IRF9 prevents CD8⁺ T cell exhaustion in an extrinsic manner during acute LCMV infection

ABSTRACT

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.