Type I and III IFNs Produced by Plasmacytoid Dendritic Cells in Response to a Member of theFlaviviridaeSuppress Cellular Immune Responses

Abstract

The pestivirus noncytopathic bovine viral diarrhea virus (BVDV) can suppress IFN production in the majority of cell types in vitro. However, IFN is detectable in serum during acute infection in vivo for ∼5–7 d, which correlates with a period of leucopoenia and immunosuppression. In this study, we demonstrate that a highly enriched population of bovine plasmacytoid dendritic cells (DCs) produced IFN in response to BVDV in vitro. We further show that the majority of the IFN produced in response to infection both in vitro and in vivo is type III IFN and acid labile. Further, we show IL-28B (IFN-λ3) mRNA is induced in this cell population in vitro. Supernatant from plasmacytoid DCs harvested postinfection with BVDV or recombinant bovine IFN-α or human IL-28B significantly reduced CD4+ T cell proliferation induced by tubercle bacillus Ag 85–stimulated monocyte-derived DCs. Furthermore, these IFNs induced IFN-stimulated gene expression predominantly in monocyte-derived DCs. IFN-treated immature DCs derived from murine bone marrow also had a reduced capacity to stimulate T cell proliferative responses to tubercle bacillus Ag 85. Immature DCs derived from either source had a reduced capacity for Ag uptake following IFN treatment that is dose dependent. Immunosuppression is a feature of a number of pestivirus infections; our studies suggest type III IFN production plays a key role in the pathogenesis of this family of viruses. Overall, in a natural host, we have demonstrated a link between the induction of type I and III IFN after acute viral infection and transient immunosuppression.

Transcriptomic profiling of bovine blood dendritic cells and monocytes following TLR stimulation

“…As pDC of other species have repeatedly been described for their ability to rapidly produce large amounts of type I interferons [6], the cytokines that are essential for innate immune responses against viruses [87], we were surprised to find that bovine pDC only marginally upregulated IFN gene expression upon TLR stimulation. Most of the studies that have investigated bovine IFN responses have either detected mRNA for bovine type I IFN [88,89] or mRNA for ISGs [90,91] by quantitative RT‐PCR with total RNA samples from blood or tissues, or have looked at IFN activity by Mx‐CAT reporter assays [92‐96]. Two studies [92, 96] found type I IFN activity in cells that phenotypically resemble the current phenotypic definition of bovine pDC [14].…”

Mx Is Not Responsible for the Antiviral Activity of Interferon-α against Japanese Encephalitis Virus

“…Type I interferon (IFN) is abundantly produced in virus-infected cells soon after infection, as well as a myriad additional virus-initiated modulatory effects, including induction of cellular inhibitors or repressors of transcription, and activation of IFN-I stimulated genes (ISG) and proteins, all in order to antagonize an antiviral host response [ 35 ]. Thus, IFNs have been used as antiviral agents in the treatment of several pathogens, including Flaviviridae [ 36 ]. Previous reports have shown that IFNα has activity against JEV in PK-15 cells [ 7 , 8 ] and BHK-21 cells [ 37 ].…”

Distinct Effects of Type I and III Interferons on Enteric Viruses

“…Consistent with this observation, IFN-λ is transcribed and translated at higher rates than IFN-β in intestinal organoids [ 35 ]. Activation of an antiviral response in dendritic cells, in contrast, may stimulate production of both type I and III IFNs ( Figure 2 ) [ 37 , 41 , 42 ], which may act on a variety of cell types.…”