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

Amelia K. Pinto, Stephane Daffis, James D. Brien, Maria D. Gainey, Wayne M. Yokoyama, Kathleen C.F. Sheehan, Kenneth M. Murphy, Robert D. Schreiber, Michael S. Diamond

Research output: Contribution to journalArticlepeer-review

92 Scopus citations

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.

Original languageEnglish
Article numbere1002407
JournalPLoS Pathogens
Volume7
Issue number12
DOIs
StatePublished - Dec 2011

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

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