scholarly journals Rapid expansion and long-term persistence of elevated NK cell numbers in humans infected with hantavirus

2010 ◽  
Vol 208 (1) ◽  
pp. 13-21 ◽  
Author(s):  
Niklas K. Björkström ◽  
Therese Lindgren ◽  
Malin Stoltz ◽  
Cyril Fauriat ◽  
Monika Braun ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cell Activation ◽  
Viral Infections ◽  
Nk Cell ◽  
Killer Cell ◽  
Experimental Models ◽  
Rapid Expansion ◽  
Model Systems ◽  
Hantavirus Infection ◽  
Virus Infections

Natural killer (NK) cells are known to mount a rapid response to several virus infections. In experimental models of acute viral infection, this response has been characterized by prompt NK cell activation and expansion followed by rapid contraction. In contrast to experimental model systems, much less is known about NK cell responses to acute viral infections in humans. We demonstrate that NK cells can rapidly expand and persist at highly elevated levels for >60 d after human hantavirus infection. A large part of the expanding NK cells expressed the activating receptor NKG2C and were functional in terms of expressing a licensing inhibitory killer cell immunoglobulin-like receptor (KIR) and ability to respond to target cell stimulation. These results demonstrate that NK cells can expand and remain elevated in numbers for a prolonged period of time in humans after a virus infection. In time, this response extends far beyond what is considered normal for an innate immune response.

scholarly journals Natural killer cell activation related to clinical outcome of COVID-19

2020 ◽  
Author(s):  
Christopher Maucourant ◽  
Iva Filipovic ◽  
Andrea Ponzetta ◽  
Soo Aleman ◽  
Martin Cornillet ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Activation ◽  
Viral Infections ◽  
Nk Cell ◽  
Severe Disease ◽  
Killer Cell ◽  
Interaction Network ◽  
Host Responses ◽  
Color Flow

Understanding innate immune responses in COVID-19 is important for deciphering mechanisms of host responses and interpreting disease pathogenesis. Natural killer (NK) cells are innate effector lymphocytes that respond to acute viral infections, but might also contribute to immune pathology. Here, using 28-color flow cytometry, we describe a state of strong NK cell activation across distinct subsets in peripheral blood of COVID-19 patients, a pattern mirrored in scRNA-seq signatures of lung NK cells. Unsupervised high-dimensional analysis identified distinct immunophenotypes that were linked to disease severity. Hallmarks of these immunophenotypes were high expression of perforin, NKG2C, and Ksp37, reflecting a high presence of adaptive NK cell expansions in circulation of patients with severe disease. Finally, arming of CD56bright NK cells was observed in course of COVID-19 disease states, driven by a defined protein-protein interaction network of inflammatory soluble factors. This provides a detailed map of the NK cell activation-landscape in COVID-19 disease.

scholarly journals Natural Killer Cells: Potential Biomarkers and Therapeutic Target in Autoimmune Diseases?

2021 ◽  
Vol 12 ◽  
Author(s):  
Elena Gianchecchi ◽  
Domenico V. Delfino ◽  
Alessandra Fierabracci
Keyword(s):  
Systemic Sclerosis ◽  
Autoimmune Diseases ◽  
Cytotoxic Activity ◽  
Nk Cells ◽  
Natural Killer ◽  
T Cell Activation ◽  
Cell Activation ◽  
Nk Cell ◽  
Killer Cell

Autoimmune diseases recognize a multifactorial pathogenesis, although the exact mechanism responsible for their onset remains to be fully elucidated. Over the past few years, the role of natural killer (NK) cells in shaping immune responses has been highlighted even though their involvement is profoundly linked to the subpopulation involved and to the site where such interaction takes place. The aberrant number and functionality of NK cells have been reported in several different autoimmune disorders. In the present review, we report the most recent findings regarding the involvement of NK cells in both systemic and organ-specific autoimmune diseases, including type 1 diabetes (T1D), primary biliary cholangitis (PBC), systemic sclerosis, systemic lupus erythematosus (SLE), primary Sjögren syndrome, rheumatoid arthritis, and multiple sclerosis. In T1D, innate inflammation induces NK cell activation, disrupting the Treg function. In addition, certain genetic variants identified as risk factors for T1D influenced the activation of NK cells promoting their cytotoxic activity. The role of NK cells has also been demonstrated in the pathogenesis of PBC mediating direct or indirect biliary epithelial cell destruction. NK cell frequency and number were enhanced in both the peripheral blood and the liver of patients and associated with increased NK cell cytotoxic activity and perforin expression levels. NK cells were also involved in the perpetuation of disease through autoreactive CD4 T cell activation in the presence of antigen-presenting cells. In systemic sclerosis (SSc), in addition to phenotypic abnormalities, patients presented a reduction in CD56hi NK-cells. Moreover, NK cells presented a deficient killing activity. The influence of the activating and inhibitory killer cell immunoglobulin-like receptors (KIRs) has been investigated in SSc and SLE susceptibility. Furthermore, autoantibodies to KIRs have been identified in different systemic autoimmune conditions. Because of its role in modulating the immune-mediated pathology, NK subpopulation could represent a potential marker for disease activity and target for therapeutic intervention.

