The Combination of Type I IFN, TNF-α, and Cell Surface Receptor Engagement with Dendritic Cells Enables NK Cells To Overcome Immune Evasion by Dengue Virus

Abstract

Clinical studies have suggested the importance of the NK cell response against dengue virus (DenV), an arboviral infection that afflicts >50 million individuals each year. However, a comprehensive understanding of the NK cell response against dengue-infected cells is lacking. To characterize cell-contact mechanisms and soluble factors that contribute to the antidengue response, primary human NK cells were cocultured with autologous DenV-infected monocyte-derived dendritic cells (DC). NK cells responded by cytokine production and the lysis of target cells. Notably, in the absence of significant monokine production by DenV-infected DC, it was the combination of type I IFNs and TNF-α produced by DenV-infected DC that was important for stimulating the IFN-γ and cytotoxic responses of NK cells. Cell-bound factors enhanced NK cell IFN-γ production. In particular, reduced HLA class I expression was observed on DenV-infected DC, and IFN-γ production was enhanced in licensed/educated NK cell subsets. NK–DC cell contact was also identified as a requirement for a cytotoxic response, and there was evidence for both perforin/granzyme as well as Fas/Fas ligand–dependent pathways of killing by NK cells. In summary, our results have uncovered a previously unappreciated role for the combined effect of type I IFNs, TNF-α, and cell surface receptor–ligand interactions in triggering the antidengue response of primary human NK cells.

Type I IFNs and IL-18 Regulate the Antiviral Response of Primary Human γδ T Cells against Dendritic Cells Infected with Dengue Virus

“…3A indicate that the anti-DV IFN-g response of gd T cells is also regulated by type I IFN. However, significant amounts of type I IFN are released by purified cultures of DVinfected DC (26,34,35), so that supplementing the culture medium with type I IFN, even at doses as high as 10,000 U/ml, did not increase the anti-DV IFN-g response of purified gd T cells (Fig. 4C).…”

“…Although DV-infected DC produce significant amounts of type I IFN (26,34,35), at levels that are not limiting for IFN-g production by gd T cells (Fig. 4C), the amount of IL-18 that is released by these infected cells is sufficient only for a basal anti-DV response.…”

“…Because elevated levels of type I IFN and IL-18 have been found in the plasma of patients infected with DV (43, 44), IFN-g production by gd T cells triggered by this cytokine combination may represent a physiologically relevant source of early IFN-g that fosters an effective anti-DV Th1 adaptive-immune response. A possible mechanism is by helping to reverse the early defect in IL-12 secretion that was observed in DV-infected DC (26,35).…”

Peripheral Organs of Dengue Fatal Cases Present Strong Pro-Inflammatory Response with Participation of IFN-Gamma-, TNF-Alpha- and RANTES-Producing Cells

“…Due to the close morphology, NK cells and mucosal-associated invariant T (MAIT) cells are examples of CD8-expressing subsets that may also present roles in severe dengue. While the participation of NK cells in DENV infection has been extensively reported [53–57], the role of MAIT cells in such disease is still a novel and eye-catching mater of debate [58]. …”

Dendritic Cell–Derived IL-32α: A Novel Inhibitory Cytokine of NK Cell Function

“…For example, fractalkine promotes NK activation by DCs (17), IL-15 is important for the induction of effector molecules (18,19), whereas IL-12, IL-18, and TNF-a are important for IFN-g production by NK cells (20)(21)(22).…”