scholarly journals NATURAL KILLER CELL EFFECTS UPON ANGIOGENESIS UNDER CONDITIONS OF CONTACT-DEPENDENT AND DISTANT CO-CULTURING WITH ENDOTHELIAL AND TROPHOBLAST CELLS

2019 ◽  
Vol 21 (3) ◽  
pp. 427-440 ◽  
Author(s):  
K. L. Markova ◽  
O. I. Stepanova ◽  
A. R. Sheveleva ◽  
N. A. Kostin ◽  
V. A. Mikhailova ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Killer Cell ◽  
Cell System ◽  
Trophoblast Invasion ◽  
Trophoblast Cells ◽  
Cell Functions ◽  
Placental Angiogenesis ◽  
Component Cell ◽  
Culturing Conditions

Regulation of angiogenesis in the utero-placental bed determines adequate trophoblast invasion, placenta formation and development, as well as successful course of pregnancy. Natural killer (NK) cells, macrophages and trophoblast have the most significant effect on angiogenesis. To date, the functions of cells participating in placenta formation have been described in detail, both individually (in vitrо) and in tissues (in situ). However, no models have yet been created that reflect the interactions of NK cells, trophoblast and endothelium during angiogenesis. It remains unclear, how each cell population contributes to placental angiogenesis regulation, and to the cross-regulation of participating cell functions. Therefore, the aim of this research was to study contact and distant effects of NK cells upon formation of tube-like structures through co-culture of endothelial and trophoblast cells influenced by various cytokines (bFGF, VEGF, PlGF, TGF-β, IL-8, IFNγ and IL-1β). Introduction of NK cells to the co-culture of endothelial and trophoblast cells under conditions of both contact and distance-dependent culturing did not change the length of tube-like structures formed by endothelial cells. During contact-dependent culturing of NK cells with co-culture of endothelial and trophoblast cells in presence of IL-1β, the length of tubule-like structures remained unchanged, compared with the length of tube-like structures formed under the same culturing conditions, but without the cytokine added. During distant culturing of NK cells with co-culture of endothelial and trophoblast cells in the presence of IL-1β, the length of tube-like structures increased as compared with those formed under the same culturing conditions but without the cytokine. During contact-dependent (but not distant) culturing of NK cells with the co-culture of endothelial and trophoblast cells in the presence of VEGF, the length of tube-like structures was greater than those formed under the same culturing conditions but without the cytokine. When used in a three-component cell system, the pro-inflammatory cytokine IFNγhad no effect upon angiogenesis. During distant (but not contact-dependent) culturing of NK cells with co-culture of endothelial and trophoblast cells in the presence of TGF-β, the length of tube-like structures was less than the length of tube-like structures formed under the same culturing conditions but without the cytokine. Under conditions of distant culturing, TGF-βtriggered a signal in NK cells that inhibited angiogenesis. Decreased length of tube-like structures under conditions of a three-component cell co-culture in the presence of the following pro-angiogenic factors was revealed: IL-8, PlGF (during contact-dependent culturing only) and bFGF (during both contact-dependent and distant culturing). Thus, the effects of cytokines upon angiogenesis in a three-component co-culture (NK cells, trophoblast and endothelium) differed from those revealed previously in single-component (endothelium only) and two-component (co-culture of endothelium and trophoblast) cell models. The results of these experiments indicated that regulation of placental cell interactions involved both cellular contacts and effects produced by cytokines.

scholarly journals The Potential for Cancer Immunotherapy in Targeting Surgery-Induced Natural Killer Cell Dysfunction

Cancers ◽  
2018 ◽  
Vol 11 (1) ◽  
pp. 2 ◽  
Author(s):  
Marisa Market ◽  
Katherine Baxter ◽  
Leonard Angka ◽  
Michael Kennedy ◽  
Rebecca Auer
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Biology ◽  
Nk Cell ◽  
Clonal Selection ◽  
Killer Cell ◽  
Cancer Recurrence ◽  
Effector Functions ◽  
Cell Dysfunction ◽  
Cell Functions

