scholarly journals The m15 Locus of Murine Cytomegalovirus Modulates Natural Killer Cell Responses to Promote Dissemination to the Salivary Glands and Viral Shedding

Pathogens ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 866
Author(s):  
Baca Chan ◽  
Maja Arapović ◽  
Laura Masters ◽  
Francois Rwandamuiye ◽  
Stipan Jonjić ◽  
...  
Keyword(s):  
Nk Cells ◽  
Salivary Glands ◽  
Natural Killer ◽  
Nk Cell ◽  
Acute Infection ◽  
Killer Cell ◽  
Viral Escape ◽  
Murine Cytomegalovirus ◽  
Viral Shedding ◽  
Cell Responses

As the largest herpesviruses, the 230 kb genomes of cytomegaloviruses (CMVs) have increased our understanding of host immunity and viral escape mechanisms, although many of the annotated genes remain as yet uncharacterised. Here we identify the m15 locus of murine CMV (MCMV) as a viral modulator of natural killer (NK) cell immunity. We show that, rather than discrete transcripts from the m14, m15 and m16 genes as annotated, there are five 3′-coterminal transcripts expressed over this region, all utilising a consensus polyA tail at the end of the m16 gene. Functional inactivation of any one of these genes had no measurable impact on viral replication. However, disruption of all five transcripts led to significantly attenuated dissemination to, and replication in, the salivary glands of multiple strains of mice, but normal growth during acute infection. Disruption of the m15 locus was associated with heightened NK cell responses, including enhanced proliferation and IFNγ production. Depletion of NK cells, but not T cells, rescued salivary gland replication and viral shedding. These data demonstrate the identification of multiple transcripts expressed by a single locus which modulate, perhaps in a concerted fashion, the function of anti-viral NK cells.

scholarly journals Glycosylation Affects Ligand Binding and Function of the Activating Natural Killer Cell Receptor 2B4 (CD244) Protein

2011 ◽  
Vol 286 (27) ◽  
pp. 24142-24149 ◽  
Author(s):  
Stefanie Margraf-Schönfeld ◽  
Carolin Böhm ◽  
Carsten Watzl
Keyword(s):  
Ligand Binding ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Function ◽  
Nk Cell ◽  
Negative Impact ◽  
Killer Cell ◽  
Target Cells ◽  
Functional Assay ◽  
Cell Responses

2B4 (CD244) is an important activating receptor for the regulation of natural killer (NK) cell responses. Here we show that 2B4 is heavily and differentially glycosylated in primary human NK cells and NK cell lines. The differential glycosylation could be attributed to sialic acid residues on N- and O-linked carbohydrates. Using a recombinant fusion protein of the extracellular domain of 2B4, we demonstrate that N-linked glycosylation of 2B4 is essential for the binding to its ligand CD48. In contrast, sialylation of 2B4 has a negative impact on ligand binding, as the interaction between 2B4 and CD48 is increased after the removal of sialic acids. This was confirmed in a functional assay system, where the desialylation of NK cells or the inhibition of O-linked glycosylation resulted in increased 2B4-mediated lysis of CD48-expressing tumor target cells. These data demonstrate that glycosylation has an important impact on 2B4-mediated NK cell function and suggest that regulated changes in glycosylation during NK cell development and activation might be involved in the regulation of NK cell responses.

scholarly journals Age-dependent susceptibility to a viral disease due to decreased natural killer cell numbers and trafficking

2010 ◽  
Vol 207 (11) ◽  
pp. 2369-2381 ◽  
Author(s):  
Min Fang ◽  
Felicia Roscoe ◽  
Luis J. Sigal
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Function ◽  
Nk Cell ◽  
Killer Cell ◽  
Viral Disease ◽  
Viral Diseases ◽  
Cell Responses ◽  
Loss Of Resistance ◽  
Age Dependent

Although it is well known that aged hosts are generally more susceptible to viral diseases than the young, specific dysfunctions of the immune system directly responsible for this increased susceptibility have yet to be identified. We show that mice genetically resistant to mousepox (the mouse parallel of human smallpox) lose resistance at mid-age. Surprisingly, this loss of resistance is not a result of intrinsically defective T cell responses. Instead, the primary reason for the loss of resistance results from a decreased number of total and mature natural killer (NK) cells in the blood and an intrinsic impairment in their ability to migrate to the lymph node draining the site of infection, which is essential to curb systemic virus spread. Hence, our work links the age-dependent increase in susceptibility to a viral disease to a specific defect of NK cells, opening the possibility of exploring treatments to improve NK cell function in the aged with the goal of enhancing their resistance to viral diseases.

scholarly journals Natural Killer Cell Responses during Human γ-Herpesvirus Infections

