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

作者: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
来源:PLoS Pathogens, 2011, 7(12): e1002407.
DOI:10.1371/journal.ppat.1002407

摘要

A genetic absence of the common IFN-alpha/beta 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-alpha 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.

  • 出版日期2011-12