Hastings Andrew K, Erickson John J, Schuster Jennifer E, Boyd Kelli L, Tollefson Sharon J, Johnson Monika, Gilchuk Pavlo, Joyce Sebastian, Williams John V
Departments of Pathology, Microbiology & Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Department of Pediatrics, Children's Mercy Hospital, Kansas City, Missouri, USA.
J Virol. 2015 Apr;89(8):4405-20. doi: 10.1128/JVI.03275-14. Epub 2015 Feb 4.
Type I IFN signaling, which is initiated through activation of the alpha interferon receptor (IFNAR), regulates the expression of proteins that are crucial contributors to immune responses. Paramyxoviruses, including human metapneumovirus (HMPV), have evolved mechanisms to inhibit IFNAR signaling, but the specific contribution of IFNAR signaling to the control of HMPV replication, pathogenesis, and adaptive immunity is unknown. We used IFNAR-deficient (IFNAR(-/-)) mice to assess the effect of IFNAR signaling on HMPV replication and the CD8(+) T cell response. HMPV-infected IFNAR(-/-) mice had a higher peak of early viral replication but cleared the virus with kinetics similar to those of wild-type (WT) mice. However, IFNAR(-/-) mice infected with HMPV displayed less airway dysfunction and lung inflammation. CD8(+) T cells of IFNAR(-/-) mice after HMPV infection expressed levels of the inhibitory receptor programmed death 1 (PD-1) similar to those of WT mice. However, despite lower expression of inhibitory programmed death ligand 1 (PD-L1), HMPV-specific CD8(+) T cells of IFNAR(-/-) mice were more functionally impaired than those of WT mice and upregulated the inhibitory receptor Tim-3. Analysis of the antigen-presenting cell subsets in the lungs revealed that the expansion of PD-L1(low) dendritic cells (DCs), but not PD-L1(high) alveolar macrophages, was dependent on IFNAR signaling. Collectively, our results indicate a role for IFNAR signaling in the early control of HMPV replication, disease progression, and the development of an optimal adaptive immune response. Moreover, our findings suggest an IFNAR-independent mechanism of lung CD8(+) T cell impairment.
Human metapneumovirus (HMPV) is a leading cause of acute respiratory illness. CD8(+) T cells are critical for clearing viral infection, yet recent evidence shows that HMPV and other respiratory viruses induce CD8(+) T cell impairment via PD-1-PD-L1 signaling. We sought to understand the role of type I interferon (IFN) in the innate and adaptive immune responses to HMPV by using a mouse model lacking IFN signaling. Although HMPV titers were higher in the absence of type I IFN, virus was nonetheless cleared and mice were less ill, indicating that type I IFN is not required to resolve HMPV infection but contributes to pathogenesis. Further, despite lower levels of the inhibitory ligand PD-L1 in mice lacking type I IFN, CD8(+) T cells were more impaired in these mice than in WT mice. Our data suggest that specific antigen-presenting cell subsets and the inhibitory receptor Tim-3 may contribute to CD8(+) T cell impairment.
I型干扰素信号通过α干扰素受体（IFNAR）的激活而启动，可调节对免疫反应起关键作用的蛋白质的表达。包括人偏肺病毒（HMPV）在内的副粘病毒已进化出抑制IFNAR信号的机制，但IFNAR信号对控制HMPV复制、发病机制和适应性免疫的具体作用尚不清楚。我们使用IFNAR缺陷（IFNAR(-/-)）小鼠来评估IFNAR信号对HMPV复制和CD8(+) T细胞反应的影响。感染HMPV的IFNAR(-/-)小鼠早期病毒复制峰值较高，但清除病毒的动力学与野生型（WT）小鼠相似。然而，感染HMPV的IFNAR(-/-)小鼠气道功能障碍和肺部炎症较轻。HMPV感染后，IFNAR(-/-)小鼠的CD8(+) T细胞表达的抑制性受体程序性死亡1（PD-1）水平与WT小鼠相似。然而，尽管抑制性程序性死亡配体1（PD-L1）表达较低，但IFNAR(-/-)小鼠的HMPV特异性CD8(+) T细胞功能比WT小鼠更受损，并上调了抑制性受体Tim-3。对肺中抗原呈递细胞亚群的分析表明，PD-L1(低)树突状细胞（DCs）的扩增依赖于IFNAR信号，而PD-L1(高)肺泡巨噬细胞则不然。总体而言，我们的结果表明IFNAR信号在早期控制HMPV复制、疾病进展和最佳适应性免疫反应的发展中发挥作用。此外，我们的发现提示了一种不依赖IFNAR的肺CD8(+) T细胞损伤机制。
人偏肺病毒（HMPV）是急性呼吸道疾病的主要病因。CD8(+) T细胞对清除病毒感染至关重要，但最近的证据表明，HMPV和其他呼吸道病毒通过PD-1-PD-L1信号诱导CD8(+) T细胞损伤。我们试图通过使用缺乏IFN信号的小鼠模型来了解I型干扰素（IFN）在对HMPV的先天性和适应性免疫反应中的作用。尽管在缺乏I型IFN的情况下HMPV滴度较高，但病毒仍被清除，小鼠病情较轻，这表明解决HMPV感染不需要I型IFN，但它会促进发病机制。此外，尽管缺乏I型IFN的小鼠中抑制性配体PD-L1水平较低，但这些小鼠中的CD8(+) T细胞比WT小鼠中的更受损。我们的数据表明，特定的抗原呈递细胞亚群和抑制性受体Tim-3可能导致CD8(+) T细胞损伤。
