title: The Wiskott-Aldrich syndrome protein is required for iNKT cell maturation and function.
abstract: The Wiskott-Aldrich syndrome (WAS) protein (WASp) is a regulator of actin cytoskeleton in hematopoietic cells. Mutations of the WASp gene cause WAS. Although WASp is involved in various immune cell functions, its role in invariant natural killer T (iNKT) cells has never been investigated. Defects of iNKT cells could indeed contribute to several WAS features, such as recurrent infections and high tumor incidence. We found a profound reduction of circulating iNKT cells in WAS patients, directly correlating with the severity of clinical phenotype. To better characterize iNKT cell defect in the absence of WASp, we analyzed was(-/-) mice. iNKT cell numbers were significantly reduced in the thymus and periphery of was(-/-) mice as compared with wild-type controls. Moreover analysis of was(-/-) iNKT cell maturation revealed a complete arrest at the CD44(+) NK1.1(-) intermediate stage. Notably, generation of BM chimeras demonstrated a was(-/-) iNKT cell-autonomous developmental defect. was(-/-) iNKT cells were also functionally impaired, as suggested by the reduced secretion of interleukin 4 and interferon gamma upon in vivo activation. Altogether, these results demonstrate the relevance of WASp in integrating signals critical for development and functional differentiation of iNKT cells and suggest that defects in these cells may play a role in WAS pathology.
authors.affiliation: Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Locci
authors.forename: Elena
authors.initials: E
authors.lastname: Draghici
authors.forename: Francesco
authors.initials: F
authors.lastname: Marangoni
authors.forename: Marita
authors.initials: M
authors.lastname: Bosticardo
authors.forename: Marco
authors.initials: M
authors.lastname: Catucci
authors.forename: Alessandro
authors.initials: A
authors.lastname: Aiuti
authors.forename: Caterina
authors.initials: C
authors.lastname: Cancrini
authors.forename: Laszlo
authors.initials: L
authors.lastname: Marodi
authors.forename: Teresa
authors.initials: T
authors.lastname: Espanol
authors.forename: Robbert G M
authors.initials: RG
authors.lastname: Bredius
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Thrasher
authors.forename: Ansgar
authors.initials: A
authors.lastname: Schulz
authors.forename: Jiri
authors.initials: J
authors.lastname: Litzman
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Roncarolo
authors.forename: Giulia
authors.initials: G
authors.lastname: Casorati
authors.forename: Paolo
authors.initials: P
authors.lastname: Dellabona
authors.forename: Anna
authors.initials: A
authors.lastname: Villa
mesh_terms: D000818:Animals; D016207:Cytokines / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D055611:Natural Killer T-Cells / Q000276:immunology*; D010641:Phenotype; D014923:Wiskott-Aldrich Syndrome / Q000235:genetics / Q000276:immunology*
chemical_list: C476399:Cd44 protein, mouse; D016207:Cytokines; D018960:Hyaluronan Receptors