Vaccines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 655
Author(s):  
Christian Münz
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Epstein Barr Virus ◽  
Nk Cell ◽  
Killer Cell ◽  
Kaposi Sarcoma ◽  
Antibody Dependent Cellular Cytotoxicity ◽  
Barr Virus ◽  
Cell Responses ◽  
Epstein Barr

Herpesviruses are main sculptors of natural killer (NK) cell repertoires. While the β-herpesvirus human cytomegalovirus (CMV) drives the accumulation of adaptive NKG2C-positive NK cells, the human γ-herpesvirus Epstein–Barr virus (EBV) expands early differentiated NKG2A-positive NK cells. While adaptive NK cells support adaptive immunity by antibody-dependent cellular cytotoxicity, NKG2A-positive NK cells seem to preferentially target lytic EBV replicating B cells. The importance of this restriction of EBV replication during γ-herpesvirus pathogenesis will be discussed. Furthermore, the modification of EBV-driven NK cell expansion by coinfections, including by the other human γ-herpesvirus Kaposi sarcoma-associated herpesvirus (KSHV), will be summarized.

scholarly journals Tim-3 marks human natural killer cell maturation and suppresses cell-mediated cytotoxicity

Blood ◽  
2012 ◽  
Vol 119 (16) ◽  
pp. 3734-3743 ◽  
Author(s):  
Lishomwa C. Ndhlovu ◽  
Sandra Lopez-Vergès ◽  
Jason D. Barbour ◽  
R. Brad Jones ◽  
Aashish R. Jha ◽  
...  
Keyword(s):  
T Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Subset ◽  
Target Cells ◽  
Type I ◽  
Human Natural Killer Cell ◽  
Cell Responses

Abstract Natural killer (NK) cells are innate lymphocytes that play an important role against viral infections and cancer. This effect is achieved through a complex mosaic of inhibitory and activating receptors expressed by NK cells that ultimately determine the magnitude of the NK-cell response. The T-cell immunoglobulin– and mucin domain–containing (Tim)–3 receptor was initially identified as a T-helper 1–specific type I membrane protein involved in regulating T-cell responses. Human NK cells transcribe the highest amounts of Tim-3 among lymphocytes. Tim-3 protein is expressed on essentially all mature CD56dimCD16+ NK cells and is expressed heterogeneously in the immature CD56brightCD16– NK-cell subset in blood from healthy adults and in cord blood. Tim-3 expression was induced on CD56brightCD16− NK cells after stimulation with IL-15 or IL-12 and IL-18 in vitro, suggesting that Tim-3 is a maturation marker on NK cells. Whereas Tim-3 has been used to identify dysfunctional T cells, NK cells expressing high amounts of Tim-3 are fully responsive with respect to cytokine production and cytotoxicity. However, when Tim-3 was cross-linked with antibodies it suppressed NK cell–mediated cytotoxicity. These findings suggest that NK-cell responses may be negatively regulated when NK cells encounter target cells expressing cognate ligands of Tim-3.

scholarly journals Induction of Natural Killer Cell Responses by Ectromelia Virus Controls Infection

2007 ◽  
Vol 81 (8) ◽  
pp. 4070-4079 ◽  
Author(s):  
April Keim Parker ◽  
Scott Parker ◽  
Wayne M. Yokoyama ◽  
John A. Corbett ◽  
R. Mark L. Buller
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Intracellular Cytokine Staining ◽  
Killer Cell ◽  
Murine Cytomegalovirus ◽  
Virus Infectivity ◽  
Ectromelia Virus ◽  
Ifn Γ

ABSTRACT Natural killer (NK) cells play a pivotal role in the innate immune response to viral infections, particularly murine cytomegalovirus (MCMV) and human herpesviruses. In poxvirus infections, the role of NK cells is less clear. We examined disease progression in C57BL/6 mice after the removal of NK cells by both antibody depletion and genetic means. We found that NK cells were crucial for survival and the early control of virus replication in spleen and to a lesser extent in liver in C57BL/6 mice. Studies of various knockout mice suggested that γδ T cells and NKT cells are not important in the C57BL/6 mousepox model and CD4+ and CD8+ T cells do not exhibit antiviral activity at 6 days postinfection, when the absence of NK cells has a profound effect on virus titers in spleen and liver. NK cell cytotoxicity and/or gamma interferon (IFN-γ) secretion likely mediated the antiviral effect needed to control virus infectivity in target organs. Studies of the effects of ectromelia virus (ECTV) infection on NK cells demonstrated that NK cells proliferate within target tissues (spleen and liver) and become activated following a low-dose footpad infection, although the mechanism of activation appears distinct from the ligand-dependent activation observed with MCMV. NK cell IFN-γ secretion was detected by intracellular cytokine staining transiently at 32 to 72 h postinfection in the lymph node, suggesting a role in establishing a Th1 response. These results confirm a crucial role for NK cells in controlling an ECTV infection.

