4 years ago

The dose of retroviral infection determines the induction of anti-viral NK cell responses.

Dittmer U, Littwitz-Salomon E, Schimmer S
Natural killer (NK) cells are part of the innate immune system and recognize virus-infected cells as well as tumor cells. Conflicting data about the beneficial or even detrimental role of NK cells in different infectious diseases were described. While the type of pathogen strongly influences NK cell functionality, less is known about how the infection dose influences the quality of a NK cell response against retroviruses. Here we used the well-established Friend retrovirus (FV) mouse model to investigate the impact of virus dose on the induction of anti-viral NK cell functions. High-dose virus inoculation increased initial virus replication compared to medium- or low-dose viral challenge and significantly improved NK cell activation. Anti-viral NK cell activity, including in vivo cytotoxicity towards infected target cells, was also enhanced by high-dose virus infection. NK cell activation following high-dose viral challenge was likely mediated by activated dendritic cells (DCs) and macrophages and the NK cell-stimulating cytokines, IL-15 and IL-18. Neutralization of these cytokines decreased NK cell functions and increased viral loads whereas IL-15 and IL-18 therapy improved the NK cell activity. Here we demonstrate that virus dose positively correlates with anti-viral NK cell activity and function, which is at least partly driven by IL-15 and IL-18. Our results suggest that NK cell activity may be therapeutically enhanced by administering IL-15 and IL-18 in virus infections that inadequately activate NK cells.IMPORTANCE In infections with retroviruses, like HIV and FV infection of mice, NK cells clearly mediate anti-viral activities, but they are usually not sufficient to prevent severe pathology. Here, we show that the initial infection dose impacts the induction of an anti-viral NK cell response during an acute retroviral infection, which was not investigated so far. High-dose infection resulted in a strong NK cell functionality, whereas no anti-viral activities were detected after low- or medium-dose infection. Interestingly, DCs and macrophages were highly activated after high-dose FV challenge, which corresponded with increased levels of NK cell-stimulating cytokines, IL-15 and IL-18. IL-15 and IL-18 neutralization decreased NK cell functions whereas IL-15 and IL-18 therapy improved the NK cell activity. Here, we show the importance of cytokines for NK cell activation in retroviral infections and may suggest that immunotherapy combining the well-tolerable cytokines IL-15 and IL-18 might be an interesting approach for anti-retroviral treatment.

Publisher URL: https://www.ncbi.nlm.nih.gov/pubmed/28904191

DOI: PubMed:28904191

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