Sharifi Reza, Sinclair Joanna C, Gilmour Kimberly C, Arkwright Peter D, Kinnon Christine, Thrasher Adrian J, Gaspar H Bobby
Molecular Immunology Unit, Institute of Child Health, University College London, London, United Kingdom.
Blood. 2004 May 15;103(10):3821-7. doi: 10.1182/blood-2003-09-3359. Epub 2004 Jan 15.
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 (signaling lymphocytic activation molecule [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-gamma) 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-gamma 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.
细胞毒性T细胞（CTLs）和自然杀伤细胞在对爱泼斯坦-巴尔病毒（EBV）感染的免疫反应中起主要作用。在X连锁淋巴增殖性（XLP）疾病（一种严重免疫缺陷病）中，EBV感染后会出现免疫失调现象，这表明这些效应细胞群体存在缺陷。XLP中缺陷的基因是SAP（信号淋巴细胞激活分子[SLAM]相关蛋白），它是一种衔接蛋白，通过SLAM和包括2B4在内的其他免疫球蛋白超家族受体介导信号。我们从对照者和XLP患者中生成了EBV特异性T细胞系，并检测了其对不同刺激的CTL功能。我们发现XLP患者能够产生与对照者表型相似的EBV-T细胞系。XLP患者的EBV-T细胞系在受到2B4和自体EBV转化的淋巴母细胞系（LCL）刺激时，干扰素-γ（IFN-γ）产生显著减少，但对SLAM刺激无反应。此外，XLP EBV-T细胞系对自体LCL的细胞毒性活性明显降低。通过将SAP基因逆转录病毒基因转移到XLP EBV-T细胞系中，我们发现IFN-γ产生和细胞毒性活性得以恢复，证实了SAP依赖性缺陷。这些研究表明，在XLP中，SAP的缺乏影响特定信号通路，导致CTL功能严重受损。
