Activation of Natural Killer Cells by Newcastle Disease Virus Hemagglutinin-Neuraminidase

Jarahian, Mostafa; Watzl, Carsten; Fournier, Philippe; Arnold, Annette; Djandji, Dominik; Zahedi, Sarah; Cerwenka, Adelheid; Paschen, Annette; Schirrmacher, Volker; Momburg, Frank

doi:10.1128/jvi.00211-09

Cited by 151 publications

(167 citation statements)

References 69 publications

(77 reference statements)

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“…6A-F). Moreover, VLP internalization induced transient down-modulation of CD16, but no change in NKp46 expression, a receptor involved in Newcastle disease virus binding [35] (data not shown). Our findings are in agreement with those showing that binding of HPV-VLPs is mediated by CD16 on DCs [36] and that uptake of HPV-VLPs by DCs from FcgRIII-deficient mice is strongly reduced compared with wildtype mice [17].…”

Section: Discussionmentioning

confidence: 99%

Human papillomavirus entry into NK cells requires CD16 expression and triggers cytotoxic activity and cytokine secretion

et al. 2011

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Human papillomavirus (HPV) infections account for more than 50% of infection-linked cancers in women worldwide. The immune system controls, at least partially, viral infection and around 90% of HPV-infected women clear the virus within two years. However, it remains unclear which immune cells are implicated in this process and no study has evaluated the direct interaction between HPVs and NK cells, a key player in host resistance to viruses and tumors. We demonstrated an NK-cell infiltration in HPVassociated preneoplastic cervical lesions. Since HPVs cannot grow in vitro, virus-like particles (VLPs) were used as a model for studying the NK-cell response against the virus. Interestingly, NK cells displayed higher cytotoxic activity and cytokine production (TNF-a and IFN-c) in the presence of HPV-VLPs. Using flow cytometry and microscopy, we observed that NK-cell stimulation was linked to rapid VLP entry into these cells by macropinocytosis. Using CD16 1 and CD16 À NK-cell lines and a CD16-blocking antibody, we demonstrated that CD16 is necessary for HPV-VLP internalization, as well as for degranulation and cytokine production. Thus, we show for the first time that NK cells interact with HPVs and can participate in the immune response against HPV-induced lesions. IntroductionHigh-risk human papillomaviruses (HPVs) are the causative agents of uterine cervical cancer and are also etiologically associated with other anogenital tumors and with head and neck carcinomas [1].Among the 100 HPV genotypes already characterized, 15 are oncogenic and more than 50% of uterine cervical cancers are associated with HPV16 [2]. Because of their keratinocyte differentiation-dependent life cycle, virus production in vitro has required complex cell culture systems and only low virus titers can be obtained [3]. Consequently, most studies aiming to investigate interactions between virus and host cells have used virus-like particles (VLPs), which result from HPV L1 major capsid protein self-assembly and which are morphologically and immunologically [5,6]. Yet, these vaccines have no therapeutic efficacy and it has been estimated that there will be no measurable decline of HPVassociated tumors before 2040 [7].HPV infection can be controlled by the host immune response and the vast majority of HPV-infected women clear the virus within two years [8]. Moreover, the prevalence of HPV-induced tumors is higher in immunodeficient patients [9]. However, it remains unclear which immune cells are implicated in this process and no study has been performed evaluating the direct interaction between HPVs and NK cells, although these cells play a key role in host resistance to viruses [10] (Fig. 1A and B), but not in squamous cell carcinoma (SCC) (Fig. 1D) despite the presence of more numerous NK cells in the surrounding stroma (Supporting Information Fig. 1). Interestingly, virus particles have been detected mainly in SILs and not in SCC [19] where the virus is usually integrated into the host genome [20]. Our results thus suggest that NK cells could...

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Section: Discussionmentioning

confidence: 99%

Human papillomavirus entry into NK cells requires CD16 expression and triggers cytotoxic activity and cytokine secretion

et al. 2011

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“…Viral HAs from pathogens such influenza virus and poxvirus (36,37), as well as the HA-neuraminidase from Sendai virus and Newcastle disease virus, can bind to natural cytotoxic receptors, NKp46 and NKp44, and are able to activate NK cells independent of antibodies (38)(39)(40). In addition, HIV and herpes simplex virus also up-regulate the expression of other natural cytotoxic receptors (41,42).…”

Section: Discussionmentioning

confidence: 99%

Optimal activation of Fc-mediated effector functions by influenza virus hemagglutinin antibodies requires two points of contact

