scholarly journals ADNKA overcomes SARS-CoV2-mediated NK cell inhibition through non-spike antibodies

2021 ◽  
Author(s):  
CA Fielding ◽  
P Sabberwal ◽  
JC Williamson ◽  
EJD Greenwood ◽  
TWM Crozier ◽  
...  
Keyword(s):  
Cell Activation ◽  
Nk Cell ◽  
Dominant Role ◽  
Natural Infection ◽  
Surface Protein ◽  
Lung Epithelial Cells ◽  
Interferon Response ◽  
Minor Role ◽  
Mhc I ◽  
Proteomic Approach

AbstractSARS-CoV-2 antagonises the cellular interferon response, but whether the virus manipulates cellular immunity is unclear. An unbiased proteomic approach to determine how cell surface protein expression is altered on SARS-CoV-2-infected lung epithelial cells showed downregulation of activating NK cell ligands: B7-H6, MICA, ULBP2, and Nectin1, but no effect on surface MHC-I expression. NK ligand downregulation correlated with a reduction in NK cell activation by infected cells, and was overcome by antibody-dependent NK cell activation (ADNKA). Depletion of spike-specific antibodies confirmed their dominant role in virus neutralisation, but these antibodies played only a minor role in ADNKA compared to antibodies to other viral proteins, including ORF3a, Membrane, and Nucleocapsid. In contrast, ADNKA induced following vaccination was focussed solely on spike, was weaker than ADNKA following natural infection, and was not boosted by the second dose. These insights have important implications for understanding disease progression, vaccine efficacy, and vaccine design.

scholarly journals NT5E/CD73 as Correlative Factor of Patient Survival and Natural Killer Cell Infiltration in Glioblastoma

2019 ◽  
Vol 8 (10) ◽  
pp. 1526 ◽  
Author(s):  
Jiao Wang ◽  
Sandro Matosevic
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Activation ◽  
Patient Survival ◽  
Nk Cell ◽  
Killer Cell ◽  
Surface Protein ◽  
The Cancer Genome Atlas ◽  
Negative Prognostic Factor ◽  
A Cell

CD73, a cell-surface protein encoded by the gene NT5E, is overexpressed in glioblastoma (GBM), where it contributes to the tumor’s pathophysiology via the generation of immunosuppressive adenosine. Adenosinergic signaling, in turn, drives immunosuppression of natural killer (NK) cells through metabolic and functional reprogramming. The correlation of CD73 with patient survival in relation to GBM pathology and the intratumoral infiltration of NK cells has not been comprehensively studied before. Here, we present an analysis of the prognostic relevance of CD73 in GBM based on transcriptional gene expression from patient data from The Cancer Genome Atlas (TCGA) database. Utilizing bioinformatics data mining tools, we explore the relationship between GBM prognosis, NT5E expression, and intratumoral presence of NK cells. Our analysis demonstrates that CD73 is a negative prognostic factor for GBM and that presence of NK cells may associate with improved prognosis. Moreover, the interplay between expression of NT5E and specific NK genes hints to potential functional effects of CD73 on NK cell activation.

scholarly journals SARS-CoV-2 Spike 1 Protein Controls Natural Killer Cell Activation via the HLA-E/NKG2A Pathway

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 1975 ◽  
Author(s):  
Daria Bortolotti ◽  
Valentina Gentili ◽  
Sabrina Rizzo ◽  
Antonella Rotola ◽  
Roberta Rizzo
Keyword(s):  
Epithelial Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Activation ◽  
Nk Cell ◽  
Killer Cell ◽  
Lung Epithelial Cells ◽  
Lung Epithelial ◽  
Spike Proteins

