Littwitz-Salomon Elisabeth, Schimmer Simone, Dittmer Ulf
Institute for Virology of the University Hospital Essen, University of Duisburg-Essen, Essen, Germany
Institute for Virology of the University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
J Virol. 2017 Oct 27;91(22). doi: 10.1128/JVI.01122-17. Print 2017 Nov 15.
Natural killer (NK) cells are part of the innate immune system and recognize virus-infected cells as well as tumor cells. Conflicting data about the beneficial or even detrimental role of NK cells in different infectious diseases have been described previously. While the type of pathogen strongly influences NK cell functionality, less is known about how the infection dose influences the quality of a NK cell response against retroviruses. In this study, we used the well-established Friend retrovirus (FV) mouse model to investigate the impact of virus dose on the induction of antiviral NK cell functions. High-dose virus inoculation increased initial virus replication compared to that with medium- or low-dose viral challenge and significantly improved NK cell activation. Antiviral NK cell activity, including cytotoxicity toward infected target cells, was also enhanced by high-dose virus infection. NK cell activation following high-dose viral challenge was likely mediated by activated dendritic cells (DCs) and macrophages and the NK cell-stimulating cytokines interleukin 15 (IL-15) and IL-18. Neutralization of these cytokines decreased NK cell functions and increased viral loads, whereas IL-15 and IL-18 therapy improved NK cell activity. Here we demonstrate that virus dose positively correlates with antiviral NK cell activity and function, which are at least partly driven by IL-15 and IL-18. Our results suggest that NK cell activity may be therapeutically enhanced by administering IL-15 and IL-18 in virus infections that inadequately activate NK cells. In infections with retroviruses, like HIV and FV infection of mice, NK cells clearly mediate antiviral activities, but they are usually not sufficient to prevent severe pathology. Here we show that the initial infection dose impacts the induction of an antiviral NK cell response during an acute retroviral infection, which had not investigated before. High-dose infection resulted in a strong NK cell functionality, whereas no antiviral activities were detected after low- or medium-dose infection. Interestingly, DCs and macrophages were highly activated after high-dose FV challenge, which corresponded with increased levels of NK cell-stimulating cytokines IL-15 and IL-18. IL-15 and IL-18 neutralization decreased NK cell functions, whereas IL-15 and IL-18 therapy improved NK cell activity. Here we show the importance of cytokines for NK cell activation in retroviral infections; our findings suggest that immunotherapy combining the well-tolerated cytokines IL-15 and IL-18 might be an interesting approach for antiretroviral treatment.
自然杀伤（NK）细胞是先天免疫系统的一部分，可识别病毒感染细胞和肿瘤细胞。此前已有关于NK细胞在不同传染病中有益甚至有害作用的相互矛盾的数据报道。虽然病原体类型强烈影响NK细胞功能，但关于感染剂量如何影响NK细胞对逆转录病毒反应的质量却知之甚少。在本研究中，我们使用成熟的Friend逆转录病毒（FV）小鼠模型来研究病毒剂量对抗病毒NK细胞功能诱导的影响。与中剂量或低剂量病毒攻击相比，高剂量病毒接种增加了初始病毒复制，并显著改善了NK细胞活化。高剂量病毒感染还增强了抗病毒NK细胞活性，包括对感染靶细胞的细胞毒性。高剂量病毒攻击后的NK细胞活化可能由活化的树突状细胞（DC）和巨噬细胞以及NK细胞刺激细胞因子白细胞介素15（IL-15）和IL-18介导。中和这些细胞因子会降低NK细胞功能并增加病毒载量，而IL-15和IL-18治疗则可改善NK细胞活性。在此我们证明病毒剂量与抗病毒NK细胞活性和功能呈正相关，这至少部分由IL-15和IL-18驱动。我们的结果表明，在不能充分激活NK细胞的病毒感染中，通过给予IL-15和IL-18可能在治疗上增强NK细胞活性。在逆转录病毒感染中，如小鼠的HIV和FV感染，NK细胞显然介导抗病毒活性，但它们通常不足以预防严重病变。在此我们表明，初始感染剂量会影响急性逆转录病毒感染期间抗病毒NK细胞反应的诱导，这在此前尚未得到研究。高剂量感染导致强烈的NK细胞功能，而低剂量或中剂量感染后未检测到抗病毒活性。有趣的是，高剂量FV攻击后DC和巨噬细胞被高度激活，这与NK细胞刺激细胞因子IL-15和IL-18水平升高相对应。IL-15和IL-18中和降低了NK细胞功能，而IL-15和IL-18治疗改善了NK细胞活性。在此我们展示了细胞因子在逆转录病毒感染中对NK细胞活化的重要性；我们的发现表明，将耐受性良好的细胞因子IL-15和IL-18联合进行免疫治疗可能是一种有趣的抗逆转录病毒治疗方法。
