Blood Journal
Leading the way in experimental and clinical research in hematology

Impaired NK-cell migration in WAS/XLT patients: role of Cdc42/WASp pathway in the control of chemokine-induced β2 integrin high-affinity state

  1. Helena Stabile1,
  2. Claudia Carlino1,
  3. Cinzia Mazza2,
  4. Silvia Giliani2,
  5. Stefania Morrone1,
  6. Lucia D. Notarangelo3,
  7. Luigi D. Notarangelo2,4,
  8. Angela Santoni1,5, and
  9. Angela Gismondi1
  1. 1Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy;
  2. 2Institute of Molecular Medicine, Angelo Nocivelli, Brescia, Italy;
  3. 3Oncology-Haematology and BMT Unit, Ospedale dei Bambini, Spedali Civili, Brescia, Italy;
  4. 4Division of Immunology, Children's Hospital, Boston, MA; and
  5. 5Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy

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 β1 or 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 NK-cell 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.

  • Submitted July 30, 2009.
  • Accepted January 11, 2010.
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