Evolutionary struggles between NK cells and viruses

Abstract

Natural killer (NK) cells are well recognized for their ability to provide a first line of defence against viral pathogens and they are increasingly being implicated in immune responses against certain bacterial and parasitic infections. Reciprocally, viruses have devised numerous strategies to evade the activation of NK cells and have influenced the evolution of NK-cell receptors and their ligands. NK cells contribute to host defence by their ability to rapidly secrete cytokines and chemokines, as well as to directly kill infected host cells. In addition to their participation in the immediate innate immune response against infection, interactions between NK cells and dendritic cells shape the nature of the subsequent adaptive immune response to pathogens.

Figure 1. Activating and inhibitory NK-cell receptors for MCMV

a. Natural killer (NK) cells from C57BL/6 mice express the DAPl2-associated activating Ly49H receptor, which initiates cell-mediated cytotoxicity (through perforin and granzymes), cytokine production (such as interferon-γ (IFNγ)) and proliferation when these NK cells encounter mouse cytomegalovirus (MCMV)-infected cells that express the viral protein m157 on their cell surface, b. NK cells in certain other strains of mice, such as 129/J mice, have inhibitory receptors such as Ly49l¹²⁹, which binds to m157 on the cell surface of MCMV-infected cells and dampens the NK-cell response. Ly49l¹²⁹ binds both host MHC class I ligands and MCMV m157, whereas Ly49H binds only m157 and not host MHC class I molecules. ITAM, immunoreceptor tyrosine-based activation motif; HIM, immunoreceptor tyrosine-based inhibitory motif.

Figure 2. HCMV and MCMV proteins affecting NK-cell-mediated recognition of virus-infected cells

The virus-encoded proteins m04, m06 and m152 inhibit MHC class I expression on the surface of mouse cytomegalovirus (MCMV)-infected cells by a complex process that differs depending on the MHC class I alleles present in the host. m04 can be expressed on the cell surface of MCMV-infected cells in a complex with MHC class I molecules; however, how this influences the recognition of MHC class I molecules by receptors on natural killer (NK) cells or T cells is unknown. Human cytomegalovirus (HCMV) also blocks the expression of MHC class I molecules in infected cells in an allele-specific manner (reviewed in REF. 65). The HCMV proteins US2, US3, US10 and US11 interact with the MHC class I heavy chains on their own or with the heavy chains complexed with β₂-microglobulin, ultimately resulting in their degradation, whereas US6 blocks TAP (transporter associated with antigen processing) function and UL83 inhibits protein entry into the proteasome. UL40 provides a leader peptide that binds to HLA-E allowing its expression on the surface of HCMV-infected cells, presumably for interactions with the inhibitory CD94-NKG2A(NK group 2, member A) receptor on NK cells. Both MCMV and HCMV inhibit expression of the NKG2D ligands in infected cells. The MCMV-encoded m152 protein targets RAE1 (retinoicacid early transcript 1), as well as MHC class I molecules, for degradation; m145 and m138 cooperate to prevent MULTl (murine UL16-binding protein (ULBP)-like transcript 1) expression; and m138 and m155 cause degradation of H60. In humans, the HCMV-encoded UL16 protein inhibits expression of MICB (MHC-class-I-polypeptide-related sequence B), ULBP1, ULBP2 and RAET1G (retinoic-acid early transcript 1C), whereas UL142 prevents expression of MICA. Certain allelesof MICA, such as the common allele MICA*008, are resistant to downregulation by HMCV because of a truncation of the cytoplasmic domain. CD155, a ligand for the activating NK-cell receptors DNAM1 (DNAX adhesion molecule 1)and CD96, is targeted by UL141.

Figure 3. Interactions between DCs and NK cells during MCMV infection

Infection with mouse cytomegalovirus (MCMV) triggers the production of type I interferons(IFNs) by plasmacytoid dendritic cells (pDCs; also known as interferon-producing cells (IPCs)) through Toll-like receptor 9 (TLR9) and the production of cytokines, such as interleukin-12 (IL-12), by DCs through TLR3, as well as type I IFN-induced production of IL-15 by DCs. IL-15 is presented to natural killer (NK) cells by the IL-15 receptor α-chain (IL-15Rα) on the cell surface of DCs, resulting in NK-cell activation. IL-12, in combination with IL-15 and potentially other pro-inflammatory cytokines, induces the secretion of IFNγ by NK cells. About half of the NK cells in C57BL/6 mice express the DAP12-associated Ly49H receptor and recognize the MCMV-encoded m157 glycoprotein that is present on the cell surface of MCMV-infected cells. Interactions between Ly49H on the NK cells and m157 on the infected cells cause extensive proliferation of the Ly49H⁺ NK cells, as well as cell-mediated cytotoxicity (due to the directional release of perforin and granzymes) and cytokine production. IFNγ produced by activated NK cells amplifies the maturation and effector functions of DCs and other cells in the microenvironment. ITAM, immunoreceptor tyrosine-based activation motif.