scholarly journals The effect of interleukin-15 on the expression of killer-cell immunoglobulin-like receptors on peripheral natural killer cells in human

2002 ◽  
Vol 11 (4) ◽  
pp. 219-224 ◽  
Author(s):  
Toshiaki Kogure ◽  
Naoki Mantani ◽  
Hirozo Goto ◽  
Yutaka Shimada ◽  
Jun'ichi Tamura ◽  
...  
Keyword(s):  
Natural Killer ◽  
Nk Cell ◽  
Critical Role ◽  
Killer Cell ◽  
The Body ◽  
Peripheral Lymphocytes ◽  
Nk Cell Differentiation ◽  
Human Peripheral Lymphocytes ◽  
Interleukin 15 ◽  
Natural Killing Activity

Interleukin (IL)-15 has emerged as a key regulator of both natural killer (NK) cell differentiation and activation. The aim of the present study was to investigate the expansion of the population of cells expressing killer-cell immunoglobulin-like receptors (CD158a and CD158b) in human peripheral lymphocytes by treatment with IL-15. One million peripheral lymphocytes were cultured in RPMI1640 medium alone or in medium containing IL-2 at 100 U/ml or IL-15 at 0.1, 1.0, or 10.0 ng/ml for 48 h. After each incubation, we assessed the natural killing activity and the population of CD16+CD158a+/b+cells and CD8+CD158a+/b+cells. IL-15 increased the NK activity and expanded the populations of CD16+CD158a+/b+cells and CD8+CD158a+/b+cells. These actions were dose dependent, and the effects of IL-15 at 1.0 ng/ml were close to those of IL-2 at 100 U/ml. These findings suggest that IL-15 induces the effector functions of resting NK cells throughout the body, and thereby plays a critical role in the activation of tissue-associated immune responses.

scholarly journals Prognostic significance of natural killer cell-associated markers in gastric cancer: quantitative analysis using multiplex immunohistochemistry

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Hee Young Na ◽  
Yujun Park ◽  
Soo Kyung Nam ◽  
Jiwon Koh ◽  
Yoonjin Kwak ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
T Cells ◽  
B Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Immune Cells ◽  
Nk Cell ◽  
Critical Role ◽  
Killer Cell ◽  
Prognostic Significance

Abstract Background Natural killer (NK) cells mediate the anti-tumoral immune response as an important component of innate immunity. The aim of this study was to investigate the prognostic significance and functional implication of NK cell-associated surface receptors in gastric cancer (GC) by using multiplex immunohistochemistry (mIHC). Methods We performed an mIHC on tissue microarray slides, including 55 GC tissue samples. A total of 11 antibodies including CD57, NKG2A, CD16, HLA-E, CD3, CD20, CD45, CD68, CK, SMA, and ki-67 were used. CD45 + CD3-CD57 + cells were considered as CD57 + NK cells. Results Among CD45 + immune cells, the proportion of CD57 + NK cell was the lowest (3.8%), whereas that of CD57 + and CD57- T cells (65.5%) was the highest, followed by macrophages (25.4%), and B cells (5.3%). CD57 + NK cells constituted 20% of CD45 + CD57 + immune cells while the remaining 80% were CD57 + T cells. The expression of HLA-E in tumor cells correlated with that in tumoral T cells, B cells, and macrophages, but not CD57 + NK cells. The higher density of tumoral CD57 + NK cells and tumoral CD57 + NKG2A + NK cells was associated with inferior survival. Conclusions Although the number of CD57 + NK cells was lower than that of other immune cells, CD57 + NK cells and CD57 + NKG2A + NK cells were significantly associated with poor outcomes, suggesting that NK cell subsets play a critical role in GC progression. NK cells and their inhibitory receptor, NKG2A, may be potential targets in GC.

scholarly journals Evidence for discrete stages of human natural killer cell differentiation in vivo

