Reciprocal Interaction of Monocytes and NK Cells by Activation-Induced Expression of Ligands for the Activating Immunoreceptor NKG2D.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2212-2212
Author(s):  
Matthias Krusch ◽  
Mercedes Kloss ◽  
Andrea Peterfi ◽  
Ingrid Kumbier ◽  
Lothar Kanz ◽  
...  
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Adaptive Immune System ◽  
Surface Expression ◽  
Pcr Analysis ◽  
High Plasticity ◽  
Blood Monocytes ◽  
Cell Functions ◽  
Adaptive Immune ◽  
Mrna Induction

Abstract Reciprocal Interactions of NK cells with Dendritic Cells (DC) can induce activation of NK cells, maturation or lysis of DC and influence subsequent adaptive immune responses. However, little is known about the interaction of peripheral blood monocytes with NK cells, especially regarding involved immunoregulatory surface molecules. Here we report that monocytes express ligands for the activating immunoreceptor NKG2D expressed on NK cells upon treatment with various stimuli. Incubation of monocytes with TNF, GM-CSF, IFN-g and various TLR ligands (LPS, Pam3Cys, R848, PolyI:C) induced surface expression of the NKG2D ligands (NKG2DL) MICA and to a lesser extent MICB, but no relevant changes of ULBP molecules, as determined by FACS analysis. Expression was confirmed by quantitative PCR analysis of NKG2DL mRNA induction. To elucidate the functional consequences of NKG2DL expression on monocytes for NK cell functions we performed coculture assays of monocytes and autologous NK cells. NKG2DL expression on stimulated monocytes lead to a significant induction of IFN-g release into the culture supernatant by NK cells as determined by ELISA. This IFN-g release was blocked by addition of a NKG2D-Ig fusionprotein, but not by isotype control demonstrating that the induction of NK cell IFN-g production was in fact specifically due to NKG2DL expression on monocytes. Since both monocytes and NK cells rapidly migrate to sites of inflammation, and monocytes display a high plasticity regarding their function and maturation which is influenced by IFN-g, our data indicate that NKG2DL expression on monocytes might not only mediate reciprocal activation of NK cells and monocytes but also might influence other components of the innate and adaptive immune system and thereby determine the course of subsequent immune reactions.

scholarly journals Harnessing CD16-Mediated NK Cell Functions to Enhance Therapeutic Efficacy of Tumor-Targeting mAbs

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2500
Author(s):  
Cristina Capuano ◽  
Chiara Pighi ◽  
Simone Battella ◽  
Davide De Federicis ◽  
Ricciarda Galandrini ◽  
...  
Keyword(s):  
Nk Cells ◽  
Tumor Targeting ◽  
Nk Cell ◽  
Intrinsic Resistance ◽  
Cell Functions ◽  
Adaptive Immune ◽  
Cytokines And Chemokines ◽  
Affinity Receptor ◽  
Immunosuppressive Microenvironment

Natural killer (NK) cells hold a pivotal role in tumor-targeting monoclonal antibody (mAb)-based activity due to the expression of CD16, the low-affinity receptor for IgG. Indeed, beyond exerting cytotoxic function, activated NK cells also produce an array of cytokines and chemokines, through which they interface with and potentiate adaptive immune responses. Thus, CD16-activated NK cells can concur to mAb-dependent “vaccinal effect”, i.e., the development of antigen-specific responses, which may be highly relevant in maintaining long-term protection of treated patients. On this basis, the review will focus on strategies aimed at potentiating NK cell-mediated antitumor functions in tumor-targeting mAb-based regimens, represented by (a) mAb manipulation strategies, aimed at augmenting recruitment and efficacy of NK cells, such as Fc-engineering, and the design of bi- or trispecific NK cell engagers and (b) the possible exploitation of memory NK cells, whose distinctive characteristics (enhanced responsiveness to CD16 engagement, longevity, and intrinsic resistance to the immunosuppressive microenvironment) may maximize therapeutic mAb antitumor efficacy.

scholarly journals IL-2–dependent tuning of NK cell sensitivity for target cells is controlled by regulatory T cells

2013 ◽  
Vol 210 (6) ◽  
pp. 1167-1178 ◽  
Author(s):  
Georg Gasteiger ◽  
Saskia Hemmers ◽  
Matthew A. Firth ◽  
Audrey Le Floc’h ◽  
Morgan Huse ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Nk Cells ◽  
Immune Cell ◽  
Nk Cell ◽  
Adaptive Immune System ◽  
Target Cells ◽  
Cell Reactivity ◽  
Adaptive Immune ◽  
Missing Self