scholarly journals Cytokine induced natural killer cell training is dependent on cellular metabolism and is defective in obesity

2021 ◽  
Author(s):  
Nidhi Kedia-Mehta ◽  
Laura Tobin ◽  
Vanessa Zaiatz-Bittencourt ◽  
Marta Pisarska ◽  
Conor De Barra ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Cell Metabolism ◽  
Initial Period ◽  
Killer Cell ◽  
Cellular Metabolism ◽  
Cell Responses ◽  
Cytokine Activation ◽  
Metabolic Signalling

Natural killer (NK) cells are a population of innate immune cells which can rapidily kill cancer cells and produce cytokines such as interferon gamma (IFN-gamma). A key feature of NK cells is their ability to respond without prior sensitation, however it is now well established that NK cells can possess memory-like features. After activation with cytokines, NK cells demonstrate enhanced effector functions upon restimulation days or weeks later. This demonstrates that NK cells may be "trained" to be more effective killers and harnessed as more potent cancer immunotherapy agents. We have previously demonstrated that cellular metabolism is essential for NK cell responses, with NK cells upregulating both glycolysis and oxidative phosphorylation upon cytokine stimulation. Limiting NK cell metabolism results in reduced cytotoxicity and cytokine production. We have also demonstrated that defective NK cell responses in obesity are linked to defective cellular metabolism. In the current study we investigated if cellular metabolism is required during the initial period of NK cell cytokine training, and if NK cells from people with obesity (PWO) can be effectively trained. We show that increased flux through glycolysis and OXPHOS during the initial cytokine activation period is essential for NK cell training, as is the metabolic signalling factor Srepb. We show that NK cells from PWO, which are metabolically defective, display impaired NK cell training, which may have implications for immunotherapy in this particularly vulnerable group.

scholarly journals Pivotal Role of KARAP/DAP12 Adaptor Molecule in the Natural Killer Cell–mediated Resistance to Murine Cytomegalovirus Infection

2002 ◽  
Vol 195 (7) ◽  
pp. 825-834 ◽  
Author(s):  
Hanna Sjölin ◽  
Elena Tomasello ◽  
Mehrdad Mousavi-Jazi ◽  
Armando Bartolazzi ◽  
Klas Kärre ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Interferon Γ ◽  
Mutant Mice ◽  
Murine Cytomegalovirus ◽  
Activating Receptors ◽  
And Function

Natural killer (NK) cells are major contributors to early defense against infections. Their effector functions are controlled by a balance between activating and inhibiting signals. To date, however, the involvement of NK cell activating receptors and signaling pathways in the defense against pathogens has not been extensively investigated. In mice, several NK cell activating receptors are coexpressed with and function through the immunoreceptor tyrosine-based activation motif (ITAM)-bearing molecule KARAP/DAP12. Here, we have analyzed the role of KARAP/DAP12 in the early antiviral response to murine cytomegalovirus (MCMV). In KARAP/DAP12 mutant mice bearing a nonfunctional ITAM, we found a considerable increase in viral titers in the spleen (30–40-fold) and in the liver (2–5-fold). These effects were attributed to NK cells. The formation of hepatic inflammatory foci appeared similar in wild-type and mutant mice, but the latter more frequently developed severe hepatitis with large areas of focal necrosis. Moreover, the percentage of hepatic NK cells producing interferon γ was reduced by 56 ± 22% in the absence of a functional KARAP/DAP12. This is the first study that shows a crucial role for a particular activating signaling pathway, in this case the one induced through KARAP/DAP12, in the NK cell–mediated resistance to an infection. Our results are discussed in relation to recent reports demonstrating that innate resistance to MCMV requires the presence of NK cells expressing the KARAP/DAP12-associated receptor Ly49H.

scholarly journals Durable natural killer cell responses after heterologous two-dose Ebola vaccination

npj Vaccines ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Helen R. Wagstaffe ◽  
Giada Susannini ◽  
Rodolphe Thiébaut ◽  
Laura Richert ◽  
Yves Lévy ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Activation ◽  
Ebola Virus ◽  
Nk Cell ◽  
Ex Vivo ◽  
Killer Cell ◽  
Post Dose ◽  
Vaccine Regimen ◽  
Cell Responses