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 A novel mechanism of natural killer cell response to anti-CTLA-4 therapy identified by integrative analysis of mouse and human tumors

2020 ◽  
Author(s):  
Emily F. Davis-Marcisak ◽  
Allison A. Fitzgerald ◽  
Michael D. Kessler ◽  
Ludmila Danilova ◽  
Elizabeth M. Jaffee ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Activation ◽  
Nk Cell ◽  
Killer Cell ◽  
Mouse Tumors ◽  
Natural Killer Cell Response ◽  
Melanoma Patients ◽  
Inhibitory Antibodies ◽  
The Impact

AbstractImmune checkpoint-inhibitory antibodies (ICIs) are well-established immunotherapies. Despite this, the impact of ICI therapy on non-T cell intratumoral immune cells is ill-defined, restraining the improvement of ICI efficacy. Preclinical murine models of human disease are infrequently validated in clinical trials, impairing the identification of novel biological factors impacting clinical ICI response. To address this barrier, we used our previously described computational approach that integrates high-throughput single-cell RNA sequencing datasets to identify known and novel cellular alterations induced by ICIs that are conserved in mice and humans. We found a signature of intratumoral natural killer (NK) cell activation that is enriched in anti-CTLA-4 treated mouse tumors and correlates with longer overall survival and is predictive of anti-CTLA-4 (ipilimumab) response in melanoma patients. We demonstrate that human NK cells express CTLA-4, which directly binds anti-CTLA-4. These data reveal a novel role for NK cells in anti-CTLA-4 treatment and present opportunities to enhance ICI efficacy. Importantly, we provide a new computational tool for onco-immunology that can identify and validate biological observations across species.

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.

scholarly journals Interactions of Human Myeloid Cells with Natural Killer Cell Subsets In Vitro and In Vivo

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Obinna Chijioke ◽  
Christian Münz
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Experimental Models ◽  
Human Pathogens ◽  
Innate And Adaptive Immunity ◽  
Antigen Presenting

In both human and mouse it has been recently realized that natural killer (NK) cells do not emerge from the bone marrow with full functional competence but rather acquire functions in interaction with antigen-presenting cells (APCs), primarily dendritic cells (DCs). Here we review the mechanisms and the consequences of this NK-cell preactivation, as well as discuss new experimental models that now allow investigating these interactions for human NK cells and their response to human pathogens in vivo. These investigations will allow harnessing NK cells during vaccination for improved innate and adaptive immunity.

scholarly journals Screening for Active Compounds Targeting Human Natural Killer Cell Activation Identifying Daphnetin as an Enhancer for IFN-γ Production and Direct Cytotoxicity

2021 ◽  
Vol 12 ◽  
Author(s):  
Baige Yao ◽  
Qinglan Yang ◽  
Yao Yang ◽  
Yana Li ◽  
Hongyan Peng ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Activation ◽  
Nk Cell ◽  
Killer Cell ◽  
Mtor Signaling ◽  
Human Natural Killer Cell ◽  
Active Compounds ◽  
Direct Cytotoxicity ◽  
Ifn Γ

Natural killer (NK) cells are a potent weapon against tumor and viral infection. Finding active compounds with the capacity of enhancing NK cell effector functions will be effective to develop new anti-cancer drugs. In this study, we initially screened 287 commercially available active compounds by co-culturing with peripheral blood mononuclear cells (PBMCs). We found that five compounds, namely, Daphnetin, MK-8617, LW6, JIB-04, and IOX1, increased the IFN-γ+ NK cell ratio in the presence of IL-12. Further studies using purified human primary NK cells revealed that Daphnetin directly promoted NK cell IFN-γ production in the presence of IL-12 but not IL-15, while the other four compounds acted on NK cells indirectly. Daphnetin also improved the direct cytotoxicity of NK cells against tumor cells in the presence of IL-12. Through RNA-sequencing, we found that PI3K-Akt-mTOR signaling acted as a central pathway in Daphnetin-mediated NK cell activation in the presence of IL-12. This was further confirmed by the finding that both inhibitors of PI3K-Akt and its main downstream signaling mTOR, LY294002, and rapamycin, respectively, can reverse the increase of IFN-γ production and cytotoxicity in NK cells promoted by Daphnetin. Collectively, we identify a natural product, Daphnetin, with the capacity of promoting human NK cell activation via PI3K-Akt-mTOR signaling in the presence of IL-12. Our current study opens up a new potential application for Daphnetin as a complementary immunomodulator for cancer treatments.