Natural Killer (NK) cells are granular lymphocytes of the innate immune system that are able to recognize and kill tumor cells without undergoing clonal selection. Discovered over 40 years ago, they have since been recognized to possess both cytotoxic and cytokine-producing effector functions. Following trauma, NK cells are suppressed and their effector functions are impaired. This is especially important for cancer patients undergoing the removal of solid tumors, as surgery has shown to contribute to the development of metastasis and cancer recurrence postoperatively. We have recently shown that NK cells are critical mediators in the formation of metastasis after surgery. While research into the mechanism(s) responsible for NK cell dysfunction is ongoing, knowledge of these mechanisms will pave the way for perioperative therapeutics with the potential to improve cancer outcomes by reversing NK cell dysfunction. This review will discuss mechanisms of suppression in the postoperative environment, including hypercoagulability, suppressive soluble factors, the expansion of suppressive cell populations, and how this affects NK cell biology, including modulation of cell surface receptors, the potential for anergy, and immunosuppressive NK cell functions. This review will also outline potential immunotherapies to reverse postoperative NK dysfunction, with the goal of preventing surgery-induced metastasis.

scholarly journals A Human Histocompatibility Leukocyte Antigen (HLA)-G–specific Receptor Expressed on All Natural Killer Cells

1999 ◽  
Vol 189 (7) ◽  
pp. 1093-1100 ◽  
Author(s):  
Sumati Rajagopalan ◽  
Eric O. Long
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Killer Cell ◽  
Hla Class I ◽  
Class I ◽  
Target Cells ◽  
Trophoblast Cells ◽  
Leukocyte Antigen ◽  
Hla Class I Molecules ◽  
Decidual Cells

Human natural killer (NK) cells express several killer cell immunoglobulin (Ig)-like receptors (KIRs) that inhibit their cytotoxicity upon recognition of human histocompatibility leukocyte antigen (HLA) class I molecules on target cells. Additional members of the KIR family, including some that deliver activation signals, have unknown ligand specificity and function. One such KIR, denoted KIR2DL4, is structurally divergent from other KIRs in the configuration of its two extracellular Ig domains and of its transmembrane and cytoplasmic domains. Here we show that recombinant soluble KIR2DL4 binds to cells expressing HLA-G but not to cells expressing other HLA class I molecules. Unlike other HLA class I–specific KIRs, which are clonally distributed on NK cells, KIR2DL4 is expressed at the surface of all NK cells. Furthermore, functional transfer of KIR2DL4 into the cell line NK-92 resulted in inhibition of lysis of target cells that express HLA-G, but not target cells that express other class I molecules including HLA-E. Therefore, given that HLA-G expression is restricted to fetal trophoblast cells, KIR2DL4 may provide important signals to maternal NK decidual cells that interact with trophoblast cells at the maternal–fetal interface during pregnancy.

scholarly journals Identification of Primary Natural Killer Cell Modulators by Chemical Library Screening with a Luciferase-Based Functional Assay

2018 ◽  
Vol 24 (1) ◽  
pp. 25-37 ◽  
Author(s):  
Simon Hayek ◽  
Nassima Bekaddour ◽  
Laurie Besson ◽  
Rodolphe Alves de Sousa ◽  
Nicolas Pietrancosta ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Activity ◽  
Target Cells ◽  
Functional Assay ◽  
Functional Screening ◽  
Cell Functions ◽  
Ifn Γ

Natural killer (NK) cells are essential players of the innate immune response that secrete cytolytic factors and cytokines such as IFN-γ when contacting virus-infected or tumor cells. They represent prime targets in immunotherapy as defects in NK cell functions are hallmarks of many pathological conditions, such as cancer and chronic infections. The functional screening of chemical libraries or biologics would greatly help identify new modulators of NK cell activity, but commonly used methods such as flow cytometry are not easily scalable to high-throughput settings. Here we describe an efficient assay to measure the natural cytotoxicity of primary NK cells where the bioluminescent enzyme NanoLuc is constitutively expressed in the cytoplasm of target cells and is released in co-culture supernatants when lysis occurs. We fully characterized this assay using either purified NK cells or total peripheral blood mononuclear cells (PBMCs), including some patient samples, as effector cells. A pilot screen was also performed on a library of 782 metabolites, xenobiotics, and common drugs, which identified dextrometorphan and diphenhydramine as novel NK cell inhibitors. Finally, this assay was further improved by developing a dual-reporter cell line to simultaneously measure NK cell cytotoxicity and IFN-γ secretion in a single well, extending the potential of this system.

