Myeloid-derived suppressor cells regulate natural killer cell response to adenovirus-mediated gene transfer

J Zhu, X Huang, Y Yang - Journal of virology, 2012 - Am Soc Microbiol
J Zhu, X Huang, Y Yang
Journal of virology, 2012Am Soc Microbiol
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 …
Abstract
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.
American Society for Microbiology