scholarly journals PGC-1α-Dependent Mitochondrial Adaptation Is Necessary to Sustain IL-2-Induced Activities in Human NK Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Dante Miranda ◽  
Claudia Jara ◽  
Jorge Ibañez ◽  
Viviana Ahumada ◽  
Claudio Acuña-Castillo ◽  
...  
Keyword(s):  
Cytotoxic Activity ◽  
Nk Cells ◽  
Cell Function ◽  
Nk Cell ◽  
Interleukin 2 ◽  
Dependent Manner ◽  
Killer Activity ◽  
Mitochondrial Mass ◽  
Mitochondrial Adaptation ◽  
Lak Activity

Human Natural Killer (NK) cells are a specialized heterogeneous subpopulation of lymphocytes involved in antitumor defense reactions. NK cell effector functions are critically dependent on cytokines and metabolic activity. Among various cytokines modulating NK cell function, interleukin-2 (IL-2) can induce a more potent cytotoxic activity defined as lymphokine activated killer activity (LAK). Our aim was to determine if IL-2 induces changes at the mitochondrial level in NK cells to support the bioenergetic demand for performing this enhanced cytotoxic activity more efficiently. Purified human NK cells were cultured with high IL-2 concentrations to develop LAK activity, which was assessed by the ability of NK cells to lyse NK-resistant Daudi cells. Here we show that, after 72 h of culture of purified human NK cells with enough IL-2 to induce LAK activity, both the mitochondrial mass and the mitochondrial membrane potential increased in a PGC-1α-dependent manner. In addition, oligomycin, an inhibitor of ATP synthase, inhibited IL-2-induced LAK activity at 48 and 72 h of culture. Moreover, the secretion of IFN-γfrom NK cells with LAK activity was also partially dependent on PGC-1αexpression. These results indicate that PGC-1αplays a crucial role in regulating mitochondrial function involved in the maintenance of LAK activity in human NK cells stimulated with IL-2.

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 Monoclonal antibody to a triggering structure expressed on rat natural killer cells and adherent lymphokine-activated killer cells.

1989 ◽  
Vol 169 (4) ◽  
pp. 1373-1389 ◽  
Author(s):  
W H Chambers ◽  
N L Vujanovic ◽  
A B DeLeo ◽  
M W Olszowy ◽  
R B Herberman ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cell Function ◽  
Nk Cell ◽  
Cytolytic Activity ◽  
Lak Cells ◽  
Target Cells ◽  
Lymphokine Activated Killer Cells ◽  
Killer Cells ◽  
And Function ◽  
Lak Activity

To study the cellular structures involved in NK and lymphokine-activated killer (LAK) cell function, we have produced a panel of mAbs that modulate the cytolytic function of a population of cells with LAK activity that derive from large granular lymphocyte (LGL)/NK cells (adherent LAK [A-LAK] cells). In this report, we describe an mAb (3.2.3; IgG1k) that recognizes a triggering structure that is expressed on rat LGL/NK cells and A-LAK cells. This epitope is also expressed on polymorphonuclear leukocytes (PMN). The expression of the epitope identified by mAb 3.2.3 increased progressively on A-LAK cells after culture in the presence of rIL-2. mAb 3.2.3 enhanced the cytolytic activity of NK and A-LAK cells against FcR+ target cells, but not FcR- target cells. However, this effect was not induced by F(ab')2 fragments of 3.2.3. This antibody also induced the release of N-alpha-benzyloxycarbonyl-L-lysine thiobenzy esteresterase by A-LAK cells. These data suggest that the epitope identified by mAb 3.2.3 is on a triggering structure expressed on rat NK cells and A-LAK cells. The expression of the epitope recognized by mAb 3.2.3 on LGL/NK cells and PMN suggests that this structure may be analogous to that identified by the anti-CD16 (-FcR) mAbs. However, the molecule immunoprecipitated by mAb 3.2.3 was a 60-kD dimer composed of two 30-kD chains. These data suggest that mAb 3.2.3 recognizes a unique triggering structure. As mAb 3.2.3 is the first antibody recognizing a determinant with functional significance, selectively expressed on both rat NK cells and A-LAK cells, it will be a useful tool for the study of NK cell ontogeny and function, and the development of cells with LAK activity from the NK cell compartment.

scholarly journals Response of human natural killer (NK) cells to NK cell stimulatory factor (NKSF): cytolytic activity and proliferation of NK cells are differentially regulated by NKSF.

