SAP mediates specific cytotoxic T-cell functions in X-linked lymphoproliferative disease
SAP mediates specific cytotoxic T-cell functions in X-linked lymphoproliferative disease
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DOI：
10.1182/blood-2003-09-3359
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发表时间：
2004-05-15
期刊：
影响因子：
20.3
通讯作者：
Gaspar, HB
中科院分区：
文献类型：
--
作者：
Sharifi, R;Sinclair, JC;Gaspar, HB
细胞毒性T细胞（ctl）和自然杀伤细胞在eb病毒（EBV）感染的免疫反应中起主要作用。在x连锁淋巴细胞增生性疾病（XLP）中，EBV感染后观察到严重的免疫缺陷和免疫调节失调现象，表明这些效应人群中存在缺陷。XLP中有缺陷的基因是SAP（信号淋巴细胞激活分子[SLAM]相关蛋白），这是一种通过SLAM和其他免疫球蛋白超家族受体（包括2B4）介导信号的接头蛋白。我们从对照组和XLP患者中生成ebv特异性t细胞系，并检测CTL对不同刺激的反应。我们发现XLP患者可以产生与对照组表型相似的ebv - t细胞系。XLP患者ebv -t细胞系在2B4和自身ebv转化的淋巴母细胞样细胞系（LCL）刺激下显示干扰素γ (ifn - γ)产生显著减少，但对SLAM没有反应。此外，XLP ebv - t细胞株对自体lcl的细胞毒活性显著降低。通过将SAP基因的逆转录病毒基因转移到XLP ebv - t细胞系中，我们显示了ifn - γ产生的重建和细胞毒性活性，证实了SAP依赖性缺陷。这些研究表明，在XLP中，SAP的缺乏会影响特定的信号通路，导致CTL功能的严重破坏。(C) 2004年由美国血液病学会出版。
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. (C) 2004 by The American Society of Hematology.