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, Angela Santoni

Research output: Contribution to journalArticle

Abstract

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 detects 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 β2-integrin engagement on NK cells.

Original languageEnglish
Pages (from-to)436-443
Number of pages8
JournalBlood
Volume104
Issue number2
DOIs
Publication statusPublished - Jul 15 2004

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ASJC Scopus subject areas

  • Hematology

Cite this

Gismondi, A., Cifaldi, L., Mazza, C., Giliani, S., Parolini, S., Morrone, S., Jacobelli, J., Bandiera, E., Notarangelo, L., & Santoni, A. (2004). Impaired natural and CD16-mediated NK cell cytotoxicity in patients with WAS and XLT: Ability of IL-2 to correct NK cell functional defect. Blood, 104(2), 436-443. https://doi.org/10.1182/blood-2003-07-2621