Natural killer cells are important in the control of viral infections. However, the role of NK cells during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has previously not been identified. Peripheral blood NK cells from SARS-CoV and SARS-CoV-2 naïve subjects were evaluated for their activation, degranulation, and interferon-gamma expression in the presence of SARS-CoV and SARS-CoV-2 spike proteins. K562 and lung epithelial cells were transfected with spike proteins and co-cultured with NK cells. The analysis was performed by flow cytometry and immune fluorescence. SARS-CoV and SARS-CoV-2 spike proteins did not alter NK cell activation in a K562 in vitro model. On the contrary, SARS-CoV-2 spike 1 protein (SP1) intracellular expression by lung epithelial cells resulted in NK cell-reduced degranulation. Further experiments revealed a concomitant induction of HLA-E expression on the surface of lung epithelial cells and the recognition of an SP1-derived HLA-E-binding peptide. Simultaneously, there was increased modulation of the inhibitory receptor NKG2A/CD94 on NK cells when SP1 was expressed in lung epithelial cells. We ruled out the GATA3 transcription factor as being responsible for HLA-E increased levels and HLA-E/NKG2A interaction as implicated in NK cell exhaustion. We show for the first time that NK cells are affected by SP1 expression in lung epithelial cells via HLA-E/NKG2A interaction. The resulting NK cells’ exhaustion might contribute to immunopathogenesis in SARS-CoV-2 infection.

scholarly journals Vaccination with Live Leishmania major and CpG DNA Promotes Interleukin-2 Production by Dermal Dendritic Cells and NK Cell Activation

2009 ◽  
Vol 16 (11) ◽  
pp. 1601-1606 ◽  
Author(s):  
Eva Maria Laabs ◽  
Wenhui Wu ◽  
Susana Mendez
Keyword(s):  
Dendritic Cells ◽  
Nk Cells ◽  
Cell Activation ◽  
Leishmania Major ◽  
Nk Cell ◽  
Natural Infection ◽  
Interleukin 2 ◽  
Innate Immune Responses ◽  
Cpg Dna ◽  
Ifn Γ

ABSTRACT Cutaneous leishmaniasis due to Leishmania major is an emerging, chronic parasitic disease that causes disfigurement and social stigmatization. Drug therapy is inadequate, and there is no vaccine. Inoculation of virulent parasites (leishmanization) is the only intervention that has ever provided protection, because it mimics natural infection and immunity, but it was discontinued due to safety concerns (uncontrolled vaccinal lesions). In an effort to retain the benefits (immunity) while avoiding the side effects (lesions) of leishmanization, we immunized C57BL/6 mice with L. major and CpG DNA (Lm/CpG). This combination prevented lesions while inducing immunity. Also, the vaccination with live parasites and the Toll-like receptor 9 agonist enhanced innate immune responses by activating dermal dendritic cells (DCs) to produce cytokines. Here we report that the Lm/CpG vaccine induced dermal DCs, but not bone marrow-derived DCs, to produce interleukin-2 (IL-2). The release of this unusual DC-derived cytokine was concomitant with a peak in numbers of NK cells that produced gamma interferon (IFN-γ) and also enhanced activation of proliferation of IFN-γ+ CD4+ T cells. Parasite growth was controlled in Lm/CpG-vaccinated animals. This is the first demonstration of the ability of dermal DCs to produce IL-2 and of the activation of NK cells by vaccination in the context of leishmaniasis. Understanding how the Lm/CpG vaccine enhances innate immunity may provide new tools to develop vaccines against L. major, other chronic infectious diseases, or other conditions, such as cancer.

scholarly journals Sars-Cov-2 Spike 1 protein control Natural killer cells activation via HLA-E/NKG2A pathway.

2020 ◽  
Author(s):  
Daria Bortolotti ◽  
Valentina Gentili ◽  
Sabrina Rizzo ◽  
Antonella Rotola ◽  
Roberta Rizzo
Keyword(s):  
Epithelial Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Activation ◽  
Viral Infections ◽  
Nk Cell ◽  
Lung Epithelial Cells ◽  
Lung Epithelial ◽  
Spike Proteins

