scholarly journals Expression of the Pseudorabies Virus gB Glycoprotein Triggers NK Cell Cytotoxicity and Increases Binding of the Activating NK Cell Receptor PILRβ

2019 ◽  
Vol 93 (7) ◽  
Author(s):  
Steffi De Pelsmaeker ◽  
Evelien Dierick ◽  
Barbara Klupp ◽  
Thomas C. Mettenleiter ◽  
Claudia Cantoni ◽  
...  
Keyword(s):  
Nk Cells ◽  
Pseudorabies Virus ◽  
Nk Cell ◽  
Cell Receptor ◽  
Transfected Cells ◽  
Infected Cells ◽  
Nk Cell Cytotoxicity ◽  
Nk Cell Receptor ◽  
Receptor Beta

ABSTRACT Natural killer (NK) cells are components of the innate immunity and are key players in the defense against virus-infected and malignant cells. NK cells are particularly important in the innate defense against herpesviruses, including alphaherpesviruses. Aggravated and life-threatening alphaherpesvirus-induced disease has been reported in patients with NK cell deficiencies. NK cells are regulated by a diversity of activating and inhibitory cell surface receptors that recognize specific ligands on the plasma membrane of virus-infected or malignant target cells. Although alphaherpesviruses have developed several evasion strategies against NK cell-mediated attack, alphaherpesvirus-infected cells are still readily recognized and killed by NK cells. However, the (viral) factors that trigger NK cell activation against alphaherpesvirus-infected cells are largely unknown. In this study, we show that expression of the gB glycoprotein of the alphaherpesvirus pseudorabies virus (PRV) triggers NK cell-mediated cytotoxicity, both in PRV-infected and in gB-transfected cells. In addition, we report that, like their human and murine counterpart, porcine NK cells express the activating receptor paired immunoglobulin-like type 2 receptor beta (PILRβ), and we show that gB expression triggers increased binding of recombinant porcine PILRβ to the surfaces of PRV-infected cells and gB-transfected cells. IMPORTANCE Natural killer (NK) cells display a prominent cytolytic activity against virus-infected cells and are indispensable in the innate antiviral response, particularly against herpesviruses. Despite their importance in the control of alphaherpesvirus infections, relatively little is known about the mechanisms that trigger NK cell cytotoxicity against alphaherpesvirus-infected cells. Here, using the porcine alphaherpesvirus pseudorabies virus (PRV), we found that the conserved alphaherpesvirus glycoprotein gB triggers NK cell-mediated cytotoxicity, both in virus-infected and in gB-transfected cells. In addition, we report that gB expression results in increased cell surface binding of porcine paired immunoglobulin-like type 2 receptor beta (PILRβ), an activating NK cell receptor. The interaction between PILRβ and viral gB may have consequences that stretch beyond the interaction with NK cells, including virus entry into host cells. The identification of gB as an NK cell-activating viral protein may be of importance in the construction of future vaccines and therapeutics requiring optimized interactions of alphaherpesviruses with NK cells.

scholarly journals Pseudorabies Virus US3 Protein Kinase Protects Infected Cells from NK Cell-Mediated Lysis via Increased Binding of the Inhibitory NK Cell Receptor CD300a

2015 ◽  
Vol 90 (3) ◽  
pp. 1522-1533 ◽  
Author(s):  
K. Grauwet ◽  
M. Vitale ◽  
S. De Pelsmaeker ◽  
T. Jacob ◽  
K. Laval ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Nk Cells ◽  
Natural Killer ◽  
Pseudorabies Virus ◽  
Nk Cell ◽  
Cell Receptor ◽  
Target Cells ◽  
Group I ◽  
Infected Cells ◽  
Nk Cell Receptor

ABSTRACTSeveral reports have indicated that natural killer (NK) cells are of particular importance in the innate response against herpesvirus infections. As a consequence, herpesviruses have developed diverse mechanisms for evading NK cells, although few such mechanisms have been identified for the largest herpesvirus subfamily, the alphaherpesviruses. The antiviral activity of NK cells is regulated by a complex array of interactions between activating/inhibitory receptors on the NK cell surface and the corresponding ligands on the surfaces of virus-infected cells. Here we report that the US3 protein kinase of the alphaherpesvirus pseudorabies virus (PRV) displays previously uncharacterized immune evasion properties: it triggers the binding of the inhibitory NK cell receptor CD300a to the surface of the infected cell, thereby providing increased CD300a-mediated protection of infected cells against NK cell-mediated lysis. US3-mediated CD300a binding was found to depend on aminophospholipid ligands of CD300a and on group I p21-activated kinases. These data identify a novel alphaherpesvirus strategy for evading NK cells and demonstrate, for the first time, a role for CD300a in regulating NK cell activity upon contact with virus-infected target cells.IMPORTANCEHerpesviruses have developed fascinating mechanisms to evade elimination by key elements of the host immune system, contributing to their ability to cause lifelong infections with recurrent reactivation events. Natural killer (NK) cells are central in the innate antiviral response. Here we report that the US3 protein kinase of the alphaherpesvirus pseudorabies virus displays a previously uncharacterized capacity for evasion of NK cells. Expression of US3 protects infected cells from NK cell-mediated lysis via increased binding of the inhibitory NK cell receptor CD300a. We show that this US3-mediated increase in CD300a binding depends on aminophospholipids and on cellular p21-activated kinases (PAKs). The identification of this novel NK cell evasion strategy may contribute to the design of improved herpesvirus vaccines and may also have significance for other PAK- and CD300a-modulating viruses and cancer cells.

scholarly journals Pseudorabies Virus Infection Causes Downregulation of Ligands for the Activating NK Cell Receptor NKG2D

Viruses ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 266
Author(s):  
Sofie Denaeghel ◽  
Steffi De Pelsmaeker ◽  
Cliff Van Waesberghe ◽  
Herman W. Favoreel
Keyword(s):  
Cell Surface ◽  
Nk Cells ◽  
Pseudorabies Virus ◽  
Nk Cell ◽  
Cell Receptor ◽  
Host Cells ◽  
Nkg2d Ligand ◽  
Antiviral Immune Response ◽  
Nkg2d Ligands ◽  
Nk Cell Receptor

Herpesviruses display a complex and carefully balanced interaction with important players in the antiviral immune response of immunocompetent natural hosts, including natural killer (NK) cells. With regard to NK cells, this delicate balance is illustrated on the one hand by severe herpesvirus disease reported in individuals with NK cell deficiencies and on the other hand by several NK cell evasion strategies described for herpesviruses. In the current study, we report that porcine cells infected with the porcine alphaherpesvirus pseudorabies virus (PRV) display a rapid and progressive downregulation of ligands for the major activating NK cell receptor NKG2D. This downregulation consists both of a downregulation of NKG2D ligands that are already expressed on the cell surface of an infected cell and an inhibition of cell surface expression of newly expressed NKG2D ligands. Flow cytometry and RT-qPCR assays showed that PRV infection results in downregulation of the porcine NKG2D ligand pULBP1 from the cell surface and a very substantial suppression of mRNA expression of pULBP1 and of another potential NKG2D ligand, pMIC2. Furthermore, PRV-induced NKG2D ligand downregulation was found to be independent of late viral gene expression. In conclusion, we report that PRV infection of host cells results in a very pronounced downregulation of ligands for the activating NK cell receptor NKG2D, representing an additional NK evasion strategy of PRV.

scholarly journals Ly49P recognition of cytomegalovirus-infected cells expressing H2-Dk and CMV-encoded m04 correlates with the NK cell antiviral response

2009 ◽  
Vol 206 (3) ◽  
pp. 515-523 ◽  
Author(s):  
Agnieszka Kielczewska ◽  
Michal Pyzik ◽  
Tianhe Sun ◽  
Astrid Krmpotic ◽  
Melissa B. Lodoen ◽  
...  
Keyword(s):  
Nk Cells ◽  
Deletion Mutant ◽  
Viral Infections ◽  
Nk Cell ◽  
Cell Receptor ◽  
Major Histocompatability Complex ◽  
Wild Type ◽  
Mcmv Infection ◽  
Host Protection ◽  
Infected Cells

Natural killer (NK) cells are crucial in resistance to certain viral infections, but the mechanisms used to recognize infected cells remain largely unknown. Here, we show that the activating Ly49P receptor recognizes cells infected with mouse cytomegalovirus (MCMV) by a process that requires the presence of H2-Dk and the MCMV m04 protein. Using H2 chimeras between H2-Db and -Dk, we demonstrate that the H2-Dk peptide-binding platform is required for Ly49P recognition. We identified m04 as a viral component necessary for recognition using a panel of MCMV-deletion mutant viruses and complementation of m04-deletion mutant (Δm04) virus infection. MA/My mice, which express Ly49P and H2-Dk, are resistant to MCMV; however, infection with Δm04 MCMV abrogates resistance. Depletion of NK cells in MA/My mice abrogates their resistance to wild-type MCMV infection, but does not significantly affect viral titers in mice infected with Δm04 virus, implicating NK cells in host protection through m04-dependent recognition. These findings reveal a novel mechanism of major histocompatability complex class I–restricted recognition of virally infected cells by an activating NK cell receptor.

Dual function for the adaptor MIST in IFN-γ production by NK and CD4+NKT cells regulated by the Src kinase Fgr

Blood ◽  
2006 ◽  
Vol 107 (9) ◽  
pp. 3647-3655 ◽  
Author(s):  
Hiroki Sasanuma ◽  
Akiko Tatsuno ◽  
Shinya Hidano ◽  
Keiko Ohshima ◽  
Yumi Matsuzaki ◽  
...  
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Adaptor Protein ◽  
Adaptor Proteins ◽  
Cell Receptor ◽  
Nkt Cells ◽  
Cell Populations ◽  
Dual Function ◽  
Ifn Γ ◽  
Nk Cell Receptor

Natural killer (NK) cells and NKT cells play critical early roles in host defense. Here we show that MIST, an adaptor protein belonging to the SLP-76 family, functions negatively in NK cells but positively in CD4+NKT cells. NK-cell receptor-mediated IFN-γ production was enhanced in NK cells, whereas TCR- or NK-cell receptor-mediated cytokine production was reduced in CD4+NKT cells from MIST-deficient mice. These opposite effects of MIST paralleled the exclusive expression of the Src family kinase, Fgr, in NK cells between the 2 cell populations. We further demonstrated that interaction of MIST with Fgr, mediated by the C-terminal proline-rich region of MIST and the SH3 domain of Fgr, was required for the suppression of NK-cell receptor-induced IFN-γ production. This functional interdependence of signaling molecules demonstrates a new mechanism by which adaptor proteins can act as molecular switches to control diverse responses in different cell populations.

Phospholipase C-γ2 is essential for NK cell cytotoxicity and innate immunity to malignant and virally infected cells

Blood ◽  
2006 ◽  
Vol 107 (3) ◽  
pp. 994-1002 ◽  
Author(s):  
Anouk Caraux ◽  
Nayoung Kim ◽  
Sarah E. Bell ◽  
Simona Zompi ◽  
Thomas Ranson ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Nk Cells ◽  
Phospholipase C ◽  
Mhc Class I ◽  
Nk Cell ◽  
Class I ◽  
Target Cells ◽  
Cell Cytotoxicity ◽  
Infected Cells ◽  
Nk Cell Cytotoxicity

AbstractPhospholipase C-γ2 (PLC-γ2) is a key component of signal transduction in leukocytes. In natural killer (NK) cells, PLC-γ2 is pivotal for cellular cytotoxicity; however, it is not known which steps of the cytolytic machinery it regulates. We found that PLC-γ2-deficient NK cells formed conjugates with target cells and polarized the microtubule-organizing center, but failed to secrete cytotoxic granules, due to defective calcium mobilization. Consequently, cytotoxicity was completely abrogated in PLC-γ2-deficient cells, regardless of whether targets expressed NKG2D ligands, missed self major histocompatibility complex (MHC) class I, or whether NK cells were stimulated with IL-2 and antibodies specific for NKR-P1C, CD16, CD244, Ly49D, and Ly49H. Defective secretion was specific to cytotoxic granules because release of IFN-γ on stimulation with IL-12 was normal. Plcg2-/- mice could not reject MHC class I-deficient lymphoma cells nor could they control CMV infection, but they effectively contained Listeria monocytogenes infection. Our results suggest that exocytosis of cytotoxic granules, but not cellular polarization toward targets, depends on intracellular calcium rise during NK cell cytotoxicity. In vivo, PLC-γ2 regulates selective facets of innate immunity because it is essential for NK cell responses to malignant and virally infected cells but not to bacterial infections.

scholarly journals Effects of obesity on NK cells in a mouse model of postmenopausal breast cancer

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Julia Spielmann ◽  
Laura Mattheis ◽  
Juliane-Susanne Jung ◽  
Henrik Rauße ◽  
Markus Glaß ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Adipose Tissue ◽  
Nk Cells ◽  
Tumor Cells ◽  
Nk Cell ◽  
Postmenopausal Breast Cancer ◽  
Cell Receptor ◽  
Receptor Expression ◽  
Obese Mice ◽  
Nk Cell Receptor

AbstractObesity is a widely spread disease and a crucial risk factor for malign disorders, including breast cancer of women in the postmenopause. Studies demonstrated that in case of obesity crucial natural killer (NK) cell functions like combating tumor cells are affected. This study aims to analyze NK cells and NK cell receptor expression of obese mice in a model for postmenopausal breast cancer. Therefore, female BALB/c mice were fed either a high fat or a standard diet. Thereafter, ovaries were ectomized and a syngeneic and orthotopical injection of 4T1-luc2 mouse mammary tumor cells into the mammary adipose tissue pad was performed. Obese mice showed increased body weights and visceral fat mass as well as increased levels of leptin and IL-6 in plasma. Moreover, compared to the lean littermates, tumor growth was increased and the NKp46-expression on circulating NK cells was decreased. Furthermore, the activating NK cell receptor NKG2D ligand (MULT1) expression was enhanced in adipose tissue of obese tumor bearing mice. The present study gives novel insights into gene expression of NK cell receptors in obesity and aims to promote possible links of the obesity-impaired NK cell physiology and the elevated breast cancer risk in obese women.

Alteration of inhibitory and activating NK cell receptor expression on NK cells in HIV-infected Chinese

2011 ◽  
Vol 271 (2) ◽  
pp. 219-226 ◽  
Author(s):  
Yongjun Jiang ◽  
Lei He ◽  
Huan Chen ◽  
Tristan Bice ◽  
Zining Zhang ◽  
...  
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Cell Receptor ◽  
Receptor Expression ◽  
Nk Cell Receptor

scholarly journals The Role of Natural Killer (NK) Cells and NK Cell Receptor Polymorphisms in the Assessment of HIV-1 Neutralization

PLoS ONE ◽  
2012 ◽  
Vol 7 (4) ◽  
pp. e29454 ◽  
Author(s):  
Bruce K. Brown ◽  
Lindsay Wieczorek ◽  
Gustavo Kijak ◽  
Kara Lombardi ◽  
Jeffrey Currier ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Cell Receptor ◽  
Nk Cell Receptor ◽  
Hiv 1

scholarly journals Mass cytometry analysis of the NK cell receptor-ligand repertoire reveals unique differences between dengue-infected children and adults

2020 ◽  
Author(s):  
Julia L. McKechnie ◽  
Davis Beltrán ◽  
Anne-Maud M. Ferreira ◽  
Rosemary Vergara ◽  
Lisseth Saenz ◽  
...  
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Myeloid Cell ◽  
Cell Receptor ◽  
Denv Infection ◽  
Severe Dengue ◽  
Mass Cytometry ◽  
Receptor Ligand ◽  
Nk Cell Receptor ◽  
Cell Expression

AbstractDengue virus (DENV) is a significant cause of morbidity in many regions of the world, with children at the greatest risk of developing severe dengue. Natural killer (NK) cells, characterized by their ability to rapidly recognize and kill virally infected cells, are activated during acute DENV infection. However, their role in viral clearance versus pathogenesis has not been fully elucidated. Our goal was to profile the NK cell receptor-ligand repertoire to provide further insight into the function of NK cells during pediatric and adult DENV infection. We used mass cytometry (CyTOF) to phenotype isolated NK cells and peripheral blood mononuclear cells (PBMCs) from a cohort of DENV-infected children and adults. Using unsupervised clustering, we found that pediatric DENV infection leads to a decrease in total NK cell frequency with a reduction in the percentage of CD56dimCD38bright NK cells and an increase in the percentage of CD56dimperforinbright NK cells. No such changes were observed in adults. Next, we identified markers predictive of DENV infection using a differential state test. In adults, NK cell expression of activation markers, including CD69, perforin, and Fas-L, and myeloid cell expression of activating NK cell ligands, namely Fas, were predictive of infection. In contrast, NK cell expression of the maturation marker CD57 and increased myeloid cell expression of inhibitory ligands, such as HLA class I molecules, were predictive of pediatric DENV infection. These findings suggest that acute pediatric DENV infection may result in diminished NK cell activation, which could contribute to enhanced pathogenesis and disease severity.

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