Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, PA 15261; and.
Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261.
J Immunol. 2020 Dec 15;205(12):3429-3442. doi: 10.4049/jimmunol.2000430. Epub 2020 Nov 13.
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.
尽管自然杀伤 (NK) 细胞是高效的先天杀伤细胞，但它们也是抗病毒防御中的关键辅助细胞，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 细胞功能障碍外，HIV-1 感染还导致 FcRγ（一种与 CD16 相关的细胞内衔接蛋白）缺陷的 NK 细胞稀有群体的扩增。在治疗性 HIV-1 感染中，这种膨胀的 NK 细胞亚群的影响仍不清楚。在这项研究中，我们探讨了人类 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其辅助活性，其特征是能够产生 IFN-γ并驱动高 IL-12 产生 DC 的成熟。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，特别是由于 IL-18Rα的诱导表达受损，不仅限于无法产生 IFN-γ，因为 FcRγ NK 细胞显示出有限的潜力分化为 CD16/CD25/CD83 辅助细胞。尽管它们对先天环境线索的反应性不足，但 FcRγ NK 细胞对适应性 Ab 介导的信号通过 CD16 表现出强烈的反应。具有降低的对 IL-18 反应能力和有效调节 DC 功能的能力的 FcRγ NK 细胞的扩增群体的存在可能导致与 HIV-1 感染相关的适当免疫稳态的紊乱，并导致适应性抗病毒反应的启动缺陷。
