Dengue virus replicon expressing the nonstructural proteins suffices to enhance membrane expression of HLA class I and inhibit lysis by human NK cells
Dengue virus replicon expressing the nonstructural proteins suffices to enhance membrane expression of HLA class I and inhibit lysis by human NK cells
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DOI：
10.1128/jvi.02274-07
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发表时间：
2008-08-01
影响因子：
5.4
通讯作者：
Porgador, Angel
中科院分区：
文献类型：
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作者：
Hershkovitz, Oren;Zilka, Alon;Porgador, Angel
许多病毒通过下调主要组织相容性复合体（MHC） I类分子的细胞表面表达来逃避细胞免疫应答。然而，黄病毒感染细胞可以上调这些分子的表达。在这项研究中，我们分析了MHC类I在K562和THP-1人细胞系中的表达，这些细胞系稳定地转染了自我复制的登革病毒亚基因组RNA（复制子），并一起表达所有登革病毒非结构蛋白。我们发现，在登革病毒复制子表达细胞中，MHC I类表达上调，并且自然杀伤（NK）抑制受体与这些细胞的结合增强。这种上调导致登革病毒复制子表达细胞对NK细胞裂解的易感性降低，表明登革病毒逃避NK细胞识别的可能机制。通过共聚焦显微镜观察含有复制子的K562和THP-1细胞中MHC I类分子的表达，发现MHC I类分子在细胞表面聚集。最后，表达复制子的K562细胞表现出TAP（与抗原加工相关的转运蛋白）和LMP（低分子质量蛋白）基因转录的增加，而表达复制子的THP-1细胞表现出NF-kappa B活性和MHC I类转录的增加。我们认为，登革热病毒非结构蛋白的表达足以通过tap依赖和tap独立的机制诱导MHC I类上调。此外，细胞膜上MHC I类分子的聚集也有助于低亲和力NK抑制受体的结合，导致对NK细胞裂解的敏感性降低。
Many viruses escape the cellular immune response by downregulating cell surface expression of major histocompatibility complex (MHC) class I molecules. However, infection of cells with flaviviruses can upregulate the expression of these molecules. In this study we analyzed the expression of MHC class I in K562 and THP-1 human cell lines that were stably transfected with self-replicating subgenomic dengue virus RNA (replicons) and express all the dengue virus nonstructural proteins together. We show that MHC class I expression is upregulated in the dengue virus replicon-expressing cells and that the binding of natural killer (NK) inhibitory receptors to these cells is augmented. This upregulation results in reduced susceptibility of the dengue virus replicon-expressing cells to NK lysis, indicating a possible mechanism for evasion of the dengue virus from NK cell recognition. Visualizing MHC class I expression in replicon-containing K562 and THP-1 cells by confocal microscopy demonstrated aggregation of MHC class I molecules on the cell surface. Finally, replicon-expressing K562 cells manifested increased TAP (transporter associated with antigen processing) and LMP (low-molecular-mass protein) gene transcription, while replicon-expressing THP-1 cells manifested increased NF-kappa B activity and MHC class I transcription. We suggest that expression of dengue virus nonstructural proteins is sufficient to induce MHC class I upregulation through both TAP-dependent and -independent mechanisms. Additionally, aggregation of MHC class I molecules on the cell membrane also contributes to significantly higher binding of low-affinity NK inhibitory receptors, resulting in lower sensitivity to lysis by NK cells.