Amsterdam Rheumatology and Immunology Center, location Academic Medical Center (AMC), Amsterdam, The Netherlands.
Amsterdam UMC, University of Amsterdam, Department of Experimental Immunology, Amsterdam, The Netherlands.
Eur J Immunol. 2018 Nov;48(11):1796-1809. doi: 10.1002/eji.201847615. Epub 2018 Sep 14.
Type I and type III interferons (IFNs) are fundamental for antiviral immunity, but prolonged expression is also detrimental to the host. Therefore, upon viral infection high levels of type I and III IFNs are followed by a strong and rapid decline. However, the mechanisms responsible for this suppression are still largely unknown. Here, we show that IgG opsonization of model viruses influenza and respiratory syncytial virus (RSV) strongly and selectively suppressed type I and III IFN production by various human antigen-presenting cells. This suppression was induced by selective inhibition of TLR, RIG-I-like receptor, and STING-dependent type I and III IFN gene transcription. Surprisingly, type I and III IFN suppression was mediated by Syk and PI3K independent inhibitory signaling via FcγRIIa, thereby identifying a novel non-canonical FcγRIIa pathway in myeloid cells. Together, these results indicate that IgG opsonization of viruses functions as a novel negative feedback mechanism in humans, which may play a role in the selective suppression of type I and III IFN responses during the late-phase of viral infections. In addition, activation of this pathway may be used as a tool to limit type I IFN-associated pathology.
I 型和 III 型干扰素 (IFN) 是抗病毒免疫的基础，但长期表达也对宿主有害。因此，在病毒感染后，I 型和 III 型 IFN 的水平会先升高，然后迅速下降。然而，负责这种抑制的机制在很大程度上仍不清楚。在这里，我们表明，模型病毒流感和呼吸道合胞病毒 (RSV) 的 IgG 调理作用强烈而选择性地抑制了各种人类抗原呈递细胞的 I 型和 III 型 IFN 的产生。这种抑制是通过 TLR、RIG-I 样受体和 STING 依赖性 I 型和 III 型 IFN 基因转录的选择性抑制诱导的。令人惊讶的是，I 型和 III 型 IFN 的抑制是通过 Syk 和 PI3K 非依赖性抑制信号通路通过 FcγRIIa 介导的，从而在髓样细胞中鉴定出一种新型非经典 FcγRIIa 通路。总之，这些结果表明，病毒的 IgG 调理作用在人类中是一种新的负反馈机制，它可能在病毒感染后期选择性抑制 I 型和 III 型 IFN 反应中发挥作用。此外，激活该途径可作为限制 I 型 IFN 相关病理的一种工具。
