Key Points A rare subset of FcRγ– NK cells is highly expanded in chronic HIV-1 infection. IL-18Rα impairment renders FcRγ– NK cells deficient in helper cell differentiation. Deficits in IFN-γ due to FcRγ– NK cell expansions lead to inferior NK–DC cross-talk. Despite being prolific innate killers, NK cells are also key helper cells in antiviral defense, influencing adaptive immune responses via interactions with dendritic cells (DCs). In addition to causing NK cell dysfunction, HIV-1 infection contributes to the expansion of a rare population of NK cells deficient in FcRγ (FcRγ−), an intracellular adaptor protein that associates with CD16. The implications of this inflated NK cell subset in treated HIV-1 infection remain unclear. In this study, we explored the helper function of human NK cells in chronic HIV-1 infection, with a particular focus on characterizing FcRγ− NK cells. Exposure of NK cells to innate DC-derived costimulatory factors triggered their helper activity, defined by their ability to produce IFN-γ and to drive the maturation of high IL-12–producing DCs. In this setting, however, FcRγ− NK cells were defective at producing the dominant DC-polarizing agent IFN-γ. The reduced responsiveness of FcRγ− NK cells to IL-18 in particular, which was attributable to impaired inducible expression of IL-18Rα, extended beyond an inability to produce IFN-γ, as FcRγ− NK cells showed limited potential to differentiate into CD16−/CD25+/CD83+ helper cells. Notwithstanding their deficiencies in responsiveness to innate environmental cues, FcRγ− NK cells responded robustly to adaptive Ab-mediated signaling through CD16. The presence of an expanded population of FcRγ− NK cells with a diminished capacity to respond to IL-18 and to effectively modulate DC function may contribute to disturbances in proper immune homeostasis associated with HIV-1 infection and to defects in the initiation of optimal adaptive antiviral responses.

中文翻译：

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IL-18 反应性定义了特殊 FcRγ– NK 细胞免疫帮助的局限性

关键点 FcRγ– NK 细胞的一个罕见亚群在慢性 HIV-1 感染中高度扩增。IL-18Rα 损伤导致 FcRγ-NK 细胞在辅助细胞分化方面存在缺陷。由于 FcRγ-NK 细胞扩增导致的 IFN-γ 缺陷导致较差的 NK-DC 串扰。尽管是多产的先天杀手，但 NK 细胞还是抗病毒防御的关键辅助细胞，通过与树突状细胞 (DC) 的相互作用影响适应性免疫反应。除了导致 NK 细胞功能障碍之外，HIV-1 感染还会导致缺乏 FcRγ (FcRγ-) 的罕见 NK 细胞群的扩增，FcRγ- 是一种与 CD16 相关的细胞内衔接蛋白。这种膨胀的 NK 细胞亚群在治疗的 HIV-1 感染中的影响仍不清楚。在这项研究中，我们探索了人类 NK 细胞在慢性 HIV-1 感染中的辅助功能，特别关注表征 FcRγ- NK 细胞。NK 细胞暴露于先天 DC 衍生的共刺激因子会触发它们的辅助活性，定义为它们产生 IFN-γ 和驱动高产生 IL-12 的 DC 成熟的能力。然而，在这种情况下，FcRγ- NK 细胞在产生主要的 DC 极化剂 IFN-γ 方面存在缺陷。FcRγ- NK 细胞对 IL-18 的反应性降低，尤其是由于 IL-18Rα 的可诱导表达受损，超出了无法产生 IFN-γ 的范围，因为 FcRγ- NK 细胞显示出有限的分化成 CD16- 的潜力/CD25+/CD83+ 辅助细胞。尽管 FcRγ- NK 细胞在对先天环境线索的反应方面存在缺陷，但它们对通过 CD16 的适应性 Ab 介导的信号传导反应强烈。