Abstract
Natural Killer (NK) cells are lymphocytes of the innate immune response that play a vital role in controlling infections and cancer. Their pro-inflammatory role has been well-established; however, less is known about the regulatory functions of NK cells, in particular, their production of the anti-inflammatory cytokine IL-10. In this study, we investigated the immunoregulatory function of NK cells during MCMV infection and demonstrated that NK cells are major producers of IL-10 during the early stage of infection. To investigate the effect of NK cell-derived IL-10, we have generated NK cell-specific IL-10-deficient mice (NKp46-Cre-Il10fl/fl) displaying no signs of age-related spontaneous inflammation, with NK cells that show no detectable IL-10 production upon in vitro stimulation. In NKp46-Cre-Il10fl/fl mice, the levels of IL-10 and IFNγ, viral burdens and T cell activation were similar between NKp46-Cre-Il10fl/fl mice and their control littermates, suggesting that NK cell-derived IL-10 is dispensable during acute MCMV infection in immunocompetent hosts. In perforin-deficient mice that show a more sustained infection, NK cells produce more sustained levels of IL-10. By crossing NKp46-Cre-Il10fl/fl mice with perforin-deficient mice, we demonstrated that NK cell-derived IL-10 regulates T cell activation, prevents liver damage, and allows for better disease outcome. Taken together, NK cell-derived IL-10 can be critical in regulating the immune response during early phases of infection and therefore protecting the host from excessive immunopathology.
Highlights
The immune system has evolved over time to defend the host against pathogens while protecting the host from collateral tissue damage
To determine whether Natural Killer (NK) cells play an immunoregulatory role in immunocompetent mice by producing IL-10, we infected IL-10-green fluorescence protein (GFP) reporter mice (C57BL/6 background), which allows us to study the complete kinetics of IL-10 production during MCMV infection
Flow cytometric analysis showed that NK cells were predominantly expressing IL-10-GFP on D4 post MCMV infection in the peripheral blood (Figure 1A), whereas almost negligible IL-10-GFP expression was observed in T cells at that time
Summary
The immune system has evolved over time to defend the host against pathogens while protecting the host from collateral tissue damage. Various immune cells are activated to exert their allotted roles in order to combat the evading microbes. The recognition of a pathogen by immune cells triggers a cascade of antimicrobial mechanisms that lead to the clearance of the pathogen [1]. NK cells are lymphocytes of the innate immune response that play a critical role in controlling viruses during the early stage of infection [2,3,4,5]. The immune response exerted by either NK cells or T cells during microbial infections must be tightly regulated to maintain sufficient levels of inflammation for pathogen elimination while avoiding excessive tissue injury to the host [8]
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