scholarly journals Molecular regulation of the plasma membrane-proximal cellular steps involved in NK cell cytolytic function

2020 ◽  
Vol 133 (5) ◽  
pp. jcs240424 ◽  
Author(s):  
Prasad V. Phatarpekar ◽  
Daniel D. Billadeau
Keyword(s):  
Plasma Membrane ◽  
Nk Cell ◽  
Molecular Regulation ◽  
Cytolytic Function

Natural Killer Cell Cytolytic Function in Korean Patients with Adult-onset Still’s Disease

2012 ◽  
Vol 39 (10) ◽  
pp. 2000-2007 ◽  
Author(s):  
JEONG HA PARK ◽  
HEE-SUN KIM ◽  
JIN SOOK LEE ◽  
JIN JU KIM ◽  
KYONG-HEE JUNG ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Adult Onset Still’S Disease ◽  
Adult Onset ◽  
Still’S Disease ◽  
Cytolytic Function ◽  
Cell Proportion ◽  
Cytotoxic Function ◽  
Adult Onset Still's Disease

Objective.To investigate natural killer (NK) cell proportions, NK cell cytotoxicity, and interleukin 18 (IL-18) expression, in patients with adult-onset Still’s disease (AOSD).Methods.Forty-five patients with AOSD (active = 22, inactive = 23) and 32 healthy controls were included. The proportions of NK cells among peripheral blood mononuclear cells were assessed by flow cytometry. IL-18 and IL-18-binding protein (IL-18BP) concentrations were measured by ELISA. Twenty-four patients with AOSD and 18 controls were examined for cytotoxic activity of NK cells by co-incubating NK cells with NK-sensitive K562 cells. The association of NK cell function with clinical and laboratory measures was investigated.Results.The proportions of NK cells were significantly lower in patients with active AOSD than in patients with inactive disease and controls. NK cell cytotoxic function was significantly lower in patients with AOSD than in controls. NK cell proportions and cytotoxic functions were reexamined in 11 and 6 patients, respectively, after treatment. Low NK cell proportion and cytotoxic dysfunction were improved with clinical improvements of the patients. IL-18 and IL-18BP levels were much higher in patients with active AOSD than in controls. NK cell cytotoxic functions were consistently low and IL-18 and IL-18BP levels were constantly high in patients with AOSD, regardless of disease activity.Conclusion.Low NK cell proportion, defective cytotoxic function, and elevated IL-18 levels may be significant features of AOSD. After resolution of the acute phase, low NK cell proportion was recovered and NK cell cytolytic function was restored along with clinical improvement. These findings possibly contribute to immunologic abnormalities in AOSD.

The Ability of NK Cell and Granulocyte Forms of CD 16 to Trigger Cytolytic Function

2015 ◽  
pp. 50-54
Author(s):  
Olli Carp�n ◽  
Periasamy Selvaraj ◽  
Margaret L. Hibbs ◽  
Timothy A. Springer
Keyword(s):  
Nk Cell ◽  
Cytolytic Function

scholarly journals The two-pore domain K2P channel TASK2 drives human NK-cell proliferation and cytolytic function

2015 ◽  
Vol 45 (9) ◽  
pp. 2602-2614 ◽  
Author(s):  
Andreas Schulte-Mecklenbeck ◽  
Stefan Bittner ◽  
Petra Ehling ◽  
Frank Döring ◽  
Erhard Wischmeyer ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Nk Cell ◽  
K2p Channel ◽  
Cytolytic Function ◽  
Pore Domain

Correlation Between Defective NK Activity and Low Expression of CD16, NKp44 and NKG2D in Beta Thalassemia Patients

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5425-5425
Author(s):  
Belkis Atasever ◽  
Serap Erdem Kuruca ◽  
Zeynep Karakas ◽  
Batu Erman ◽  
Arzu Ergen ◽  
...  
Keyword(s):  
Cytotoxic Activity ◽  
Nk Cells ◽  
Cell Function ◽  
Nk Cell ◽  
K562 Cells ◽  
Tnf Alpha ◽  
Beta Thalassemia ◽  
Nk Activity ◽  
Ifn Gamma ◽  
Cytolytic Function

