title: 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.
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Republic of Singapore;
authors.forename: Daniel Say Liang
authors.initials: DS
authors.lastname: Lim
authors.affiliation: Infection and Immunity Programme, Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, Singapore 117609, Republic of Singapore; Singapore Eye Research Institute, Singapore 168751, Republic of Singapore; Office of Clinical Sciences, Duke-National University of Singapore Graduate Medical School, Singapore 169857, Republic of Singapore;
authors.forename: Nobuyo
authors.initials: N
authors.lastname: Yawata
authors.affiliation: Infection and Immunity Programme, Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, Singapore 117609, Republic of Singapore;
authors.forename: Kevin John
authors.initials: KJ
authors.lastname: Selva
authors.affiliation: Singapore-Massachusetts Institute of Technology Alliance for Research and Technology, Singapore 138602, Republic of Singapore;
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Republic of Singapore;
authors.forename: Chen Yu
authors.initials: CY
authors.lastname: Tsai
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Republic of Singapore;
authors.forename: Lai Han
authors.initials: LH
authors.lastname: Yeong
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Republic of Singapore;
authors.forename: Ka Hang
authors.initials: KH
authors.lastname: Liong
authors.affiliation: Program in Emerging Infectious Diseases, Duke-National University of Singapore Graduate Medical School, Singapore 169857, Republic of Singapore;
authors.forename: Eng Eong
authors.initials: EE
authors.lastname: Ooi
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Republic of Singapore;
authors.forename: Mun Keat
authors.initials: MK
authors.lastname: Chong
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Republic of Singapore;
authors.forename: Mah Lee
authors.initials: ML
authors.lastname: Ng
authors.affiliation: Department of Infectious Diseases, Tan Tock Seng Hospital, Singapore 308433, Republic of Singapore;
authors.forename: Yee Sin
authors.initials: YS
authors.lastname: Leo
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Republic of Singapore; Infection and Immunity Programme, Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, Singapore 117609, Republic of Singapore; Singapore Eye Research Institute, Singapore 168751, Republic of Singapore; Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Republic of Singapore; paeym@nus.edu.sg micwongj@nus.edu.sg.
authors.forename: Makoto
authors.initials: M
authors.lastname: Yawata
authors.affiliation: 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; and Department of Pathology, National University Hospital, Singapore 119074, Republic of Singapore paeym@nus.edu.sg micwongj@nus.edu.sg.
authors.forename: Soon Boon Justin
authors.initials: SB
authors.lastname: Wong
mesh_terms: D002450:Cell Communication / Q000276:immunology; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology; D003716:Dengue Virus / Q000276:immunology*; D053222:Fas Ligand Protein / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D053804:Granzymes / Q000235:genetics / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology*; D006801:Humans; D057131:Immune Evasion; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000821:virology; D054353:Perforin / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology*; D019014:fas Receptor / Q000235:genetics / Q000276:immunology
chemical_list: C491901:FAS protein, human; D053222:Fas Ligand Protein; D015395:Histocompatibility Antigens Class I; D007370:Interferon Type I; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D054353:Perforin; D053804:Granzymes