A temporal role of type I interferon signaling in CD8+ T cell maturation during acute West Nile virus infection

• Published in: PLoS pathogens 2011-12, Vol.7 (12), p.e1002407-e1002407
• Main Authors: Pinto, Amelia K, Daffis, Stephane, Brien, James D, Gainey, Maria D, Yokoyama, Wayne M, Sheehan, Kathleen C F, Murphy, Kenneth M, Schreiber, Robert D, Diamond, Michael S
• Format: Article
• Language: English
• Subjects: Acute Disease; Animals; Antibodies, Neutralizing - pharmacology; Basic-Leucine Zipper Transcription Factors - genetics; Basic-Leucine Zipper Transcription Factors - immunology; Biology; CD8 Antigens - genetics; CD8 Antigens - immunology; CD8-Positive T-Lymphocytes - immunology; Dendritic Cells - immunology; Immune system; Infections; Interferon; Interferon Type I - genetics; Interferon Type I - immunology; Mice; Mice, Knockout; Receptor, Interferon alpha-beta - antagonists & inhibitors; Receptor, Interferon alpha-beta - genetics; Receptor, Interferon alpha-beta - immunology; Repressor Proteins - genetics; Repressor Proteins - immunology; Signal Transduction - drug effects; Signal Transduction - genetics; Signal Transduction - immunology; Time Factors; Viral infections; West Nile Fever - genetics; West Nile Fever - immunology; West Nile virus; West Nile virus - immunology
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1002407

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.