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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.
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IMMUNOBIOLOGY
SAP controls the cytolytic activity of CD8+ T cells against EBV-infected cells
Loïc Dupré,
Grazia Andolfi,
Stuart G. Tangye,
Rita Clementi,
Franco Locatelli,
Maurizio Aricò,
Alessandro Aiuti, and
Maria-Grazia Roncarolo
From the San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milan, Italy; the Centenary Institute of Cancer Medicine and Cell Biology, Newtown, Australia; the Pediatric Hematology/Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy; the Children's Hospital G. Di Cristina, Palermo, Italy; and the Vita-Salute San Raffaele University, Milan, Italy.
The adaptor protein SAP regulates signaling through signaling lymphocytic activation molecule (SLAM)–family receptors expressed on T and natural killer (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. T-cell–receptor (TCR) activation of CD8+ cytotoxic T cells (CTLs) results in down-regulation of SAP, suggesting that this protein is involved in early activation events. Here, we show that SAP-deficient CTLs from patients with XLP and hemophagocytic lymphohistiocytosis (HLH) display a specific lytic defect against autologous and allogeneic Epstein-Barr virus (EBV)–positive B cells. This defect is associated with the defective polarization of 2B4, perforin, and lipid rafts at the contact area of CTLs with EBV-positive targets. Blockade of 2B4 in normal CTLs reproduces the defects in lysis and polarization observed in SAP-deficient CTLs. 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 CTLs. In addition, TCR stimulation leads to normal proliferation and production of interleukin 2 (IL-2), IL-4, and interferon- (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.
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