Human NK cells inhibit cytomegalovirus replication through a noncytolytic mechanism involving lymphotoxin-dependent induction of IFN-beta.
NK cells play a key role in host defense against the beta-herpesvirus CMV through perforin-dependent cytolysis. In this study, we show that human NK cells can also control human CMV (HCMV) infection by a noncytolytic mechanism involving induction of IFN-beta in the virus-infected cell. Both IL-2-activated primary NK cells and an IL-2-dependent NK cell line (NK-92) exhibited potent, noncytolytic anti-HCMV activity at very low E:T cell ratios (<0.1:1). Activated NK cells expressed lymphotoxin (LT)alphabeta on their cell surface, and secreted LTalpha and TNF, all of which contributed to the NF-kappaB-dependent release of IFN-beta from infected fibroblasts. IFN-beta produced by fibroblasts and NK cell-produced IFN-gamma combined to inhibit HCMV replication after immediate early gene expression. These results highlight an efficient mechanism used by NK cells to activate IFN-beta expression in the infected target cell that contributes to the arrest of virion production and virus spread without cellular elimination.
Iversen
Ann-Charlotte
AC
Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121, USA.
Norris
Paula S
PS
Ware
Carl F
CF
Benedict
Chris A
CA
D000818:Animals; D003587:Cytomegalovirus / Q000276:immunology*; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D006801:Humans; D016899:Interferon-beta / Q000096:biosynthesis / Q000276:immunology*; D007376:Interleukin-2 / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D008233:Lymphotoxin-alpha / Q000096:biosynthesis / Q000276:immunology*; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism
D007376:Interleukin-2; D008233:Lymphotoxin-alpha; D016328:NF-kappa B; D016899:Interferon-beta