Abstract Natural killer (NK) cells are important in the control of viral infections. However, the role of NK cells during Sars-Cov-2 infection has previously not been identified. Peripheral blood NK cells from Sars-Cov and Sars-Cov-2 naïve subjects were evaluated for their activation, degranulation, interferon-gamma expression in the presence of Sars-Cov and Sars-Cov-2 spike proteins. K562 and lung epithelial cells were transfected with spike proteins and co-cultured with NK cells. The analysis was performed by flow cytometry and immune-fluorescence. Sars-Cov and Sars-Cov-2 spike proteins did not alter NK cell activation in K562 in vitro model. On the contrary, Sars-Cov-2 spike 1 protein (SP1) intracellular expression by lung epithelial cells resulted in NK cell reduced degranulation. Further experiments revealed a concomitant induction of HLA-E expression on the surface of lung epithelial cells and the recognition of a SP1-derived HLA-E-binding peptide. Simultaneously, there was the up-modulation of the inhibitory receptor NKG2A/CD94 on NK cells when SP1 is expressed in lung epithelial cells. We ruled out GATA3 transcription factor as responsible for HLA-E increased levels and HLA-E/NKG2A interaction as implicate in NK cells exhaustion. We show for the first time that NK cells are affected by SP1 expression in lung epithelial cells via HLA-E/NKG2A interaction. The resulting NK cells exhaustion might contribute to immunopathogenesis in Sars-Cov-2 infection.

CD155: A Key Receptor Playing Diversified Roles

2021 ◽  
Vol 21 ◽  
Author(s):  
Shyam Sundar Nandi ◽  
Trupti Gohil ◽  
Sonali Ankush Sawant ◽  
Upendra Pradeep Lambe ◽  
Sudip Ghosh ◽  
...  
Keyword(s):  
Defense Mechanism ◽  
Nk Cell ◽  
Transmembrane Protein ◽  
Immune Surveillance ◽  
Surface Protein ◽  
Viral Receptor ◽  
Mhc I ◽  
Invasion And Migration ◽  
Host Interaction ◽  
Poliovirus Receptor

: Cluster of differentiation (CD155), formerly identified as poliovirus receptor (PVR) and later as immunoglobulin molecule involved in cell adhesion, proliferation, invasion and migration. It is a surface protein expressed mostly on normal and transformed malignant cells. The expression of the receptor varies based on the origin of tissue. The expression of the protein is determined by factors involved in sonic hedgehog pathway, Ras-MEK-ERK pathway and during stress conditions like DNA damage response. The protein uses alternate splicing mechanism, producing four isoforms - two being soluble (CD155β and CD155γ) and two being transmembrane protein (CD155α and CD155δ). Apart from being a viral receptor, researchers have identified CD155 having important roles in cancer research and cell signaling field. The receptor is recognized as biomarker for identifying cancerous tissue. The receptor interacts with molecules involved in cells defense mechanism. The immune-surveillance role of CD155 is being deciphered to understand the mechanistic approach it utilizes as onco-immunologic molecule. CD155 is a non-MHC-I ligand which helps in identifying non-self to NK cells via an inhibitory TIGIT ligand. The TIGIT–CD155 pathway is a novel MHC-I-independent education mechanism for cell tolerance and activation of NK cell. The receptor also has a role in metastasis of cancer and trans endothelial mechanism. In this review, authors discuss the virus-host interaction that occurs via single transmembrane receptor, the poliovirus infection pathway, which is being exploited as therapeutic pathway. The oncolytic virotherapy is now promising way for curing cancer.

scholarly journals Expression of m157, a Murine Cytomegalovirus-Encoded Putative Major Histocompatibility Class I (MHC-I)-Like Protein, Is Independent of Viral Regulation of Host MHC-I

2006 ◽  
Vol 80 (1) ◽  
pp. 545-550 ◽  
Author(s):  
Sandeep K. Tripathy ◽  
Hamish R. C. Smith ◽  
Erika A. Holroyd ◽  
Jeanette T. Pingel ◽  
Wayne M. Yokoyama
Keyword(s):  
Antigen Processing ◽  
Cell Activation ◽  
Nk Cell ◽  
Class I ◽  
Murine Cytomegalovirus ◽  
Viral Gene ◽  
Major Histocompatibility ◽  
Class I Mhc ◽  
Mhc I ◽  
Beta 2 Microglobulin

