Abstract
A genetic absence of the common IFN- α/β signaling receptor (IFNAR) in mice is associated with enhanced viral replication and altered adaptive immune responses. However, analysis of IFNAR-/- mice is limited for studying the functions of type I IFN at discrete stages of viral infection. To define the temporal functions of type I IFN signaling in the context of infection by West Nile virus (WNV), we treated mice with MAR1-5A3, a neutralizing, non cell-depleting anti-IFNAR antibody. Inhibition of type I IFN signaling at or before day 2 after infection was associated with markedly enhanced viral burden, whereas treatment at day 4 had substantially less effect on WNV dissemination. While antibody treatment prior to infection resulted in massive expansion of virus-specific CD8+ T cells, blockade of type I IFN signaling starting at day 4 induced dysfunctional CD8+ T cells with depressed cytokine responses and expression of phenotypic markers suggesting exhaustion. Thus, only the later maturation phase of anti-WNV CD8+ T cell development requires type I IFN signaling. WNV infection experiments in BATF3 -/- mice, which lack CD8-α dendritic cells and have impaired priming due to inefficient antigen cross-presentation, revealed a similar effect of blocking IFN signaling on CD8+ T cell maturation. Collectively, our results suggest that cell non-autonomous type I IFN signaling shapes maturation of antiviral CD8+ T cell response at a stage distinct from the initial priming event.
Highlights
Type I interferons (IFN) comprise a family of cytokines that that were identified originally for their ability to render cells resistant to virus infection [1]
Type I IFN binds to a common IFN-ab receptor (IFNAR), which initiates a signaling cascade that results in phosphorylation and nuclear translocation of STAT1 and STAT2, and induction of expression of hundreds of interferonstimulated genes (ISG) [2]
IFNAR-/- mice are exquisitely vulnerable to West Nile virus (WNV) infection, with expanded tissue tropism, uncontrolled viral replication, and rapidly uniform death, with all animals succumbing within four days of infection after inoculation with a single plaque forming unit (PFU) of virus [8]
Summary
Type I interferons (IFN) comprise a family of cytokines that that were identified originally for their ability to render cells resistant to virus infection [1]. Type I IFN binds to a common IFN-ab receptor (IFNAR), which initiates a signaling cascade that results in phosphorylation and nuclear translocation of STAT1 and STAT2, and induction of expression of hundreds of interferonstimulated genes (ISG) [2] These ISG control viral infections through a diverse range of direct antiviral effector functions [3] and by modulating adaptive immune responses [4]. Diminished effector functions of memory CD8+ T cells in IFNAR-/- mice have been described after infection with influenza and vaccinia (VV) viruses [15,16] This could be due in part, to defects in cross-priming of CD8+ T cells, which is believed to require both virus-induced type I IFN [9,13,17] and CD8-a dendritic cells [18]
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