These data suggest that the substantial increase in total peritoneal cavity NK cells is a result of NK cell proliferation as well as NK cells migrated from other places such as spleen.
In this study, we showed that MDSCs rapidly accumulated at the site of infection with VV. Removal of MDSCs in vivo led to enhanced NK cell proliferation, activation and function in response to VV infection as well as an increase in mortality and IFNγ production. We further demonstrated that CD244 expression characterized the G-MDSC subset responsible for the suppression on NK cells, and that this suppression was mediated by ROS.
NK cells are critical for the control of viral infections. Thus, in the setting of VV infection, multiple pathways have evolved to ensure effective activation of NK cells and the subsequent control of VV infection in vivo. Previous studies have shown that efficient NK cell activation depends on both TLR2-dependent and –independent pathways (7
), as well as the NKG2D pathway (10
). This study demonstrates for the first time that NK cell response to VV infection is also negatively regulated by G-MDSCs. This tight control of NK cell activation could potentially avoid collateral damage such as mortality and systemic inflammation elicited by the exuberant NK cell activation.
The accumulation of MDSCs in mice in response to viral infection has been shown in different viral infections (29
). However, the role of MDSCs in regulating NK cell responses during the early phase of infection has not been addressed. Thus, this is the first study, to our knowledge, showing a critical role of G-MDSCs in regulating the NK cell response to a viral infection. Although MDSCs have been shown to modulate NK cell function in tumor models, it still remains unknown which MDSC subset is responsible for modulation of NK cell function in tumor-bearing hosts (17
). Our results also provided evidence that both M-MDSCs and G-MDSCs accumulate in the peritoneal cavity in response to VV infection. Although M-MDSCs appear not involved in the suppression of NK cells, we cannot rule out the possibility of its role in regulating T cell response late in VV infection.
The observation that mice depleted of MDSCs in vivo were associated with an increase in mortality and systemic IFNγ production, but a reduction in viral load, suggests that the increased mortality is likely due to an uncontrolled inflammatory response rather than an infection. Although it is correlated with an increase in systemic IFNγ production, other cytokines and factors may also contribute to the increased mortality. In line with this notion, a recent study indicates that hepatic acute-phase proteins can control inflammatory responses during infection by promoting MDSC function (26
). Further studies are needed to dissect whether other elements are also deregulated, contributing to the increased mortality upon MDSC-depletion in vivo.
Several mechanisms have been proposed for MDSC-mediated suppression of immune responses, ranging from receptor-ligand interactions to soluble mediators (11
). While most of the studies involving mechanism(s) of suppression were performed in tumor models, there are a few utilizing infectious models. In a model of Mycobacterium bovis
bacillus Calmette-Guérin infection, M-MDSCs were found to impair T cell priming in draining lymph nodes by NO production (28
). In polymicrobial sepsis, MDSC-mediated suppression was found to be associated with the secretion of IL-10 (25
). In models of parasitic infection, IFNγ-induced NO production was responsible for MDSC-mediated suppression of T cell responses (38
In contrast to MDSC-mediated suppression on T cells, here we found that ROS production was required for NK cell suppression by G-MDSCs. This may explain why M-MDSCs do not suppress NK cells as M-MDSCs produced little ROS (11
). While this result suggests that ROS produced by G-MDSCs may be delivered to NK cells to mediate the suppression, we cannot exclude the possibility that receptor-ligand interactions may also be required for the suppression of NK cell activation. Indeed, membrane-bound TGFβ on MDSCs has been shown to be responsible for the induction of NK cell anergy in tumor-bearing mice (17
), and the blockade of NKp30 on NK cells in hepatocellular carcinoma patients reversed the suppression by MDSCs (18
). These observations suggest that in some tumor models, the suppression of NK cells by MDSCs involves receptor-ligand interactions. It is not clear whether receptor-ligand interactions are also involved in G-MDSC-mediated NK cell suppression in the setting of VV infection. Future studies are required to investigate this possibility. A recent report showed that lack of Ly49H+
NK cells may afford additional protection against ectromelia viral infection (40
). Thus, it is possible that G-MDSCs may interact with Ly49H+
NK cells for the suppressive effect.
In summary, we have provided evidence that MDSCs accumulate rapidly at site of viral infection and suppress NK cell activation and function during the early phase of the immune response against VV infection. We have further shown that it is the G-MDSC subset that mediates ROS-dependent suppression on NK cells. Our study may suggest a novel strategy using G-MDSCs to modulate NK cell activity for potential therapeutic benefits in viral infections.