Abstract Beta thalassemia patients have a major global impact on health and mortality and are characterized by absence of beta globin chain production. In most patients, multiple blood transfusions can induce differences of immune response Therefore, they are often associated with bone marrow expansion and immunodeficiency in terms of lymphocyte subsets and cytokine levels in the peripheral blood and presence of alloantibodies. We have previously shown that children with beta thalassemia major have had decreased NK cells. Natural killer (NK) cells are lymphocyte subpopulations that are important effectors of innate immune responses against infectious pathogens and tumor cells. The cytotoxic activity of NK cells is regulated by the equilibrium between positive and negative signals from multiple receptors expressed on their cell surface; signals that can trigger the cytolytic machinery as well as cytokine or chemokine secretion. The activator receptors of NK cells are natural cytotoxicity receptors (NCR) and NKG2D. NCR are represented by NKp46, NKp44, and NKp30. These receptors, upon engagement by their specific ligands, induce a strong activation of NK-mediated cytotoxic activity. NKp44, a triggering receptor selectively expressed by activated NK cells. NK cells can make cytolytic function by regulating pro-inflammatory cytokines as IFN-gamma, TNF-alpha and IL10. This study was carried out to investigate details NK cell function of 27 transfusion-dependent children with beta thalassemia. Data from 18 age- and sex-balanced children served as controls. For this purpose, we analyzed their cytolytic function against K562 cells in both pure NK cells (CD56+CD16+CD3−) and PBMC. Before and after the assessment of NK activity, we have examined the levels of NK activating receptors expressed on NK cells. The expression levels of the activation receptors (NKp30, NKp44, NKG2D) on CD56+CD16+CD3− NK cells was quantified by multicolour immunofluorescent analysis using flow cytometry. In addition, supernatant IL2, IL12, IFN-gamma, TNF-alpha, TFG-beta, IL10 levels after induced K562 cells were measured by ELISA. We observed that beta thalassemia patients had lower NK activity than controls. Before the assessment of NK activity, we found that NKG2D (2064.03+/−638.64/molecule, p<0.04) and NKp44 (1057.03+/−211.21/molecule, p<0.01) surface density was reduced in a statistically significant manner in beta thalassemia patients. This phenotype correlated with low cytolytic activity. No statistically significant differences were found in the expression of NKp30. In our experimental setting where NK cells encountered K562 targets, samples from patients had significantly increased TGF-beta (544.25+/−521.5 pg/ml, p<0.03), IL10 (16.14+/−11.1 pg/ml p<0.04) when compared with controls. In addition, expression of CD16 of NK cells that induced against K562 only (12924.47+/−6913.37/molecule, p<0.006) significantly increased in controls. As a result, our findings demonstrate that environmental factors such as ineffective cytokine production and functionally defective monocytes, may cause low NK activity in beta thalassemia patients.

A family with Papillon-Lefèvre syndrome reveals a requirement for cathepsin C in granzyme B activation and NK cell cytolytic activity

Blood ◽  
2006 ◽  
Vol 107 (9) ◽  
pp. 3665-3668 ◽  
Author(s):  
Josephine L. Meade ◽  
Erika A. de Wynter ◽  
Peter Brett ◽  
Saghira Malik Sharif ◽  
C. Geoffrey Woods ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cell Function ◽  
Nk Cell ◽  
Granzyme B ◽  
Interleukin 2 ◽  
Target Cells ◽  
Loss Of Function ◽  
Cathepsin C ◽  
Cytolytic Function

Activation of granzyme B, a key cytolytic effector molecule of natural killer (NK) cells, requires removal of an N-terminal pro-domain. In mice, cathepsin C is required for granzyme processing and normal NK cell cytolytic function, whereas in patients with Papillon-Lefèvre syndrome (PLS), loss-of-function mutations in cathepsin C do not affect lymphokine activated killer (LAK) cell function. Here we demonstrate that resting PLS NK cells do have a cytolytic defect and fail to induce the caspase cascade in target cells. NK cells from these patients contain inactive granzyme B, indicating that cathepsin C is required for granzyme B activation in unstimulated human NK cells. However, in vitro activation of PLS NK cells with interleukin-2 restores cytolytic function and granzyme B activity by a cathepsin C-independent mechanism. This is the first documented example of a human mutation affecting granzyme B activity and highlights the importance of cathepsin C in human NK cell function.

scholarly journals Effects of bacterial lipopolysaccharide and calmodulin on Ca2(+)-ATPase and calcium in human natural killer cells, studied by a combined technique of immunoelectron microscopy and ultracytochemistry.

