Binding of WIP to Actin Is Essential for T Cell Actin Cytoskeleton Integrity and Tissue Homing.

[wiskott-aldrich syndrome]

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 CD 4 (+) 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 .