A Viral Immunoevasin Controls Innate Immunity by Targeting the Prototypical Natural Killer Cell Receptor Family
A Viral Immunoevasin Controls Innate Immunity by Targeting the Prototypical Natural Killer Cell Receptor Family
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DOI：
10.1016/j.cell.2017.03.002
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发表时间：
2017-03-23
期刊：
影响因子：
64.5
通讯作者：
Carlyle, James R.
中科院分区：
文献类型：
--
作者：
Aguilar, Oscar A.;Berry, Richard;Carlyle, James R.
自然杀伤(NK)细胞通过成对的NK细胞受体(NKRs)检测自身和非自身配体的变化，在先天免疫中发挥关键作用。尽管鉴定了许多NKR与配体的相互作用，但典型的NK1.1孤儿受体的生理配体仍然难以捉摸。在这里，我们确定了一种抑制和激活NKRP1(NK1.1)受体的病毒配体。这种小鼠巨细胞病毒(MCMV)编码的蛋白M12通过直接与抑制的NKR-P1B受体结合来抑制NK细胞效应器的功能。然而，M12也与激活的NKR-P1a/C受体相互作用，以抵消M12的诱骗功能。结构分析表明，M12通过“极爪”机制隔离了大的NKR-P1表面积。病毒M12蛋白和宿主NKR-P1B/C等位基因的多态和消融会影响体内的NK细胞反应。因此，我们确定了这个关键的免疫调节NKR家族长期寻找的外来配体，并揭示了它如何在宿主-病原体相互作用过程中控制免疫识别的进化平衡。
Natural killer (NK) cells play a key role in innate immunity by detecting alterations in self and non-self ligands via paired NK cell receptors (NKRs). Despite identification of numerous NKR-ligand interactions, physiological ligands for the prototypical NK1.1 orphan receptor remain elusive. Here, we identify a viral ligand for the inhibitory and activating NKRP1 (NK1.1) receptors. This murine cytomegalovirus (MCMV)-encoded protein, m12, restrains NK cell effector function by directly engaging the inhibitory NKR-P1B receptor. However, m12 also interacts with the activating NKR-P1A/ C receptors to counterbalance m12 decoy function. Structural analyses reveal that m12 sequesters a large NKR-P1 surface area via a `` polar claw'' mechanism. Polymorphisms in, and ablation of, the viral m12 protein and host NKR-P1B/ C alleles impact NK cell responses in vivo. Thus, we identify the long-sought foreign ligand for this key immunoregulatory NKR family and reveal how it controls the evolutionary balance of immune recognition during host-pathogen interplay.