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

Little is known about the cellular mechanisms of innate immunity against dengue virus (DV) infection. Specifically, the gamma delta T cell response to DV has not been characterized in detail. In this article, we demonstrate that markers of activation, proliferation, and degranulation are upregulated on gamma delta T cells in PBMC isolated from individuals with acute dengue fever. Primary gamma delta T cells responded rapidly in vitro to autologous DV-infected dendritic cells by secreting IFN-gamma and upregulating CD107a. The anti-DV IFN-gamma response is regulated by type I IFN and IL-18 in a TCR-independent manner, and IFN-gamma secreting gamma delta T cells predominantly expressed IL-18Ra. Antagonizing the ATP-dependent P2X(7) receptor pathway of inflammasome activation significantly inhibited the anti-DV IFN-gamma response of gamma delta T cells. Overnight priming with IL-18 produced effector gamma delta T cells with significantly increased ability to lyse autologous DV-infected dendritic cells. Monocytes were identified as accessory cells that augmented the anti-DV IFN-gamma response of gamma delta T cells. Lack of monocytes in culture is associated with lower IL-18 levels in culture supernatant and diminished production of IFN-gamma by gamma delta T cells, whereas addition of exogenous IL-18 restored the IFN-gamma response of gamma delta T cells in monocyte-depleted cocultures with DV-infected DC. Our results indicate that primary gamma delta T cells contribute to the immune response during DV infection by providing an early source of IFN-gamma, as well as by killing DV-infected cells, and suggest that monocytes participate as accessory cells that sense DV infection and amplify the cellular immune response against this virus in an IL-18-dependent manner.