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¹ Vita-Salute San Raffaele University, 20132 Milan, Italy
² Tor Vergata University, 00133 Rome, Italy
³ San Raffaele Telethon Institute for Gene Therapy, 20132 Milan, Italy
⁴ Department of Infectious and Pediatric Immunology, University of Debrecen Medical and Health Science Center, H4012 Debrecen, Hungary
⁵ Paediatric Immunology and Infectious Disease Unit, Vall d'Hebron Hospital, 08035 Barcelona, Spain
⁶ Department of Pediatrics, Leiden University Medical Center, 2300 RC Leiden, Netherlands
⁷ Institute of Child Health, University College London and Great Ormond Street Hospital for Children, WCIN 1EH London, England, UK
⁸ Department of Pediatrics and Adolescent Medicine, University Hospital Ulm, 89075 Ulm, Germany
⁹ Department of Clinical Immunology and Allergology, Faculty of Medicine, Masaryk University, St. Anne's University Hospital, 656 91 Brno, Czech Republic
¹⁰ Experimental Immunology Unit, Cancer Immunotherapy and Gene Therapy Program, Dipartimento di Biotecnologie, San Raffaele Scientific Institute, 20132 Milan, Italy
¹¹ Istituto Tecnologie Biomediche, Consiglio Nazionale delle Ricerche, 20090 Segrate-Milan, Italy

CORRESPONDENCE A.Villa: villa.anna{at}hsr.it

The Wiskott-Aldrich syndrome (WAS) protein (WASp) is a regulator of actin cytoskeleton in hematopoietic cells. Mutations of the WASp gene cause WAS. Although WASp is involved in various immune cell functions, its role in invariant natural killer T (iNKT) cells has never been investigated. Defects of iNKT cells could indeed contribute to several WAS features, such as recurrent infections and high tumor incidence. We found a profound reduction of circulating iNKT cells in WAS patients, directly correlating with the severity of clinical phenotype. To better characterize iNKT cell defect in the absence of WASp, we analyzed was^–/– mice. iNKT cell numbers were significantly reduced in the thymus and periphery of was^–/– mice as compared with wild-type controls. Moreover analysis of was^–/– iNKT cell maturation revealed a complete arrest at the CD44⁺ NK1.1^– intermediate stage. Notably, generation of BM chimeras demonstrated a was^–/– iNKT cell-autonomous developmental defect. was^–/– iNKT cells were also functionally impaired, as suggested by the reduced secretion of interleukin 4 and interferon upon in vivo activation. Altogether, these results demonstrate the relevance of WASp in integrating signals critical for development and functional differentiation of iNKT cells and suggest that defects in these cells may play a role in WAS pathology.

© 2009 Locci et al.
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This article has been cited by other articles:

• Locci, M., Draghici, E., Marangoni, F., Bosticardo, M., Catucci, M., Aiuti, A., Cancrini, C., Marodi, L., Espanol, T., Bredius, R. G.M., Thrasher, A. J., Schulz, A., Litzman, J., Roncarolo, M. G., Casorati, G., Dellabona, P., Villa, A. (2009). The Wiskott-Aldrich syndrome protein is required for iNKT cell maturation and function. JCB 185: i1-i1 [Full Text]  

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