Huber Magdalena, Suprunenko Tamara, Ashhurst Thomas, Marbach Felix, Raifer Hartmann, Wolff Svenja, Strecker Thomas, Viengkhou Barney, Jung So Ri, Obermann Hannah-Lena, Bauer Stefan, Xu Haifeng C, Lang Philipp A, Tom Adomati, Lang Karl S, King Nicholas J C, Campbell Iain L, Hofer Markus J
Institute of Medical Microbiology and Hygiene, University of Marburg, Marburg, Germany
School of Life and Environmental Sciences, the Marie Bashir Institute for Infectious Diseases and Biosecurity, the Charles Perkins Centre, and the Bosch Institute, The University of Sydney, Sydney, Australia.
J Virol. 2017 Oct 27;91(22). doi: 10.1128/JVI.01219-17. Print 2017 Nov 15.
Effective CD8 T cell responses play an important role in determining the course of a viral infection. Overwhelming antigen exposure can result in suboptimal CD8 T cell responses, leading to chronic infection. This altered CD8 T cell differentiation state, termed exhaustion, is characterized by reduced effector function, upregulation of inhibitory receptors, and altered expression of transcription factors. Prevention of overwhelming antigen exposure to limit CD8 T cell exhaustion is of significant interest for the control of chronic infection. The transcription factor interferon regulatory factor 9 (IRF9) is a component of type I interferon (IFN-I) signaling downstream of the IFN-I receptor (IFNAR). Using acute infection of mice with lymphocytic choriomeningitis virus (LCMV) strain Armstrong, we show here that IRF9 limited early LCMV replication by regulating expression of interferon-stimulated genes and IFN-I and by controlling levels of IRF7, a transcription factor essential for IFN-I production. Infection of IRF9- or IFNAR-deficient mice led to a loss of early restriction of viral replication and impaired antiviral responses in dendritic cells, resulting in CD8 T cell exhaustion and chronic infection. Differences in the antiviral activities of IRF9- and IFNAR-deficient mice and dendritic cells provided further evidence of IRF9-independent IFN-I signaling. Thus, our findings illustrate a CD8 T cell-extrinsic function for IRF9, as a signaling factor downstream of IFNAR, in preventing overwhelming antigen exposure resulting in CD8 T cell exhaustion and, ultimately, chronic infection. During early viral infection, overwhelming antigen exposure can cause functional exhaustion of CD8 T cells and lead to chronic infection. Here we show that the transcription factor interferon regulatory factor 9 (IRF9) plays a decisive role in preventing CD8 T cell exhaustion. Using acute infection of mice with LCMV strain Armstrong, we found that IRF9 limited early LCMV replication by regulating expression of interferon-stimulated genes and , encoding a transcription factor crucial for type I interferon (IFN-I) production, as well as by controlling the levels of IFN-I. Infection of IRF9-deficient mice led to a chronic infection that was accompanied by CD8 T cell exhaustion due to defects extrinsic to T cells. Our findings illustrate an essential role for IRF9, as a mediator downstream of IFNAR, in preventing overwhelming antigen exposure causing CD8 T cell exhaustion and leading to chronic viral infection.
有效的CD8 T细胞反应在决定病毒感染进程中起重要作用。过量的抗原暴露可导致CD8 T细胞反应欠佳，进而引发慢性感染。这种改变的CD8 T细胞分化状态，即耗竭，其特征为效应功能降低、抑制性受体上调以及转录因子表达改变。预防过量抗原暴露以限制CD8 T细胞耗竭对于控制慢性感染具有重要意义。转录因子干扰素调节因子9（IRF9）是I型干扰素（IFN-I）受体（IFNAR）下游I型干扰素信号通路的一个组成部分。利用淋巴细胞性脉络丛脑膜炎病毒（LCMV）阿姆斯特朗株对小鼠进行急性感染，我们在此表明，IRF9通过调节干扰素刺激基因和IFN-I的表达以及控制IRF7的水平来限制早期LCMV复制，IRF7是IFN-I产生所必需的转录因子。感染IRF9或IFNAR缺陷小鼠会导致病毒复制早期限制丧失以及树突状细胞抗病毒反应受损，从而导致CD8 T细胞耗竭和慢性感染。IRF9缺陷小鼠和树突状细胞抗病毒活性的差异进一步证明了不依赖IRF9的IFN-I信号通路。因此，我们的研究结果阐明了IRF9作为IFNAR下游的信号因子在预防导致CD8 T细胞耗竭并最终导致慢性感染的过量抗原暴露方面具有CD8 T细胞外在功能。在病毒感染早期，过量的抗原暴露可导致CD8 T细胞功能耗竭并引发慢性感染。在此我们表明，转录因子干扰素调节因子9（IRF9）在预防CD8 T细胞耗竭中起决定性作用。利用LCMV阿姆斯特朗株对小鼠进行急性感染，我们发现IRF9通过调节干扰素刺激基因的表达以及控制IFN-I的水平来限制早期LCMV复制，IFN-I是I型干扰素（IFN-I）产生所必需的转录因子。感染IRF9缺陷小鼠会导致慢性感染，并伴有由于T细胞外在缺陷导致的CD8 T细胞耗竭。我们的研究结果阐明了IRF9作为IFNAR下游的介质在预防导致CD8 T细胞耗竭并引发慢性病毒感染的过量抗原暴露方面的重要作用。
