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A Temporal Role Of Type I Interferon Signaling in CD8+ T Cell Maturation during Acute West Nile Virus Infection

Authors
Journal
PLoS Pathogens
1553-7366
Publisher
Public Library of Science
Publication Date
Volume
7
Issue
12
Identifiers
DOI: 10.1371/journal.ppat.1002407
Keywords
  • Research Article
  • Biology
  • Immunology
  • Immunity
  • Adaptive Immunity
  • Immune Activation
  • Immune Defense
  • Immunity To Infections
  • Innate Immunity
  • Immune Response
  • Microbiology
  • Virology
  • Animal Models Of Infection
  • Emerging Viral Diseases
  • Emerging Infectious Diseases
  • Host-Pathogen Interaction
  • Microbial Pathogens

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.

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