2006 ◽  
Vol 203 (4) ◽  
pp. 1033-1043 ◽  
Author(s):  
Aharon G. Freud ◽  
Akihiko Yokohama ◽  
Brian Becknell ◽  
Melissa T. Lee ◽  
Hsiaoyin C. Mao ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Intermediate Stage ◽  
Cell Surface Expression ◽  
Lymphoid Tissues ◽  
Human Natural Killer Cell ◽  
Nk Cell Differentiation

Human natural killer (NK) cells originate from CD34(+) hematopoietic progenitor cells, but the discrete stages of NK cell differentiation in vivo have not been elucidated. We identify and functionally characterize, from human lymph nodes and tonsils, four NK cell developmental intermediates spanning the continuum of differentiation from a CD34(+) NK cell progenitor to a functionally mature NK cell. Analyses of each intermediate stage for CD34, CD117, and CD94 cell surface expression, lineage differentiation potentials, capacity for cytokine production and natural cytotoxicity, and ETS-1, GATA-3, and T-BET expression provide evidence for a new model of human NK cell differentiation in secondary lymphoid tissues.

scholarly journals NKG2D-mediated Natural Killer Cell Protection Against Cytomegalovirus Is Impaired by Viral gp40 Modulation of Retinoic Acid Early Inducible 1 Gene Molecules

2003 ◽  
Vol 197 (10) ◽  
pp. 1245-1253 ◽  
Author(s):  
Melissa Lodoen ◽  
Kouetsu Ogasawara ◽  
Jessica A. Hamerman ◽  
Hisashi Arase ◽  
Jeffrey P. Houchins ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Natural Killer ◽  
Nk Cell ◽  
Critical Role ◽  
Killer Cell ◽  
Cell Surface Expression ◽  
Wild Type Virus ◽  
Wild Type ◽  
Infected Cells

Natural killer (NK) cells play a critical role in the innate immune response against cytomegalovirus (CMV) infections. Although CMV encodes several gene products committed to evasion of adaptive immunity, viral modulation of NK cell activity is only beginning to be appreciated. A previous study demonstrated that the mouse CMV m152-encoded gp40 glycoprotein diminished expression of ligands for the activating NK cell receptor NKG2D on the surface of virus-infected cells. Here we have defined the precise ligands that are affected and have directly implicated NKG2D in immune responses to CMV infection in vitro and in vivo. Murine CMV (MCMV) infection potently induced transcription of all five known retinoic acid early inducible 1 (RAE-1) genes (RAE-1α, RAE-1β, RAE-1δ, RAE-1ε, and RAE-1γ), but not H-60. gp40 specifically down-regulated the cell surface expression of all RAE-1 proteins, but not H-60, and diminished NK cell interferon γ production against CMV-infected cells. Consistent with previous findings, a m152 deletion mutant virus (Δm152) was less virulent in vivo than the wild-type Smith strain of MCMV. Treatment of BALB/c mice with a neutralizing anti-NKG2D antibody before infection increased titers of Δm152 virus in the spleen and liver to levels seen with wild-type virus. These experiments demonstrate that gp40 impairs NK cell recognition of virus-infected cells through disrupting the RAE-1–NKG2D interaction.

scholarly journals Functional Dichotomy in Natural Killer Cell Signaling

2001 ◽  
Vol 193 (12) ◽  
pp. 1413-1424 ◽  
Author(s):  
Francesco Colucci ◽  
Eleftheria Rosmaraki ◽  
Søren Bregenholt ◽  
Sandrine I. Samson ◽  
Vincenzo Di Bartolo ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Surface Receptors ◽  
Nk T Cells ◽  
Nk Cell Differentiation ◽  
Ifn Γ

