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Clement C. Leong^*, Tara L. Chapman, Pamela J. Bjorkman, Danuska Formankova, Edward S. Mocarski, Joseph H. Phillips^*, and Lewis L. Lanier^*

From the ^* Department of Immunobiology, DNAX Institute of Molecular and Cell Biology, Palo Alto, California 94304; the Division of Biology 156-29 and Howard Hughes Medical Institute, California Institute of Technology, Pasadena, California 91125; and the Department of Microbiology and Immunology, Stanford University, Stanford, California 94305

Natural killer (NK) cells have been implicated in early immune responses against certain viruses, including cytomegalovirus (CMV). CMV causes downregulation of class I major histocompatibility complex (MHC) expression in infected cells; however, it has been proposed that a class I MHC homolog encoded by CMV, UL18, may act as a surrogate ligand to prevent NK cell lysis of CMV-infected cells. In this study, we examined the role of UL18 in NK cell recognition and lysis using fibroblasts infected with either wild-type or UL18 knockout CMV virus, and by using cell lines transfected with the UL18 gene. In both systems, the expression of UL18 resulted in the enhanced killing of target cells. We also show that the enhanced killing is due to both UL18-dependent and -independent mechanisms, and that the killer cell inhibitory receptors (KIRs) and CD94/NKG2A inhibitory receptors for MHC class I do not play a role in affecting susceptibility of CMV-infected fibroblasts to NK cell–mediated cytotoxicity.

Key Words: cytomegalovirus • class I major histocompatibility complex • UL18 • natural killer cell • cytotoxicity

DNAX Research Institute is supported by the Schering Plough Corporation. T.L Chapman is supported by a National Defense Science and Engineering Pre-Doctoral Fellowship.

Abbreviations used: β₂M, β₂-microglobulin; CHO, Chinese hamster ovary; cIg, control Ig; hCMV, human cytomegalovirus; HFF, human foreskin fibroblasts; ICAM-1, intracellular adhesion molecule 1; KIR, killer cell inhibitory receptor; MOI, multiplicity of infection.

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