scholarly journals Redefining Memory: Building the Case for Adaptive NK Cells

2017 ◽  
Vol 91 (20) ◽  
Author(s):  
Silke Paust ◽  
Catherine A. Blish ◽  
R. Keith Reeves
Keyword(s):  
Nk Cells ◽  
Molecular Mechanisms ◽  
Nk Cell ◽  
Murine Cytomegalovirus ◽  
The Novel ◽  
Antigen Specificity ◽  
Cell Memory ◽  
Viral Pathogens ◽  
Adaptive Capabilities ◽  
Cell Subpopulations

ABSTRACT Classically, natural killer (NK) cells have been defined by nonspecific innate killing of virus-infected and tumor cells. However, burgeoning evidence suggests that the functional repertoire of NK cells is far more diverse than has been previously appreciated, thus raising the possibility that there may be unexpected functional specialization and even adaptive capabilities among NK cell subpopulations. Some of the first evidence that NK cells respond in an antigen-specific fashion came from experiments revealing that subpopulations of murine NK cells were able to respond to a specific murine cytomegalovirus (MCMV) protein and that in the absence of T and B cells, murine NK cells also mediated adaptive immune responses to a secondary challenge with specific haptens. These data have been followed by demonstrations of NK cell memory of viruses and viral antigens in mice and primates. Herein, we discuss different forms of NK cell antigen specificity and how these responses may be tuned to specific viral pathogens, and we provide assessment of the current literature that may explain molecular mechanisms of the novel phenomenon of NK cell memory.

scholarly journals NK Cell Memory to Cytomegalovirus: Implications for Vaccine Development

Vaccines ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 394
Author(s):  
Calum Forrest ◽  
Ariane Gomes ◽  
Matthew Reeves ◽  
Victoria Male
Keyword(s):  
Immune System ◽  
Nk Cells ◽  
Innate Immune System ◽  
Vaccine Development ◽  
Nk Cell ◽  
Innate Immune ◽  
Lymphoid Cells ◽  
Murine Cytomegalovirus ◽  
Immune Memory ◽  
Cell Memory

Natural killer (NK) cells are innate lymphoid cells that recognize and eliminate virally-infected and cancerous cells. Members of the innate immune system are not usually considered to mediate immune memory, but over the past decade evidence has emerged that NK cells can do this in several contexts. Of these, the best understood and most widely accepted is the response to cytomegaloviruses, with strong evidence for memory to murine cytomegalovirus (MCMV) and several lines of evidence suggesting that the same is likely to be true of human cytomegalovirus (HCMV). The importance of NK cells in the context of HCMV infection is underscored by the armory of NK immune evasion genes encoded by HCMV aimed at subverting the NK cell immune response. As such, ongoing studies that have utilized HCMV to investigate NK cell diversity and function have proven instructive. Here, we discuss our current understanding of NK cell memory to viral infection with a focus on the response to cytomegaloviruses. We will then discuss the implications that this will have for the development of a vaccine against HCMV with particular emphasis on how a strategy that can harness the innate immune system and NK cells could be crucial for the development of a vaccine against this high-priority pathogen.

scholarly journals Critical role for the Ly49 family of class I MHC receptors in adaptive natural killer cell responses

2018 ◽  
Vol 115 (45) ◽  
pp. 11579-11584 ◽  
Author(s):  
Andrew Wight ◽  
Ahmad Bakur Mahmoud ◽  
Michal Scur ◽  
Megan M. Tu ◽  
Mir Munir A. Rahim ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Critical Role ◽  
Killer Cell ◽  
Class I ◽  
Antigen Specificity ◽  
Cell Memory ◽  
Class I Mhc ◽  
Memory Response

