NK cell-extrinsic IL-18 signaling is required for efficient NK-cell activation by vaccinia virus.
NK cells are important for the control of vaccinia virus (VV) in vivo. Recent studies have shown that multiple pathways are required for effective activation of NK cells. These include both TLR-dependent and -independent pathways, as well as the NKG2D activating receptor that recognizes host stress-induced NKG2D ligands. However, it remains largely unknown what controls the upregulation of NKG2D ligands in response to VV infection. In this study using C57BL/6 mice, we first showed that IL-18 is critical for NK-cell activation and viral clearance. We then demonstrated that IL-18 signaling on both NK cells and DCs is required for efficient NK-cell activation upon VV infection in vitro. We further showed in vivo that efficient NK-cell activation in response to VV is dependent on DCs and IL-18 signaling in non-NK cells, suggesting an essential role for NK cell-extrinsic IL-18 signaling in NK-cell activation. Mechanistically, IL-18 signaling in DCs promotes expression of Rae-1, an NKG2D ligand. Collectively, our data reveal a previously unrecognized role for NK cell-extrinsic IL-18 signaling in NK-cell activation through upregulation of NKG2D ligands. These observations may provide insights into the design of effective NK-cell-based therapies for viral infections and cancer.
Molecular Cancer Biology Program, Duke University Medical Center, Durham, North Carolina, USA.
Joshua D
JD
Brandstadter
Xiaopei
X
Huang
Yiping
Y
Yang
D000818:Animals; D003713:Dendritic Cells / Q000276:immunology; D020382:Interleukin-18 / Q000235:genetics / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics / Q000276:immunology; D034521:Nuclear Matrix-Associated Proteins / Q000235:genetics / Q000276:immunology; D029543:Nucleocytoplasmic Transport Proteins / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D014615:Vaccinia / Q000235:genetics / Q000276:immunology*; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology*
D020382:Interleukin-18; C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K; D034521:Nuclear Matrix-Associated Proteins; D029543:Nucleocytoplasmic Transport Proteins; C490521:Rae1 protein, mouse
IL-18; NK cells; NKG2D; Rae-1; Vaccinia virus