1992 ◽  
Vol 175 (3) ◽  
pp. 779-788 ◽  
Author(s):  
M J Robertson ◽  
R J Soiffer ◽  
S F Wolf ◽  
T J Manley ◽  
C Donahue ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Function ◽  
Nk Cell ◽  
Human Peripheral Blood ◽  
Killer Cell ◽  
Interleukin 2 ◽  
Cytolytic Activity ◽  
Stimulatory Factor

Natural killer cell stimulatory factor (NKSF) is a 70-kD heterodimeric cytokine that was initially isolated from conditioned medium of human B lymphoblastoid cell lines. The effects of recombinant NKSF on the function of human peripheral blood NK cells were examined. NKSF directly augmented the cytolytic activity of freshly isolated NK cells. Both CD56dim and CD56bright NK cells demonstrated enhanced cytotoxicity after brief exposure to NKSF. In contrast, highly purified T lymphocytes did not exhibit major histocompatibility complex-unrestricted cytotoxicity after short-term culture with NKSF. Like interleukin 2 (IL-2), NKSF augmented the lysis of NK-sensitive, NK-resistant, and antibody-coated targets. Both NKSF and IL-2 induced marked upregulation of several NK cell adhesion molecules known to participate in cytolysis, including CD2, CD11a, and CD54. However, NKSF activates NK cells through a pathway distinct from that of IL-2, since the presence of anti-IL-2 receptor (anti-IL-2R) antibodies or IL-4 did not inhibit the effects of NKSF. NKSF by itself induced very little proliferation of resting NK cells. NK cells preactivated in vitro with IL-2 demonstrated enhanced proliferation to NKSF, but the degree of proliferation was always inferior to that induced by IL-2 alone. Moreover, NKSF strongly inhibited IL-2-induced proliferation of either resting or preactivated NK cells. This inhibition was not the result of decreased IL-2R expression, because NKSF-activated NK cells expressed higher levels of both IL-2Rs p75 and p55. Furthermore, NKSF did not inhibit the proliferation of mitogen-activated T cells, indicating a selective effect on NK cell proliferation. Human NK cells expanded in vivo by prolonged continuous infusions of IL-2 remained fully responsive to NKSF. Picomolar concentrations of NKSF were as effective as nanomolar concentrations of IL-2 in augmenting the cytolytic activity of NK cells expanded in vivo by IL-2. NKSF may play an important role in the regulation of human NK cell function, and its possible use as a therapeutic cytokine deserves further investigation.

Serotonin Shapes the Migratory Potential of NK Cells – An in vitro Approach

2017 ◽  
Vol 38 (11) ◽  
pp. 857-863 ◽  
Author(s):  
Philipp Zimmer ◽  
Wilhelm Bloch ◽  
Markus Kieven ◽  
Lukas Lövenich ◽  
Jonas Lehmann ◽  
...  
Keyword(s):  
Nk Cells ◽  
Acute Exercise ◽  
Cell Function ◽  
Nk Cell ◽  
Ex Vivo ◽  
Killer Cell ◽  
Dependent Manner ◽  
The Impact ◽  
Dose Dependent

AbstractIncreased serotonin (5-HT) levels have been shown to influence natural killer cell (NK cell) function. Acute exercise mobilizes and activates NK cells and further increases serum 5-HT concentrations in a dose-dependent manner. The aim of this study was to investigate the impact of different serum 5-HT concentrations on NK cell migratory potential and cytotoxicity. The human NK cell line KHYG-1 was assigned to 4 conditions, including 3 physiological concentrations of 5-HT (100, 130 or 170 µg/l 5-HT) and one control condition. NK cells were analyzed regarding cytotoxicity, migratory potential and expression of adhesion molecules. No treatment effect on NK cell cytotoxicity and expression of integrin subunits was detected. Migratory potential was increased in a dose dependent manner, indicating the highest protease activity in cells that were incubated with 170 µg/l 5-HT (170 µg/l vs. control, p<0.001, 170 µg/l vs. 100 µg/l, p<0.001; 170 µg/l vs. 130 µg/l, p=0.003; 130 µg/l vs. control, p<0.001, 130 µg/l vs. 100 µg/l, p<0.001). These results suggest that elevated 5-HT serum levels play a mediating role in NK cell function. As exercise has been shown to be involved in NK cell mobilization and redistribution, the influence of 5-HT should be investigated in ex vivo and in vivo experiments.