The product of the protooncogene Vav1 participates in multiple signaling pathways and is a critical regulator of antigen–receptor signaling in B and T lymphocytes, but its role during in vivo natural killer (NK) cell differentiation is not known. Here we have studied NK cell development in Vav1−/− mice and found that, in contrast to T and NK-T cells, the absolute numbers of phenotypically mature NK cells were not reduced. Vav1−/− mice produced normal amounts of interferon (IFN)-γ in response to Listeria monocytogenes and controlled early infection but showed reduced tumor clearance in vivo. In vitro stimulation of surface receptors in Vav1−/− NK cells resulted in normal IFN-γ production but reduced tumor cell lysis. Vav1 was found to control activation of extracellular signal-regulated kinases and exocytosis of cytotoxic granules. In contrast, conjugate formation appeared to be only mildly affected, and calcium mobilization was normal in Vav1−/− NK cells. These results highlight fundamental differences between proximal signaling events in T and NK cells and suggest a functional dichotomy for Vav1 in NK cells: a role in cytotoxicity but not for IFN-γ production.

Combined deficiency in IκBα and IκBϵ reveals a critical window of NF-κB activity in natural killer cell differentiation

Blood ◽  
2004 ◽  
Vol 103 (12) ◽  
pp. 4573-4580 ◽  
Author(s):  
Sandrine I. Samson ◽  
Sylvie Mémet ◽  
Christian A. J. Vosshenrich ◽  
Francesco Colucci ◽  
Odile Richard ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Nuclear Factor Κb ◽  
Interferon Γ ◽  
Cell Development ◽  
Critical Window ◽  
Proliferation And Apoptosis ◽  
Nk Cell Differentiation

Abstract Nuclear factor κB (NF-κB) transcription factors are key regulators of immune, inflammatory, and acute-phase responses and are also implicated in the control of cell proliferation and apoptosis. While perturbations in NF-κB activity impact strongly on B- and T-cell development, little is known about the role for NF-κB in natural killer (NK) cell differentiation. Inhibitors of NF-κB (IκBs) act to restrain NF-κB activation. We analyzed the cell-intrinsic effects of deficiencies in 2 IκB members (IκBα and IκBϵ) on NK cell differentiation. Neither IκBα nor IκBϵ deficiency had major effects on NK cell generation, while their combined absence led to NF-κB hyperactivation, resulting in reduced NK cell numbers, incomplete NK cell maturation, and defective interferon γ (IFN-γ) production. Complementary analysis of transgenic mice expressing an NF-κB-responsive reporter gene showed increased NF-κB activity at the stage of NK cell development corresponding to the partial block observed in IκBα × IκBϵ-deficient mice. These results define a critical window in NK cell development in which NF-κB levels may be tightly controlled. (Blood. 2004;103:4573-4580)

scholarly journals Monocytes control natural killer cell differentiation to effector phenotypes

Blood ◽  
2011 ◽  
Vol 117 (17) ◽  
pp. 4511-4518 ◽  
Author(s):  
Katrina Soderquest ◽  
Nick Powell ◽  
Carmelo Luci ◽  
Nico van Rooijen ◽  
Andrés Hidalgo ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
In Vivo Model ◽  
Dependent Manner ◽  
Nk Cell Differentiation

Abstract Natural killer (NK) cells play a major role in immunologic surveillance of cancer. Whether NK-cell subsets have specific roles during antitumor responses and what the signals are that drive their terminal maturation remain unclear. Using an in vivo model of tumor immunity, we show here that CD11bhiCD27low NK cells migrate to the tumor site to reject major histocompatibility complex class I negative tumors, a response that is severely impaired in Txb21−/− mice. The phenotypical analysis of Txb21-deficient mice shows that, in the absence of Txb21, NK-cell differentiation is arrested specifically at the CD11bhiCD27hi stage, resulting in the complete absence of terminally differentiated CD11bhiCD27low NK cells. Adoptive transfer experiments and radiation bone marrow chimera reveal that a Txb21+/+ environment rescues the CD11bhiCD27hi to CD11bhiCD27low transition of Txb21−/− NK cells. Furthermore, in vivo depletion of myeloid cells and in vitro coculture experiments demonstrate that spleen monocytes mediate the terminal differentiation of peripheral NK cells in a Txb21- and IL-15Rα–dependent manner. Together, these data reveal a novel, unrecognized role for Txb21 expression in monocytes in promoting NK-cell development and help appreciate how various NK-cell subsets are generated and participate in antitumor immunity.

