Abstract
Natural killer (NK) cells play a key role in host defense against cancer and viral infections. It was shown that NK cells are important for the control of acute retroviral infections, but their antiviral activity depends on multiple parameters such as viral inoculation dose, interactions with myeloid cell types and the cytokine milieu. In addition, during an ongoing retroviral infection regulatory T cells (Tregs) can suppress NK cell functions. However, the precise role of Tregs on the initial NK cell response and their immediate antiviral activity after an acute retroviral infection is still unknown. Here we show that thymus-derived Tregs suppress the proliferation, effector functions and cytotoxicity of NK cells very early during acute Friend Retrovirus (FV) infection. Tregs exhibited an activated phenotype and increased the production of the immunosuppressive cytokines IL-10 and TGF-β after FV infection of mice. Neutralization of the immunosuppressive cytokine IL-10 resulted in a significant augmentation of NK cell functions. Although the activation of dendritic cells (DCs) and macrophages as well as the IL-15 cytokine levels were increased after Treg depletion, Tregs mainly affect the NK cell activity in an IL-10-regulated pathway. In this study we demonstrate an IL-10-dependent suppression of NK cells by activated Tregs during the first days of a retroviral infection.
Highlights
Natural killer (NK) cells are very important for the control of viral infections
Initial Friend Retrovirus (FV) infection resulted in moderate numbers of gp70+ cells whereas depletion of Tregs led to a significant increase in gp70+ dendritic cells (DCs), erythroblasts, granulocytes and macrophages (Figure 3B)
We demonstrate a suppressive effect of Tregs on the antiviral NK cell response during the first days of acute retrovirus infection through a mechanism involving the immunosuppressive cytokine IL-10, but not TGF-β
Summary
Natural killer (NK) cells are very important for the control of viral infections. NK cells belong to the innate immune system and express germline-encoded receptors. NK cell activation and expansion during viral infections strongly depend on the cytokine milieu and the interaction with other immune cells [3, 4]. The immediate activation of NK cells is very important for the efficient control of viral infections [13, 14] Viruses such as influenza viruses, herpes viruses or retroviruses cause a number of health issues. NK cells are able to recognize retrovirus-infected cells via the interaction of the activating receptor natural-killer group 2, member D (NKG2D) and its ligand Retinoic acid early inducible 1 (RAE-1) on target cells, a virus-mediated inhibition of ligand expression was reported [17, 18]. The viral inoculation dose was important for this cytokine-mediated induction of NK cells, because only a high-dose infection induced the antiviral activity of NK cells. Our results highlight a novel aspect of Treg-mediated NK cell regulation during the very early phase of retrovirus infection
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