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.
"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 . 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]. "
[Show abstract][Hide abstract] 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.
"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 . 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. "
[Show abstract][Hide abstract] 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.
"Either this immunomodulation or latency-associated innate immune activation, as shown for MuHV-4 in laboratory mice (Barton et al., 2007), could underlie the survival cost observed here. For example, although a state of heightened immune activation has been shown to protect against bacterial challenge and lethal lymphoma in laboratory mice (Barton et al., 2007; White et al., 2010), it could be costly in the wild. Immune activation may reduce resources available for other important physiological functions or cause immunopathology (Eraud et al., 2005; Bertrand et al., 2006; Hanssen, 2006). "
[Show abstract][Hide abstract] ABSTRACT: Rodent gammaherpesviruses have become important models for understanding human herpesvirus diseases. In particular, interactions between murid herpesvirus 4 and Mus musculus (a non-natural host species) have been extensively studied under controlled laboratory conditions. However, several fundamental aspects of murine gammaherpesvirus biology are not well understood, including how these viruses are transmitted from host to host, and their impacts on host fitness under natural conditions. Here, we investigate the epidemiology of a gammaherpesvirus in free-living wood mice (Apodemus sylvaticus) and bank voles (Myodes glareolus) in a 2-year longitudinal study. Wood mouse herpesvirus (WMHV) was the only herpesvirus detected and occurred frequently in wood mice and also less commonly in bank voles. Strikingly, WMHV infection probability was highest in reproductively active, heavy male mice. Infection risk also showed a repeatable seasonal pattern, peaking in spring and declining through the summer. We show that this seasonal decline can be at least partly attributed to reduced recapture of WMHV-infected adults. These results suggest that male reproductive behaviours could provide an important natural route of transmission for these viruses. They also suggest that gammaherpesvirus infection may have significant detrimental effects in wild hosts, questioning the view that these viruses have limited impacts in natural, co-evolved host species.
Journal of General Virology 08/2012; 93(Pt 11):2447-56. DOI:10.1099/vir.0.044826-0 · 3.18 Impact Factor
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