Evaluation of purified natural killer cell functions in familial hemophagocytic lymphohistiocytosis

2015 ◽  
Vol 2 (4) ◽  
pp. 207-212 ◽  
Author(s):  
Benyamin Rosental ◽  
Avishai Shemesh ◽  
Michal Yaron-Mendelson ◽  
Lauren C. Klein ◽  
Yona Kodman ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Nk Cell ◽  
Killer Cell ◽  
Positive Family History ◽  
False Negative ◽  
Specific Lysis ◽  
Familial Hemophagocytic Lymphohistiocytosis ◽  
Cell Functions

Background: Familial hemophagocytic lymphohistiocytosis (FHL) is a rare, genetic, immune dysregulation disorder of aberrant hyperactivation of lymphocytes causing inflammation and hemophagocytosis. We report on a 3-month old male who was evaluated for the possibility of FHL because of a positive family history. The patient was asymptomatic; however, levels of the soluble interleukin 2 (IL-2) receptor were elevated and the quantity and function of the natural killer (NK) cells were severely decreased. Methods: Purification of NK cells and evaluation of the cytotoxicity and IFNγ/TNFα secretion of NK cells after IL-2 activation relative to the patient's family members. Results: The patient's NK specific lysis was enhanced compared with his mother, and it was slightly higher than his sister. The IFNγ and TNFα secretion by the patient's NK cells after challenge with target 721 cells or anti-natural cytotoxicity receptors (NKp30 and NKp44) antibodies showed levels that are close to the mother's and sister's NK secretion levels. Owing to a low yield of NK cells from the patient's father the results for his NK cells are incomplete. The patient did not undergo HSCT and continued to be followed. He is now 7 years old and thriving without signs of FHL. His last examination was in August 2012 for functionality of isolated NK cells. The results showed normal cytotoxicity, cytokine secretion, and CD107a up-regulation to the NK cell surface. Conclusion: We propose that NK function assessment in patients with presumed FHL should be performed on isolated NK cell populations. This practice may reduce the number of false-negative results in NK function assays. Statement of novelty: In this case report we show that functional assessment of unpurified NK cells could lead to a false-negative assessment in 1 of the parameters in FHL. Assessment of NK function without NK purification may lead to an erroneous diagnosis of poor NK function.

scholarly journals Neutrophil depletion impairs natural killer cell maturation, function, and homeostasis

2012 ◽  
Vol 209 (3) ◽  
pp. 565-580 ◽  
Author(s):  
Baptiste N. Jaeger ◽  
Jean Donadieu ◽  
Céline Cognet ◽  
Claire Bernat ◽  
Diana Ordoñez-Rueda ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Immature Stage ◽  
Immune Defense ◽  
Cell Reactivity ◽  
Cell Functions

Natural killer (NK) cells are bone marrow (BM)–derived granular lymphocytes involved in immune defense against microbial infections and tumors. In an N-ethyl N-nitrosourea (ENU) mutagenesis strategy, we identified a mouse mutant with impaired NK cell reactivity both in vitro and in vivo. Dissection of this phenotype showed that mature neutrophils were required both in the BM and in the periphery for proper NK cell development. In mice lacking neutrophils, NK cells displayed hyperproliferation and poor survival and were blocked at an immature stage associated with hyporesponsiveness. The role of neutrophils as key regulators of NK cell functions was confirmed in patients with severe congenital neutropenia and autoimmune neutropenia. In addition to their direct antimicrobial activity, mature neutrophils are thus endowed with immunoregulatory functions that are conserved across species. These findings reveal novel types of cooperation between cells of the innate immune system and prompt examination of NK cell functional deficiency in patients suffering from neutropenia-associated diseases.