Leon

Mullarkey

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

106

107

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Influenza virus strain-specific monoclonal antibodies (mAbs) provide protection independent of Fc gamma receptor (FcγR) engagement. In contrast, optimal in vivo protection achieved by broadly reactive mAbs requires Fc-FcγR engagement. Most strain-specific mAbs target the head domain of the viral hemagglutinin (HA), whereas broadly reactive mAbs typically recognize epitopes within the HA stalk. This observation has led to questions regarding the mechanism regulating the activation of Fc-dependent effector functions by broadly reactive antibodies. To dissect the molecular mechanism responsible for this dichotomy, we inserted the FLAG epitope into discrete locations on HAs. By characterizing the interactions of several FLAG-tagged HAs with a FLAG-specific antibody, we show that in addition to Fc-FcγR engagement mediated by the FLAG-specific antibody, a second intermolecular bridge between the receptor-binding region of the HA and sialic acid on effector cells is required for optimal activation. Inhibition of this second molecular bridge, through the use of an F(ab′) 2 or the mutation of the sialic acid-binding site, renders the Fc-FcγR interaction unable to optimally activate effector cells. Our findings indicate that broadly reactive mAbs require two molecular contacts to possibly stabilize the immunologic synapse and potently induce antibody-dependent cell-mediated antiviral responses: (i) the interaction between the Fc of a mAb bound to HA with the FcγR of the effector cell and (ii) the interaction between the HA and its sialic acid receptor on the effector cell. This concept might be broadly applicable for protective antibody responses to viral pathogens that have suitable receptors on effector cells. hemagglutinin | influenza virus | antibody-dependent cell-mediated immunity | broadly reactive antibodies | Fcγ receptor

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“…5-7 NKp46 is encoded by Ncr1 and associates with the ITAM-containing CD3ζ or FcRγ polypeptides. Several endogenous ligands of NKp46 have been described including the complement factor P, 8 the intracellular filamentous cytoskeletal protein vimentin expressed on the surface of Mycobacterium tuberculosis –infected monocytes, 9 and several viral proteins such as hemagglutinin and hemagglutinin neuraminidases of the influenza, 10,11 Sendai, 12 Newcastle disease, 13 ectromelia and vaccinia viruses. 14 NKp46 was also shown to recognize PfEMP1 of Plasmodium falciparum , 14 an unknown ligand from Fusobacterium nucleatum , 15 adhesins from Candida glabrata .…”

Section: Introductionmentioning

confidence: 99%

A point mutation in the Ncr1 signal peptide impairs the development of innate lymphoid cell subsets

et al. 2018

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NKp46 (CD335) is a surface receptor shared by both human and mouse natural killer (NK) cells and innate lymphoid cells (ILCs) that transduces activating signals necessary to eliminate virus-infected cells and tumors. Here, we describe a spontaneous point mutation of cysteine to arginine (C14R) in the signal peptide of the NKp46 protein in congenic Ly5.1 mice and the newly generated NCRB6C14R strain. Ly5.1C14R NK cells expressed similar levels of Ncr1 mRNA as C57BL/6, but showed impaired surface NKp46 and reduced ability to control melanoma tumors in vivo. Expression of the mutant NKp46C14R in 293T cells showed that NKp46 protein trafficking to the cell surface was compromised. Although Ly5.1C14R mice had normal number of NK cells, they showed an increased number of early maturation stage NK cells. CD49a+ILC1s were also increased but these cells lacked the expression of TRAIL. ILC3s that expressed NKp46 were not detectable and were not apparent when examined by T-bet expression. Thus, the C14R mutation reveals that NKp46 is important for NK cell and ILC differentiation, maturation and function.SignificanceInnate lymphoid cells (ILCs) play important roles in immune protection. Various subsets of ILCs express the activating receptor NKp46 which is capable of recognizing pathogen derived and tumor ligands and is necessary for immune protection. Here, we describe a spontaneous point mutation in the signal peptide of the NKp46 protein in congenic Ly5.1 mice which are widely used for tracking cells in vivo. This Ncr1 C14R mutation impairs NKp46 surface expression resulting in destabilization of Ncr1 and accumulation of NKp46 in the endoplasmic reticulum. Loss of stable NKp46 expression impaired the maturation of NKp46+ ILCs and altered the expression of TRAIL and T-bet in ILC1 and ILC3, respectively.

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Activation of Natural Killer Cells by Newcastle Disease Virus Hemagglutinin-Neuraminidase

Cited by 151 publications

References 69 publications

Human papillomavirus entry into NK cells requires CD16 expression and triggers cytotoxic activity and cytokine secretion

Human papillomavirus entry into NK cells requires CD16 expression and triggers cytotoxic activity and cytokine secretion

Optimal activation of Fc-mediated effector functions by influenza virus hemagglutinin antibodies requires two points of contact

A point mutation in the Ncr1 signal peptide impairs the development of innate lymphoid cell subsets

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