Adaptive natural killer (NK) cell memory represents a new frontier in immunology. Work over the last decade has discovered and confirmed the existence of NK cells with antigen-specific memories, which had previously been considered a unique property of T and B cells. These findings have shown that antigen-specific NK cells gain their specificity without the use of RAG proteins, representing a novel mechanism for generating antigen specificity, but the details of this mechanism have remained a mystery. We have discovered that members of the Ly49 family of surface receptors are critically involved in both the sensitization and the challenge phases of an NK cell memory response, as is antigen presentation from their binding partner, the class I MHC. Moreover, we demonstrate that the Ly49-interacting component of a presented antigen dictates the specificity of the NK cell memory response, implicating Ly49 receptors themselves in antigen-specific recognition. Finally, we demonstrate that adaptive NK cell memories can protect against an otherwise lethal melanoma without T cell or B cell support. These findings offer insight into the mechanism behind NK cell antigen specificity and demonstrate the clinical potential of this adaptive immune cell.

scholarly journals NK cells acquire epigenetic memory of LPS-induced systemic inflammation

2018 ◽  
Author(s):  
Orhan Rasid ◽  
Christine Chevalier ◽  
Tiphaine Camarasa ◽  
Catherine Fitting ◽  
Jean-Marc Cavaillon ◽  
...  
Keyword(s):  
Bacterial Infection ◽  
Nk Cells ◽  
Systemic Inflammation ◽  
Molecular Mechanisms ◽  
Nk Cell ◽  
Epigenetic Mechanism ◽  
Immune Memory ◽  
Dependent Manner ◽  
Cell Memory ◽  
Secondary Stimulation

Natural killer cells are unique mediators of innate immunity, and as such, an attractive target for immunotherapy. Following viral infection, NK cells display immune memory properties, defined by heightened responses to re-stimulation, an expansion of specific NK cell sup-populations and a protective role against re-infection. However, similar memory to bacterial infection or systemic inflammation, and the molecular mechanisms behind NK cell memory remain elusive. Here we show that following LPS-induced endotoxemia in mice, NK cells acquire cell-intrinsic memory properties as displayed by an amplified production of IFNγ upon secondary stimulation. NK cell memory is acquired even under the post-endotoxemic suppressive environment and is detectable for at least 9 weeks. Furthermore, we define an epigenetic mechanism essential for NK cell memory, where an H3K4me1-marked latent enhancer is uncovered at the ifng locus. Chemical inhibition of histone methyltransferase activity erased the enhancer and prevented NK cells from acquiring memory. Thus, NK cells develop memory to LPS during endotoxemia, in a histone methylation-dependent manner, which ensures a heightened response to secondary stimulation and confers protection against bacterial infection.

scholarly journals Human Cytokine-Induced Memory-Like Natural Killer Cells

2015 ◽  
Vol 7 (6) ◽  
pp. 563-571 ◽  
Author(s):  
Melissa M. Berrien-Elliott ◽  
Julia A. Wagner ◽  
Todd A. Fehniger
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Molecular Mechanisms ◽  
Nk Cell ◽  
Hematologic Malignancies ◽  
Lymphoid Cells ◽  
Cell Memory ◽  
And Function ◽  
Activation Event ◽  
Cell Effector

Natural killer (NK) cells are innate lymphoid cells that are important for host defense against infection and mediate antitumor responses. Recent reports from several laboratories have identified that NK cells can remember a prior activation event and consequently respond more robustly when restimulated, a property termed innate NK cell memory. NK cell memory has now been identified following hapten exposure, viral infection, and combined cytokine preactivation with IL-12, IL-15, and IL-18. Many questions in the field remain regarding the cellular and molecular mechanisms regulating memory NK cells and their responses, as well as their formation and function in mice and humans. Here we review our current understanding of cytokine-induced memory-like (CIML) NK cells that are generated by combined preactivation with IL-12, IL-15, and IL-18. These cells exhibit enhanced NK cell effector functions weeks after the initial cytokine preactivation. Further, we highlight the preclinical rationale and ongoing therapeutic application of CIML NK cells for adoptive immunotherapy in patients with hematologic malignancies.

scholarly journals Human antigen-specific memory natural killer cell responses develop against HIV-1 and influenza virus and are dependent on MHC-E restriction

2020 ◽  
Author(s):  
Stephanie Jost ◽  
Olivier Lucar ◽  
Taylor Yoder ◽  
Kyle Kroll ◽  
Sho Sugawara ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Health Priorities ◽  
Antigen Specificity ◽  
Cell Memory ◽  
Specific Memory ◽  
Hiv 1 ◽  
Memory Nk Cells

