Barr Daniel P, Belz Gabrielle T, Reading Patrick C, Wojtasiak Magdalena, Whitney Paul G, Heath William R, Carbone Francis R, Brooks Andrew G
Department of Microbiology and Immunology, The University of Melbourne, Melbourne, Australia.
Eur J Immunol. 2007 May;37(5):1334-42. doi: 10.1002/eji.200636362.
Natural killer (NK) cells play a crucial role in the initial response to viral infections but the mechanisms controlling their activation are unclear. We show a rapid and transient activation of NK cells that results in the production of IFN-gamma immediately following infection with herpes simplex virus type 1 (HSV-1). Activation of NK cells leading to synthesis of IFN-gamma was not mediated by a direct interaction with virus but required the presence of additional cell types and was largely dependent on the cytokine IL-18, but not IL-12. HSV-1-induced IFN-gamma expression by NK cells in vitro was impaired in spleen cultures depleted of CD11c(+) cells. Conversely, coculture of NK cells with virus-exposed conventional DC or plasmacytoid (p)DC restored the production of IFN-gamma, indicating that multiple DC subsets could mediate NK cell activation. While conventional DC populations stimulated NK cells independently of IL-18, they were less effective than pDC in promoting NK cell IFN-gamma expression. In contrast, the potent stimulation of NK cells by pDC was dependent on IL-18 as pDC from IL-18-deficient mice only activated a similar proportion of NK cells as conventional DC. These data identify IL-18 as a crucial factor for pDC-mediated NK cell regulation.
自然杀伤（NK）细胞在对病毒感染的初始反应中起关键作用，但控制其激活的机制尚不清楚。我们发现，感染单纯疱疹病毒1型（HSV-1）后，NK细胞会迅速且短暂地激活，随即产生γ干扰素。NK细胞激活并导致γ干扰素合成并非通过与病毒直接相互作用介导，而是需要其他细胞类型的存在，且很大程度上依赖于细胞因子白细胞介素-18（IL-18），而非白细胞介素-12（IL-12）。在缺乏CD11c(+)细胞的脾细胞培养物中，HSV-1体外诱导NK细胞产生γ干扰素的能力受损。相反，将NK细胞与接触过病毒的传统树突状细胞（DC）或浆细胞样树突状细胞（pDC）共培养可恢复γ干扰素的产生，这表明多个DC亚群可介导NK细胞激活。虽然传统DC群体可独立于IL-18刺激NK细胞，但在促进NK细胞γ干扰素表达方面，它们不如pDC有效。相比之下，pDC对NK细胞的强烈刺激依赖于IL-18，因为来自IL-18缺陷小鼠的pDC激活的NK细胞比例与传统DC相似。这些数据表明IL-18是pDC介导的NK细胞调节的关键因子。
