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Evolutionary struggles between NK cells and viruses

Key Points

  • Natural killer (NK) cells can participate in immune responses either directly or indirectly. In the absence of cognate recognition of virus-infected cells, bystander NK cells can respond to interferons and cytokines, such as interleukin-12 (IL-12) and IL-18, induced during viral infections, and respond by secreting interferon-γ, as well as other cytokines and chemokines. Alternatively, NK cells can directly interact with and kill virus-infected cells by the release of perforin and granzymes.

  • NK-cell-mediated resistance to mouse cytomegalovirus (MCMV) is conferred by the activating, DAP12-associated Ly49H receptor in C57BL/6 mice, which binds the MCMV-encoded m157 glycoprotein on the surface of virus-infected cells. In certain other mouse strains, m157 binds to the inhibitory Ly49I receptor, thereby providing potential protection of the virus-infected cells from NK-cell attack. Recently, another activating NK-cell receptor, Ly49P, in the Ma/My mouse strain has been shown to recognize MCMV-infected cells that express H2-Dk.

  • NK cells also provide resistance against mousepox virus in certain mouse strains, such as C57BL/6, and mousepox resistance has been mapped to the NK-cell complex (NKC) on mouse chromosome 6, which contains the Ly49 genes and other genes preferentially expressed by NK cells, including NKR-P1, CD94 and the NKG2 genes.

  • Population-based studies in humans have implicated genes in the KIR family and MHC class I in resistance to progression to AIDS in HIV-infected individuals and in the resolution of hepatitis C virus infections. Further studies are needed to establish the molecular basis for these correlations.

  • Viruses have evolved sophisticated mechanisms to evade recognition by NK cells. Both human and mouse cytomegalovirus have evolved several genes encoding proteins that interact with and degrade the protein ligands of the activating NKG2D receptors expressed by NK cells and T cells. Similarly, certain monkeypox and cowpox viruses have also evolved genes that encode soluble, secreted NKG2D antagonists, presumably to avoid detection by this receptor. Viral mimics of MHC class I molecules expressed by the cytomegaloviruses can function as agonists for the inhibitory receptors on NK cells. These observations indicate an evolutionary struggle between NK cells and viruses to allow preservation of both the host and the pathogen.

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.

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Figure 1: Activating and inhibitory NK-cell receptors for MCMV.
Figure 2: HCMV and MCMV proteins affecting NK-cell-mediated recognition of virus-infected cells.
Figure 3: Interactions between DCs and NK cells during MCMV infection.

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Acknowledgements

I thank R. Welsh, L. Sigal, M. Fang, E. Mocarski, S. Vilarinho and members of my laboratory for helpful discussion. I am an American Cancer Society Research Professor supported by grants from the National Institutes of Health, USA.

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Glossary

Granzymes

Proteolytic enzymes that are present in the cytoplasmic granules of cytotoxic T lymphocytes and natural killer cells. Granzymes activate caspases in the target cells, and this causes apoptosis.

Perforin

A protein with similarity to the ninth component of complement. It is present in the cytoplasmic granules of cytotoxic T lymphocytes and natural killer cells. Perforin subunits assemble into a pore-forming structure that causes membrane damage in the target cell.

Ma/My mice

A strain of inbred mice that is relatively resistant to infection with mouse cytomegalovirus (MCMV). These mice express the activating NK-cell receptor Ly49P, which recognizes MCMV-infected cells that express H2-Dk.

Plasmacytoid dendritic cells

(pDCs). Also known as interferon-producing cells. A type of dendritic cell that is specialized for the production of type I interferons after stimulation by viruses.

HLA-E

A human MHC class I molecule that is composed of the HLA-E heavy chain, β2-microglobulin, and a peptide that is often derived from the leader peptides of other MHC class I polypeptides or from certain microbial pathogens.

Missing-self hypothesis

A hypothesis by Klas Karre and colleagues proposing that natural killer cells can recognize and attack cells that do not express MHC class I molecules — in other words, that are 'missing self'. This provides a surveillance mechanism to patrol for cells infected with viruses that downregulate MHC class I expression to evade detection by cytotoxic T lymphocytes.

NKT cells

(Natural killer T cells). A subset of T cells expressing an invariant αβ T-cell receptor (TCR) that can recognize the lipid α-galactoceramide bound to CD1d. Another population referred to as non-classical or type II NKT cells also recognize CD1 d-associated antigens, but are unable to bind α-galactoceramide and do not express the invariant αβ TCR.

Bw4 epitope

The proteins encoded by the HLA-B gene (960 alleles) are divided into two groups, designated Bw4 and Bw6, based on a serologically defined epitope at amino-acid residues 77–83 in the α1 domain of the HLA-B heavy chain. The Bw4 epitope is also present in a small subset of HLA-A proteins. The Bw4 epitope is recognized by the inhibitory natural-killer-cell receptor KIR3DL1.

Immunoreceptor tyrosine-based inhibitory motif

(ITIM). A sequence motif, defined as Ile/Val/Leu/Ser-x-Tyr-x-x-Leu/Val (where x denotes any amino acid), present in the cytoplasmic domain of inhibitory receptors. When the tyrosine residue is phosphorylated, ITIMs recruit lipid or tyrosine phosphatases, such as SHP1, SHP2 or SHIP, which mediate the inhibitory function of these receptors.

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Lanier, L. Evolutionary struggles between NK cells and viruses. Nat Rev Immunol 8, 259–268 (2008). https://doi.org/10.1038/nri2276

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