Abstract
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 β1or β2 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 NKcell migration through ICAM-1 and β2 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.
| Original language | English |
|---|---|
| Pages (from-to) | 2818-2826 |
| Number of pages | 9 |
| Journal | Blood |
| Volume | 115 |
| Issue number | 14 |
| DOIs | |
| Publication status | Published - Apr 8 2010 |
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ASJC Scopus subject areas
- Hematology
- Biochemistry
- Cell Biology
- Immunology
Cite this
Impaired NK-cell migration in WAS/XLT patients : Role of Cdc42/WASp pathway in the control of chemokine-induced β2 integrin high-affinity state. / Stabile, Helena; Carlino, Claudia; Mazza, Cinzia; Giliani, Silvia; Morrone, Stefania; Notarangelo, Lucia D.; Notarangelo, Luigi D.; Santoni, Angela; Gismondi, Angela.
In: Blood, Vol. 115, No. 14, 08.04.2010, p. 2818-2826.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Impaired NK-cell migration in WAS/XLT patients
T2 - Role of Cdc42/WASp pathway in the control of chemokine-induced β2 integrin high-affinity state
AU - Stabile, Helena
AU - Carlino, Claudia
AU - Mazza, Cinzia
AU - Giliani, Silvia
AU - Morrone, Stefania
AU - Notarangelo, Lucia D.
AU - Notarangelo, Luigi D.
AU - Santoni, Angela
AU - Gismondi, Angela
PY - 2010/4/8
Y1 - 2010/4/8
N2 - 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 β1or β2 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 NKcell migration through ICAM-1 and β2 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.
AB - 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 β1or β2 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 NKcell migration through ICAM-1 and β2 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.
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U2 - 10.1182/blood-2009-07-235804
DO - 10.1182/blood-2009-07-235804
M3 - Article
VL - 115
SP - 2818
EP - 2826
JO - Blood
JF - Blood
SN - 0006-4971
IS - 14
ER -