ABSTRACT A murine cytomegalovirus (MCMV)-encoded protein, m157, has a putative major histocompatibility complex class I (MHC-I) structure and is recognized by the Ly49H NK cell activation receptor. Using a monoclonal antibody against m157, in this study we directly demonstrated that m157 is a cell surface-expressed glycophosphatidylinositol-anchored protein with early viral gene kinetics. Beta-2 microglobulin and TAP1 (transporter associated with antigen processing 1) were not required for its expression. MCMV-encoded proteins that down-regulate MHC-I did not affect the expression of m157. Thus, m157 is expressed on infected cells in a manner independent of viral regulation of host MHC-I.

scholarly journals HCMV glycoprotein B subunit vaccine efficacy mediated by nonneutralizing antibody effector functions

2018 ◽  
Vol 115 (24) ◽  
pp. 6267-6272 ◽  
Author(s):  
Cody S. Nelson ◽  
Tori Huffman ◽  
Jennifer A. Jenks ◽  
Eduardo Cisneros de la Rosa ◽  
Guanhua Xie ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Subunit Vaccine ◽  
Cell Activation ◽  
Nk Cell ◽  
Natural Infection ◽  
Congenital Infection ◽  
Glycoprotein B ◽  
Vaccine Platform ◽  
Effector Functions ◽  
Domain I

Human cytomegalovirus (HCMV) is the most common congenital infection worldwide, frequently causing hearing loss and brain damage in afflicted infants. A vaccine to prevent maternal acquisition of HCMV during pregnancy is necessary to reduce the incidence of infant disease. The glycoprotein B (gB) + MF59 adjuvant subunit vaccine platform is the most successful HCMV vaccine tested to date, demonstrating ∼50% efficacy in preventing HCMV acquisition in multiple phase 2 trials. However, the mechanism of vaccine protection remains unknown. Plasma from 33 postpartum women gB/MF59 vaccinees at peak immunogenicity was tested for gB epitope specificity as well as neutralizing and nonneutralizing anti-HCMV effector functions and compared with an HCMV-seropositive cohort. gB/MF59 vaccination elicited IgG responses with gB-binding magnitude and avidity comparable to natural infection. Additionally, IgG subclass distribution was similar with predominant IgG1 and IgG3 responses induced by gB vaccination and HCMV infection. However, vaccine-elicited antibodies exhibited limited neutralization of the autologous virus, negligible neutralization of multiple heterologous strains, and limited binding responses against gB structural motifs targeted by neutralizing antibodies including AD-1, AD-2, and domain I. Vaccinees had high-magnitude IgG responses against AD-3 linear epitopes, demonstrating immunodominance against this nonneutralizing, cytosolic region. Finally, vaccine-elicited IgG robustly bound membrane-associated gB on the surface of transfected or HCMV-infected cells and mediated virion phagocytosis, although were poor mediators of NK cell activation. Altogether, these data suggest that nonneutralizing antibody functions, including virion phagocytosis, likely played a role in the observed 50% vaccine-mediated protection against HCMV acquisition.

scholarly journals Cytomegalovirus immunoevasin reveals the physiological role of “missing self” recognition in natural killer cell dependent virus control in vivo

2010 ◽  
Vol 207 (12) ◽  
pp. 2663-2673 ◽  
Author(s):  
Marina Babić ◽  
Michal Pyzik ◽  
Biljana Zafirova ◽  
Maja Mitrović ◽  
Višnja Butorac ◽  
...  
Keyword(s):  
Natural Killer ◽  
Cell Activation ◽  
Nk Cell ◽  
Killer Cell ◽  
Physiological Role ◽  
Dependent Manner ◽  
Class I Mhc ◽  
Mhc I ◽  
Missing Self

