IL-18-dependent NKG2D ligand upregulation on accessory cells is mediated by the PI3K/GSK-3 pathway.


Journal Article

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.

Full Text

Cited Authors

  • Brandstadter, JD; Chen, H; Jiang, S; Huang, X; Yang, Y

Published Date

  • June 2017

Published In

Volume / Issue

  • 101 / 6

Start / End Page

  • 1317 - 1323

PubMed ID

  • 28283665

Pubmed Central ID

  • 28283665

Electronic International Standard Serial Number (EISSN)

  • 1938-3673

International Standard Serial Number (ISSN)

  • 0741-5400

Digital Object Identifier (DOI)

  • 10.1189/jlb.2A0816-342R


  • eng