期刊
BLOOD
卷 105, 期 11, 页码 4383-4389出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2004-08-3269
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资金
- Telethon [TGT03A03, TGT06S01] Funding Source: Medline
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 2134, perforin, and lipid rafts at the contact area of CTLs with EBV-positive targets. Blockade of 2134 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-gamma (IFN-gamma). These results demonstrate that the SAP/2 beta 4 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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