The herpesviral Fc receptor fcr-1 down-regulates the NKG2D ligands MULT-1 and H60

Lenac, Tihana; Budt, Matthias; Arapović, Jurica; Hasan, Milena; Zimmermann, Albert; Šimić, Hrvoje; Krmpotić, Astrid; Messerle, Martin; Ruzsics, Zsolt; Koszinowski, Ulrich H.; Hengel, Hartmut; Jonjić, Stipan

doi:10.1084/jem.20060514

Cited by 91 publications

(111 citation statements)

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“…Until now, no report including our preliminary study (data not shown) demonstrates that HBsAg has the character. Also, virus proteins such as MCMV m155-, m145-, m152-or m138-encoded glycoprotein may induce the virus infected cells to down-express or upexpress the ligands of activating NK cell receptor (so called ''induced-self'' or ''missing-self'', respectively), by which NK cells may attack self-tissue too [34][35][36][37][38]. We practiced the experiments to explore the ligands of activating NK cell receptor on hepatocytes of HBsAg transgenic mice, and no significant change was found (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Liver-specific HBsAg transgenic mice are over-sensitive to Poly(I:C)-induced liver injury in NK cell- and IFN-γ-dependent manner

Chen

Sun

Jiang

et al. 2007

Journal of Hepatology

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Background/Aims: The role of natural killer (NK) cells in the development of hepatitis B virus (HBV)-associated liver injury remains obscure. In this study, we elucidated the role of NK cells in liver injury of HBsAg transgenic mice (HBs-B6), a mimic of human healthy chronic HBsAg carriers, triggered by polyinosinic:polycytidylic acid [Poly(I:C)].Methods: HBs-B6 or wild B6 mice were intraperitoneally injected with Poly(I:C) at different doses. Liver injury was evaluated by serum transaminase activity and histopathologic changes.Results: HBs-B6 mice were over-sensitive to Poly(I:C)-induced liver injury, which was absolutely dependent on the presence of NK cells and IFN-c produced by intrahepatic NK cells. Much stronger IFN-c receptor expression was observed on hepatocytes of HBs-B6 mice, which was significantly enhanced by Poly(I:C) injection. Treatment with IFN-c in vitro triggered much higher activation of downstream signals (pSTAT1-IRF-1) in hepatocytes of HBs-B6 mice. Depletion of Kupffer cells and neutralization of endogenous IL-12 did not affect Poly(I:C)-induced over-sensitive liver injury in HBs-B6 mice.Conclusions: NK cells played a critical role in an IFN-c dependent, Kupffer cell-and IL-12-independent manner in oversensitive liver injury triggered by Poly(I:C) in murine chronic HBsAg carriers. Ó

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Section: Discussionmentioning

confidence: 99%

Liver-specific HBsAg transgenic mice are over-sensitive to Poly(I:C)-induced liver injury in NK cell- and IFN-γ-dependent manner

Chen

Sun

Jiang

et al. 2007

Journal of Hepatology

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“…The importance of NKG2D receptor signaling on NK cells has been demonstrated in many tumor and pathogen models (11,13,15,20,21,38,46,50,57,58,84). The interaction between the NKG2D receptor and specific ligands results in enhanced effector functions by NK cells, including the secretion of IFN-␥ and cytotoxic activity that augments the killing of NKG2D ligand-bearing target cells (14,15,20,21,57).…”

Section: Discussionmentioning

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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“…Viral mutants lacking either of these genes are no longer able to regulate NKG2D ligands and are therefore sensitive to NK cell control in vivo virus was also attenuated in B cell-deWcient mice, suggesting an additional function of this protein [55]. We have shown that this mutant virus was attenuated as early as three days post infection [53]. Since this attenuation could be reversed by the depletion of NK cells, or even by blocking the NKG2D receptor, the observed phenotype is most likely due to the expression of NKG2D ligands on the surface of infected cells.…”

Section: Avoidance Of Nk Cell Activation Via Nkg2dmentioning

confidence: 99%

“…1c). We have recently shown that the expression of MULT-1 and H60 is also inhibited by m138/fcr-1 [53]. The m138/fcr-1 was originally described as an MCMV receptor for the Fc portion of immunoglobulin G (IgG) and was designated fcr-1 [54].…”

Section: Avoidance Of Nk Cell Activation Via Nkg2dmentioning

confidence: 99%

“…A better understanding of the molecular mechanisms by which MCMV proteins m145 and m155 interfere with the expression of MULT-1 and H60 is further complicated by the fact that both proteins are also targeted by m138/fcr-1 [53]. The study showed that m138/fcr-1 targets MULT-1 and H60 for down-regulation and thus contributes to viral resistance to NK cell-control in vivo.…”

Section: Down-modulation Of Surface Resident Mult-1: a Joint Evort Ofmentioning

confidence: 99%

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Murine cytomegalovirus regulation of NKG2D ligands

Lenac

Arapović

Traven

et al. 2008

Med Microbiol Immunol

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Human cytomegalovirus (HCMV) is a ubiquitous pathogen that causes morbidity risk in immunologically suppressed and immunodeWcient patients including congenital infections. Approaches to curb the consequences of HCMV infections are restricted by a lack of complete understanding of viral pathogenesis. The infection of mice with murine cytomegalovirus (MCMV) as a model of HCMV infection has been particularly useful in elucidating the role of innate and adaptive immune response mechanisms. A large number of cytomegalovirus genes modulate the innate and the adaptive host immune response. The products of several MCMV genes are involved in subverting the natural killer (NK) cell response by down-modulating cellular ligands for the NKG2D receptor expressed on NK cells and CD8 + T cells. Mutant viruses lacking these immunoevasion genes are attenuated with respect to virus growth in vivo. Given the importance of the NKG2D receptor in controlling both NK-and T cell-mediated immunity, it is of tremendous importance to understand the molecular mechanisms and consequences of viral regulation of the NKG2D ligands.

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The herpesviral Fc receptor fcr-1 down-regulates the NKG2D ligands MULT-1 and H60

Cited by 91 publications

References 20 publications

Liver-specific HBsAg transgenic mice are over-sensitive to Poly(I:C)-induced liver injury in NK cell- and IFN-γ-dependent manner

Liver-specific HBsAg transgenic mice are over-sensitive to Poly(I:C)-induced liver injury in NK cell- and IFN-γ-dependent manner

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

Murine cytomegalovirus regulation of NKG2D ligands

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The herpesviral Fc receptor fcr-1 down-regulates the NKG2D ligands MULT-1 and H60

Cited by 91 publications

References 20 publications

Liver-specific HBsAg transgenic mice are over-sensitive to Poly(I:C)-induced liver injury in NK cell- and IFN-γ-dependent manner

Liver-specific HBsAg transgenic mice are over-sensitive to Poly(I:C)-induced liver injury in NK cell- and IFN-γ-dependent manner

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

Murine cytomegalovirus regulation of NKG2D ligands

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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