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Blood, 15 July 2004, Vol. 104, No. 2, pp. 436-443.
Prepublished online as a Blood First Edition Paper on March 4, 2004; DOI 10.1182/blood-2003-07-2621.
Submitted August 1, 2003
Accepted February 25, 2004
Impaired natural and CD16-mediated NK cell cytotoxic function in WAS and XLT patients: ability of IL-2 to correct NK cell functional defect
Angela Gismondi*, Loredana Cifaldi, Cinzia Mazza, Silvia Giliani, Silvia Parolini, Stefania Morrone, Jordan Jacobelli, Elisabetta Bandiera, Luigi Notarangelo, and Angela Santoni
Department of Experimental Medicine and Pathology, Istituto Pasteur-Fondazione Cenci Bolognetti, University 'La Sapienza', Rome, Italy
Institute of Molecular Medicine Angelo Nocivelli, Department of Pediatrics, University of Brescia, Brescia, Italy
Department of Biomedical and Biotechnological Sciences, University of Brescia, Brescia, Italy
* Corresponding author; email: angela.gismondi{at}uniroma1.it.
In this study we show that WASp, a critical regulator of actin cytoskeleton that belongs to the Scar/WAVE family, plays a crucial role in the control of NK cell cytotoxic function. Analysis of NK cell numbers and cytotoxic activity in patients carrying different mutations in the WASP coding gene, indicated that although the percentage of NK cells was normal or rather increased, both natural and antibody-mediated NK cell cytotoxicity were inhibited in all the patients with classical WAS phenotype and in most of the patients carrying mutations associated with XLT phenotype. The inhibition of NK cell-mediated cytotoxicity was associated with reduced ability of WAS or XLT NK cells to form conjugates with susceptible target cells and to accumulate F-actin upon binding. Treatment with IL-2 was able to correct the NK cell functional defect by affecting their ability to bind to sensitive target cells and to accumulate F-actin. We also provide information on the molecular mechanisms that control WASp function demonstrating that binding of NK cells to sensitive targets or triggering through CD16 by means of reverse ADCC, rapidly activates Cdc42; in addition we found that WASp undergoes tyrosine phosphorylation upon CD16 or  2 integrin engagement on NK cells.
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