X-linked lymphoproliferative disease. 2B4 molecules displaying inhibitory rather than activating function are responsible for the inability of natural killer cells to kill Epstein-Barr virus-infected cells.
X-linked lymphoproliferative disease. 2B4 molecules displaying inhibitory rather than activating function are responsible for the inability of natural killer cells to kill Epstein-Barr virus-infected cells.
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DOI：
10.1084/jem.192.3.337
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发表时间：
2000-08-07
期刊：
影响因子：
--
通讯作者：
Moretta A
中科院分区：
文献类型：
--
作者：
Parolini S;Bottino C;Falco M;Augugliaro R;Giliani S;Franceschini R;Ochs HD;Wolf H;Bonnefoy JY;Biassoni R;Moretta L;Notarangelo LD;Moretta A
2B4是一种参与自然杀伤（NK）细胞介导的细胞毒性激活的表面分子。它结合一种被称为含Src同源2结构域蛋白（SH2D1A）或信号淋巴细胞激活分子（SLAM）相关蛋白（SAP）的蛋白质，而该蛋白质又被认为是2B4相关信号转导途径的调节因子。在这项研究中，我们分析了X连锁淋巴增殖性疾病（XLP）患者，这是一种严重的遗传性免疫缺陷疾病，其特征是SH2D1A基因发生关键突变以及无法控制爱泼斯坦 - 巴尔病毒（EBV）感染。我们表明，在这些患者中，2B4不仅无法转导触发信号，而且还对NK介导的细胞溶解产生强烈抑制作用。其他参与NK细胞触发的受体，包括CD16、NKp46、NKp44和NKp30，显示出正常的功能能力。然而，当2B4分子参与作用时，它们的激活功能受到抑制。2B4的天然配体CD48在EBV + B细胞系表面高度表达。值得注意的是，XLP患者的NK细胞无法杀死EBV + B细胞系。这种失败被发现是2B4和CD48之间相互作用产生抑制信号的结果，因为抗体介导的2B4 - CD48相互作用的阻断恢复了对缺乏人类组织相容性白细胞抗原（HLA）I类分子的EBV +靶细胞的溶解。对于自体或同种异体（HLA I类 +）EBV +淋巴母细胞样细胞系，只有同时阻断2B4 - CD48和NK受体 - HLA I类相互作用才能实现溶解的恢复。分子分析显示，从XLP或正常NK细胞中分离出的2B4分子是相同的。正如预期的那样，在XLP - NK细胞中，2B4不与SH2D1A结合，而与从正常NK细胞中分离出的2B4分子类似，它确实与含Src同源2结构域的磷酸酶1结合。
2B4 is a surface molecule involved in activation of the natural killer (NK) cell–mediated cytotoxicity. It binds a protein termed Src homology 2 domain–containing protein (SH2D1A) or signaling lymphocyte activation molecule (SLAM)-associated protein (SAP), which in turn has been proposed to function as a regulator of the 2B4-associated signal transduction pathway. In this study, we analyzed patients with X-linked lymphoproliferative disease (XLP), a severe inherited immunodeficiency characterized by critical mutations in the SH2D1A gene and by the inability to control Epstein-Barr virus (EBV) infections. We show that, in these patients, 2B4 not only fails to transduce triggering signals, but also mediates a sharp inhibition of the NK-mediated cytolysis. Other receptors involved in NK cell triggering, including CD16, NKp46, NKp44, and NKp30, displayed a normal functional capability. However, their activating function was inhibited upon engagement of 2B4 molecules. CD48, the natural ligand of 2B4, is highly expressed on the surface of EBV+ B cell lines. Remarkably, NK cells from XLP patients could not kill EBV+ B cell lines. This failure was found to be the consequence of inhibitory signals generated by the interaction between 2B4 and CD48, as the antibody-mediated disruption of the 2B4–CD48 interaction restored lysis of EBV+ target cells lacking human histocompatibility leukocyte antigen (HLA) class I molecules. In the case of autologous or allogeneic (HLA class I+) EBV+ lymphoblastoid cell lines, restoration of lysis was achieved only by the simultaneous disruption of 2B4–CD48 and NK receptor–HLA class I interactions. Molecular analysis revealed that 2B4 molecules isolated from either XLP or normal NK cells were identical. As expected, in XLP-NK cells, 2B4 did not associate with SH2D1A, whereas similar to 2B4 molecules isolated from normal NK cells, it did associate with Src homology 2 domain–containing phosphatase 1.
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DOI：
10.1084/jem.188.5.953
发表时间：
1998-09-07
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Pessino A;Sivori S;Bottino C;Malaspina A;Morelli L;Moretta L;Biassoni R;Moretta A
通讯作者：
Moretta A
DOI：
10.1016/s0167-5699(00)01596-6
发表时间：
2000-05-01
期刊：
IMMUNOLOGY TODAY
影响因子：
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作者：
Moretta, A;Biassoni, R;Moretta, L
通讯作者：
Moretta, L
影响因子：
30.8
作者：
Coffey, AJ;Brooksbank, RA;Bentley, DR
通讯作者：
Bentley, DR
DOI：
10.1016/0090-1229(90)90054-t
发表时间：
1990-03-01
期刊：
CLINICAL IMMUNOLOGY AND IMMUNOPATHOLOGY
影响因子：
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作者：
OKANO, M;PIRRUCCELLO, SJ;PURTILO, DT
通讯作者：
PURTILO, DT
DOI：
10.1084/jem.190.10.1505
发表时间：
1999-11-15
期刊：
The Journal of experimental medicine
影响因子：
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作者：
Pende D;Parolini S;Pessino A;Sivori S;Augugliaro R;Morelli L;Marcenaro E;Accame L;Malaspina A;Biassoni R;Bottino C;Moretta L;Moretta A
通讯作者：
Moretta A