Freeman Bailey E, Raué Hans-Peter, Hill Ann B, Slifka Mark K
Division of Neuroscience, Oregon National Primate Research Center, Beaverton, Oregon, USA Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, Oregon, USA.
Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, Oregon, USA.
J Virol. 2015 Aug;89(15):7922-31. doi: 10.1128/JVI.00199-15. Epub 2015 May 20.
Natural killer (NK) cells provide a first line of defense against infection via the production of antiviral cytokines and direct lysis of target cells. Cytokines such as interleukin 12 (IL-12) and IL-18 are critical regulators of NK cell activation, but much remains to be learned about how cytokines interact to regulate NK cell function. Here, we have examined cytokine-mediated activation of NK cells during infection with two natural mouse pathogens, lymphocytic choriomeningitis virus (LCMV) and murine cytomegalovirus (MCMV). Using a systematic screen of 1,849 cytokine pairs, we identified the most potent combinations capable of eliciting gamma interferon (IFN-γ) production in NK cells. We observed that NK cell responses to cytokine stimulation were reduced 8 days after acute LCMV infection but recovered to preinfection levels by 60 days postinfection. In contrast, during MCMV infection, NK cell responses to cytokines remained robust at all time points examined. Ly49H-positive (Ly49H+) NK cells recognizing viral ligand m157 showed preferential proliferation during early MCMV infection. A population of these cells was still detected beyond 60 days postinfection, but these divided cells did not demonstrate enhanced IFN-γ production in response to innate cytokine stimulation. Instead, the maturation state of the NK cells (as determined by CD11b or CD27 surface phenotype) was predictive of responsiveness to cytokines, regardless of Ly49H expression. These results help define cytokine interactions that regulate NK cell activation and highlight variations in NK cell function during two unrelated viral infections.
Natural killer cells play an important role in immunity to many viral infections. From an initial screen of 1,849 cytokine pairs, we identified the most stimulatory cytokine combinations capable of inducing IFN-γ production by NK cells. Ly49H+ NK cells, which can be directly activated by MCMV protein m157, preferentially proliferated during MCMV infection but did not show enhanced IFN-γ production following direct ex vivo cytokine stimulation. Instead, mature CD11b+ and/or CD27+ NK cells responded similarly to innate cytokine stimulation regardless of Ly49H expression. Collectively, our data provide a better foundation for understanding cytokine-mediated NK cell activation during viral infection.
自然杀伤（NK）细胞通过产生抗病毒细胞因子和直接裂解靶细胞，为抵御感染提供第一道防线。白细胞介素12（IL-12）和IL-18等细胞因子是NK细胞活化的关键调节因子，但关于细胞因子如何相互作用以调节NK细胞功能，仍有许多有待了解之处。在此，我们研究了感染两种天然小鼠病原体——淋巴细胞脉络丛脑膜炎病毒（LCMV）和鼠巨细胞病毒（MCMV）期间细胞因子介导的NK细胞活化。通过对1849对细胞因子进行系统筛选，我们确定了能够在NK细胞中引发γ干扰素（IFN-γ）产生的最有效组合。我们观察到，急性LCMV感染8天后，NK细胞对细胞因子刺激的反应降低，但在感染后60天恢复到感染前水平。相比之下，在MCMV感染期间，NK细胞在所有检测时间点对细胞因子的反应都保持强劲。识别病毒配体m157的Ly49H阳性（Ly49H+）NK细胞在MCMV感染早期表现出优先增殖。在感染后60天以上仍可检测到这群细胞中的一部分，但这些分裂细胞在接受天然细胞因子刺激后并未表现出增强的IFN-γ产生。相反，NK细胞的成熟状态（由CD11b或CD27表面表型确定）可预测其对细胞因子的反应性，而与Ly49H表达无关。这些结果有助于确定调节NK细胞活化的细胞因子相互作用，并突出两种无关病毒感染期间NK细胞功能的差异。
自然杀伤细胞在对许多病毒感染的免疫中发挥重要作用。通过对1849对细胞因子的初步筛选，我们确定了能够诱导NK细胞产生IFN-γ的最具刺激性的细胞因子组合。可被MCMV蛋白m157直接激活的Ly49H+NK细胞在MCMV感染期间优先增殖，但在直接体外细胞因子刺激后未表现出增强的IFN-γ产生。相反，成熟的CD11b+和/或CD27+NK细胞对天然细胞因子刺激的反应相似，而与Ly49H表达无关。总体而言，我们的数据为理解病毒感染期间细胞因子介导的NK细胞活化提供了更好的基础。
