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

• DOI: 10.1371/journal.ppat.1002407
• Publication Date: 2011-12-03T04:42:41Z
• Authors: Amelia K. Pinto; Stephane Daffis; James D. Brien; Maria D. Gainey; Wayne M. Yokoyama; Kathleen C. F. Sh...; Kenneth M. Murphy; Robert D. Schreiber; Michael S. Diamond
• Keywords: Time Factors; QH301-705.5; CD8 Antigens; Receptor, Interferon alpha-beta; CD8-Positive T-Lymphocytes; Mice; 03 medical and health sciences; 0302 clinical medicine; Medicine and Health Sciences; Animals; Biology (General); Mice, Knockout; Dendritic Cells; RC581-607; Antibodies, Neutralizing; 3. Good health; Repressor Proteins; Basic-Leucine Zipper Transcription Factors; Acute Disease; Interferon Type I; Immunologic diseases. Allergy; West Nile virus; West Nile Fever; Research Article; Signal Transduction

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.