scholarly journals TXNIP Regulates Natural Killer Cell-Mediated Innate Immunity by Inhibiting IFN-γ Production during Bacterial Infection

2020 ◽  
Vol 21 (24) ◽  
pp. 9499
Author(s):  
Dong Oh Kim ◽  
Jae-Eun Byun ◽  
Won Sam Kim ◽  
Mi Jeong Kim ◽  
Jung Ha Choi ◽  
...  
Keyword(s):  
Bacterial Infection ◽  
Nk Cells ◽  
Natural Killer ◽  
Transforming Growth Factor ◽  
Nk Cell ◽  
Critical Role ◽  
Killer Cell ◽  
Transforming Growth Factor Β ◽  
Primary Mouse ◽  
Ifn Γ

The function of natural killer (NK) cell-derived interferon-γ (IFN-γ) expands to remove pathogens by increasing the ability of innate immune cells. Here, we identified the critical role of thioredoxin-interacting protein (TXNIP) in the production of IFN-γ in NK cells during bacterial infection. TXNIP inhibited the production of IFN-γ and the activation of transforming growth factor β-activated kinase 1 (TAK1) activity in primary mouse and human NK cells. TXNIP directly interacted with TAK1 and inhibited TAK1 activity by interfering with the complex formation between TAK1 and TAK1 binding protein 1 (TAB1). Txnip−/− (KO) NK cells enhanced the activation of macrophages by inducing IFN-γ production during Pam3CSK4 stimulation or Staphylococcus aureus (S. aureus) infection and contributed to expedite the bacterial clearance. Our findings suggest that NK cell-derived IFN-γ is critical for host defense and that TXNIP plays an important role as an inhibitor of NK cell-mediated macrophage activation by inhibiting the production of IFN-γ during bacterial infection.

Effect of Conventional Chemotherapies on Natural Killer Cell Activity

2021 ◽  
Vol 17 ◽  
Author(s):  
Idris Kirhan ◽  
Huseyin Taskiran ◽  
Ataman Gönel
Keyword(s):  
Immune System ◽  
Natural Killer ◽  
Cancer Patients ◽  
Nk Cell ◽  
Metastatic Cancer ◽  
Critical Role ◽  
Killer Cell ◽  
Cell Activity ◽  
Activity Levels ◽  
Nk Cell Activity

Background: The effects of chemotherapeutics agents are considered to influence immune system and cells due to their myelosuppressive and immunosuppressive functions. Natural Killer Cells are one of the important components of innate immune system and have a critical role against tumor cells and infections. Objective: The study was aimed to demonstrate whether conventional chemotherapies had an effect on Natural Killer (NK) cell activity. Methods: 49 adjuvant, 19 first time metastatic chemotherapy-naïve cancer patients were recruited into the study. Pre-chemotherapy and post-chemotherapy, at 1th and 4th cycles, blood samples were obtained for NK cell activity. Results: We found no difference between baseline and post-chemotherapy NK cell activity levels. In addition, we found no difference between pre-chemotherapy and post-chemotherapy NK cell activity in both adjuvant and metastatic cancer patients separately. Conclusion: Conventional chemotherapy seems to no affect NK cell activity levels in cancer patients in both metastatic and adjuvant settings.

scholarly journals The septin cytoskeleton regulates natural killer cell lytic granule release

2020 ◽  
Vol 219 (11) ◽  
Author(s):  
Prasad V. Phatarpekar ◽  
Brittany L. Overlee ◽  
Alexander Leehan ◽  
Katelynn M. Wilton ◽  
Hyoungjun Ham ◽  
...  
Keyword(s):  
Natural Killer ◽  
Nk Cell ◽  
Critical Role ◽  
Killer Cell ◽  
Lytic Granules ◽  
Cytoskeletal Component ◽  
Syntaxin 11 ◽  
Nk Cell Cytotoxicity ◽  
Lytic Granule ◽  
Granule Release

