A Role for NKG2D in NK Cell–Mediated Resistance to Poxvirus Disease

Fang, Min; Lanier, Lewis L.; Sigal, Luis J.

doi:10.1371/journal.ppat.0040030

Cited by 143 publications

(268 citation statements)

References 61 publications

(71 reference statements)

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“…In humans, NK cells are essential for resistance to several viral infections, such as EBV, human CMV, varicella-zoster virus, and HSV (11)(12)(13)(14). In mice, NK cells are clearly critical to control mouse CMV (15)(16)(17) and the agent of mousepox, ectromelia virus (18)(19)(20). The roles that NK cells play during influenza virus infection are intricate.…”

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Swift and Strong NK Cell Responses Protect 129 Mice against High-Dose Influenza Virus Infection

Zhou

Wang

et al. 2016

The Journal of Immunology

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It is generally unclear what roles NK cells play during influenza virus infection with regard to different host genetic backgrounds. In this study, we show that in six inbred mouse strains, NK cells play an important protective role only in 129 mice during high-dose influenza A H1N1 virus infection. Swift and strong NK cell responses efficiently control early pulmonary viral replication in 129 mice, providing survival privilege. In addition, we identified that early activation of TLRs and RIG-I signaling in 129 mice resulted in quick production of type 1 IFNs and inflammatory cytokines, which are important reasons for the swift kinetics of NK cell responses post influenza virus infection. Thus, under different microenvironments, NK cells play differential roles against viral infections. The kinetics and magnitude of NK cell responses correlate with the distinct roles that NK cells play against influenza virus infections. Thus, our works further our understandings about the complex role of NK cells during influenza virus infection.

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Swift and Strong NK Cell Responses Protect 129 Mice against High-Dose Influenza Virus Infection

Zhou

Wang

et al. 2016

The Journal of Immunology

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“…Poxviruses use a wide variety of immune evasion strategies, including interference with cytokines that impact the NK cell response (17,18). The immune response in mice to both the mouse pathogen ectromelia virus (ECTV) and the prototypic poxvirus vaccinia virus (VV) involves NK cells (19)(20)(21)(22). A very recent study indicates that NK cells even develop memory for VV (23).…”

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confidence: 99%

“…A very recent study indicates that NK cells even develop memory for VV (23). Various activating receptors on NK cells such as CD94/NKG2E and NKG2D are required for NK cell defense against ECTV in mouse (20,24), and recognition of VV infection by human NK cells involves NKG2D (25) and perhaps loss of HLA-E and classical MHC-I molecules (26,27). Moreover, certain strains of mice, particularly C57BL/6, are resistant to VV and ECTV infection (22,(28)(29)(30), and depletion of NK cells converts resistant mice to a susceptible phenotype (22).…”

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Poxvirus Infection-Associated Downregulation of C-Type Lectin-Related-b Prevents NK Cell Inhibition by NK Receptor Protein-1B

Williams

Wilson

Davidson

et al. 2012

The Journal of Immunology

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Innate immune recognition of virus-infected cells includes NK cell detection of changes to endogenous cell-surface proteins through inhibitory receptors. One such receptor system is the NK cell receptor protein-1B (NKR-P1B) and its ligand C-type lectin-related-b (Clr-b). NKR-P1B and Clr-b are encoded within the NK cell gene complex, a locus that has been linked to strain-dependent differences in susceptibility to infection by poxviruses. In this study, we report the impact of vaccinia virus (VV) and ectromelia virus infection on expression of Clr-b and Clr-b–mediated protection from NK cells. We observed a loss of Clr-b cell-surface protein upon VV and ectromelia virus infection of murine cell lines and bone marrow-derived macrophages. The reduction of Clr-b is more rapid than MHC class I, the prototypic ligand of NK cell inhibitory receptors. Reduction of Clr-b requires active viral infection but not expression of late viral genes, and loss of mRNA appears to lag behind loss of Clr-b surface protein. Clr-b–mediated protection from NK cells is lost following VV infection. Together, these results provide the second example of Clr-b modulation during viral infection and suggest reductions of Clr-b may be involved in sensitizing poxvirus-infected cells to NK cells.

