Campbell IL, Bauer S, Hofer MJ, Ashhurst T, Jung SR, Raifer H, Lang KS, Tom A, Suprunenko T, Marbach F, Lang P, Wolff S, King NJC, Xu HC, Viengkhou B, Strecker T, Huber M, Obermann HL
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 which limits CD8+ T cell exhaustion is of significant interest for controlling 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)-Armstrong, we show for the first time 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 anti-viral responses in dendritic cells, resulting in CD8+ T cell exhaustion and chronic infection. Differences in the antiviral activity of IRF9- and IFNAR-deficient mice and dendritic cells provided further evidence for IRF9-independent IFN-I signaling. Thus, our findings illustrate a CD8+ T cell extrinsic function for IRF9, as a downstream signaling factor of IFNAR, in preventing overwhelming antigen exposure resulting in CD8+ T cell exhaustion and ultimately in chronic infection.IMPORTANCE 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 (IRF) 9 plays a decisive role in preventing CD8+ T cell exhaustion. Using acute infection of mice with the LCMV-Armstrong strain, we found that IRF9 limited early LCMV replication by regulating expression of interferon-stimulated genes and Irf7, a transcription factor crucial for of type I interferon (IFN-I) production, as well as by controlling the levels IFN-I. Infection of IRF9-deficient mice led to chronic infection that was accompanied by CD8+ T cell exhaustion due to T cell extrinsic defects. 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.
