Impaired NK-cell migration in WAS/XLT patients: role of Cdc42/WASp pathway in the control of chemokine-induced beta2 integrin high-affinity state.
We analyzed the involvement of Wiskott-Aldrich syndrome protein (WASp), a critical regulator of actin cytoskeleton remodeling, in the control of natural killer (NK)-cell migration. NK cells derived from patients with Wiskott-Aldrich syndrome/X-linked thrombocytopenia (WAS/XLT), carrying different mutations in the WASP coding gene, displayed reduced migration through intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), or endothelial cells in response to CXCL12/stromal cell-derived factor-1 and CX3CL1/fractalkine. Inhibition of WAS/XLT NK-cell migration was associated with reduced ability of these cells to up-regulate the expression of CD18 activation neoepitope and to adhere to ICAM-1 or VCAM-1 following chemokine stimulation. Moreover, chemokine receptor or beta1 or beta2 integrin engagement on NK cells rapidly resulted in Cdc42 activation and WASp tyrosine phosphorylation as well as in WASp association with Fyn and Pyk-2 tyrosine kinases. NK-cell pretreatment with wiskostatin, to prevent Cdc42/WASp association, impaired chemokine-induced NK-cell migration through ICAM-1 and beta2 integrin activation-dependent neoepitope expression. These results show that the Cdc42/WASp pathway plays a crucial role in the regulation of NK-cell migration by acting as a critical component of the chemokine-induced inside-out signaling that regulates lymphocyte function-associated antigen-1 function and suggest that after integrin or chemokine receptor engagement WASp function is regulated by the coordinate action of both Cdc42 and tyrosine kinases.
Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
Helena
H
Stabile
Claudia
C
Carlino
Cinzia
C
Mazza
Silvia
S
Giliani
Stefania
S
Morrone
Lucia D
LD
Notarangelo
Luigi D
LD
Notarangelo
Angela
A
Santoni
Angela
A
Gismondi
D018821:CD18 Antigens / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000276:immunology*; D054428:Chemokine CX3CL1 / Q000235:genetics / Q000276:immunology; D054377:Chemokine CXCL12 / Q000235:genetics / Q000276:immunology; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000276:immunology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000235:genetics / Q000276:immunology; D008297:Male; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013921:Thrombocytopenia / Q000235:genetics / Q000276:immunology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000276:immunology; D014923:Wiskott-Aldrich Syndrome / Q000235:genetics / Q000276:immunology*; D051316:Wiskott-Aldrich Syndrome Protein / Q000235:genetics / Q000276:immunology*; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000276:immunology*
D018821:CD18 Antigens; C515538:CX3CL1 protein, human; C515255:CXCL12 protein, human; D054428:Chemokine CX3CL1; D054377:Chemokine CXCL12; D016169:Lymphocyte Function-Associated Antigen-1; D019010:Vascular Cell Adhesion Molecule-1; D051316:Wiskott-Aldrich Syndrome Protein; D018799:Intercellular Adhesion Molecule-1; D020764:cdc42 GTP-Binding Protein