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“…JHMV infection of the CNS does result in elevated levels of transcripts for several TLRs, including TLR-3 and TLR-6 (T. E. Lane, unpublished observations); therefore, it is possible that TLR signaling enhances NKG2D ligand expression within the CNS in response to JHMV infection. Moreover, recent reports indicate that viral infection of both cultured cells and mice results in the increased expression of NKG2D ligands within infected cells, indicating that viral infection is sufficient to trigger ligand expression (24,27). In addition, it is possible that infiltrating leukocytes express NKG2D ligands and/or that cytokines released from activated cells enhance ligand expression on resident glial cells.…”

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confidence: 99%

NKG2D Receptor Signaling Enhances Cytolytic Activity by Virus-Specific CD8⁺T Cells: Evidence for a Protective Role in Virus-Induced Encephalitis

Walsh

Lanier

Lane

2008

J Virol

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Inoculation with the neurotropic JHM strain of mouse hepatitis virus (JHMV) into the central nervous system (CNS) of mice results in an acute encephalitis associated with an immune-mediated demyelinating disease. During acute disease, infiltrating CD8 ؉ T cells secrete gamma interferon (IFN-␥) that controls replication in oligodendrocytes, while infected astrocytes and microglia are susceptible to perforin-mediated lysis. The present study was undertaken to reveal the functional contributions of the activating NKG2D receptor in host defense and disease following JHMV infection. NKG2D ligands RAE-1, MULT1, and H60 were expressed within the CNS following JHMV infection. The immunophenotyping of infiltrating cells revealed that NKG2D was expressed on ϳ90% of infiltrating CD8 ؉ T cells during acute and chronic disease. Blocking NKG2D following JHMV infection resulted in increased mortality that correlated with increased viral titers within the CNS. Anti-NKG2D treatment did not alter T-cell infiltration into the CNS or the generation of virus-specific CD8 ؉ T cells, and the expression of IFN-␥ was not affected. However, cytotoxic T-lymphocyte (CTL) activity was dependent on NKG2D expression, because anti-NKG2D treatment resulted in a dramatic reduction in lytic activity by virus-specific CD8 ؉ T cells. Blocking NKG2D during chronic disease did not affect either T-cell or macrophage infiltration or the severity of demyelination, indicating that NKG2D does not contribute to virus-induced demyelination. These findings demonstrate a functional role for NKG2D in host defense during acute viral encephalitis by selectively enhancing CTL activity by infiltrating virus-specific CD8 ؉ T cells.Viral infection of the central nervous system (CNS) presents unique challenges to the immune system with regard to controlling and eliminating the invading pathogen. These obstacles include the presence of a blood-brain barrier that provides a physical and physiological barrier that is difficult for cells and molecules to cross, the absence of classic lymphatic drainage that may impair the generation of an adaptive immune response, and the relative absence of major histocompatibility complex (MHC) class I or II expression on resident cells (3,26,39,73). In addition, the CNS is composed of a variety of highly specialized cells, many of which have limited renewal capacity, that represent potential targets of infection by numerous different viruses (34, 81). Therefore, a significant hurdle encountered by infiltrating antigen-specific lymphocytes is the elimination of virus from infected cells while limiting the damage that may have long-term detrimental consequences to the host. Critical to this is the cellular tropism of the virus, as this is important in dictating the effector response by infiltrating lymphocytes. For example, neuronotropic viruses often are eliminated by noncytolytic mechanisms via cytokine-mediated control and/or neutralizing antibodies, whereas the infection of other cell populations can evoke cytolytic mechanisms for c...

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A Role for NKG2D in NK Cell–Mediated Resistance to Poxvirus Disease

Cited by 143 publications

References 61 publications

Swift and Strong NK Cell Responses Protect 129 Mice against High-Dose Influenza Virus Infection

Swift and Strong NK Cell Responses Protect 129 Mice against High-Dose Influenza Virus Infection

Poxvirus Infection-Associated Downregulation of C-Type Lectin-Related-b Prevents NK Cell Inhibition by NK Receptor Protein-1B

NKG2D Receptor Signaling Enhances Cytolytic Activity by Virus-Specific CD8⁺T Cells: Evidence for a Protective Role in Virus-Induced Encephalitis

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A Role for NKG2D in NK Cell–Mediated Resistance to Poxvirus Disease

Cited by 143 publications

References 61 publications

Swift and Strong NK Cell Responses Protect 129 Mice against High-Dose Influenza Virus Infection

Swift and Strong NK Cell Responses Protect 129 Mice against High-Dose Influenza Virus Infection

Poxvirus Infection-Associated Downregulation of C-Type Lectin-Related-b Prevents NK Cell Inhibition by NK Receptor Protein-1B

NKG2D Receptor Signaling Enhances Cytolytic Activity by Virus-Specific CD8+T Cells: Evidence for a Protective Role in Virus-Induced Encephalitis

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NKG2D Receptor Signaling Enhances Cytolytic Activity by Virus-Specific CD8⁺T Cells: Evidence for a Protective Role in Virus-Induced Encephalitis