Binding of WIP to Actin Is Essential for T Cell Actin Cytoskeleton Integrity and Tissue Homing |
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| Authors: | Michel J Massaad Michiko K Oyoshi Jennifer Kane Suresh Koduru Pilar Alcaide Fumihiko Nakamura Narayanaswamy Ramesh Francis W Luscinskas John Hartwig Raif S Geha |
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| Institution: | aDivision of Immunology, Children''s Hospital, and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA;bCenter for Excellence in Vascular Biology, Department of Pathology, Brigham and Women''s Hospital, Harvard Medical School, Boston, Massachusetts, USA;cDivision of Translational Medicine, Brigham and Women''s Hospital, Harvard Medical School, Boston, Massachusetts, USA |
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| 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. |
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