Myeloid-Derived Suppressor Cells Regulate Natural Killer Cell Response to Adenovirus-Mediated Gene Transfer

被引:46
作者
Zhu, Jiangao [1 ,2 ]
Huang, Xiaopei [1 ]
Yang, Yiping [1 ,3 ]
机构
[1] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA
[2] Cent S Univ, Canc Res Inst, Changsha, Hunan, Peoples R China
[3] Duke Univ, Med Ctr, Div Immunol, Durham, NC 27710 USA
基金
美国国家卫生研究院;
关键词
IMMUNE-RESPONSES; IN-VIVO; VIRAL-ANTIGENS; T-LYMPHOCYTES; NK CELLS; VECTORS; INFECTION; EXPANSION; CANCER; MICE;
D O I
10.1128/JVI.01595-12
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
The attendant innate and adaptive immune responses to viral vectors have posed a significant hurdle for clinical application of viral vector-mediated gene therapy. Previous studies have shown that natural killer (NK) cells play a critical role in innate immune elimination of adenoviral vectors in the liver. However, it is not clear how the NK cell response to adenoviral vectors is regulated. In this study, we identified a role for granulocytic myeloid-derived suppressor cells (G-MDSCs) in this process. We show that in vivo administration of adenoviral vectors results in rapid accumulation of G-MDSCs early during adenoviral infection. In vivo depletion of both MDSC populations, but not monocytic MDSCs (M-MDSCs) alone, resulted in accelerated clearance of adenoviral vectors in the liver. This was accompanied by enhanced NK cell proliferation and activation, suggesting a role for MDSCs, probably G-MDSCs, in suppressing NK cell activation and function in vivo. We further demonstrate in vitro that G-MDSCs, but not M-MDSCs, are responsible for the suppression of NK cell activation. In addition, we show that adenoviral infection activated G-MDSCs to produce higher levels of reactive oxygen species (ROS) and that G-MDSC-mediated suppression of NK cells is mediated by ROS, specifically, H2O2. This study demonstrates for the first time that the NK cell response to adenoviral vectors is negatively regulated by G-MDSCs and suggests that G-MDSC-based strategies could potentially improve the outcome of viral vector-mediated gene therapy.
引用
收藏
页码:13689 / 13696
页数:8
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