Modulation of natural killer cells by human cytomegalovirus

Abstract

Human cytomegalovirus (HCMV) causes lifelong, persistent infections and its survival is under intense, continuous selective pressure from the immune system. A key aspect of HCMV's capacity for survival lies in immune avoidance. In this context, cells undergoing productive infection exhibit remarkable resistance to natural killer (NK) cell-mediated cytolysis in vitro. To date, six genes encoding proteins (UL16, UL18, UL40, UL83, UL141 and UL142) and one encoding a microRNA (miR-UL112) have been identified as capable of suppressing NK cell recognition. Even though HCMV infection efficiently activates expression of ligands for the NK cell activating receptor NKG2D, at least three functions (UL16, UL142 and miR-UL112) act in concert to suppress presentation of these ligands on the cell surface. Although HCMV downregulates expression of endogenous MHC-I, it encodes an MHC-I homologue (UL18) and also upregulates the expression of cellular HLA-E through the action of UL40. The disruption of normal intercellular connections exposes ligands for NK cell activating receptors on the cell surface, notably CD155. HCMV overcomes this vulnerability by encoding a function (UL141) that acts post-translationally to suppress cell surface expression of CD155. The mechanisms by which HCMV systematically evades (or, more properly, modulates) NK cell recognition constitutes an area of growing understanding that is enhancing our appreciation of the basic mechanisms of NK cell function in humans.

Fig. 1

Infection with low passage HCMV strains provides maximum protection against NK cell attack. (a) HFs infected with high passage strain AD169 show significant protection from NK cell lysis, compared with uninfected targets or targets infected with an AD169 UL40 deletion mutant. Cells infected with strain Toledo or other low passage isolates (not shown) were completely resistant to NK cell attack. (b) The ability to induce complete resistance to NK cell lysis could be restored by inserting the strain Toledo ULb′ sequence into high passage strain Towne to produce recombinant Tx4 (kindly provided by E. Mocarski). Modified from Tomasec et al. (2005).

Fig. 2

Upregulation of HLA-E by HCMV gpUL40. HLA-E exhibits only minor allelic variation and binds a conserved nonameric peptide derived from the leader sequence of HLA-A, -B, -C and -G in a TAP-dependent manner. The HCMV US6 protein binds TAP to inhibit peptide transport. Consequently, US6 inhibits both MHC-I antigen presentation and surface expression of HLA-E. However, the leader sequence of gpUL40 also encodes an HLA-E-binding peptide that is released to the ER independently of TAP. UL40 thus upregulates cell surface expression of HLA-E, a recognized ligand for the NK cell inhibitory receptor CD94/NKG2A.

Fig. 3

Gene map of the HCMV strain Merlin genome. Inverted repeat regions are shown in a thicker format than the two unique regions. Protein-coding regions are indicated by coloured arrows grouped according to the key, with gene nomenclature below. Introns are shown as narrow white bars. Genes whose names commence with RL, TRS and IRS are given in full, but the UL and US prefixes have been omitted from UL1-UL150 (12–194 kbp) and US1-US34A (199–231 kbp). Colours differentiate between genes on the basis of conservation among the Alpha, Beta- and Gammaherpesvirinae (core genes) or between the Beta- and Gammaherpesvirinae (sub-core genes), with subsets of the remaining non-core genes grouped into gene families. The location of the UL/b′ region (UL148 to UL150) is highlighted by thick horizontal lines. Modified from Dolan et al. (2004) by permission of the Society for General Microbiology.