The immunostimulatory effect of lenalidomide on NK-cell function is profoundly inhibited by concurrent dexamethasone therapy

Blood ◽  
2011 ◽  
Vol 117 (5) ◽  
pp. 1605-1613 ◽  
Author(s):  
Andy K. Hsu ◽  
Hang Quach ◽  
Tsin Tai ◽  
H. Miles Prince ◽  
Simon J. Harrison ◽  
...  
Keyword(s):  
T Cell ◽  
Nk Cells ◽  
Cell Function ◽  
Nk Cell ◽  
Interleukin 2 ◽  
Cell Number ◽  
Cd4 T Cell ◽  
Normal Donor ◽  
Dexamethasone Therapy

Abstract Lenalidomide combined with dexamethasone is an effective treatment for refractory/relapsed multiple myeloma (MM). Lenalidomide stimulates natural killer (NK) cells and enhances antitumor responses. We assessed NK cell number and function in 25 patients with MM participating in a clinical trial of lenalidomide and dexamethasone. NK cell numbers increased from a mean of 2.20 ± 0.05 × 105/mL (baseline) to a mean of 3.90 ± 0.03 × 105/mL (cycle 6; P = .05); however, in vitro NK-cell–mediated cytotoxicity decreased from 48.9% ± 6.8% to 27.6% ± 5.1% (P = .0028) and could not be rescued by lenalidomide retreatment. Lenalidomide increased normal donor NK-cell cytotoxicity in vitro from 38.5% to 53.3%, but this was completely abrogated by dexamethasone. Dexamethasone suppression of NK cell–mediated cytotoxicity was partially reversed by a 3-day washout, but these cells remained refractory to lenalidomide-induced enhanced function. Lymphocyte subset depletion experiments revealed that lenalidomide's enhancement of NK cell–mediated cytotoxicity was mediated by CD4+ T-cell production of interleukin 2 and that dexamethasone acted by suppressing interleukin-2 production. Similarly, the reduced ability of NK cells from patients with MM to respond to lenalidomide was also due to impaired CD4 T-cell function. Our findings indicate that lenalidomide immunostimulatory effects on patient NK cells are severely blunted by concurrent dexamethasone administration.

scholarly journals Mannan-Binding Lectin Regulates Inflammatory Cytokine Production, Proliferation, and Cytotoxicity of Human Peripheral Natural Killer Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Jia Zhou ◽  
Mengyao Hu ◽  
Jie Li ◽  
Yan Liu ◽  
Jialiang Luo ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Inflammatory Cytokine ◽  
Cell Function ◽  
Nk Cell ◽  
Interleukin 2 ◽  
Lymphoid Cells ◽  
Necrosis Factor Alpha ◽  
Cytokine Tumor Necrosis Factor ◽  
Binding Lectin

Natural killer (NK) cells represent the founding members of innate lymphoid cells (ILC) and play critical roles in inflammation and the immune response. NK cell effector functions are regulated and fine-tuned by various immune modulators. Mannan (or mannose)-binding lectin (MBL), a soluble C-type lectin, is traditionally recognized as an initiator of the complement pathway. Recently, it is also considered as an immunomodulator by its interaction with kinds of immune cells. However, the effect of MBL on NK cell function remains unexplored. In this study, we found that human plasma MBL could interact directly with peripheral NK cells partially via its collagen-like region (CLR). This MBL binding markedly suppressed the interleukin-2- (IL-2-) induced inflammatory cytokine tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) production but increased the IL-10 production in NK cells. In addition, the expression of activation surface markers such as CD25 and CD69 declined after MBL treatment. Also, MBL impaired the proliferation and lymphokine-activated killing (LAK) of NK cells. Moreover, we demonstrated that MBL inhibited IL-2-induced signal transducers and activators of transcription 5 (STAT5) activation in NK cells. In conclusion, we have uncovered a far unknown regulatory role of MBL on NK cells, a new clue that could be important in the immunomodulatory networks of immune responses.

scholarly journals NK cells clear α-synuclein and the depletion of NK cells exacerbates synuclein pathology in a mouse model of α-synucleinopathy

2020 ◽  
Vol 117 (3) ◽  
pp. 1762-1771 ◽  
Author(s):  
Rachael H. Earls ◽  
Kelly B. Menees ◽  
Jaegwon Chung ◽  
Claire-Anne Gutekunst ◽  
Hyun Joon Lee ◽  
...  
Keyword(s):  
Mouse Model ◽  
Nk Cells ◽  
Cell Function ◽  
Nk Cell ◽  
Biological Fluids ◽  
Lewy Body Dementia ◽  
Motor Deficits ◽  
Dependent Manner

