The mechanisms controlling the recognition of tumor- and virus-infected cells by NKp46
The mechanisms controlling the recognition of tumor- and virus-infected cells by NKp46
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DOI：
10.1182/blood-2003-05-1716
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发表时间：
2004-01-15
期刊：
影响因子：
20.3
通讯作者：
Mandelboim, O
中科院分区：
文献类型：
--
作者：
Arnon, TI;Achdout, H;Mandelboim, O
病毒感染细胞和肿瘤细胞的破坏部分通过自然杀伤（NK）细胞的裂解受体NKp46介导。然而，其裂解配体在靶细胞上表达的性质尚不明确。最近，我们发现裂解受体NKp46和NKp44与流感的血凝素和仙台病毒的血凝素-神经氨酸酶之间存在一种新的功能相互作用。这种识别依赖于NKp46和NKp44受体的唾液化。在这项研究中，我们通过展示来自不同病毒株的各种血凝素识别NKp46和NKp44的保守模式，扩大了这些观察结果的意义。我们进一步确定这种识别是直接的，主要通过NKp46携带的α 2,6-链唾液酸介导。此外，我们证明NKp46识别靶细胞的能力仅限于膜近端结构域，并且在很大程度上依赖于高度保守的携带糖残基Thr 225。这个残基在NKp46与病毒血凝素和未知肿瘤配体通过不同机制的相互作用中起着关键的双重作用。这些结果可以解释NK细胞杀死如此广泛的病毒感染细胞和肿瘤细胞的能力。
The destruction of viral-infected and tumor cells is mediated in part via the lysis receptor of natural killer (NK) cells, NKp46. The nature, however, of its lysis ligands expressed on target cells is poorly defined. Recently, we have identified a novel functional interaction between the lysis receptors NKp46 and NKp44 and the hemagglutinin of influenza and hemgglutinin-neuroaminidase of Sendai viruses. This recognition depends on the sialylation of NKp46 and NKp44 receptors. In this study, we expand the significance of these observations by demonstrating a conserved pattern of NKp46 and NKp44 recognition by various hemagglutinins derived from different viral strains. We further establish that this recognition is direct and mainly mediated via alpha2,6-linked sialic acid carried by NKp46. In addition, we demonstrate that the ability of NKp46 to recognize target cells is confined to the membrane proximal domain, and largely relies on the highly conserved sugar-carrying residue, Thr 225. This residue plays a critical dual role in NKp46 interactions with both viral hemagglutinins and the unknown tumor ligands via different mechanisms. These results may explain the ability of NK cells to kill such a broad spectrum of viral-infected and tumor cells.