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.

Download full-text


Available from: Gary D Luker
  • Source
    • "It is likely that this population is not specific to HCV as increased Tim-3 expression on NK cells has been described not only in chronic HBV [19] infection but also in HIV [16]. Viral infection may enhance Tim-3 expression indirectly through induction of pro-inflammatory cytokines; for example, it is known that IL-12 and IL-15 are produced by dendritic cells in response to dsRNA and Type I IFN [40] [41]. In this regard, we found that IL-12 and IL-15 induced Tim-3 expression on all NK subsets. "
    [Show abstract] [Hide abstract]
    ABSTRACT: T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) is an inhibitory receptor implicated in T cell exhaustion characteristic of chronic viral infection. Limited data exist on NK cell Tim-3 expression and functional consequences. In chronic hepatitis C virus (HCV) infected subjects, we found increased Tim-3 on NKs which was associated with an activated phenotype. The high level of Tim-3 was not reversed by successful IFN-alpha based anti-viral therapy. Tim-3(high) NK cells up-regulated TRAIL in response to IFN-alpha to a greater extent and demonstrated greater lymphokine-activated killing activity, viral control and degranulation but similar cytokine production than their Tim-3(low) counterparts. Our results suggest that Tim-3 on NKs is associated with activation of this innate lymphocyte population that is polarized towards cytotoxicity in chronic HCV. These findings reveal roles for Tim-3 in the regulation of NKs that might represent targets for treatment of chronic viral infections. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Mar 2015 · Clinical Immunology
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Anti-tumor immunity can eliminate existing cancer cells and also maintain a constant surveillance against possible relapse. Such an antigen-specific adaptive response begins when tumor-specific T cells become activated. T-cell activation requires two signals on antigen presenting cells (APCs): antigen presentation through major histocombatibility complex (MHC) molecules and co-stimulation. In the absence of one or both these signals, T cells remain inactivated or can even become tolerized. Cancer cells and their associated microenvironment strategically hinder the processing and presentation of tumor antigens and consequently prevent the development of anti-tumor immunity. Many studies, however, demonstrate that interventions that over-turn tumor-associated immune evasion mechanisms can establish anti-tumor immune responses of therapeutic potential. One such intervention is oncolytic virus (OV)-based anti-cancer therapy. Here, we discuss how OV-induced immunological events override tumor-associated antigen presentation impairment and promote appropriate T cell-APC interaction. Detailed understanding of this phenomenon is pivotal for devising the strategies that will enhance the efficacy of OV-based anti-cancer therapy by complementing its inherent oncolytic activities with desired anti-tumor immune responses.
    Full-text · Article · Apr 2014 · Frontiers in Oncology
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Unlabelled: Type I interferons (IFNs) are produced early upon virus infection and signal through the alpha/beta interferon (IFN-α/β) receptor (IFNAR) to induce genes that encode proteins important for limiting viral replication and directing immune responses. To investigate the extent to which type I IFNs play a role in the local regulation of inflammation in the airways, we examined their importance in early lung responses to infection with respiratory syncytial virus (RSV). IFNAR1-deficient (IFNAR1(-/-)) mice displayed increased lung viral load and weight loss during RSV infection. As expected, expression of IFN-inducible genes was markedly reduced in the lungs of IFNAR1(-/-) mice. Surprisingly, we found that the levels of proinflammatory cytokines and chemokines in the lungs of RSV-infected mice were also greatly reduced in the absence of IFNAR signaling. Furthermore, low levels of proinflammatory cytokines were also detected in the lungs of IFNAR1(-/-) mice challenged with noninfectious innate immune stimuli such as selected Toll-like receptor (TLR) agonists. Finally, recombinant IFN-α was sufficient to potentiate the production of inflammatory mediators in the lungs of wild-type mice challenged with innate immune stimuli. Thus, in addition to its well-known role in antiviral resistance, type I IFN receptor signaling acts as a central driver of early proinflammatory responses in the lung. Inhibiting the effects of type I IFNs may therefore be useful in dampening inflammation in lung diseases characterized by enhanced inflammatory cytokine production. Importance: The initial response to viral infection is characterized by the production of interferons (IFNs). One group of IFNs, the type I IFNs, are produced early upon virus infection and signal through the IFN-α/β receptor (IFNAR) to induce proteins important for limiting viral replication and directing immune responses. Here we examined the importance of type I IFNs in early responses to respiratory syncytial virus (RSV). Our data suggest that type I IFN production and IFNAR receptor signaling not only induce an antiviral state but also serve to amplify proinflammatory responses in the respiratory tract. We also confirm this conclusion in another model of acute inflammation induced by noninfectious stimuli. Our findings are of relevance to human disease, as RSV is a major cause of infant bronchiolitis and polymorphisms in the IFN system are known to impact disease severity.
    Full-text · Article · Mar 2014 · Journal of Virology
Show more