Robbins Scott H, Bessou Gilles, Cornillon Amélie, Zucchini Nicolas, Rupp Brigitte, Ruzsics Zsolt, Sacher Torsten, Tomasello Elena, Vivier Eric, Koszinowski Ulrich H, Dalod Marc
Centre d'Immunologie de Marseille-Luminy, Université de la Méditerranée, Marseille, France.
PLoS Pathog. 2007 Aug 24;3(8):e123. doi: 10.1371/journal.ppat.0030123.
Understanding the mechanisms that help promote protective immune responses to pathogens is a major challenge in biomedical research and an important goal for the design of innovative therapeutic or vaccination strategies. While natural killer (NK) cells can directly contribute to the control of viral replication, whether, and how, they may help orchestrate global antiviral defense is largely unknown. To address this question, we took advantage of the well-defined molecular interactions involved in the recognition of mouse cytomegalovirus (MCMV) by NK cells. By using congenic or mutant mice and wild-type versus genetically engineered viruses, we examined the consequences on antiviral CD8 T cell responses of specific defects in the ability of the NK cells to control MCMV. This system allowed us to demonstrate, to our knowledge for the first time, that NK cells accelerate CD8 T cell responses against a viral infection in vivo. Moreover, we identify the underlying mechanism as the ability of NK cells to limit IFN-alpha/beta production to levels not immunosuppressive to the host. This is achieved through the early control of cytomegalovirus, which dramatically reduces the activation of plasmacytoid dendritic cells (pDCs) for cytokine production, preserves the conventional dendritic cell (cDC) compartment, and accelerates antiviral CD8 T cell responses. Conversely, exogenous IFN-alpha administration in resistant animals ablates cDCs and delays CD8 T cell activation in the face of NK cell control of viral replication. Collectively, our data demonstrate that the ability of NK cells to respond very early to cytomegalovirus infection critically contributes to balance the intensity of other innate immune responses, which dampens early immunopathology and promotes optimal initiation of antiviral CD8 T cell responses. Thus, the extent to which NK cell responses benefit the host goes beyond their direct antiviral effects and extends to the prevention of innate cytokine shock and to the promotion of adaptive immunity.
了解有助于促进针对病原体的保护性免疫反应的机制是生物医学研究中的一项重大挑战，也是设计创新治疗或疫苗接种策略的重要目标。虽然自然杀伤（NK）细胞可以直接有助于控制病毒复制，但它们是否以及如何有助于协调整体抗病毒防御在很大程度上尚不清楚。为了解决这个问题，我们利用了NK细胞识别小鼠巨细胞病毒（MCMV）所涉及的明确分子相互作用。通过使用同基因或突变小鼠以及野生型与基因工程病毒，我们研究了NK细胞控制MCMV能力的特定缺陷对抗病毒CD8 T细胞反应的影响。据我们所知，这个系统首次使我们能够证明NK细胞在体内加速针对病毒感染的CD8 T细胞反应。此外，我们确定潜在机制是NK细胞将IFN-α/β产生限制在对宿主无免疫抑制作用的水平的能力。这是通过对巨细胞病毒的早期控制实现的，这极大地减少了浆细胞样树突状细胞（pDC）产生细胞因子的激活，保留了传统树突状细胞（cDC）区室，并加速了抗病毒CD8 T细胞反应。相反，在抗性动物中给予外源性IFN-α会消除cDC，并在NK细胞控制病毒复制的情况下延迟CD8 T细胞激活。总体而言，我们的数据表明，NK细胞对巨细胞病毒感染的早期反应能力对于平衡其他先天免疫反应的强度至关重要，这减轻了早期免疫病理学并促进了抗病毒CD8 T细胞反应的最佳启动。因此，NK细胞反应使宿主受益的程度超出了它们直接的抗病毒作用，还延伸到预防先天细胞因子休克和促进适应性免疫。
