Latent herpesvirus infection arms NK cells

Division of Rheumatology, Department of Internal Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.
Blood (Impact Factor: 10.45). 02/2010; 115(22):4377-83. DOI: 10.1182/blood-2009-09-245464
Source: PubMed


Natural killer (NK) cells were identified by their ability to kill target cells without previous sensitization. However, without an antecedent "arming" event, NK cells can recognize, but are not equipped to kill, target cells. How NK cells become armed in vivo in healthy hosts is unclear. Because latent herpesviruses are highly prevalent and alter multiple aspects of host immunity, we hypothesized that latent herpesvirus infection would arm NK cells. Here we show that NK cells from mice latently infected with Murid herpesvirus 4 (MuHV-4) were armed as evidenced by increased granzyme B protein expression, cytotoxicity, and interferon-gamma production. NK-cell arming occurred rapidly in the latently infected host and did not require acute viral infection. Furthermore, NK cells armed by latent infection protected the host against a lethal lymphoma challenge. Thus, the immune environment created by latent herpesvirus infection provides a mechanism whereby host NK-cell function is enhanced in vivo.

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    • "However, recent evidence suggests that latent herpesviruses (including CMV) may play a pivotal role in cancer immunosurveillance by 'arming' NK-cells to adequately destroy malignant target cells [4] [5]. For example, NK-cells in mice with latent Murid herpesvirus 4 infection show increased Granzyme B expression, IFN-c production and cytotoxicity, which protects infected mice from a lethal lymphoma challenge [4]. Further, we have reported increased NK-cell-mediated cytotoxicity against HLA-E+ human tumor cell lines in healthy people previously exposed to CMV [5]. "
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    ABSTRACT: CMV markedly alters the phenotype and function of NK-cells and T-cells and has been linked to immunosenescence. We show here that subjects with effective CMV control (evidenced by low CMV IgG titers) have functional responses to CMV that are driven by either NKG2C+ NK-cells or CMV-specific T-cells (15 of 24 subjects), but not both. These data indicate that people with effective CMV control are either NK-cell or T-cell responders, and corroborates the idea that NK-cells have rheostat-like properties that regulate anti-viral T-cell responses. Whether or not lifelong CMV control through either NK-cell or T-cell responses have implications for immunosenescence remains to be determined.
    Full-text · Article · Nov 2015 · Cellular Immunology
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    • "Further, when activating ligands are increased (induced or abnormal self), activation predominates and in some circumstance results in NK cell triggering without loss of MHC class I [39, 40]. When deciding whether to respond to a target cell or not, these signals are combined, including integration of the NK cell activation status influenced by cytokine priming [30, 31, 41, 42] or other events, such as latent viral infection [43]. Recently, prior exposure to CMV and Hantavirus infection has been linked to altered populations of human NK cells, resulting in an expanded NKG2C+ NK cells that exhibit enhanced functionality upon restimulation [44–46]. "
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    ABSTRACT: Natural killer (NK) cells are innate lymphoid cells important for host defense against pathogens and mediate antitumor immunity. Cytokine receptors transduce important signals that regulate proliferation, survival, activation status, and trigger effector functions. Here, we review the roles of major cytokines that regulate human NK cell development, survival, and function, including IL-2, IL-12, IL-15, IL-18, and IL-21, and their translation to the clinic as immunotherapy agents. We highlight a recent development in NK cell biology, the identification of innate NK cell memory, and focus on cytokine-induced memory-like (CIML) NK cells that result from a brief, combined activation with IL-12, IL-15, and IL-18. This activation results in long lived NK cells that exhibit enhanced functionality when they encounter a secondary stimulation and provides a new approach to enable NK cells for enhanced responsiveness to infection and cancer. An improved understanding of the cellular and molecular aspects of cytokine-cytokine receptor signals has led to a resurgence of interest in the clinical use of cytokines that sustain and/or activate NK cell antitumor potential. In the future, such strategies will be combined with negative regulatory signal blockade and enhanced recognition to comprehensively enhance NK cells for immunotherapy.
    Full-text · Article · Jun 2014
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    • "However, we also examined the role of NK cells in the innate immune response to viral infection. Recently, it was demonstrated that latent herpesvirus infection causes NK cells to produce more granzyme B and IFN-γ and to display increased cytotoxity [24]. Our NK cell depletion studies (>90 % of NK cells were depleted in the lungs) resulted in no significant difference in viral titers (data not shown) suggesting that NK cells are dispensable in the innate response to influenza virus. "
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    ABSTRACT: Murine gammaherpesvirus 68 (MHV68) is a natural rodent pathogen that has been used as a model to study the pathogenesis of human gammaherpesviruses. Like other herpesviruses, MHV68 causes acute infection and establishes life-long latency in the host. Recently, it has been shown that mice latently infected with MHV68 have resistance to unrelated pathogens in secondary infection models. We therefore hypothesized that latent MHV68 infection could modulate the host response to influenza A virus. To test this hypothesis, mice were infected intranasally with influenza virus following the establishment of MHV68 latency. Mice latently infected with MHV68 showed significantly higher survival to influenza A virus infection than did PBS mock-infected mice. Latent MHV68 infection led to lower influenza viral loads and decreased inflammatory pathology in the lungs. Alveolar macrophages of mice latently infected with MHV68 showed activated status, and adoptive transfer of those activated macrophages into mice followed the infection with influenza A virus had significantly greater survival rates than control mice, suggesting that activated alveolar macrophages are a key mechanistic component in protection from secondary infections.
    Full-text · Article · Jun 2013 · Inflammation
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