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 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 CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor–β–dependent manner

2005 ◽  
Vol 202 (8) ◽  
pp. 1075-1085 ◽  
Author(s):  
François Ghiringhelli ◽  
Cédric Ménard ◽  
Magali Terme ◽  
Caroline Flament ◽  
Julien Taieb ◽  
...  
Keyword(s):  
Growth Factor ◽  
Natural Killer ◽  
Cell Activation ◽  
Transforming Growth Factor ◽  
Nk Cell ◽  
Killer Cell ◽  
Receptor Expression ◽  
Dependent Manner ◽  
Cell Functions

Tumor growth promotes the expansion of CD4+CD25+ regulatory T (T reg) cells that counteract T cell–mediated immune responses. An inverse correlation between natural killer (NK) cell activation and T reg cell expansion in tumor-bearing patients, shown here, prompted us to address the role of T reg cells in controlling innate antitumor immunity. Our experiments indicate that human T reg cells expressed membrane-bound transforming growth factor (TGF)–β, which directly inhibited NK cell effector functions and down-regulated NKG2D receptors on the NK cell surface. Adoptive transfer of wild-type T reg cells but not TGF-β−/− T reg cells into nude mice suppressed NK cell–mediated cytotoxicity, reduced NKG2D receptor expression, and accelerated the growth of tumors that are normally controlled by NK cells. Conversely, the depletion of mouse T reg cells exacerbated NK cell proliferation and cytotoxicity in vivo. Human NK cell–mediated tumor recognition could also be restored by depletion of T reg cells from tumor-infiltrating lymphocytes. These findings support a role for T reg cells in blunting the NK cell arm of the innate immune system.

scholarly journals Primary adrenal insufficiency is associated with impaired natural killer cell function: a potential link to increased mortality

2017 ◽  
Vol 176 (4) ◽  
pp. 471-480 ◽  
Author(s):  
Irina Bancos ◽  
Jon Hazeldine ◽  
Vasileios Chortis ◽  
Peter Hampson ◽  
Angela E Taylor ◽  
...  
Keyword(s):  
Nk Cells ◽  
Adrenal Insufficiency ◽  
Natural Killer ◽  
Nk Cell ◽  
Respiratory Infections ◽  
Immune Defense ◽  
Innate Immune ◽  
Receptor Expression ◽  
Cell Surface Receptor ◽  
Primary Adrenal Insufficiency

Objective Mortality in patients with primary adrenal insufficiency (PAI) is significantly increased, with respiratory infections as a major cause of death. Moreover, patients with PAI report an increased rate of non-fatal infections. Neutrophils and natural killer (NK) cells are innate immune cells that provide frontline protection against invading pathogens. Thus, we compared the function and phenotype of NK cells and neutrophils isolated from PAI patients and healthy controls to ascertain whether altered innate immune responses could be a contributory factor for the increased susceptibility of PAI patients to infection. Design and methods We undertook a cross-sectional study of 42 patients with PAI due to autoimmune adrenalitis (n = 37) or bilateral adrenalectomy (n = 5) and 58 sex- and age-matched controls. A comprehensive screen of innate immune function, consisting of measurements of neutrophil phagocytosis, reactive oxygen species production, NK cell cytotoxicity (NKCC) and NK cell surface receptor expression, was performed on all subjects. Results Neutrophil function did not differ between PAI and controls. However, NKCC was significantly reduced in PAI (12.0 ± 1.5% vs 21.1 ± 2.6%, P < 0.0001). Phenotypically, the percentage of NK cells expressing the activating receptors NKG2D and NKp46 was significantly lower in PAI, as was the surface density of NKG2D (all P < 0.0001). Intracellular granzyme B expression was significantly increased in NK cells from PAI patients (P < 0.01). Conclusions Adrenal insufficiency is associated with significantly decreased NKCC, thereby potentially compromising early recognition and elimination of virally infected cells. This potential impairment in anti-viral immune defense may contribute to the increased rate of respiratory infections and ultimately mortality in PAI.

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 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 Essential role of the TNF-TNFR2 cognate interaction in mouse dendritic cell–natural killer cell crosstalk

Blood ◽  
2006 ◽  
Vol 109 (8) ◽  
pp. 3333-3341 ◽  
Author(s):  
Jun Xu ◽  
Ayan K. Chakrabarti ◽  
Jennifer L. Tan ◽  
Lisheng Ge ◽  
Andrea Gambotto ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Contact ◽  
Cell Functions ◽  
Essential Components ◽  
Cell Crosstalk

Abstract Dendritic cells (DCs) and natural killer (NK) cells are essential components of the innate immune system and have a central role in initiation and regulation of adaptive immune responses. During the early critical immune activities, DCs and NK cells interact and reciprocally regulate each other via cell-cell contact. The molecular mediators of the DC–NK-cell crosstalk are largely undefined. In the present study, we show in mice that DC stimulation of NK-cell IFN-γ secretion requires DC membranebound but not secreted products; is increased by augmenting the expression of DC transmembrane tumor necrosis factor (tmTNF) and NK-cell transmembrane TNF receptor type 2 (tmTNFR2); is inhibited by blocking TNF or TNFR2 but not TNFR1; is impaired by knocking out DC Tnf or NK-cell Tnfr2 but not DC Tnfr1 or Tnfr2 and NK-cell Tnf or Tnfr1; and is restored in TNF-deficient DCs by reconstituting tmTNF, but cannot be mimicked by soluble TNF. We also demonstrate that DC TNF and NK-cell TNFR2 are required for DC-mediated NK-cell proliferation and amplification of cytotoxic activity. These novel findings provide the first evidence that DC–NK-cell crosstalk mediates enhancement of NK-cell functions via triggering NK-cell tmTNFR2 by DC tmTNF.

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