Cytomegaloviruses (CMVs) are renowned for interfering with the immune system of their hosts. To sidestep antigen presentation and destruction by CD8+ T cells, these viruses reduce expression of major histocompatibility complex class I (MHC I) molecules. However, this process sensitizes the virus-infected cells to natural killer (NK) cell–mediated killing via the “missing self” axis. Mouse cytomegalovirus (MCMV) uses m152 and m06 encoded proteins to inhibit surface expression of MHC I molecules. In addition, it encodes another protein, m04, which forms complexes with MHC I and escorts them to the cell surface. This mechanism is believed to prevent NK cell activation and killing by restoring the “self” signature and allowing the engagement of inhibitory Ly49 receptors on NK cells. Here we show that MCMV lacking m04 was attenuated in an NK cell– and MHC I–dependent manner. NK cell–mediated control of the infection was dependent on the presence of NK cell subsets expressing different inhibitory Ly49 receptors. In addition to providing evidence for immunoevasion strategies used by CMVs to avoid NK cell control via the missing-self pathway, our study is the first to demonstrate that missing self–dependent NK cell activation is biologically relevant in the protection against viral infection in vivo.

scholarly journals How the Virus Outsmarts the Host: Function and Structure of Cytomegalovirus MHC-I-Like Molecules in the Evasion of Natural Killer Cell Surveillance

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
Maria Jamela Revilleza ◽  
Rui Wang ◽  
Janet Mans ◽  
Manqing Hong ◽  
Kannan Natarajan ◽  
...  
Keyword(s):  
Natural Killer ◽  
Host Response ◽  
Cell Activation ◽  
Nk Cell ◽  
Killer Cell ◽  
Viral Fitness ◽  
Protein Fold ◽  
Viral Pathogens ◽  
Mhc I ◽  
Functional Features

Natural killer (NK) cells provide an initial host immune response to infection by many viral pathogens. Consequently, the viruses have evolved mechanisms to attenuate the host response, leading to improved viral fitness. One mechanism employed by members of theβ-herpesvirus family, which includes the cytomegaloviruses, is to modulate the expression of cell surface ligands recognized by NK cell activation molecules. A novel set of cytomegalovirus (CMV) genes, exemplified by the mouse m145 family, encode molecules that have structural and functional features similar to those of host major histocompatibility-encoded (MHC) class I molecules, some of which are known to contribute to immune evasion. In this review, we explore the function, structure, and evolution of MHC-I-like molecules of the CMVs and speculate on the dynamic development of novel immunoevasive functions based on the MHC-I protein fold.

scholarly journals Unconventional Peptide Presentation by Classical MHC Class I and Implications for T and NK Cell Activation

2020 ◽  
Vol 21 (20) ◽  
pp. 7561
Author(s):  
Dirk M. Zajonc
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class I ◽  
Cell Activation ◽  
Nk Cell ◽  
Class I ◽  
Immune Recognition ◽  
Mhc I ◽  
Peptide Presentation ◽  
Binding Groove

T cell-mediated immune recognition of peptides is initiated upon binding of the antigen receptor on T cells (TCR) to the peptide-MHC complex. TCRs are typically restricted by a particular MHC allele, while polymorphism within the MHC molecule can affect the spectrum of peptides that are bound and presented to the TCR. Classical MHC Class I molecules have a confined binding groove that restricts the length of the presented peptides to typically 8–11 amino acids. Both N- and C-termini of the peptide are bound within binding pockets, allowing the TCR to dock in a diagonal orientation above the MHC-peptide complex. Longer peptides have been observed to bind either in a bulged or zig-zag orientation within the binding groove. More recently, unconventional peptide presentation has been reported for different MHC I molecules. Here, either N- or C-terminal amino acid additions to conventionally presented peptides induced a structural change either within the MHC I molecule that opened the confined binding groove or within the peptide itself, allowing the peptide ends to protrude into the solvent. Since both TCRs on T cells and killer immunoglobulin receptors on Natural Killer (NK) cells contact the MHC I molecule above or at the periphery of the peptide binding groove, unconventionally presented peptides could modulate both T cell and NK cell responses. We will highlight recent advances in our understanding of the functional consequences of unconventional peptide presentation in cellular immunity.

Sign in / Sign up

Export Citation Format

Share Document