The pathological hallmark of synucleinopathies, including Lewy body dementia and Parkinson’s disease (PD), is the presence of Lewy bodies, which are primarily composed of intracellular inclusions of misfolded α-synuclein (α-syn) among other proteins. α-Syn is found in extracellular biological fluids in PD patients and has been implicated in modulating immune responses in the central nervous system (CNS) and the periphery. Natural killer (NK) cells are innate effector lymphocytes that are present in the CNS in homeostatic and pathological conditions. NK cell numbers are increased in the blood of PD patients and their activity is associated with disease severity; however, the role of NK cells in the context of α-synucleinopathies has never been explored. Here, we show that human NK cells can efficiently internalize and degrade α-syn aggregates via the endosomal/lysosomal pathway. We demonstrate that α-syn aggregates attenuate NK cell cytotoxicity in a dose-dependent manner and decrease the release of the proinflammatory cytokine, IFN-γ. To address the role of NK cells in PD pathogenesis, NK cell function was investigated in a preformed fibril α-syn–induced mouse PD model. Our studies demonstrate that in vivo depletion of NK cells in a preclinical mouse PD model resulted in exacerbated motor deficits and increased phosphorylated α-syn deposits. Collectively, our data provide a role of NK cells in modulating synuclein pathology and motor symptoms in a preclinical mouse model of PD, which could be developed into a therapeutic for PD and other synucleinopathies.

scholarly journals Selective long-term elimination of natural killer cells in vivo by an anti-interleukin 2 receptor beta chain monoclonal antibody in mice.

1993 ◽  
Vol 178 (3) ◽  
pp. 1103-1107 ◽  
Author(s):  
T Tanaka ◽  
F Kitamura ◽  
Y Nagasaka ◽  
K Kuida ◽  
H Suwa ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Cell ◽  
Nk Cells ◽  
Cell Function ◽  
Nk Cell ◽  
Interleukin 2 ◽  
Beta Chain ◽  
Receptor Beta

The interleukin 2 receptor beta chain (IL-2R beta) is preferentially expressed in natural killer (NK) cells, but is not detected in a majority of resting T and B cells. We recently established a novel monoclonal antibody (mAb) to murine IL-2R beta and examined in vivo the effect of the mAb in mice. We found that intraperitoneal injection of the anti-IL-2R beta mAb into adult mice resulted in a selective in vivo elimination of splenic NK function in various mouse strains. The reduction of NK cell function is associated with complete disappearance of NK1.1+ cells in C57BL/6 mice. Other lymphocyte subsets in the thymus and spleen were uncompromised. T cell function was not affected by the mAb treatment as judged by allogeneic cytotoxic T cell induction. The single injection of anti-IL-2R beta mAb caused a long-term elimination of splenic NK cells, lasting for at least 5 wk. We also found that NK and/or NK precursor cells become susceptible to the mAb treatment only after birth, suggesting that functional maturation of NK cells in terms of IL-2R beta expression is a later event in the course of NK cell development. The use of the anti-IL-2R beta mAb will be useful in defining the physiological role of NK cells in host defense as well as dissecting their developmental pathway in vivo.

scholarly journals Sialic Acids and Their Influence on Human NK Cell Function

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 263
Author(s):  
Philip Rosenstock ◽  
Thomas Kaufmann
Keyword(s):  
Nk Cells ◽  
Immune Cells ◽  
Cell Function ◽  
Nk Cell ◽  
Sialic Acids ◽  
Innate Immune ◽  
Target Cells ◽  
Carbon Backbone ◽  
Nk Cell Receptors ◽  
Cell Inhibition

Sialic acids are sugars with a nine-carbon backbone, present on the surface of all cells in humans, including immune cells and their target cells, with various functions. Natural Killer (NK) cells are cells of the innate immune system, capable of killing virus-infected and tumor cells. Sialic acids can influence the interaction of NK cells with potential targets in several ways. Different NK cell receptors can bind sialic acids, leading to NK cell inhibition or activation. Moreover, NK cells have sialic acids on their surface, which can regulate receptor abundance and activity. This review is focused on how sialic acids on NK cells and their target cells are involved in NK cell function.

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