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Blood, 1 June 2005, Vol. 105, No. 11, pp. 4383-4389. Prepublished online as a Blood First Edition Paper on January 27, 2005; DOI 10.1182/blood-2004-08-3269. This Article Full Text (PDF) All Versions of this Article: 2004-08-3269v1 105/11/4383    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 Dupre, L. Articles by Roncarolo, M.-G. Search for Related Content PubMed PubMed Citation Articles by Dupre, L. Articles by Roncarolo, M.-G. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted August 24, 2004 Accepted December 30, 2004 SAP controls the cytolytic activity of CD8+ T cells against EBV-infected cells Loic Dupre, Grazia Andolfi, Stuart G Tangye, Rita Clementi, Franco Locatelli, Maurizio Arico, Alessandro Aiuti, and Maria-Grazia Roncarolo* San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milan, Italy Centenary Institute of Cancer Medicine and Cell Biology, Newtown, Australia Pediatric Hematology/Oncology, IRCCS Policlinico San Matteo, Pavia, Italy Children's Hospital G. Di Cristina, Palermo, Italy San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy * Corresponding author; email: m.roncarolo{at}hsr.it. The adaptor protein SAP regulates signaling through SLAM-family receptors expressed on T and NK cells. In patients affected by X-linked lymphoproliferative (XLP) disease, mutations in the SH2D1A gene result in defective lytic activity. However, the mechanism by which SAP controls cytotoxic activity remains unclear. TCR activation of CD8+ cytotoxic T cells (CTL) results in down-regulation of SAP, suggesting that this protein is involved in early activation events. Here, we show that SAP-deficient CTL from patients with XLP and hemophagocytic lympho-histiocytosis (HLH) display a specific lytic defect against autologous and allogeneic EBV-positive B cells. This defect is associated with the defective polarization of 2B4, perforin and lipid rafts at the contact area of CTL with EBV-positive targets. Blockade of 2B4 in normal CTL reproduces the defects in lysis and polarization observed in SAP-deficient CTL. Expression and regulation of the SLAM-family receptors SLAM, CD84 and 2B4. as well as the lytic effectors perforin and granzyme-B are normal in SAP-deficient CTL. In addition, TCR stimulation leads to normal proliferation and production of IL-2, IL-4 and IFN-. These results demonstrate that the SAP/2B4 pathway plays a key role in CTL lytic activity against EBV-positive targets by promoting the polarization of the lytic machinery. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: N. G. Clarkson and M. H. Brown Inhibition and Activation by CD244 Depends on CD2 and Phospholipase C-{gamma}1 J. Biol. Chem., September 11, 2009; 284(37): 24725 - 24734. [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] N. G. Clarkson, S. J. Simmonds, M. J. Puklavec, and M. H. 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