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,
* San Raffaele Telethon Institute for Gene Therapy, Milan, Italy;
Immunopathogenesis of Liver Infections Unit, San Raffaele Scientific Institute, Milan, Italy;
Vita-Salute San Raffaele University, Milan, Italy;
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037;
¶ Department of Pediatrics, University of Turin, Turin, Italy; and
|| Department of Pediatrics, University of Brescia, Spedali Civili, Brescia, Italy
Wiskott-Aldrich syndrome (WAS) protein (WASP) plays a key role in TCR-mediated activation and immunological synapse formation. However, the effects of WASP deficiency on effector functions of human CD4+ and CD8+ T cells remain to be determined. In this study, we report that TCR/CD28-driven proliferation and secretion of IL-2, IFN-
, and TNF-
are strongly reduced in CD8+ T cells from WAS patients, compared with healthy donor CD8+ T cells. Furthermore, WAS CD4+ T cells secrete low levels of IL-2 and fail to produce IFN- and TNF-, while the production of IL-4, IL-5, and IL-10 is only minimally affected. Defective IL-2 and IFN- production persists after culture of naive WAS CD4+ T cells in Th1-polarizing conditions. The defect in Th1 cytokine production by WAS CD4+ and CD8+ T cells is also present at the transcriptional level, as shown by reduced IL-2 and IFN- mRNA transcripts after TCR/CD28 triggering. The reduced transcription of Th1 cytokine genes in WAS CD4+ T cells is associated with a defective induction of T-bet mRNA and a reduction in the early nuclear recruitment of NFAT-1, while the defective activation of WAS CD8+ T cells correlates with reduced nuclear recruitment of both NFAT-1 and NFAT-2. Together, our data indicate that WASP regulates the transcriptional activation of T cells and is required specifically for Th1 cytokine production.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the Italian Telethon Foundation and the Italian Ministry of University and Research (MIUR/FIRB No. RBNE03FMCJ-008).
2 Address correspondence and reprint requests to Dr. Maria-Grazia Roncarolo, San Raffaele Telethon Institute for Gene Therapy, Via Olgettina 58, 20132, Milan, Italy. E-mail address: m.roncarolo{at}hsr.it
3 Abbreviations used in this paper: WAS, Wiskott-Aldrich syndrome; WASP, WAS protein; h, human; XLT, X-linked thrombocytopenia; TPA, 12-O-tetradecanoylphorbol-13-acetate; RPA, RNase protection assay; HD, healthy donor.
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