1990 ◽  
Vol 38 (3) ◽  
pp. 359-370 ◽  
Author(s):  
Y H Kang
Keyword(s):  
Plasma Membrane ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Enzyme Reaction ◽  
Bacterial Lipopolysaccharide ◽  
Immunogold Electron Microscopy ◽  
Cytochemical Localization ◽  
Atpase Reaction ◽  
Combined Technique

Our previous studies indicate that bacterial lipopolysaccharide (LPS) enhances natural killer (NK) cell-mediated cytotoxicity and increases intracellular calcium (Ca2+) in hepatocytes. Calmodulin (CAM) regulates Ca2(+)-ATPase activity, intracellular Ca2+, and is also implicated in NK cell-mediated cytolysis. In the present work, the effects of LPS and CAM on Ca2(+)-ATPase and intracellular Ca2+ in human NK cells were studied by a combined technique of immunogold electron microscopy and ultracytochemistry. Peripheral blood mononuclear cells were treated with 100 micrograms/ml E. coli (0111:B4) LPS and/or 5 micrograms/ml CAM in RPMI 1640 medium at 37 degrees C for 1 or 4 hr. NK cells labeled with monoclonal anti-Leu-11a (CD16) antibody and colloidal gold-conjugated anti-mouse IgG were processed for cytochemical localization of Ca2(+)-ATPase and Ca2+. Ca2(+)-ATPase was localized in the plasma membrane of NK cells, and its activity was suppressed by LPS but was enhanced by CAM. However, no apparent changes in the enzyme reaction were observed when cells were exposed to CAM concomitantly with LPS or stimulated with LPS before CAM. Apparent reduction of the enzyme reaction was observed when LPS stimulation was preceded by CAM. Ca2(+)-ATPase reaction in mitochondria was observed only in NK cells exposed to CAM. Computer image analysis showed no changes in the intracellular Ca2+ in NK cells treated with LPS for 1 hr, whereas a significant increase in Ca2+ was found in cells exposed to LPS for 4 hr. The intracellular Ca2+ significantly decreased in NK cells treated with CAM or with a combination of LPS and CAM as compared to that of controls (p less than 0.05). The results indicate that CAM is capable of blocking or reversing the inhibitory effect of LPS on Ca2(+)-ATPase, and suggest that in human NK cells the plasma membrane-associated Ca2(+)-ATPase is responsible for extrusion of intracellular Ca2+.

scholarly journals Immunomodulatory effect of NEDD8-activating enzyme inhibition in Multiple Myeloma: upregulation of NKG2D ligands and sensitization to Natural Killer cell recognition

2021 ◽  
Vol 12 (9) ◽  
Author(s):  
Sara Petillo ◽  
Cristina Capuano ◽  
Rosa Molfetta ◽  
Cinzia Fionda ◽  
Abdelilah Mekhloufi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Membrane ◽  
Natural Killer ◽  
Nk Cell ◽  
Hematologic Malignancy ◽  
Mrna Level ◽  
Killer Cell ◽  
Mrna Levels ◽  
Cell Recognition ◽  
Nkg2d Ligands

AbstractMultiple Myeloma (MM) is an incurable hematologic malignancy of terminally differentiated plasma cells (PCs), where immune interactions play a key role in the control of cancer cell growth and survival. In particular, MM is characterized by a highly immunosuppressive bone marrow microenvironment where the anticancer/cytotoxic activity of Natural Killer (NK) cells is impaired. This study is focused on understanding whether modulation of neddylation can regulate NK cell-activating ligands expression and sensitize MM to NK cell killing. Neddylation is a post-translational modification that adds a ubiquitin-like protein, NEDD8, to selected substrate proteins, affecting their stability, conformation, subcellular localization, and function. We found that pharmacologic inhibition of neddylation using a small-molecule inhibitor, MLN4924/Pevonedistat, increases the expression of the NK cell-activating receptor NKG2D ligands MICA and MICB on the plasma membrane of different MM cell lines and patient-derived PCs, leading to enhanced NK cell degranulation. Mechanistically, MICA expression is upregulated at mRNA level, and this is the result of an increased promoter activity after the inhibition of IRF4 and IKZF3, two transcriptional repressors of this gene. Differently, MLN4924/Pevonedistat induced accumulation of MICB on the plasma membrane with no change of its mRNA levels, indicating a post-translational regulatory mechanism. Moreover, inhibition of neddylation can cooperate with immunomodulatory drugs (IMiDs) in upregulating MICA surface levels in MM cells due to increased expression of CRBN, the cellular target of these drugs. In summary, MLN4924/Pevonedistat sensitizes MM to NK cell recognition, adding novel information on the anticancer activity of neddylation inhibition.

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