Blockade of Chronic Type I Interferon Signaling to Control Persistent LCMV Infection

Department of Microbiology, Immunology and Molecular Genetics and the UCLA AIDS Institute, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.
Science (Impact Factor: 33.61). 04/2013; 340(6129):202-7. DOI: 10.1126/science.1235208
Source: PubMed


Type I interferons (IFN-I) are critical for antiviral immunity; however, chronic IFN-I signaling is associated with hyperimmune activation and disease progression in persistent infections. We demonstrated in mice that blockade of IFN-I signaling diminished chronic immune activation and immune suppression, restored lymphoid tissue architecture, and increased immune parameters associated with control of virus replication, ultimately facilitating clearance of the persistent infection. The accelerated control of persistent infection induced by blocking IFN-I signaling required CD4 T cells and was associated with enhanced IFN-γ production. Thus, we demonstrated that interfering with chronic IFN-I signaling during persistent infection redirects the immune environment to enable control of infection.

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    • "Some studies suggest that local cytokine exposure during infection might play a polarizing role on naive CD4 + T cells toward a certain T helper (Th) cell subset upon subsequent coinfection with a secondary pathogen (Perona-Wright et al., 2010). Other studies suggest that elevated cytokine concentrations might play a role in propagating the exhaustion that occurs during chronic infections (Teijaro et al., 2013; Wilson et al., 2013). Immune stimulatory therapies are being increasingly successfully applied as cancer treatments. "
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    ABSTRACT: Primary T cell activation involves the integration of three distinct signals delivered in sequence: (1) antigen recognition, (2) costimulation, and (3) cytokine-mediated differentiation and expansion. Strong immunostimulatory events such as immunotherapy or infection induce profound cytokine release causing "bystander" T cell activation, thereby increasing the potential for autoreactivity and need for control. We show that during strong stimulation, a profound suppression of primary CD4(+) T-cell-mediated immune responses ensued and was observed across preclinical models and patients undergoing high-dose interleukin-2 (IL-2) therapy. This suppression targeted naive CD4(+) but not CD8(+) T cells and was mediated through transient suppressor of cytokine signaling-3 (SOCS3) inhibition of the STAT5b transcription factor signaling pathway. These events resulted in complete paralysis of primary CD4(+) T cell activation, affecting memory generation and induction of autoimmunity as well as impaired viral clearance. These data highlight the critical regulation of naive CD4(+) T cells during inflammatory conditions. Copyright © 2015 Elsevier Inc. All rights reserved.
    Immunity 07/2015; 43(2). DOI:10.1016/j.immuni.2015.06.023 · 21.56 Impact Factor
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    • "Important functions of this family of cytokines include inducing an antimicrobial state, moderating innate immunity, and activating adaptive immunity. Although IFN-Is have generally been thought to be beneficial to the immune response against microbial infections, recent research has shown that IFN-I signaling may be detrimental in several pathogenic infections (Davidson et al., 2014; Harris et al., 2010; Mayer-Barber et al., 2014; Teijaro et al., 2013; Teles et al., 2013; Wilson et al., 2013). Further, persistent viral infections such as HIV, SIV, and HCV are characterized by high interferon signatures suggesting that high levels of IFN-I signaling may play a role in disease pathogenesis (Bolen et al., 2013; Hardy et al., 2013; Sedaghat et al., 2008; Stylianou et al., 2000). "
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    ABSTRACT: Although type I interferon (IFN-I) is thought to be beneficial against microbial infections, persistent viral infections are characterized by high interferon signatures suggesting that IFN-I signaling may promote disease pathogenesis. During persistent lymphocytic choriomeningitis virus (LCMV) infection, IFNα and IFNβ are highly induced early after infection, and blocking IFN-I receptor (IFNAR) signaling promotes virus clearance. We assessed the specific roles of IFNβ versus IFNα in controlling LCMV infection. While blockade of IFNβ alone does not alter early viral dissemination, it is important in determining lymphoid structure, lymphocyte migration, and anti-viral T cell responses that lead to accelerated virus clearance, approximating what occurs during attenuation of IFNAR signaling. Comparatively, blockade of IFNα was not associated with improved viral control, but with early dissemination of virus. Thus, despite their use of the same receptor, IFNβ and IFNα have unique and distinguishable biologic functions, with IFNβ being mainly responsible for promoting viral persistence. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell host & microbe 05/2015; 17(5):653-61. DOI:10.1016/j.chom.2015.04.005 · 12.33 Impact Factor
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    • "Thus modest improvements in T cell function may be insufficient to improve viral control. Studies of chronic LCMV infections have shown that, paradoxically , the number one enemy of many viral infections, IFN-I, enhances CD4 T cell exhaustion and promotes viral persistence, possibly as a tactic for avoiding immunopathology (Teijaro et al., 2013; Wilson et al., 2013). "
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    ABSTRACT: Although robust and highly effective anti-viral T cells contribute to the clearance of many acute infections, viral persistence is associated with the development of functionally inferior, exhausted, T cell responses. Exhaustion develops in a step-wise and progressive manner, ranges in severity, and can culminate in the deletion of the anti-viral T cells. This disarming of the response is consequential as it compromises viral control and potentially serves to dampen immune-mediated damage. Exhausted T cells are unable to elaborate typical anti-viral effector functions. They are characterized by the sustained upregulation of inhibitory receptors and display a gene expression profile that distinguishes them from prototypic effector and memory T cell populations. In this review we discuss the properties of exhausted T cells; the virological and immunological conditions that favor their development; the cellular and molecular signals that sustain the exhausted state; and strategies for preventing and reversing exhaustion to favor viral control. Copyright © 2014 Elsevier Inc. All rights reserved.
    Virology 01/2015; 361. DOI:10.1016/j.virol.2014.12.033 · 3.32 Impact Factor
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