title: IL-18-dependent NKG2D ligand upregulation on accessory cells is mediated by the PI3K/GSK-3 pathway.
abstract: NK cells are critical for the control of viral infections. Studies have shown that efficient NK cell activation in response to infection with VV in vivo requires multiple pathways, including the NKG2D pathway. We have recently shown that IL-18 is necessary for the activation of NK cells through upregulation of the NKG2D ligand Rae-1 on DCs upon VV infection. However, how IL-18R signaling on the accessory cells contributes to Rae-1 up-regulation remains to be defined. In this study, we found IL-18-mediated Rae-1 up-regulation in accessory cells, including macrophages and DCs, to be dependent on the MyD88-PI3K pathway. We further found that IL-18 signaling through PI3K led to inhibition of GSK-3, which we found to be a negative regulator of Rae-1. Finally, we demonstrated that in vivo inhibition of GSK-3 could restore Rae-1 up-regulation on IL18R-/-DCs and partially rescue NK-cell activation against VV, leading to improved viral control in IL-18R-/-mice. Our results showed that IL18-dependent Rae-1 up-regulation on accessory cells is mediated by the MyD88-PI3K-GSK3 pathway. These observations may provide important insights into the design of effective NK cell-based immunotherapies.
authors.affiliation: Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Brandstadter
authors.affiliation: Department of Hematology, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China; and.
authors.forename: Huiyao
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Hematology, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China; and.
authors.forename: Songfu
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA; huang027@mc.duke.edu.
authors.forename: Xiaopei
authors.initials: X
authors.lastname: Huang
authors.affiliation: Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA; yang0029@mc.duke.edu.|Department of Immunology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Yang
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology*; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D053724:Receptors, Interleukin-18 / Q000502:physiology*
chemical_list: C527086:Klrk1 protein, mouse; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D055655:NK Cell Lectin-Like Receptor Subfamily K; D053724:Receptors, Interleukin-18; D019869:Phosphatidylinositol 3-Kinases; D038362:Glycogen Synthase Kinase 3
keywords: NK cells; Rae-1; Vaccinia virus