Journal
JOURNAL OF VIROLOGY
Volume 91, Issue 22, Pages -Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.01219-17
Keywords
CD8(+) T cell exhaustion; interferon regulatory factor 9; lymphocytic choriomeningitis virus; type I interferon
Categories
Funding
- Deutsche Forschungsgemeinschaft (DFG) [Ho32298/2-1, CRC1021, SFB974, RTG1949, LA2558/5-1]
- von-Behring-Rontgen-Stiftung
- Universitatsklinikum Giessen und Marburg GmbH to Magdalena Huber
Ask authors/readers for more resources
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. 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 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 Irf7, 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available