scholarly journals The transcriptional repressor ID2 supports natural killer cell maturation by controlling TCF1 amplitude

2021 ◽  
Vol 218 (6) ◽  
Author(s):  
Zhong-Yin Li ◽  
Rosemary E. Morman ◽  
Emma Hegermiller ◽  
Mengxi Sun ◽  
Elizabeth T. Bartom ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Temporal Dynamics ◽  
Nk Cell ◽  
Killer Cell ◽  
Regulatory Protein ◽  
Receptor Expression ◽  
Cell Surface Receptor ◽  
Cell Functions ◽  
Differentiated Cells

Gaining a mechanistic understanding of the expansion and maturation program of natural killer (NK) cells will provide opportunities for harnessing their inflammation-inducing and oncolytic capacity for therapeutic purposes. Here, we demonstrated that ID2, a transcriptional regulatory protein constitutively expressed in NK cells, supports NK cell effector maturation by controlling the amplitude and temporal dynamics of the transcription factor TCF1. TCF1 promotes immature NK cell expansion and restrains differentiation. The increased TCF1 expression in ID2-deficient NK cells arrests their maturation and alters cell surface receptor expression. Moreover, TCF1 limits NK cell functions, such as cytokine-induced IFN-γ production and the ability to clear metastatic melanoma in ID2-deficient NK cells. Our data demonstrate that ID2 sets a threshold for TCF1 during NK cell development, thus controlling the balance of immature and terminally differentiated cells that support future NK cell responses.

scholarly journals Natural Killer Cell Dysfunction in Hepatocellular Carcinoma: Pathogenesis and Clinical Implications

2018 ◽  
Author(s):  
Pil Soo Sung ◽  
Jeong Won Jang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Function ◽  
Nk Cell ◽  
Critical Role ◽  
Killer Cell ◽  
Cell Therapies ◽  
Cell Dysfunction ◽  
Cell Functions

Hepatocellular carcinoma (HCC) is currently the third leading cause of malignancy-related mortalities worldwide. Natural killer (NK) cells are involved in the critical role of first line immunological defense against cancer development. Defects in NK cell functions are recognized as important mechanisms for immune evasion of tumor cells. NK cell function appears to be attenuated in HCC, and many previous reports suggested that NK cells play a critical role in controlling HCC, suggesting that boosting the activity of dysfunctional NK cells can enhance tumor cell killing. However, the detailed mechanisms of NK cell dysfunction in tumor microenvironment of HCC remain largely unknown. A better understanding of the mechanisms of NK cell dysfunction in HCC will help in the NK cell-mediated eradication of cancer cells and prolong patient survival. In this review, we describe the various mechanisms underlying NK cell dysfunction in HCC. Further, we summarize current advances in the approaches to enhance endogenous NK cell function and in adoptive NK cell therapies, to cure this difficult-to-treat cancer.

scholarly journals Natural Killer Cell Dysfunction in Hepatocellular Carcinoma: Pathogenesis and Clinical Implications

2018 ◽  
Vol 19 (11) ◽  
pp. 3648 ◽  
Author(s):  
Pil Soo Sung ◽  
Jeong Won Jang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Function ◽  
Nk Cell ◽  
Critical Role ◽  
Killer Cell ◽  
Cell Therapies ◽  
Cell Dysfunction ◽  
Cell Functions

Hepatocellular carcinoma (HCC) is currently the third leading cause of malignancy-related mortalities worldwide. Natural killer (NK) cells are involved in the critical role of first line immunological defense against cancer development. Defects in NK cell functions are recognized as important mechanisms for immune evasion of tumor cells. NK cell function appears to be attenuated in HCC, and many previous reports suggested that NK cells play a critical role in controlling HCC, suggesting that boosting the activity of dysfunctional NK cells can enhance tumor cell killing. However, the detailed mechanisms of NK cell dysfunction in tumor microenvironment of HCC remain largely unknown. A better understanding of the mechanisms of NK cell dysfunction in HCC will help in the NK cell-mediated eradication of cancer cells and prolong patient survival. In this review, we describe the various mechanisms underlying human NK cell dysfunction in HCC. Further, we summarize current advances in the approaches to enhance endogenous NK cell function and in adoptive NK cell therapies, to cure this difficult-to-treat cancer.

