Type I Interferon Regulates Respiratory Virus Infected Dendritic Cell Maturation and Cytokine Production

Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Viral Immunology (Impact Factor: 1.45). 01/2008; 20(4):531-40. DOI: 10.1089/vim.2007.0057
Source: PubMed


Activation of dendritic cells (DCs) by viruses is critical for both innate and adaptive immune responses. In this report, we investigated the role of type I interferon (IFN) in the activation of DCs by respiratory syncytial virus (RSV). Using DCs from type I IFNR-/- mice, these studies indicate that maturation, including upregulation of co-stimulatory molecules and optimal cytokine production, by RSV infection was dependent on type I IFN receptor signaling. Subsequently, studies using DCs from wild type mice demonstrate that continued production of type I IFN during later stages of DC maturation could alter their activation profiles. IFN-alpha and IFN-beta were upregulated in DCs grown from bone marrow of wild type mice after infection with RSV. In order to determine their function in competent DCs, blocking antibodies were used to specifically inhibit IFN-alpha/beta . The data demonstrate that production of IFN-beta, but not IFN-alpha, in RSV-infected wild type DCs promotes chemokine production and toll-like receptor (TLR) expression, while limiting IL-12 production. The inhibition of IL-12p70 by IFN-beta correlated with suppressed IL-12p40 expression levels. Furthermore, the addition of recombinant IFN-beta potently inhibited IL-12p40 expression in mature DC subsets during RSV infection, while only the highest dose of IFN-alpha had any inhibitory effect. Together, our studies provide insight into the complex regulation of DC maturation and IL-12 production co-ordinated by type I interferons in RSV-infected dendritic cells, and demonstrate that type I IFN has specific roles depending upon the stage of DC maturation.

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Available from: Gary D Luker, Oct 05, 2015
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    • "The recognition of viral PAMPs through PRRs drives the immediate innate immune response that constitutes the production of type I interferons, including multiple forms of IFN-α and -β (62–64). These Type I interferons enhance the expression of MHC class I and II, CD40, CD80, CD83, and CD86 on the surface of DCs (46, 65, 66). Such IFN-α/β response further stimulates the production of cytokines (e.g., IL-1β, IL-6, IL-12, TNF-α) and chemokines [e.g., IL-8, monocyte chemotactic protein-1 (MCP-1)], and amplifies the initial innate response when these cytokines act through autocrine and paracrine fashion (67). "
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    • "In addition, previous studies have shown that type I IFNs play a critical role in induction of IFN-γ gene expression through the activation of STAT4 (32, 33) or increased signaling through other cytokine receptors such as IFN-γ receptor by increased levels of STAT1 (19, 34). Furthermore, since the IFN responses were reduced in IFNAR1−/− mice, this resulted in a diminished induction of ISGs as has previously been shown for TLR stimulation (35, 36) and for bone marrow-derived DCs (BMDCs) stimulated with RSV (37). Therefore, type I IFN production with subsequent IFNAR signaling is a key component of the entire IFN response early after RSV infection. "
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