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Human NK Cells Inhibit Cytomegalovirus Replication through a Noncytolytic Mechanism Involving Lymphotoxin-Dependent Induction of IFN-¹

Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121

NK cells play a key role in host defense against the -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- 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) on their cell surface, and secreted LT and TNF, all of which contributed to the NF-B-dependent release of IFN- from infected fibroblasts. IFN- produced by fibroblasts and NK cell-produced IFN- combined to inhibit HCMV replication after immediate early gene expression. These results highlight an efficient mechanism used by NK cells to activate IFN- expression in the infected target cell that contributes to the arrest of virion production and virus spread without cellular elimination.

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