ABSTRACTFor over a decade, multiple studies have disputed the notion of natural killer (NK) cells as purely innate lymphocytes by demonstrating that they are capable of putative antigen-specific immunological memory against multiple infectious agents including two critical global health priorities – HIV and influenza. However, the mechanisms underlying antigen specificity remain unknown. Herein, we demonstrate that antigen-specific human NK cell memory develops upon exposure to both HIV and influenza, unified by a conserved and epitope-specific targetable mechanism firmly dependent on the activating CD94/NKG2C receptor and its ligand HLA-E, and confirm these findings by three rigorous and novel assays. We validated the permanent acquisition of antigen-specificity by individual memory NK cells by single-cell cloning. We identified biomarkers of antigen-specific NK cell memory through RNA-Seq transcriptomic fingerprints and complex immunophenotyping by 30-parameter flow cytometry showing elevated expression of KLRG1, α4β7 and NKG2C. Finally, we show individual HLA-E-restricted peptides that may constitute the dominant response in HIV-1- and influenza-infected persons in vivo. Our findings clarify the mechanisms behind formation of antigen-specific memory NK cells, and suggest they could be targeted for future vaccines, cure strategies, or other therapeutic interventions.

scholarly journals Microfluidic tumor-on-a-chip model to evaluate the role of tumor environmental stress on NK cell exhaustion

2021 ◽  
Vol 7 (8) ◽  
pp. eabc2331 ◽  
Author(s):  
Jose M. Ayuso ◽  
Shujah Rehman ◽  
Maria Virumbrales-Munoz ◽  
Patrick H. McMinn ◽  
Peter Geiger ◽  
...  
Keyword(s):  
Nk Cells ◽  
Immune Cells ◽  
Molecular Mechanisms ◽  
Nk Cell ◽  
Checkpoint Inhibitors ◽  
Waste Product ◽  
Extended Period ◽  
Cell Exhaustion

Solid tumors generate a suppressive environment that imposes an overwhelming burden on the immune system. Nutrient depletion, waste product accumulation, hypoxia, and pH acidification severely compromise the capacity of effector immune cells such as T and natural killer (NK) cells to destroy cancer cells. However, the specific molecular mechanisms driving immune suppression, as well as the capacity of immune cells to adapt to the suppressive environment, are not completely understood. Thus, here, we used an in vitro microfluidic tumor-on-a-chip platform to evaluate how NK cells respond to the tumor-induced suppressive environment. The results demonstrated that the suppressive environment created by the tumor gradually eroded NK cell cytotoxic capacity, leading to compromised NK cell surveillance and tumor tolerance. Further, NK cell exhaustion persisted for an extended period of time after removing NK cells from the microfluidic platform. Last, the addition of checkpoint inhibitors and immunomodulatory agents alleviated NK cell exhaustion.

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.

HBV vaccination and HBV infection induces HBV-specific natural killer cell memory

Gut ◽  
2020 ◽  
pp. gutjnl-2019-319252 ◽  
Author(s):  
Ratna S Wijaya ◽  
Scott A Read ◽  
Naomi R Truong ◽  
Shuanglin Han ◽  
Dishen Chen ◽  
...  
Keyword(s):  
Hepatitis B ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Hbv Infection ◽  
Core Antigen ◽  
Dependent Manner ◽  
Antigen Specificity ◽  
Chronic Hbv

