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 cell immunotypes related to COVID-19 disease severity

2020 ◽  
Vol 5 (50) ◽  
pp. eabd6832 ◽  
Author(s):  
Christopher Maucourant ◽  
Iva Filipovic ◽  
Andrea Ponzetta ◽  
Soo Aleman ◽  
Martin Cornillet ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Disease Severity ◽  
Peripheral Blood ◽  
Cell Activation ◽  
Nk Cell ◽  
Severe Disease ◽  
Killer Cell ◽  
Interaction Network ◽  
Color Flow

Understanding innate immune responses in COVID-19 is important to decipher mechanisms of host responses and interpret disease pathogenesis. Natural killer (NK) cells are innate effector lymphocytes that respond to acute viral infections but might also contribute to immunopathology. Using 28-color flow cytometry, we here reveal strong NK cell activation across distinct subsets in peripheral blood of COVID-19 patients. This pattern was mirrored in scRNA-seq signatures of NK cells in bronchoalveolar lavage from COVID-19 patients. Unsupervised high-dimensional analysis of peripheral blood NK cells furthermore identified distinct NK cell immunotypes that were linked to disease severity. Hallmarks of these immunotypes were high expression of perforin, NKG2C, and Ksp37, reflecting increased presence of adaptive NK cells in circulation of patients with severe disease. Finally, arming of CD56bright NK cells was observed across COVID-19 disease states, driven by a defined protein-protein interaction network of inflammatory soluble factors. This study 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.

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.

scholarly journals Natural Killer Cell–mediated Lysis of Autologous Cells Modified by Gene Therapy

1999 ◽  
Vol 189 (12) ◽  
pp. 1855-1862 ◽  
Author(s):  
Concetta Liberatore ◽  
Marusca Capanni ◽  
Nicola Albi ◽  
Isabella Volpi ◽  
Elena Urbani ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Nk Cells ◽  
Natural Killer ◽  
Viral Infections ◽  
Nk Cell ◽  
Killer Cell ◽  
Marker Gene ◽  
Gene Mutations ◽  
Hla B27 ◽  
Leukocyte Antigen

This study investigated the role of natural killer (NK) cells as effectors of an immune response against autologous cells modified by gene therapy. T lymphocytes were transduced with LXSN, a retroviral vector adopted for human gene therapy that carries the selectable marker gene neo, and the autologous NK response was evaluated. We found that (i) infection with LXSN makes cells susceptible to autologous NK cell–mediated lysis; (ii) expression of the neo gene is responsible for conferring susceptibility to lysis; (iii) lysis of neo-expressing cells is clonally distributed and mediated only by NK clones that exhibit human histocompatibility leukocyte antigen (HLA)-Bw4 specificity and bear KIR3DL1, a Bw4-specific NK inhibitory receptor; and (iv) the targets are cells from HLA-Bw4+ individuals. Finally, neo peptides anchoring to the Bw4 allele HLA-B27 interfered with KIR3DL1-mediated recognition of HLA-B27, i.e., they triggered NK lysis. Moreover, neo gene mutations preventing translation of  two of the four potentially nonprotective peptides reduced KIR3DL1+ NK clone–mediated autologous lysis. Thus, individuals expressing Bw4 alleles possess an NK repertoire with the potential to eliminate autologous cells modified by gene therapy. By demonstrating that NK cells can selectively detect the expression of heterologous genes, these observations provide a general model of the NK cell–mediated control of viral infections.

scholarly journals Identification of the earliest natural killer cell–committed progenitor in murine bone marrow

Blood ◽  
2011 ◽  
Vol 118 (20) ◽  
pp. 5439-5447 ◽  
Author(s):  
John W. Fathman ◽  
Deepta Bhattacharya ◽  
Matthew A. Inlay ◽  
Jun Seita ◽  
Holger Karsunky ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Fate ◽  
Nk Cell ◽  
Ex Vivo ◽  
Killer Cell ◽  
Lineage Commitment ◽  
Color Flow ◽  
Cell Commitment

Abstract Natural killer (NK) cells develop in the bone marrow and are known to gradually acquire the ability to eliminate infected and malignant cells, yet the cellular stages of NK lineage commitment and maturation are incompletely understood. Using 12-color flow cytometry, we identified a novel NK-committed progenitor (pre-NKP) that is a developmental intermediate between the upstream common lymphoid progenitor and the downstream NKP, previously assumed to represent the first stage of NK lineage commitment. Our analysis also refined the purity of NKPs (rNKP) by 6-fold such that 50% of both pre-NKP and rNKP cells gave rise to NKp46+ NK cells at the single-cell level. On transplantation into unconditioned Rag2−/−Il2rγc−/− recipients, both pre-NKPs and rNKPs generated mature NK cells expressing a repertoire of Ly49 family members that degranulated on stimulation ex vivo. Intrathymic injection of these progenitors, however, yielded no NK cells, suggesting a separate origin of thymic NK cells. Unlike the rNKP, the pre-NKP does not express IL-2Rβ (CD122), yet it is lineage committed toward the NK cell fate, adding support to the theory that IL-15 signaling is not required for NK commitment. Taken together, our data provide a high-resolution in vivo analysis of the earliest steps of NK cell commitment and maturation.

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