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Mol Cell Biol. 2014 Dec 1;34(23):4343-54. doi: 10.1128/MCB.00533-14. Epub 2014 Sep 22.

Binding of WIP to actin is essential for T cell actin cytoskeleton integrity and tissue homing.

Author information

1
Division of Immunology, Children's Hospital, and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
2
Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
3
Division of Translational Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
4
Division of Immunology, Children's Hospital, and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA raif.geha@childrens.harvard.edu.

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.

PMID:
25246631
PMCID:
PMC4248745
DOI:
10.1128/MCB.00533-14
[Indexed for MEDLINE]
Free PMC Article

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