NK cell cytotoxicity mediated by 2B4 and NTB-A is dependent on SAP acting downstream of receptor phosphorylation
NK cell cytotoxicity mediated by 2B4 and NTB-A is dependent on SAP acting downstream of receptor phosphorylation
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DOI：
10.3389/fimmu.2013.00003
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发表时间：
2013-01-01
影响因子：
7.3
通讯作者：
Watzl, Carsten
中科院分区：
文献类型：
--
作者：
Meinke, Stephan;Watzl, Carsten
2B 4（CD 244）和NK-T-B-抗原（NIBA，CD 352）是人自然杀伤（NK）细胞上的活化受体，并且属于信号传导淋巴细胞活化分子（SLAM）相关受体（SRR）家族。这些受体的参与导致其胞质尾的磷酸化和衔接蛋白SLAM相关蛋白（SAP）和尤文肉瘤激活转录本-2（EAT 2）的募集。X连锁淋巴组织增生综合征（XLP）是一种严重的免疫缺陷，导致SAP基因突变。2B 4和NIB-A介导的细胞毒性在XLP NK细胞中消除。为了阐明这种缺陷的分子基础，我们分析了SAP敲低细胞中的早期信号事件。与XLP NK细胞类似，原代人NK细胞中SAP的敲低导致2B 4和NTB-A介导的细胞毒性降低。我们发现，早期信号事件，如筏募集和受体磷酸化不受SAP的缺乏，表明在缺乏SAP的缺陷是这些事件的下游。此外，FAT-2的敲低不损害2B 4或NIB-A介导的细胞毒性。令人惊讶的是，EAT-2对两种受体的募集
2B4 (CD244) and NK-T-B-antigen (NIB A, CD352) are activating receptors on human natural killer (NK) cells and belong to the family of signaling lymphocyte activation molecule (SLAM)-related receptors (SRR). Engagement of these receptors leads to phosphorylation of their cytoplasmic tails and recruitment of the adapter proteins SLAM-associated protein (SAP) and Ewing's sarcoma activated transcript-2 (EAT 2). X-linked lymphoproliferative syndrome (XLP) is a severe immunodeficiency that results from mutations in the SAP gene. 2B4 and NIB-A-mediated cytotoxicity are abrogated in XLP NK cells. To elucidate the molecular basis for this defect we analyzed early signaling events in SAP knockdown cells. Similar to XLP NK cells, knockdown of SAP in primary human NK cells leads to a reduction of 2B4 and NTB-A-mediated cytotoxicity. We found that early signaling events such as raft recruitment and receptor phosphorylation are not affected by the absence of SAP indicating the defect in the absence of SAP is downstream of these events. In addition, knockdown of FAT-2 does not impair 2B4 or NIB-A-mediated cytotoxicity. Surprisingly, EAT-2 recruitment to both receptors