NKG2D-mediated Natural Killer Cell Protection Against Cytomegalovirus Is Impaired by Viral gp40 Modulation of Retinoic Acid Early Inducible 1 Gene Molecules

Abstract

Natural killer (NK) cells play a critical role in the innate immune response against cytomegalovirus (CMV) infections. Although CMV encodes several gene products committed to evasion of adaptive immunity, viral modulation of NK cell activity is only beginning to be appreciated. A previous study demonstrated that the mouse CMV m152-encoded gp40 glycoprotein diminished expression of ligands for the activating NK cell receptor NKG2D on the surface of virus-infected cells. Here we have defined the precise ligands that are affected and have directly implicated NKG2D in immune responses to CMV infection in vitro and in vivo. Murine CMV (MCMV) infection potently induced transcription of all five known retinoic acid early inducible 1 (RAE-1) genes (RAE-1α, RAE-1β, RAE-1δ, RAE-1ɛ, and RAE-1γ), but not H-60. gp40 specifically down-regulated the cell surface expression of all RAE-1 proteins, but not H-60, and diminished NK cell interferon γ production against CMV-infected cells. Consistent with previous findings, a m152 deletion mutant virus (Δm152) was less virulent in vivo than the wild-type Smith strain of MCMV. Treatment of BALB/c mice with a neutralizing anti-NKG2D antibody before infection increased titers of Δm152 virus in the spleen and liver to levels seen with wild-type virus. These experiments demonstrate that gp40 impairs NK cell recognition of virus-infected cells through disrupting the RAE-1–NKG2D interaction.

Human Cytomegalovirus Encodes an MHC Class I-Like Molecule (UL142) That Functions to Inhibit NK Cell Lysis

“…However, 11 other ORFs in MCMV were also shown to have MHC-like folds and to be transmembrane glycoproteins (26). Three of these, m145, m152, and m155 have subsequently been shown to sequester stress-induced molecules (MULT1, RAE1, and H60, respectively) that would normally engage the NKG2D-activating NK receptors and interfere with NK cell activation and virus control (27)(28)(29)(30). UL16 of HCMV is known to sequester only some of the human ligands for NKG2D: it does not affect MICA or ULBP3.…”

“…Subsequent investigations have shown that three other ORFs which had been identified as having MHC-like folds in MCMV, m145 and m155, were able to mediate NK evasion, as these molecules sequestered cellular ligands that would bind the activating NK receptor NKG2D (27)(28)(29)(30).…”

Regulation of CD1d expression and function by a herpesvirus infection

“…Recent studies of CMV have focused on the selective modulation of NK cell-activating receptors by viral proteins (24,43). This is thought not only to impair NK cell-mediated lysis of infected cells, but also to delay NK cell activation of the adaptive response and subsequent polarization of the helper T cell response (44).…”

“…The large number of redundant inhibitors of MHC class I suggests an important role for CTLs in defending against herpesvirus infection. Similarly, many herpesviruses encode proteins that impair type I IFN induction or action (20)(21)(22)(23), and CMV has recently been found to encode proteins that block NK cellactivating receptors (24).…”

NKG2D Receptor Signaling Enhances Cytolytic Activity by Virus-Specific CD8+T Cells: Evidence for a Protective Role in Virus-Induced Encephalitis

“…at the same concentration as that used for the innate and acute studies. Following a single injection of anti-NKG2D CX5 MAb, antibody can be detected up to 2 weeks postinjection, with reduced NKG2D receptor expression on NK cells lasting for at least 7 days (42,57,63,64, and L. L. Lanier, unpublished observations).…”