Natural killer (NK) cell–mediated killing involves the membrane fusion of preformed lytic granules. While the roles of actin and microtubules are well accepted during this process, the function of septins, another cytoskeletal component that associates with actin and microtubules, has not been investigated. Here we show that genetic depletion or pharmacologic stabilization of the septin cytoskeleton significantly inhibited NK cell cytotoxicity. Although the stabilization of septin filaments impaired conjugate formation, depletion of septin proteins had no impact on conjugate formation, lytic granule convergence, or MTOC polarization to the cytotoxic synapse (CS). Interestingly, septins copurify and accumulate near the polarized lytic granules at the CS, where they regulate lytic granule release. Mechanistically, we find that septin 7 interacts with the SNARE protein syntaxin 11 and facilitates its interaction with syntaxin binding protein 2 to promote lytic granule fusion. Altogether, our data identify a critical role for septins in regulating the release of lytic granule contents during NK cell–mediated killing.

Expression of Activating Natural Killer Cell Receptor Ligands in Childhood Acute Lymphoblastic Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4478-4478
Author(s):  
Ulrike Mura ◽  
Matthias Pfeiffer ◽  
Rupert Handgretinger ◽  
Peter J. Lang
Keyword(s):  
Flow Cytometry ◽  
Natural Killer ◽  
Nk Cell ◽  
Lymphoblastic Leukemia ◽  
Critical Role ◽  
Killer Cell ◽  
Negative Control ◽  
Target Cells ◽  
Nkg2d Ligands ◽  
Ligand Expression

Abstract Activating and inhibitory cell surface receptors regulate natural killer (NK) cell effector functions. The extent of expression of their activating ligands on target cells probably plays a critical role in tumor immune surveillance, but the data of this expression on blasts of leukemia patients are still poor. We examined blasts of children with ALL for the activating human NKG2D ligands MICA, MICB, ULBP1, ULBP2 and ULBP3, and for the ligands of the activating human natural cytotoxic receptors (NCRs) NKp30, NKp44 and NKp46. Using ligand specific mouse monoclonal antibodies and flow cytometry, we screened 24 children (23 common-ALL, one pre-T-ALL) for the expression of NKG2D ligands and 15 children (all common-ALL) for NCR ligands. In 13 patients (all common-ALL), also the density of the NKG2D ligands was determined by quantitative flow cytometry. Considering cells positive for a particular ligand in case of a two fold increase of median fluorescence above negative control, 38 percent of the patients were positive for one or more NKG2D ligands, while only 13 percent expressed one or more NCR ligands at significant levels. ULBP1 was most frequently expressed (29 percent of patients positive), while no patients were positive for ULBP2 and NKp44 ligands. ULBP3 was positive in 17 percent of the patients, NKp30 and NKp46 ligands in 13 percent, MICA and MICB in 4 percent. The patient with pre-T-ALL was positive only for ULBP1. So ULBP1 was expressed more frequently, while the other NKG2D ligands were expressed less frequently in children than reported for adult leukemia patients before (Salih et al. Blood.2003;102:1389–1396.). The density of detected NKG2D ligand molecules was always rather low. For MICA the maximum were 1700 molecules per cell in a single patient, for MICB 900, for ULBP1 1100, and for ULBP3 1000 molecules per cell. In summary, blasts of pediatric ALL patients displayed low or negative surface levels of ligands for the human activating NK cell receptors NKG2D, NKp30, NKp44 and NKp46. QUALITATIVE LIGAND EXPRESSION QUALITATIVE LIGAND EXPRESSION QUANTITATIVE LIGAND EXPRESSION QUANTITATIVE LIGAND EXPRESSION

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