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Chapter 16 : Natural Killer Cell Response against Viruses

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Abstract:

During viral infection, cells of the innate immune system such as monocytes, dendritic cells (DCs), natural killer (NK) cells, and polymorphonuclear leukocytes serve several functions: alerting the host to invading pathogens, providing early containment of pathogens, mediating antimicrobial effects against pathogens, directing the nature of the immune response, and participating in wound healing and tissue repair. During viral infection, antigen-presenting cells (APCs) sense viral nucleic acids via members of the Toll-like receptor family (TLR3, 7, 8, and 9) and intracellular sensors such as the RNA helicases RIG-I, mda5, and LGP2. Ablating the pleiotropic activity of type I interferons (IFNs) during viral infection in mice containing a genetic deletion of the type I interferon receptor resulted in higher virus replication and severe pathology or death. The potent antiviral responses of NK cells that directly clear certain viral infections to promote host survival unmistakably demonstrate how crucial these cytotoxic cells are; at the same time, the importance of NK cell activity is equally demonstrated by the discovery of the many strategies different viruses employ to specifically evade detection by NK cells. Although viruses evolve because of the pressures exerted by cells of the immune system, there is evidence that the mammalian immune system also adapts in response to viral evasion mechanisms. As more viral ligands of activating NK cell receptors are uncovered, we will have a greater appreciation of the evolution of mammalian receptors on NK cells at the population level driven by viruses.

Citation: Sun J, Lanier L. 2011. Natural Killer Cell Response against Viruses, p 197-207. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch16

Key Concept Ranking

MHC Class I
0.5480862
Hepatitis C virus
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West nile virus
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FIGURE 1

Specific recognition of virally infected cells by the immune system. During viral infection of a target cell, NK cells, and CD8 cytotoxic T lymphocytes (CTL) can respond by sensing the presence of virus through various mechanisms. In the cytoplasm of infected cells, viral proteins generated from translation of viral transcripts can be processed by the proteosome into peptides. Viral peptides presented on MHC class I will be recognized by CTL expressing specific T-cell receptors (TCR). Viral transcription can also result in products that are directly expressed on the cell surface as whole proteins. NK cells expressing ligand-specific activating receptors, such as Ly49H, directly recognize these viral molecules. Lastly, viral infection can lead to cellular “stress” and the upregulation of stress-induced molecules such as members of the NKG2D family of ligands. All NK cells and subsets of CTL express the activating NKG2D receptor and will recognize the presence of viral infection via the expressing of NKG2D ligands, unless the virus evolves mechanisms to prevent expression of the NKG2D ligand proteins on the surface of infected cells.

Citation: Sun J, Lanier L. 2011. Natural Killer Cell Response against Viruses, p 197-207. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch16
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FIGURE 2

NK-cell activation during viral infection. During viral infection, viral particles that actively infect or are taken up by DCs will trigger TLRs and intracytosolic sensors, leading to activation and maturation of the DC. Activated DCs produce type I IFNs and proinflammatory cytokines such as IL-12. pDCs sense viral infection primarily through TLR7 and TLR9, and are cells specializing in type I IFN production. Type I IFNs and IL-12 will activate NK cells, which constitutively express receptors for these cytokines. NK cells can also be stimulated when cell surface activating receptors engage viral or virally induced ligands. Activation of the NK cell leads to multiple effector functions such as cytokine secretion and cytotoxicity.

Citation: Sun J, Lanier L. 2011. Natural Killer Cell Response against Viruses, p 197-207. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch16
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Image of FIGURE 3
FIGURE 3

Type I IFN and IL-12 signaling in NK cells augments effector functions. During many viral infections, type I IFN (IFN-α/β) and IL-12 are produced by infected cells. NK cells possess the cytokine receptors to sense inflammatory cytokines. Both type I IFNs and IL-12 bind heterodimeric receptors that signal through the JAK-STAT pathway. The type I IFN receptor induces phosphorylation of JAK1 and TYK2, resulting in phosphorylation and dimerization of STAT1 and STAT2. Along with IRF9, STAT1-STAT2 form the ISGF3 complex, and following nuclear translocation activates transcription of IFN-induced gene targets. Similarly, the IL-12 receptor consists of two chains that phosphorylate JAK2 and TYK2 during signal transduction, leading to phosphorylation and activation of various STATs including STAT4. STAT4 homodimers translocate into the nucleus and promote the transcription of target genes. Type I IFN and IL-12 signaling in NK cells can result in the induction of an “antiviral state,” the production of effector cytokines, cytotoxicity of virally infected cells, and proliferation.

Citation: Sun J, Lanier L. 2011. Natural Killer Cell Response against Viruses, p 197-207. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch16
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FIGURE 4

General immune evasion strategies used by viruses. Many viruses encode immune evasion products that target MHC class I presentation or expression of NKG2D ligands, preventing the detection of viral infection by CTL through their antigen-specific TCR and NK cells via the activating NKG2D receptor. Because down-modulation of MHC class I on the infected cell might result in NK-cell-mediated killing through missing-self recognition, some viruses encode MHC class I decoy ligands, which engage inhibitory receptors on NK cells. Cytokines and chemokines play a crucial role in the activation and recruitment of NK cells and CTL, thus viruses have acquired mechanisms to thwart the production of cytokines such as type I IFNs. Viruses can either directly block the synthesis of inflammatory cytokines or secrete virally encoded cytokine and chemokine receptor analogs that sequester and neutralize the soluble factors so that responding cells cannot receive growth and differentiation signals. Viruses also encode products that directly interfere with the host intracellular sensors that activate transcription of antiviral effector gene products. NK cells and CTL can kill virally infected cells by activating apoptotic pathways in their targets via death receptor ligation and signaling; therefore, some viruses have developed strategies to block apoptosis in the infected until they can complete their replication and new virions are produced.

Citation: Sun J, Lanier L. 2011. Natural Killer Cell Response against Viruses, p 197-207. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch16
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Tables

Generic image for table
TABLE 1

NK cells in host immunity against viruses

Citation: Sun J, Lanier L. 2011. Natural Killer Cell Response against Viruses, p 197-207. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch16
Generic image for table
TABLE 2

Virus evasion of the NK-cell response

Citation: Sun J, Lanier L. 2011. Natural Killer Cell Response against Viruses, p 197-207. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch16

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