Effects of Human Cytomegalovirus Infection on Ligands for the Activating NKG2D Receptor of NK Cells: Up-Regulation of UL16-Binding Protein (ULBP)1 and ULBP2 Is Counteracted by the Viral UL16 Protein

Abstract

Human CMV (HCMV) interferes with NK cell functions at various levels. The HCMV glycoprotein UL16 binds some of the ligands recognized by the NK-activating receptor NKG2D, namely UL16-binding proteins (ULBP) 1 and 2 and MHC class I-related chain B, possibly representing another mechanism of viral immune escape. This study addressed the expression and function of these proteins in infected cells. HCMV induced the expression of all three ULBPs, which were predominantly localized in the endoplasmic reticulum of infected fibroblasts together with UL16. However, while at a lower viral dose ULBP1 and 2 surface expression was completely inhibited compared to ULBP3, at a higher viral dose cell surface expression of ULBP1 and ULBP2 was delayed. The induction of ULBPs correlated with an increased dependency on NKG2D for recognition; however, the overall NK sensitivity did not change (suggesting that additional viral mechanisms interfere with NKG2D-independent pathways for recognition). Infection with a UL16 deletion mutant virus resulted in a different pattern compared to the wild type: all three ULBP molecules were induced with similar kinetics at the cell surface, accompanied by a pronounced, entirely NKG2D-dependent increase in NK sensitivity. Together our findings show that upon infection with HCMV, the host cell responds by expression of ULBPs and increased susceptibility to the NKG2D-mediated component of NK cell recognition, but UL16 limits these effects by interfering with the surface expression of ULBP1 and ULBP2.

Activating NK‐cell receptors co‐stimulate CD4+CD28− T cells in patients with rheumatoid arthritis

“…Also, several studies indicate increased NKR expression on T cells in CMV-infected individuals [31,50]. Interestingly, CMV downregulates expression of ligands for NKG2D (ULBP1 and ULBP2) and DNAM-1 (CD155, poliovirus receptor) on infected cells [51,52]. Downregulation of ligands for these NKR by CMV may promote persistent CMV infection.…”

Expression and function of NKG2D in CD4+ T cells specific for human cytomegalovirus

“…macrophages) or inducible by proinflammatory cytokines, and it is impaired by some virus molecules [53]. On the other hand, NKG2D ligands are displayed in HCMV-infected cells, and immune evasion mechanisms that interfere with their expression indirectly reflect the importance of the KLR in the anti-viral response [18,22,[27][28][29].…”

“…The KLR activates NK cells and costimulates the response of CD8 + CTL against human cytomegalovirus (HCMV)-infected targets [18,26]; the identification of immune evasion mechanisms that interfere with surface expression of NKG2D ligands underline its importance in the antiviral response. The UL16 glycoprotein inhibits surface expression of MICB, ULBP1, ULBP2 [22,[27][28][29] and also interacts with RAET1G [24]. The gpUL142 HCMV molecule has been recently reported to down-regulate MICA [30].…”

Inhibitory Receptor Signals Suppress Ligation-Induced Recruitment of NKG2D to GM1-Rich Membrane Domains at the Human NK Cell Immune Synapse

“…NKG2D is expressed on all NK cells and a subset of T cells and recognizes stressinducible ligands including MHC class I chain-related gene A (MICA), MICB, and UL-16-binding proteins in humans (12). NKG2D ligands are found on many tumors and are up-regulated upon infection (13,14). Several studies have demonstrated that the enhanced cell surface expression of NKG2D ligands results in increased susceptibility of MHC I expressing tumors to NK cell cytotoxicity (15)(16)(17).…”