AbstractNatural killer (NK) cells are implicated among immune effectors after vaccination against viral pathogens, including Ebola virus. The two-dose heterologous Ebola virus vaccine regimen, adenovirus type 26.ZEBOV followed by modified vaccinia Ankara-BN-Filo (EBOVAC2 consortium, EU Innovative Medicines Initiative), induces NK cell activation and anti-Ebola glycoprotein (GP) antibody-dependent NK cell activation post-dose 1, which is further elevated post-dose 2. Here, in a multicentre, phase 2 clinical trial (EBL2001), we demonstrate durable ex vivo NK cell activation 180 days after dose 2, with responses enriched in CD56bright NK cells. In vitro antibody-dependent responses to immobilised Ebola GP increased after dose 1, and remained elevated compared to pre-vaccination levels in serum collected 180 days later. Peak NK cell responses were observed post-dose 2 and NK cell IFN-γ responses remained significantly elevated at 180 days post-dose 2. Individual variation in NK cell responses were influenced by both anti-Ebola GP antibody concentrations and intrinsic interindividual differences in NK cell functional capacity. In summary, this study demonstrates durable NK cell responses after Ad26.ZEBOV, MVA-BN-Filo Ebola virus vaccination and could inform the immunological evaluation of future iterations of the vaccine regimen and vaccination schedules.

scholarly journals The Cytomegalovirus m155 Gene Product Subverts Natural Killer Cell Antiviral Protection by Disruption of H60–NKG2D Interactions

2004 ◽  
Vol 200 (8) ◽  
pp. 1075-1081 ◽  
Author(s):  
Melissa B. Lodoen ◽  
Gerardo Abenes ◽  
Sean Umamoto ◽  
Jeffrey P. Houchins ◽  
Fenyong Liu ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Proteasome Inhibitors ◽  
Mutant Virus ◽  
Murine Cytomegalovirus ◽  
Down Regulation ◽  
Mcmv Infection ◽  
Affinity Ligand

Natural killer (NK) cells are an important early mediator of host immunity to murine cytomegalovirus (MCMV) infection. However, MCMV has evolved mechanisms to elude recognition and clearance by NK cells. We have identified an MCMV immune evasion protein that impairs NKG2D-mediated NK cell antiviral activity. Infection of BALB/c 3T3 cells with the Smith strain of MCMV resulted in strong down-regulation of H60, a high affinity ligand for NKG2D, from the surface of virus-infected cells. The MCMV m155 protein specifically down-regulated H60 without affecting expression of the other known NKG2D ligands, RAE-1 and MULT-1. Treatment with the proteasome inhibitors lactacystin or epoxomicin reversed m155 down-regulation of H60. An MCMV mutant virus lacking m155 was severely attenuated in BALB/c mice; however, treatment with neutralizing anti-NKG2D monoclonal antibody or with NK-depleting anti-asialo GM1 antisera restored virulence of the mutant virus. Thus, down-regulation of H60 by m155 is a powerful mechanism of inhibiting NKG2D-mediated antiviral function.

scholarly journals Cytomegalovirus reactivation after allogeneic transplantation promotes a lasting increase in educated NKG2C+ natural killer cells with potent function

Blood ◽  
2012 ◽  
Vol 119 (11) ◽  
pp. 2665-2674 ◽  
Author(s):  
Bree Foley ◽  
Sarah Cooley ◽  
Michael R. Verneris ◽  
Michelle Pitt ◽  
Julie Curtsinger ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Response ◽  
Hematopoietic Cell Transplantation ◽  
Nk Cell ◽  
Acute Infection ◽  
Killer Cell ◽  
First Year ◽  
Cmv Infection ◽  
Cmv Reactivation

AbstractDuring mouse cytomegalovirus (CMV) infection, a population of Ly49H+ natural killer (NK) cells expands and is responsible for disease clearance through the induction of a “memory NK-cell response.” Whether similar events occur in human CMV infection is unknown. In the present study, we characterized the kinetics of the NK-cell response to CMV reactivation in human recipients after hematopoietic cell transplantation. During acute infection, NKG2C+ NK cells expanded and were potent producers of IFNγ. NKG2C+ NK cells predominately expressed killer cell immunoglobulin–like receptor, and self-killer cell immunoglobulin–like receptors were required for robust IFNγ production. During the first year after transplantation, CMV reactivation induced a more mature phenotype characterized by an increase in CD56dim NK cells. Strikingly, increased frequencies of NKG2C+ NK cells persisted and continued to increase in recipients who reactivated CMV, whereas these cells remained at low frequency in recipients without CMV reactivation. Persisting NKG2C+ NK cells lacked NKG2A, expressed CD158b, preferentially acquired CD57, and were potent producers of IFNγ during the first year after transplantation. Recipients who reactivated CMV also expressed higher amounts of IFNγ, T-bet, and IL-15Rα mRNA transcripts. Our findings support the emerging concept that CMV-induced innate memory-cell populations may contribute to malignant disease relapse protection and infectious disease control long after transplantation.

Sign in / Sign up

Export Citation Format

Share Document