title: A temporal role of type I interferon signaling in CD8+ T cell maturation during acute West Nile virus infection.
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.
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Amelia K
authors.initials: AK
authors.lastname: Pinto
authors.forename: Stephane
authors.initials: S
authors.lastname: Daffis
authors.forename: James D
authors.initials: JD
authors.lastname: Brien
authors.forename: Maria D
authors.initials: MD
authors.lastname: Gainey
authors.forename: Wayne M
authors.initials: WM
authors.lastname: Yokoyama
authors.forename: Kathleen C F
authors.initials: KC
authors.lastname: Sheehan
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Murphy
authors.forename: Robert D
authors.initials: RD
authors.lastname: Schreiber
authors.forename: Michael S
authors.initials: MS
authors.lastname: Diamond
mesh_terms: D000208:Acute Disease; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000276:immunology; D016827:CD8 Antigens / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D053633:Receptor, Interferon alpha-beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D013997:Time Factors; D014901:West Nile Fever / Q000235:genetics / Q000276:immunology*; D014902:West Nile virus / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D050976:Basic-Leucine Zipper Transcription Factors; D016827:CD8 Antigens; C409469:CD8 antigen, alpha chain; D007370:Interferon Type I; D012097:Repressor Proteins; C533289:SNFT protein, mouse; D053633:Receptor, Interferon alpha-beta