Polymorphism in Human Cytomegalovirus UL40 Impacts on Recognition of Human Leukocyte Antigen-E (HLA-E) by Natural Killer Cells
Polymorphism in Human Cytomegalovirus UL40 Impacts on Recognition of Human Leukocyte Antigen-E (HLA-E) by Natural Killer Cells
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DOI：
10.1074/jbc.m112.409672
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发表时间：
2013-03-22
影响因子：
4.8
通讯作者：
Brooks, Andrew G.
中科院分区：
文献类型：
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作者：
Heatley, Susan L.;Pietra, Gabriella;Brooks, Andrew G.
自然杀伤 (NK) 细胞对非经典人类白细胞抗原 (HLA) 分子 HLA-E 的识别依赖于源自其他 HLA 分子前导序列的九聚肽向 CD94-NKG2 受体的呈递。然而，人巨细胞病毒可以通过提供源自免疫调节糖蛋白 UL40 的 HLA 编码肽的“模拟物”来操纵这种重要的先天相互作用。在这里，我们分析了从经历巨细胞病毒再激活的 32 名造血干细胞移植受者中分离出的 UL40 序列。 UL40 蛋白在编码 HLA 前导序列模拟的区域内显示出“多态性热点”。尽管与HLA-I基因内编码的序列相同的所有序列允许HLA-E和CD94-NKG2受体之间的相互作用，但其他UL40多态性降低了HLA-E和CD94-NKG2受体之间相互作用的亲和力。此外，使用表达抑制性受体 CD94-NKG2A 或激活性受体 CD94-NKG2C 的 NK 细胞克隆进行的功能研究发现，UL40 编码的肽能够通过与 CD94-NKG2A 相互作用抑制靶细胞裂解，但几乎没有能力通过 CD94-NKG2C 激活 NK 细胞。数据表明，UL40 多态性可能通过调节与 CD94-NKG2 受体相互作用的亲和力来帮助逃避 NK 细胞免疫监视。
Natural killer (NK) cell recognition of the nonclassical human leukocyte antigen (HLA) molecule HLA-E is dependent on the presentation of a nonamer peptide derived from the leader sequence of other HLA molecules to CD94-NKG2 receptors. However, human cytomegalovirus can manipulate this central innate interaction through the provision of a "mimic" of the HLA-encoded peptide derived from the immunomodulatory glycoprotein UL40. Here, we analyzed UL40 sequences isolated from 32 hematopoietic stem cell transplantation recipients experiencing cytomegalovirus reactivation. The UL40 protein showed a "polymorphic hot spot" within the region that encodes the HLA leader sequence mimic. Although all sequences that were identical to those encoded within HLA-I genes permitted the interaction between HLA-E and CD94-NKG2 receptors, other UL40 polymorphisms reduced the affinity of the interaction between HLA-E and CD94-NKG2 receptors. Furthermore, functional studies using NK cell clones expressing either the inhibitory receptor CD94-NKG2A or the activating receptor CD94-NKG2C identified UL40-encoded peptides that were capable of inhibiting target cell lysis via interaction with CD94-NKG2A, yet had little capacity to activate NK cells through CD94-NKG2C. The data suggest that UL40 polymorphisms may aid evasion of NK cell immunosurveillance by modulating the affinity of the interaction with CD94-NKG2 receptors.