Immune evasion of natural killer cells by viruses

Abstract

Natural killer (NK) cells are important in the host resistance to viral infections. They are among the first cells to sense the release of proinflammatory cytokines, as well as the downregulation of surface MHC class I molecules and molecules induced by viral invasion of cells. Various viral functions have evolved to counter NK cell responses illustrating the evolutionary struggles between viruses and NK cells. Ligands for NK cell receptors are primary targets for viral immunoevasion. In order to counteract NK cell activation via the 'missing self'-axis, viruses encode proteins which serve as ligands for inhibitory NK cell receptors. Viruses also downmodulate the ligands for the activating NK cell receptors and encode soluble ligands which block these receptors. In addition to viral immunoregulatory proteins, regulatory RNAs can also inhibit the expression of ligands for NK cell receptors. Improving our understanding of viral regulation of NK cell function could be essential for designing more efficient measures in the prophylaxis and treatment of virus-induced pathology.

Figure 1. A schematic overview of viral intereference with NK cell activation via NKG2D

(a)MCMV downmodulates ligands for the NKG2D receptor. m145, m152, m155 affect cell surface expression of MULT-1, RAE-1 family and H60, respectively. m138 is the first described MCMV protein with a dual function on NKG2D ligands, affecting both MULT-1 and H60. The figure shows that the deletion of either of these viral proteins results in the reconstitution of the surface expression of the respective ligands and the conversion of the virus from being NK cell-resistant to become NK cell-sensitive. (b) HCMV acts in a similar manner as MCMV, also exploiting different mechanisms. HCMV UL16 downmodulates ULBP-1 and -2, and also MICB whereas UL142 downmodulates full-length MICA. The truncated form of MICA shows resistance to downmodulation by HCMV. (c) After virus enters the cell, its genome is transcribed into mRNA but also noncoding RNA molecules. By using the cellular machinery, HCMV expresses its own miRNAs, including miR-UL112, which forms the RISC complex and binds the 3′ UTR region of MICB. In this way, miR-UL112 inhibits the translation of MICB mRNA, thus preventing it in reaching the cell surface and signaling. (d) Orthopoxviruses utilize a previously undescribed mode of interference with NKG2D signaling. They secrete a soluble protein, named OMCP, which competitively binds to NKG2D and antagonizes the function of cellularly expressed ligands.