Type 1 Interferon Induction of Natural Killer Cell Gamma Interferon Production for Defense during Lymphocytic Choriomeningitis Virus Infection

Article (PDF Available)inmBio 2(4) · June 2011with9 Reads
DOI: 10.1128/mBio.00169-11 · Source: PubMed
Abstract
Unlabelled: Natural killer (NK) cells are equipped to innately produce the cytokine gamma interferon (IFN-γ) in part because they basally express high levels of the signal transducer and activator of transcription 4 (STAT4). Type 1 interferons (IFNs) have the potential to activate STAT4 and promote IFN-γ expression, but concurrent induction of elevated STAT1 negatively regulates access to the pathway. As a consequence, it has been difficult to detect type 1 IFN stimulation of NK cell IFN-γ during viral infections in the presence of STAT1 and to understand the evolutionary advantage for maintaining the pathway. The studies reported here evaluated NK cell responses following infections with lymphocytic choriomeningitis virus (LCMV) in the compartment handling the earliest events after infection, the peritoneal cavity. The production of type 1 IFNs, both IFN-α and IFN-β, was shown to be early and of short duration, peaking at 30 h after challenge. NK cell IFN-γ expression was detected with overlapping kinetics and required activating signals delivered through type 1 IFN receptors and STAT4. It took place under conditions of high STAT4 levels but preceded elevated STAT1 expression in NK cells. The IFN-γ response reduced viral burdens. Interestingly, increases in STAT1 were delayed in NK cells compared to other peritoneal exudate cell (PEC) populations. Taken together, the studies demonstrate a novel mechanism for stimulating IFN-γ production and elucidate a biological role for type 1 IFN access to STAT4 in NK cells. Importance: Pathways regulating the complex and sometimes paradoxical effects of cytokines are poorly understood. Accumulating evidence indicates that the biological consequences of type 1 interferon (IFN) exposure are shaped by modifying the concentrations of particular STATs to change access to the different signaling molecules. The results of the experiments presented conclusively demonstrate that NK cell IFN-γ can be induced through type 1 IFN and STAT4 at the first site of infection during a period with high STAT4 but prior to induction of elevated STAT1 in the cells. The response mediates a role in viral defense. Thus, a very early pathway to and source of IFN-γ in evolving immune responses to infections are identified by this work. The information obtained helps resolve long-standing controversies and advances the understanding of mechanisms regulating key type 1 IFN functions, in different cells and compartments and at different times of infection, for accessing biologically important functions.

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    • "NK cells are the major source of IFN and activation of NK cells by IFN is essential for their lytic activity (Wang et al., 2012 ). Studies have shown that the increase in frequency , activity of NK cells and IFN production by NK cells is essential for reduction of viral load in mice infected with lymphocytic choriomeningitis virus or influenza virus (Biron et al., 1983; Mack et al., 2011; Stein-Streilein et al., 1988 ). Further, production of IFN and IFN in intestine of mice was essential and sufficient to induce innate immune cells to eliminate certain bacterial pathogens in mice (Sotolongo et al., 2011). "
    [Show abstract] [Hide abstract] ABSTRACT: Porcine epidemic diarrhea (PED) is an enteric coronaviral infection that causes severe morbidity and mortality in suckling pigs, but less severe disease in older pigs. Consequently, it causes significant economic losses to the pork industry. There are limited studies on the innate immune responses to PED virus (PEDV) in pigs. The aims of our study were to investigate differences in innate immune responses to PEDV infection in suckling and weaned pigs and to examine if disease severity coincides with reduced innate immune responses. Weaned 26-day-old pigs (n = 20) and 9-day-old nursing pigs (n = 20) were assigned to PEDV inoculated or uninoculated control groups. The pigs were observed daily for clinical signs, virus shedding and were euthanized at post-inoculation days (PIDs) 1 and 5 to assay immune responses. Blood samples were collected at PIDs 1, 3 and 5. The natural killer (NK) cell frequencies, NK cell activities (lysis of target K562 tumor cells in vitro), CD3+CD4+ T cell and CD3+CD8+ T cell frequencies were measured in blood and ileum at PIDs 1 and 5. The PEDV infected suckling pigs showed severe diarrhea and vomiting at PID 1, whereas the PEDV infected weaned pigs showed milder clinical signs starting at PID 3. PEDV infected suckling pigs had significantly higher diarrhea scores, earlier fecal PEDV RNA shedding and significantly higher viremia (viral RNA in serum) compared to weaned pigs. There was no mortality in either infected suckling or infected weaned pigs. The control pigs not inoculated with PEDV did not show any clinical signs and no detectable fecal or serum PEDV RNA. Strikingly, PEDV infected suckling pigs had significantly lower NK cell frequencies, undetectable NK cell activity and lower IFN producing NK cells in blood and ileum compared to PEDV infected weaned pigs. Pro-inflammatory cytokine profiles of PEDV infected suckling pigs differed from those of PEDV infected weaned pigs and coincided with onset of fecal PEDV RNA shedding and serum PEDV RNA titers. The infected suckling pigs have higher and earlier increases in serum IFN, but lower serum IL-8 and TNF levels compared to infected weaned pigs. CD3+CD4+ T cell frequencies were significantly higher in ileum of suckling pigs than in weaned pigs, whereas there was no difference in CD3+CD8+ T cell frequencies. In conclusion, the observations of impaired lytic activity and IFN-production by NK cells in suckling pigs coincided with the increased severity of PEDV infection in the suckling pigs compared with the weaned pigs.
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    • "Indeed, wild type (WT) NK cells transferred into IFNAR À/À knockout recipient mice were efficiently primed upon viral infection. Furthermore, in LCMV infection, Mack and coauthors demonstrated that direct type I IFN-induced signalling on NK cells is required for secretion of IFN-g in vivo [34]. In support to an indirect route of activation, a first study from Lucas and co-authors demonstrated that the action of type I IFNs on accessory DCs, but not on NK cells, was required for NK cell activation in response to TLR ligands [35]. "
    [Show abstract] [Hide abstract] ABSTRACT: The role of Natural Killer cells in host defense against infections as well as in tumour surveillance has been widely appreciated for a number of years. Upon recognition of "altered" cells, NK cells release the content of cytolytic granules, leading to the death of target cells. Moreover, NK cells are powerful producers of chemokines and cytokines, particularly Interferon-γ (IFN-γ), of which they are the earliest source upon a variety of infections. Despite being armed to fight against pathogens, NK cells become fully functional upon an initial phase of activation that requires the action of several cytokines, including type I IFNs. Type I IFNs are now recognized as key players in antiviral defense and immune regulation, and evidences from both mouse models of disease and in vitro studies support the existence of an alliance between type I IFNs and NK cells to ensure effective protection against viral infections. This review will focus on the role of type I IFNs in regulating NK cell functions to elicit antiviral response and on NK cell-produced IFN-γ beneficial and pathological effects. Copyright © 2014 Elsevier Ltd. All rights reserved.
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    • "For example , quiescent NK cells express more STAT4 than STAT1, leading to constitutive association of IFNAR to STAT4 in these cells. Hence, quiescent NK cells mount pSTAT4 homodimer-dependent responses to IFN-I stimulation, including IFN-γ production and T-bet-driven proliferation (Figure 8) (194, 195). Changes in STAT levels can also occur upon the differentiation/activation of a given cell type and lead to a shift in its functional response to the cytokines (196). "
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