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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.
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IMMUNOBIOLOGY
Impaired natural and CD16-mediated NK cell cytotoxicity in patients with WAS and XLT: 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
From the Department of Experimental Medicine and Pathology, Istituto Pasteur-Fondazione Cenci Bolognetti, University "La Sapienza," Rome, Italy; Department of Pediatrics, Institute of Molecular Medicine "Angelo Nocivelli," University of Bescia, Italy; and Department of Biomedical and Biotechnological Sciences, University of Brescia, Italy.
In this study we show that Wiskott-Aldrich syndrome protein (WASp), a critical regulator of actin cytoskeleton that belongs to the Scar/WAVE family, plays a crucial role in the control of natural killer (NK) cell cytotoxicity. 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 increased, natural cytotoxicity and antibody-mediated NK cell cytotoxicity were inhibited in all patients with the classical WAS phenotype and in most patients carrying mutations associated with the X-linked thrombocytopenia (XLT) phenotype. The inhibition of NK cell-mediated cytotoxicity was associated with the reduced ability of WAS and XLT NK cells to form conjugates with susceptible target cells and to accumulate F-actin on binding. Treatment with interleukin-2 (IL-2) corrected the functional defects of NK cells by affecting their ability to bind to sensitive target cells and to accumulate F-actin. In addition, we 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 antibody-dependent cellular cytotoxicity (ADCC) rapidly activates Cdc42. We also found that WASp undergoes tyrosine phosphorylation upon CD16 or  2-integrin engagement on NK cells. (Blood. 2004;104:436-443)
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