Expression of ICP0 Is Sufficient to Trigger Natural Killer Cell Recognition of Herpes Simplex Virus–Infected Cells by Natural Cytotoxicity Receptors

Abstract

Natural killer (NK) cells are an important component of the immune response to a number of viruses; however, the molecular basis of how NK cells discriminate between healthy and virus-infected cells is largely unknown. Here, we show that expression of the immediate-early gene product ICP0 is sufficient to produce an increased susceptibility to NK lysis of herpes simplex virus (HSV)-infected cells. This effect does not depend on down-regulation of major histocompatibility complex class I molecules or on the induction of expression of ligands for the activating NKG2D receptor. Detection by NK cells of the changes in the target cell induced by HSV ICP0 gene expression depends on the natural cytotoxicity receptors (NCRs) NKp30, NKp44, and NKp46. To our knowledge, this is the first identification of a viral gene that triggers the up-regulation of cellular ligands for the NCR; moreover, these observations highlight the importance of the NCR for immunosurveillance of viral infection by NK cells.

Critical and Differential Roles of NKp46- and NKp30-Activating Receptors Expressed by Uterine NK Cells in Early Pregnancy

“…Another nonexclusive possibility is that viral infection may induce an increased expression of specific ligands of NKp46 such that the balance of positive signaling becomes dominant and favors dNK cell activation. This possibility is supported by a recent observation that the immediate early herpes simplex virus gene product ICP0 triggers the up-regulation of cellular ligands for the NCR including NKp46 (43). Some NKG2D or other NCR ligands are also up-regulated in cells infected with cytomegalovirus (39).…”

“…The recent observations that NCR1, a murine ortholog of NKp46, recognized influenza virus-infected cells and that such infection was lethal in the absence of NCR1 (42) favor such hypothesis. One can speculate that NKp46 would detect up-regulated specific ligands in virally infected cells (43). A recent report indeed indicated that infection of JEG-3 and JAR trophoblast cell lines with the same virus increased expression of NKp46 ligand and their susceptibility to killing by NK cells (O. Mandelboim, personal communication).…”

Optimal activation of Fc-mediated effector functions by influenza virus hemagglutinin antibodies requires two points of contact

“…In addition, HIV and herpes simplex virus also up-regulate the expression of other natural cytotoxic receptors (41,42). Although the genetically modified Jurkat T cells used in this study might not express pattern recognition receptors, it is plausible that HA can bind to other cell surface receptors on the Jurkat T cells and contribute to antibody-mediated effector activation.…”

Modulation of CD112 by the alphaherpesvirus gD protein suppresses DNAM-1–dependent NK cell-mediated lysis of infected cells

“…The sum of these signals determines the outcome of NK cell effector responses including cytotoxicity against NK-sensitive targets (20). A variety of NK activating receptors are involved in recognition of virus-infected cells (18,(21)(22)(23)(24)(25)(26). One of the important NK activating receptors is DNAX accessory molecule 1 (DNAM-1), which binds to CD112 (nectin-2) and CD155 (poliovirus receptor, PVR), whose expression can be induced in both virus infected and tumor cells (5,(26)(27)(28).…”