Type I IFNs and IL-18 regulate the antiviral response of primary human γδ 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 γδ 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 γδ T cells in PBMC isolated from individuals with acute dengue fever. Primary γδ T cells responded rapidly in vitro to autologous DV-infected dendritic cells by secreting IFN-γ and upregulating CD107a. The anti-DV IFN-γ response is regulated by type I IFN and IL-18 in a TCR-independent manner, and IFN-γ secreting γδ T cells predominantly expressed IL-18Rα. Antagonizing the ATP-dependent P2X7 receptor pathway of inflammasome activation significantly inhibited the anti-DV IFN-γ response of γδ T cells. Overnight priming with IL-18 produced effector γδ 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-γ response of γδ T cells. Lack of monocytes in culture is associated with lower IL-18 levels in culture supernatant and diminished production of IFN-γ by γδ T cells, whereas addition of exogenous IL-18 restored the IFN-γ response of γδ T cells in monocyte-depleted cocultures with DV-infected DC. Our results indicate that primary γδ T cells contribute to the immune response during DV infection by providing an early source of IFN-γ, 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.
Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Republic of Singapore;
Chen-Yu
CY
Tsai
Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Republic of Singapore;
Ka Hang
KH
Liong
Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Republic of Singapore;
Matilda Gertrude
MG
Gunalan
Singapore-MIT Alliance for Research and Technology, Singapore 138602, Republic of Singapore;
Na
N
Li
Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Republic of Singapore;
Daniel Say Liang
DS
Lim
Division of Infectious Diseases, National University Hospital, Singapore 119074, Republic of Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Republic of Singapore;
Dale A
DA
Fisher
Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Republic of Singapore; Immunology Programme, Life Science Institute, National University of Singapore, Singapore 117456, Republic of Singapore;
Paul A
PA
MacAry
Department of Infectious Diseases, Tan Tock Seng Hospital, Singapore 308433, Republic of Singapore;
Yee Sin
YS
Leo
Singapore Immunology Network, Agency for Science Technology and Research, Singapore 138648, Republic of Singapore; and micwongj@nus.edu.sg.
Siew-Cheng
SC
Wong
Singapore Immunology Network, Agency for Science Technology and Research, Singapore 138648, Republic of Singapore; and.
Kia Joo
KJ
Puan
Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Republic of Singapore; Immunology Programme, Life Science Institute, National University of Singapore, Singapore 117456, Republic of Singapore; Department of Pathology, National University Hospital, Singapore 119074, Republic of Singapore micwongj@nus.edu.sg.
Soon Boon Justin
SB
Wong
D000328:Adult; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D003715:Dengue / Q000276:immunology* / Q000473:pathology; D003716:Dengue Virus / Q000276:immunology*; D005260:Female; D006801:Humans; D007370:Interferon Type I; D007371:Interferon-gamma / Q000276:immunology; D020382:Interleukin-18 / Q000276:immunology*; D053727:Interleukin-18 Receptor alpha Subunit / Q000276:immunology; D052118:Lysosomal-Associated Membrane Protein 1 / Q000276:immunology; D008297:Male; D009000:Monocytes / Q000276:immunology / Q000473:pathology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D058486:Receptors, Purinergic P2X7 / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology
C573415:IFNG protein, human; C000589760:IL18 protein, human; C508572:IL18R1 protein, human; D007370:Interferon Type I; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; D052118:Lysosomal-Associated Membrane Protein 1; D016692:Receptors, Antigen, T-Cell, gamma-delta; D058486:Receptors, Purinergic P2X7; D007371:Interferon-gamma