title: Wiskott-Aldrich syndrome protein is required for NK cell cytotoxicity and colocalizes with actin to NK cell-activating immunologic synapses.
abstract: The Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency disorder caused by a mutation in WAS protein (WASp) that results in defective actin polymerization. Although the function of many hematopoietic cells requires WASp, the specific expression and function of this molecule in natural killer (NK) cells is unknown. Here, we report that WAS patients have increased percentages of peripheral blood NK cells and that fresh enriched NK cells from two patients with a WASp mutation have defective cytolytic function. In normal NK cells, WASp was expressed and localized to the activating immunologic synapse (IS) with filamentous actin (F-actin). Perforin also localized to the NK cell-activating IS but at a lesser frequency than F-actin and WASp. The accumulation of F-actin and WASp at the activating IS was decreased significantly in NK cells that had been treated with the inhibitor of actin polymerization, cytochalasin D. NK cells from WAS patients lacked expression of WASp and accumulated F-actin at the activating IS infrequently. Thus, WASp has an important function in NK cells. In patients with WASp mutations, the resulting NK cell defects are likely to contribute to their disease.
authors.affiliation: Department of Molecular and Cellular Biology, 7 Divinity Avenue, Harvard University, Cambridge, MA 02138, USA. orange@fas.harvard.edu
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Orange
authors.forename: Narayanaswamy
authors.initials: N
authors.lastname: Ramesh
authors.forename: Eileen
authors.initials: E
authors.lastname: Remold-O'Donnell
authors.forename: Yoji
authors.initials: Y
authors.lastname: Sasahara
authors.forename: Louise
authors.initials: L
authors.lastname: Koopman
authors.forename: Michael
authors.initials: M
authors.lastname: Byrne
authors.forename: Francisco A
authors.initials: FA
authors.lastname: Bonilla
authors.forename: Fred S
authors.initials: FS
authors.lastname: Rosen
authors.forename: Raif S
authors.initials: RS
authors.lastname: Geha
authors.forename: Jack L
authors.initials: JL
authors.lastname: Strominger
mesh_terms: D000199:Actins / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D015638:Cytochalasin D / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007223:Infant; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male; D018613:Microscopy, Confocal / Q000379:methods; D010033:Otitis Media / Q000276:immunology; D011506:Proteins / Q000235:genetics / Q000276:immunology*; D012016:Reference Values; D013569:Synapses / Q000276:immunology*; D013921:Thrombocytopenia / Q000276:immunology; D014923:Wiskott-Aldrich Syndrome / Q000276:immunology*; D051316:Wiskott-Aldrich Syndrome Protein
chemical_list: D000199:Actins; D011506:Proteins; C495767:WAS protein, human; D051316:Wiskott-Aldrich Syndrome Protein; D015638:Cytochalasin D