054400:Receptors, CCR7; D019718:Receptors, CXCR4; C491671:Waspip protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin