scholarly journals The Switch from Latent to Productive Infection in Epstein-Barr Virus-Infected B Cells Is Associated with Sensitization to NK Cell Killing

2006 ◽  
Vol 81 (2) ◽  
pp. 474-482 ◽  
Author(s):  
Isabel Y. Pappworth ◽  
Eddie C. Wang ◽  
Martin Rowe
Keyword(s):  
B Cells ◽  
Nk Cells ◽  
Mhc Class I ◽  
Epstein Barr Virus ◽  
Nk Cell ◽  
Class I ◽  
Inhibitory Receptors ◽  
Barr Virus ◽  
Epstein Barr ◽  
Mhc Class I Molecules

ABSTRACT Following activation of Epstein-Barr virus (EBV)-infected B cells from latent to productive (lytic) infection, there is a concomitant reduction in the level of cell surface major histocompatibility complex (MHC) class I molecules and an impaired antigen-presenting function that may facilitate evasion from EBV-specific CD8+ cytotoxic T cells. In some other herpesviruses studied, most notably human cytomegalovirus (HCMV), evasion of virus-specific CD8+ effector responses via downregulation of surface MHC class I molecules is supplemented with specific mechanisms for evading NK cells. We now report that EBV differs from HCMV in this respect. While latently infected EBV-positive B cells were resistant to lysis by two NK lines and by primary polyclonal NK cells from peripheral blood, these effectors efficiently killed cells activated into the lytic cycle. Susceptibility to NK lysis coincided not only with downregulation of HLA-A, -B, and -C molecules that bind to the KIR family of inhibitory receptors on NK cells but also with downregulation of HLA-E molecules binding the CD94/NKG2A inhibitory receptors. Conversely, ULBP-1 and CD112, ligands for the NK cell-activating receptors NKG2D and DNAM-1, respectively, were elevated. Susceptibility of the virus-producing target cells to NK cell lysis was partially reversed by blocking ULBP-1 or CD112 with specific antibodies. These results highlight a fundamental difference between EBV and HCMV with regards to evasion of innate immunity.

scholarly journals The Epstein-Barr Virus G-Protein-Coupled Receptor Contributes to Immune Evasion by Targeting MHC Class I Molecules for Degradation

2009 ◽  
Vol 5 (1) ◽  
pp. e1000255 ◽  
Author(s):  
Jianmin Zuo ◽  
Andrew Currin ◽  
Bryan D. Griffin ◽  
Claire Shannon-Lowe ◽  
Wendy A. Thomas ◽  
...  
Keyword(s):  
G Protein ◽  
Mhc Class I ◽  
Immune Evasion ◽  
Epstein Barr Virus ◽  
Class I ◽  
G Protein Coupled Receptor ◽  
Barr Virus ◽  
Epstein Barr ◽  
G Protein Coupled ◽  
Mhc Class I Molecules

scholarly journals Analysis of Major Histocompatibility Complex Class I, TAP Expression, and LMP2 Epitope Sequence in Epstein-Barr Virus–Positive Hodgkin's Disease

Blood ◽  
1998 ◽  
Vol 92 (7) ◽  
pp. 2477-2483 ◽  
Author(s):  
Paul G. Murray ◽  
Christothea M. Constandinou ◽  
John Crocker ◽  
Lawrence S. Young ◽  
Richard F. Ambinder
Keyword(s):  
Major Histocompatibility Complex ◽  
Mhc Class I ◽  
Epstein Barr Virus ◽  
Class I ◽  
Major Histocompatibility ◽  
Barr Virus ◽  
Histocompatibility Complex ◽  
Epstein Barr ◽  
Hla A2.1 ◽  
Mhc Class I Molecules

Abstract The Epstein-Barr virus (EBV)-encoded latent membrane proteins, LMP1 and LMP2, are consistently expressed by the malignant Hodgkin/Reed-Sternberg (HRS) cells of EBV-associated Hodgkin's disease (HD). Cytotoxic T lymphocyte (CTL) responses to both of these proteins have been shown in the blood of EBV-seropositive individuals, yet in HD the apparent failure of the CTL response to eliminate HRS cells expressing LMP1 and LMP2 in vivo has given rise to the suggestion that HD may be characterized by the presence of defects in antigen processing/presentation or in CTL function. This study has used immunohistochemistry to show high-level expression of major histocompatibility complex (MHC) class I molecules by the HRS cells of EBV-associated HD and either low level or absence of expression of MHC class I molecules on HRS cells of EBV-negative tumors. In addition, HRS cells expressed high levels of transporter-associated proteins (TAP-1, -2), irrespective of the presence of latent EBV infection. These results suggest that global downregulation of MHC class I molecules does not account for the apparent ability of EBV-infected HRS cells to evade CTL responses, but may be important in the understanding of EBV-negative disease.We have also sequenced an epitope in LMP2A (CLGGLLTMV) that is restricted through HLA A2.1, a relatively common allele in Caucasian populations, and showed that this epitope is wild type in a small group of EBV-associated HLA A2.1-positive HD tumors. This result may be relevant to proposed immunotherapeutic approaches for EBV-positive HD patients that target CTL epitopes.

scholarly journals Induction of the Lytic Cycle Sensitizes Epstein-Barr Virus-Infected B Cells to NK Cell Killing That Is Counteracted by Virus-Mediated NK Cell Evasion Mechanisms in the Late Lytic Cycle

2015 ◽  
Vol 90 (2) ◽  
pp. 947-958 ◽  
Author(s):  
Luke R. Williams ◽  
Laura L. Quinn ◽  
Martin Rowe ◽  
Jianmin Zuo
Keyword(s):  
B Cells ◽  
Nk Cells ◽  
Epstein Barr Virus ◽  
Nk Cell ◽  
Cell Killing ◽  
Lytic Replication ◽  
Lytic Cycle ◽  
Barr Virus ◽  
Infected Cells ◽  
Epstein Barr

ABSTRACTEpstein-Barr Virus (EBV) persists for the lifetime of the infected host despite eliciting strong immune responses. This persistence requires a fine balance between the host immune system and EBV immune evasion. Accumulating evidence suggests an important role for natural killer (NK) cells in this balance. NK cells can kill EBV-infected cells undergoing lytic replicationin vitro, and studies in both humans and mice with reconstituted human immune systems have shown that NK cells can limit EBV replication and prevent infectious mononucleosis. We now show that NK cells, via NKG2D and DNAM-1 interactions, recognize and kill EBV-infected cells undergoing lytic replication and that expression of a single EBV lytic gene, BZLF1, is sufficient to trigger sensitization to NK cell killing. We also present evidence suggesting the possibility of the existence of an as-yet-unidentified DNAM-1 ligand which may be particularly important for killing lytically infected normal B cells. Furthermore, while cells entering the lytic cycle become sensitized to NK cell killing, we observed that cells in the late lytic cycle are highly resistant. We identified expression of the vBcl-2 protein, BHRF1, as one effective mechanism by which EBV mediates this protection. Thus, contrary to the view expressed in some reports, EBV has evolved the ability to evade NK cell responses.IMPORTANCEThis report extends our understanding of the interaction between EBV and host innate responses. It provides the first evidence that the susceptibility to NK cell lysis of EBV-infected B cells undergoing lytic replication is dependent upon the phase of the lytic cycle. Induction of the lytic cycle is associated with acquired sensitization to NK cell killing, while progress through the late lytic cycle is associated with acquired resistance to killing. We provide mechanistic explanations for this novel observation, indicating important roles for the BZLF1 immediate early transactivator, the BHRF1 vBcl-2 homologue, and a novel ligand for the DNAM-1 NK cell receptor.

scholarly journals Analysis of Major Histocompatibility Complex Class I, TAP Expression, and LMP2 Epitope Sequence in Epstein-Barr Virus–Positive Hodgkin's Disease

Blood ◽  
1998 ◽  
Vol 92 (7) ◽  
pp. 2477-2483 ◽  
Author(s):  
Paul G. Murray ◽  
Christothea M. Constandinou ◽  
John Crocker ◽  
Lawrence S. Young ◽  
Richard F. Ambinder
Keyword(s):  
Major Histocompatibility Complex ◽  
Mhc Class I ◽  
Epstein Barr Virus ◽  
Class I ◽  
Major Histocompatibility ◽  
Barr Virus ◽  
Histocompatibility Complex ◽  
Epstein Barr ◽  
Hla A2.1 ◽  
Mhc Class I Molecules

The Epstein-Barr virus (EBV)-encoded latent membrane proteins, LMP1 and LMP2, are consistently expressed by the malignant Hodgkin/Reed-Sternberg (HRS) cells of EBV-associated Hodgkin's disease (HD). Cytotoxic T lymphocyte (CTL) responses to both of these proteins have been shown in the blood of EBV-seropositive individuals, yet in HD the apparent failure of the CTL response to eliminate HRS cells expressing LMP1 and LMP2 in vivo has given rise to the suggestion that HD may be characterized by the presence of defects in antigen processing/presentation or in CTL function. This study has used immunohistochemistry to show high-level expression of major histocompatibility complex (MHC) class I molecules by the HRS cells of EBV-associated HD and either low level or absence of expression of MHC class I molecules on HRS cells of EBV-negative tumors. In addition, HRS cells expressed high levels of transporter-associated proteins (TAP-1, -2), irrespective of the presence of latent EBV infection. These results suggest that global downregulation of MHC class I molecules does not account for the apparent ability of EBV-infected HRS cells to evade CTL responses, but may be important in the understanding of EBV-negative disease.We have also sequenced an epitope in LMP2A (CLGGLLTMV) that is restricted through HLA A2.1, a relatively common allele in Caucasian populations, and showed that this epitope is wild type in a small group of EBV-associated HLA A2.1-positive HD tumors. This result may be relevant to proposed immunotherapeutic approaches for EBV-positive HD patients that target CTL epitopes.

scholarly journals NK cells eliminate Epstein-Barr virus bound to B cells through a specific antibody-mediated uptake

2021 ◽  
Vol 17 (8) ◽  
pp. e1009868
Author(s):  
Elisenda Alari-Pahissa ◽  
Michelle Ataya ◽  
Ilias Moraitis ◽  
Miriam Campos-Ruiz ◽  
Mireia Altadill ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Nk Cells ◽  
Epstein Barr Virus ◽  
Actin Polymerization ◽  
Nk Cell ◽  
Lytic Cycle ◽  
Barr Virus ◽  
Early Endosomes ◽  
Epstein Barr

Epstein Barr virus (EBV) causes a highly prevalent and lifelong infection contributing to the development of some malignancies. In addition to the key role played by T cells in controlling this pathogen, NK cells mediate cytotoxicity and IFNγ production in response to EBV-infected B cells in lytic cycle, both directly and through antibody (Ab)-dependent activation. We recently described that EBV-specific Ab-dependent NK cell interaction with viral particles (VP) bound to B cells triggered degranulation and TNFα secretion but not B cell lysis nor IFNγ production. In this report we show that NK cell activation under these conditions reduced B cell transformation by EBV. NK cells eliminated VP from the surface of B cells through a specific and active process which required tyrosine kinase activation, actin polymerization and Ca2+, being independent of proteolysis and perforin. VP were displayed at the NK cell surface before being internalized and partially shuttled to early endosomes and lysosomes. VP transfer was encompassed by a trogocytosis process including the EBV receptor CD21, together with CD19 and CD20. Our study reveals a novel facet of the antibody-dependent NK cell mediated response to this viral infection.

scholarly journals Epstein–Barr virus peptides derived from latent cycle proteins alter NKG2A + NK cell effector function

