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Blood, 15 May 2004, Vol. 103, No. 10, pp. 3821-3827. Prepublished online as a Blood First Edition Paper on January 15, 2004; DOI 10.1182/blood-2003-09-3359. This Article Full Text (PDF) All Versions of this Article: 2003-09-3359v1 103/10/3821    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Sharifi, R. Articles by Gaspar, H. B Search for Related Content PubMed PubMed Citation Articles by Sharifi, R. Articles by Gaspar, H. B Related Collections Related Article in Blood Online Social Bookmarking                   What's this? Submitted September 30, 2003 Accepted December 26, 2003 SAP mediates specific cytotoxic T cell functions in X-linked lymphoproliferative disease Reza Sharifi, Joanna C Sinclair, Kimberly C Gilmour, Peter D Arkwright, Christine Kinnon, Adrian J Thrasher, and Hubert B Gaspar* Molecular Immunology Unit, Institute of Child Health, London, United Kingdom Clinical Immunology, Great Ormond Street Hospital NHS Trust, London, United Kingdom; Molecular Immunology Unit, Institute of Child Health, London, United Kingdom Child Health Unit, University of Manchester, Manchester, United Kingdom Molecular Immunology Unit, Institute of Child Health, London, United Kingdom; Clinical Immunology, Great Ormond Street Hospital NHS Trust, London, United Kingdom * Corresponding author; email: h.gaspar{at}ich.ucl.ac.uk. Cytotoxic T cells (CTLs) and natural killer cells play a major role in the immune response to Epstein-Barr virus (EBV) infection. In X-linked lymphoproliferative (XLP) disease, a severe immunodeficiency, immunodysregulatory phenomena are observed following EBV infection suggesting that defects exist in these effector populations. The gene defective in XLP is SAP (SLAM-associated protein), an adaptor protein that mediates signals through SLAM and other immunoglobulin superfamily receptors including 2B4. We generated EBV specific T cell lines from controls and XLP patients and examined CTL function in response to different stimuli. We show that XLP patients can generate EBV-T cell lines that are phenotypically similar to those from controls. XLP patient EBV-T cell lines showed a significant decrease in interferon-gamma (IFN-) production in response to 2B4 and autologous EBV transformed lymphoblastoid cell line (LCL) stimulation but not in response to SLAM. Furthermore, XLP EBV-T cell lines demonstrated markedly decreased cytotoxic activity against autologous LCLs. By retroviral gene transfer of the SAP gene into XLP EBV-T cell lines, we show reconstitution of IFN- production and of cytotoxic activity confirming SAP dependent defects. These studies demonstrate that in XLP the lack of SAP affects specific signaling pathways resulting in severe disruption of CTL function. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: SLAM "dunked"? Thomas Gross Blood 2004 103: 3613-3614. [Full Text] [PDF] This article has been cited by other articles: N. Nagy, L. Matskova, L. L. Kis, U. Hellman, G. Klein, and E. Klein The proapoptotic function of SAP provides a clue to the clinical picture of X-linked lymphoproliferative disease PNAS, July 21, 2009; 106(29): 11966 - 11971. [Abstract] [Full Text] [PDF] S. Nunez-Cruz, W. C. J. Yeo, J. Rothman, P. Ojha, H. Bassiri, M. Juntilla, D. Davidson, A. Veillette, G. A. Koretzky, and K. E. Nichols Differential Requirement for the SAP-Fyn Interaction during NK T Cell Development and Function J. Immunol., August 15, 2008; 181(4): 2311 - 2320. [Abstract] [Full Text] [PDF] S. Crotty, M. M. McCausland, R. D. Aubert, E. J. Wherry, and R. Ahmed Hypogammaglobulinemia and exacerbated CD8 T-cell-mediated immunopathology in SAP-deficient mice with chronic LCMV infection mimics human XLP disease Blood, November 1, 2006; 108(9): 3085 - 3093. [Abstract] [Full Text] [PDF] R. Bhat, P. Eissmann, J. Endt, S. Hoffmann, and C. Watzl Fine-tuning of immune responses by SLAM-related receptors J. Leukoc. Biol., March 1, 2006; 79(3): 417 - 424. [Abstract] [Full Text] [PDF] H. Komori, H. Furukawa, S. Mori, M. R. Ito, M. Terada, M.-C. Zhang, N. Ishii, N. Sakuma, M. Nose, and M. Ono A Signal Adaptor SLAM-Associated Protein Regulates Spontaneous Autoimmunity and Fas-Dependent Lymphoproliferation in MRL-Faslpr Lupus Mice J. Immunol., January 1, 2006; 176(1): 395 - 400. [Abstract] [Full Text] [PDF] G. Chen, A. K. Tai, M. Lin, F. Chang, C. Terhorst, and B. T. Huber Signaling Lymphocyte Activation Molecule-Associated Protein Is a Negative Regulator of the CD8 T Cell Response in Mice J. Immunol., August 15, 2005; 175(4): 2212 - 2218. [Abstract] [Full Text] [PDF] C. Bloch-Queyrat, M.-C. Fondaneche, R. Chen, L. Yin, F. Relouzat, A. Veillette, A. Fischer, and S. Latour Regulation of natural cytotoxicity by the adaptor SAP and the Src-related kinase Fyn J. Exp. Med., July 5, 2005; 202(1): 181 - 192. [Abstract] [Full Text] [PDF] L. Dupre, G. Andolfi, S. G. Tangye, R. Clementi, F. Locatelli, M. Arico, A. Aiuti, and M.-G. Roncarolo SAP controls the cytolytic activity of CD8+ T cells against EBV-infected cells Blood, June 1, 2005; 105(11): 4383 - 4389. [Abstract] [Full Text] [PDF]

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