Characteristics of Natural Killer Cell Interaction with Trophoblast Cells During Pregnancy

2020 ◽  
Vol 20 (3) ◽  
pp. 202-219
Author(s):  
Dmitry Olegovich Bazhenov ◽  
Evgeniya Valerevna Khokhlova ◽  
Larisa Pavlovna Viazmina ◽  
Kseniya Nikolaevna Furaeva ◽  
Valentina Anatolievna Mikhailova ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
First Trimester ◽  
Conditioned Media ◽  
Receptor Expression ◽  
Trophoblast Cells ◽  
Third Trimester ◽  
The Impact

Background:: Maternal natural killer cells (NK cells) are a prevailing leukocyte population in the uteroplacental bed. Current descriptions of the effect of cytokines from the placental microenvironment on the expression of receptors by trophoblast and NK cells are inadequate and contradictory. There is insufficient information about the ability of NK cells to migrate through trophoblast cells. Objective:: To assess the impact of conditioned media obtained during culturing of placentas from the first and the third trimesters of healthy pregnancies on the phenotype of trophoblast and NK cells and impact on adhesion and transmigration of NK cells through trophoblast cell layer. Results:: We established that conditioned media obtained from both first and third trimester placentas increased the intensity of CD106, CD49e, CD49a, CD31, CD51/61, and integrin β6 expression by trophoblast cells. Conditioned media obtained from first trimester placentas increased the intensity of CD11a, CD29, CD49d, CD58, CD29 expression by NK cells. The presence of conditioned media from third trimester placentas resulted in more intense CD29, CD49d, CD11a, CD29, CD49d, and CD58 expression by NK cells. Migration of NK cells through trophoblast cells in the presence of conditioned media from first trimester placentas was increased compared with the migration level in the presence of conditioned media from third trimester placentas. This may be associated with increased expression of CD18 by NK cells. Conclusion:: First trimester placental secretory products increase adhesion receptor expression by both trophoblast and NK cells. Under these conditions, trophoblast is capable of ensuring NK cell adhesion and transmigration.

scholarly journals Binding of the Hepatitis C Virus Envelope Protein E2 to CD81 Inhibits Natural Killer Cell Functions

2001 ◽  
Vol 195 (1) ◽  
pp. 43-50 ◽  
Author(s):  
Chien-Te K. Tseng ◽  
Gary R. Klimpel
Keyword(s):  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Nk Cells ◽  
Natural Killer ◽  
Envelope Protein ◽  
Killer Cell ◽  
Cross Linking ◽  
Cell Functions ◽  
Ifn Γ

Infection with hepatitis C virus (HCV) is a leading cause of chronic liver disease worldwide. Little is known about how this virus is able to persist or whether this persistence might be because of its ability to alter the early innate immune response. The major HCV envelope protein E2 has been shown to bind to CD81. Thus, HCV binding to natural killer (NK) cells could result in the cross-linking of CD81. To explore this possibility, we investigated whether cross-linking CD81 on NK cells could alter NK cell function. CD81 cross-linking by monoclonal antibody (mAb) specific for CD81 or by immobilized E2 have been shown to result in costimulatory signals for human T cells. In this study, we show that CD81 cross-linking via immobilized E2 or mAbs specific for CD81 inhibits not only non major histocompatibility complex–restricted cytotoxicity mediated by NK cells but also interferon (IFN)-γ production by NK cells after exposure to interleukin (IL)-2, IL-12, IL-15, or CD16 cross-linking. These results show that CD81 cross-linking mediates completely different signals in NK cells versus T cells. Importantly, these results suggest that one mechanism whereby HCV can alter host defenses and innate immunity is via the early inhibition of IFN-γ production by NK cells.

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