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Berenice Mbiribindi ◽  
Josselyn K. Pena ◽  
Matthew P. Arvedson ◽  
Claudia Moreno Romero ◽  
Sarah R. McCarthy ◽  
...  
Keyword(s):  
Nk Cells ◽  
Epstein Barr Virus ◽  
Cell Activation ◽  
Nk Cell ◽  
Human Leukocyte ◽  
Effector Function ◽  
Barr Virus ◽  
Epstein Barr ◽  
Cell Effector Function ◽  
Cell Effector

AbstractNatural killer (NK) cells control viral infection through the interaction between inhibitory receptors and human leukocyte antigen (HLA) ligands and bound peptide. NK cells expressing the inhibitory receptor NKG2A/CD94 recognize and respond to autologous B cells latently infected with Epstein–Barr virus (EBV). The mechanism is not yet understood, thus we investigated peptides derived from seven latent proteins of EBV in the interaction of NKG2A and its ligand HLA-E. Functional analysis demonstrated that EBV peptides can bind to HLA-E and block inhibition of NK cell effector function. Moreover, analysis of DNA from 79 subjects showed sequence variations in the latent protein, LMP1, which alters NK responses to EBV. We provide evidence that peptides derived from EBV latent cycle proteins can impair the recognition of NKG2A despite being presented by HLA-E, resulting in NK cell activation.

scholarly journals Tonsillar CD56brightNKG2A+ NK cells restrict primary Epstein-Barr virus infection in B cells via IFN-γ

Oncotarget ◽  
2016 ◽  
Vol 8 (4) ◽  
pp. 6130-6141 ◽  
Author(s):  
Aurelia Jud ◽  
Monika Kotur ◽  
Christoph Berger ◽  
Claudine Gysin ◽  
David Nadal ◽  
...  
Keyword(s):  
B Cells ◽  
Virus Infection ◽  
Nk Cells ◽  
Epstein Barr Virus ◽  
Epstein Barr Virus Infection ◽  
Barr Virus ◽  
Ifn Γ ◽  
Epstein Barr ◽  
Barr Virus Infection

scholarly journals Inhibition of Heavy Chain and β2-Microglobulin Synthesis as a Mechanism of Major Histocompatibility Complex Class I Downregulation during Epstein-Barr Virus Replication

2006 ◽  
Vol 81 (3) ◽  
pp. 1390-1400 ◽  
Author(s):  
Andre Ortlieb Guerreiro-Cacais ◽  
Mehmet Uzunel ◽  
Jelena Levitskaya ◽  
Victor Levitsky
Keyword(s):  
Mhc Class I ◽  
Mhc Class Ii ◽  
Heavy Chain ◽  
Epstein Barr Virus ◽  
Class I ◽  
Heavy Chains ◽  
Barr Virus ◽  
Histocompatibility Complex ◽  
Infected Cells ◽  
Epstein Barr

ABSTRACT The mechanisms of major histocompatibility complex (MHC) class I downregulation during Epstein-Barr virus (EBV) replication are not well characterized. Here we show that in several cell lines infected with a recombinant EBV strain encoding green fluorescent protein (GFP), the virus lytic cycle coincides with GFP expression, which thus can be used as a marker of virus replication. EBV replication resulted in downregulation of MHC class II and all classical MHC class I alleles independently of viral DNA synthesis or late gene expression. Although assembled MHC class I complexes, the total pool of heavy chains, and β2-microglobulin (β2m) were significantly downregulated, free class I heavy chains were stabilized at the surface of cells replicating EBV. Calnexin expression was increased in GFP+ cells, and calnexin and calreticulin accumulated at the cell surface that could contribute to the stabilization of class I heavy chains. Decreased expression levels of another chaperone, ERp57, and TAP2, a transporter associated with antigen processing and presentation, correlated with delayed kinetics of MHC class I maturation. Levels of both class I heavy chain and β2m mRNA were reduced, and metabolic labeling experiments demonstrated a very low rate of class I heavy chain synthesis in lytically infected cells. MHC class I and MHC class II downregulation was mimicked by pharmacological inhibition of protein synthesis in latently infected cells. Our data suggest that although several mechanisms may contribute to MHC class I downregulation in the course of EBV replication, inhibition of MHC class I synthesis plays the primary role in the process.

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