ObjectiveVaccination against hepatitis B virus (HBV) confers protection from subsequent infection through immunological memory that is traditionally considered the domain of the adaptive immune system. This view has been challenged following the identification of antigen-specific memory natural killer cells (mNKs) in mice and non-human primates. While the presence of mNKs has been suggested in humans based on the expansion of NK cells following pathogen exposure, evidence regarding antigen-specificity is lacking. Here, we demonstrate the existence of HBV-specific mNKs in humans after vaccination and in chronic HBV infection.DesignNK cell responses were evaluated by flow cytometry and ELISA following challenge with HBV antigens in HBV vaccinated, non-vaccinated and chronic HBV-infected individuals.ResultsNK cells from vaccinated subjects demonstrated higher cytotoxic and proliferative responses against autologous hepatitis B surface antigen (HBsAg)-pulsed monocyte-derived dendritic cells (moDCs) compared with unvaccinated subjects. Moreover, NK cell lysis of HBsAg-pulsed moDCs was significantly higher than that of hepatitis B core antigen (HBcAg)-pulsed moDCs (non-vaccine antigen) or tumour necrosis factor α-activated moDCs in a NKG2D-dependent manner. The mNKs response was mediated by CD56dim NK cells coexpressing CD57, CD69 and KLRG1. Further, mNKs from chronic hepatitis B patients exhibited greater degranulation against HBcAg-pulsed moDCs compared with unvaccinated or vaccinated patients. Notably, mNK activity was negatively correlated with HBV DNA levels.ConclusionsOur data support the presence of a mature mNKs following HBV antigen exposure either through vaccination or infection. Harnessing these antigen specific, functionally active mNKs provides an opportunity to develop novel treatments targeting HBV in chronic infection.

scholarly journals The Tumor Microenvironment—A Metabolic Obstacle to NK Cells’ Activity

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3542
Author(s):  
Joanna Domagala ◽  
Mieszko Lachota ◽  
Marta Klopotowska ◽  
Agnieszka Graczyk-Jarzynka ◽  
Antoni Domagala ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Nk Cells ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Nk Cell ◽  
Metabolic Changes ◽  
Immune Effector ◽  
Effector Cells ◽  
Immune Effector Cells ◽  
Almost All

NK cells have unique capabilities of recognition and destruction of tumor cells, without the requirement for prior immunization of the host. Maintaining tolerance to healthy cells makes them an attractive therapeutic tool for almost all types of cancer. Unfortunately, metabolic changes associated with malignant transformation and tumor progression lead to immunosuppression within the tumor microenvironment, which in turn limits the efficacy of various immunotherapies. In this review, we provide a brief description of the metabolic changes characteristic for the tumor microenvironment. Both tumor and tumor-associated cells produce and secrete factors that directly or indirectly prevent NK cell cytotoxicity. Here, we depict the molecular mechanisms responsible for the inhibition of immune effector cells by metabolic factors. Finally, we summarize the strategies to enhance NK cell function for the treatment of tumors.

scholarly journals Ly49R activation receptor drives self-MHC–educated NK cell immunity against cytomegalovirus infection

2019 ◽  
Vol 116 (52) ◽  
pp. 26768-26778 ◽  
Author(s):  
Awndre Gamache ◽  
John M. Cronk ◽  
William T. Nash ◽  
Patryk Puchalski ◽  
Alyssa Gillespie ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cytomegalovirus Infection ◽  
Nk Cell ◽  
Host Cells ◽  
Murine Cytomegalovirus ◽  
Virus Infections ◽  
Class I Mhc ◽  
Mhc I ◽  
Cell Immunity ◽  
Virus Immunity

Natural killer (NK) cells mediate vital control of cancer and viral infection. They rely on MHC class I (MHC I)-specific self-receptors to identify and lyse diseased cells without harming self-MHC I-bearing host cells. NK cells bearing inhibitory self-receptors for host MHC I also undergo education, referred to as licensing, which causes them to become more responsive to stimulation via activation receptor signaling. Previous work has shown that licensed NK cells selectively expand during virus infections and they are associated with improved clinical response in human patients experiencing certain chronic virus infections, including HIV and hepatitis C virus. However, the importance of inhibitory self-receptors in NK-mediated virus immunity is debated as they also limit signals in NK cells emanating from virus-specific activation receptors. Using a mouse model of MHC I-dependent (H-2Dk) virus immunity, we discovered that NK cells depend on the Ly49G2 inhibitory self-receptor to mediate virus control, which coincided with host survival during murine cytomegalovirus infection. This antiviral effect further requires active signaling in NK cells via the Ly49R activation receptor that also binds H-2Dk. In tandem, these functionally discordant Ly49 self-receptors increase NK cell proliferation and effector activity during infection, resulting in selective up-regulation of CD25 and KLRG1 in virus-specific Ly49R+Ly49G2+NK cells. Our findings establish that paired self-receptors act as major determinants of NK cell-mediated virus sensing and immunity.

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