Abstract P207: Mitochondrial Dysfunction And Natural Killer Cell Activation Stimulated By Il-17 Signaling From Th17 Cells In Response To Placental Ischemia During Pregnancy; Sarah Fitzgerald, Evangeline Deer, Owen Herrock, Tarek Ibrahim, Lorena Amaral, Denise Cornelius And Babbette Lamarca; 1 Department Of Pharmacology, University Of Mississippi Medical Center.

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Sarah Fitzgerald ◽  
Owen Herrock ◽  
Evangeline M Deer ◽  
Tarek Ibrahim ◽  
Babbette B Lamarca ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Th17 Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
Medical Center ◽  
Killer Cell ◽  
Multisystem Disorder ◽  
Uterine Perfusion ◽  
Placental Ischemia

Preeclampsia (PE) is a multisystem disorder characterized by new onset hypertension associated with placental ischemia (PI), mitochondrial (mt) dysfunction, and an imbalance in T helper (TH) and Natural Killer (NK) cells during pregnancy. The reduced uterine perfusion pressure (RUPP) model is an established model for PE. We have previously shown an important role for IL-17 in hypertension and activation of NK cells in the RUPP rat. We don’t know the role for IL-17 or TH17 cells in contributing to NK cell mediated mt dysfunction and ROS associated with PI. Therefore, we hypothesize that hypertension in response to PI stimulated TH17 cells causes mt ROS mediated through IL-17 signaling to NK cells. On gestation day 12 (GD12) RUPP-induced TH17s (splenic CD4+/CD25- cells) were adoptively transferred (Ad-T) into normal pregnant (NP) rats. Recombinant mouse IL-17 receptor C (IL-17RC) (100 pg/day) was administered from GD14-19 via osmotic mini-pump. On GD19, samples were collected and mean arterial pressure (MAP) was measured. Mt respiration and mt ROS data was measured in isolated mt from renal and placental tissues using the Oxygraph 2K and fluorescent microplate reader, respectively. A one-way ANOVA with Bonferroni post hoc test was used for statistical analysis. MAP was increased in Ad-T rats (112 ± 0.72mmHg, n=14) compared to NP (92 ± 3.03mmHg, n=14) (p<0.05), and was lowered with IL-17RC (97.2± 2.14 mmHg, n=13). Circulating activated NK cells were significantly increased with Ad-T (3.326± 0.76 %gated, n=9) (p<0.0001) compared to NP (0.05± 0.05 %, n=11), and were attenuated with IL-17RC (0.42± 0.4 %, n=5) (p<0.01). Placental activated NK cells were significantly increased with Ad-T (2.5± 1.01 %, n=4) (p<0.05) compared to NP (0.03± 0.03 %, n=8) and were attenuated with IL-17RC (0.21± 0.12 %, n=4) (p<0.05). Renal mtROS increased in Ad-T (312.4 ± 44.7%, n=9) compared to NP (191.9 ± 20.5%, n=5). Placental mtROS significantly increased in Ad-T (312.5 ± 23.6%, n=9) (P<0.0005) compared to NP controls (134 ± 9.6%, n=5) (p<0.0001), and was decreased by administration of IL-17RC (174.5± 42.5 %, n=5) (p<0.0001). These data demonstrate that IL-17 signaling plays an important role in NK cell activation and tissue mt function in response to TH17 cells stimulated during PE.

scholarly journals p46, a Novel Natural Killer Cell–specific Surface Molecule That Mediates Cell Activation

1997 ◽  
Vol 186 (7) ◽  
pp. 1129-1136 ◽  
Author(s):  
Simona Sivori ◽  
Massimo Vitale ◽  
Luigia Morelli ◽  
Lorenza Sanseverino ◽  
Raffaella Augugliaro ◽  
...  
Keyword(s):  
Specific Surface ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Activation ◽  
Nk Cell ◽  
Killer Cell ◽  
Cytolytic Activity ◽  
Surface Molecule ◽  
Limited Information ◽  
Cell Clones

Limited information is available on the surface molecules that are involved in natural killer (NK) cell triggering. In this study, we selected the BAB281 monoclonal antibody (mAb) on the basis of its ability to trigger NK-mediated target cell lysis. BAB281 identified a novel NK cell–specific surface molecule of 46 kD (p46) that is expressed by all resting or activated NK cells. Importantly, unlike the NK cell antigens identified so far, the expression of p46 was strictly confined to NK cells. Upon mAb-mediated cross-linking, p46 molecules induced strong cell triggering leading to [Ca2+]i increases, lymphokine production, and cytolytic activity both in resting NK cells and NK cell clones. The p46-mediated induction of Ca2+ increases or triggering of cytolytic activity was downregulated by the simultaneous engagement of inhibitory receptors including p58, p70, and CD94/NKG2A. Both the unique cellular distribution and functional capability of p46 molecules suggest a possible role in the mechanisms of non-major histocompatibility complex–restricted cytolysis mediated by human NK cells.

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