The emergence of the adaptive immune system took a toll in the form of pathologies mediated by self-reactive cells. Regulatory T cells (T reg cells) exert a critical brake on responses of T and B lymphocytes to self- and foreign antigens. Here, we asked whether T reg cells are required to restrain NK cells, the third lymphocyte lineage, whose features combine innate and adaptive immune cell properties. Although depletion of T reg cells led to systemic fatal autoimmunity, NK cell tolerance and reactivity to strong activating self- and non-self–ligands remained largely intact. In contrast, missing-self responses were increased in the absence of T reg cells as the result of heightened IL-2 availability. We found that IL-2 rapidly boosted the capacity of NK cells to productively engage target cells and enabled NK cell responses to weak stimulation. Our results suggest that IL-2–dependent adaptive-innate lymphocyte cross talk tunes NK cell reactivity and that T reg cells restrain NK cell cytotoxicity by limiting the availability of IL-2.

scholarly journals IL-27 Driven Upregulation of Surface HLA-E Expression on Monocytes Inhibits IFN-γRelease by Autologous NK Cells

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Fabio Morandi ◽  
Irma Airoldi ◽  
Vito Pistoia
Keyword(s):  
Immune Responses ◽  
Nk Cells ◽  
Nk Cell ◽  
K562 Cells ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Inhibitory Receptor ◽  
Cell Functions ◽  
Stat3 Phosphorylation ◽  
And Function

HLA-G and HLA-E are HLA-Ib molecules with several immunoregulatory properties. Their cell surface expression can be modulated by different cytokines. Since IL-27 and IL-30 may either stimulate or regulate immune responses, we have here tested whether these cytokines may modulate HLA-G and -E expression and function on human monocytes. Monocytes expressed gp130 and WSX-1, the two chains of IL27 receptor (R), and IL6Rα(that serves as IL-30R, in combination with gp130). However, only IL27R appeared to be functional, as witnessed by IL-27 driven STAT1/ STAT3 phosphorylation. IL-27, but not IL-30, significantly upregulated HLA-E (but not HLA-G) expression on monocytes. IFN-γ; secretion by activated NK cells was dampened when the latter cells were cocultured with IL-27 pretreated autologous monocytes. Such effect was not achieved using untreated or IL-30 pretreated monocytes, thus indicating that IL-27 driven HLA-E upregulation might be involved, possibly through the interaction of this molecule with CD94/NKG2A inhibitory receptor on NK cells. In contrast, cytotoxic granules release by NK cell in response to K562 cells was unaffected in the presence of IL-27 pretreated monocytes. In conclusion, we delineated a novel immunoregulatory function of IL-27 involving HLA-E upregulation on monocytes that might in turn indirectly impair some NK cell functions.

scholarly journals Generation of Natural Killer Cell Memory during Viral Infection

2015 ◽  
Vol 7 (6) ◽  
pp. 557-562 ◽  
Author(s):  
Timothy E. O'Sullivan ◽  
Joseph C. Sun
Keyword(s):  
Immune System ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Adaptive Immune System ◽  
Current Evidence ◽  
Cell Memory ◽  
Independent Manner ◽  
Adaptive Immune

Immunological memory is classically regarded as an attribute of antigen-specific T and B lymphocytes of the adaptive immune system. Cells of the innate immune system, including natural killer (NK) cells, have been considered short-lived cytolytic cells that can rapidly respond against pathogens in an antigen-independent manner and then die off. However, NK cells have recently been described to possess traits of adaptive immunity, such as clonal expansion after viral antigen exposure to generate long-lived memory cells. In this review, we will discuss the current evidence for viral-induced NK cell memory in both mice and humans.

scholarly journals NBAS Variants Are Associated with Quantitative and Qualitative NK and B Cell Deficiency

2021 ◽  
Author(s):  
Dominic Lenz ◽  
Jens Pahl ◽  
Fabian Hauck ◽  
Seham Alameer ◽  
Meena Balasubramanian ◽  
...  
Keyword(s):  
Immune System ◽  
Nk Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
Adaptive Immune System ◽  
Target Cells ◽  
Multisystem Disorder ◽  
Adaptive Immune ◽  
B Cell Deficiency

Abstract Purpose Biallelic pathogenic NBAS variants manifest as a multisystem disorder with heterogeneous clinical phenotypes such as recurrent acute liver failure, growth retardation, and susceptibility to infections. This study explores how NBAS-associated disease affects cells of the innate and adaptive immune system. Methods Clinical and laboratory parameters were combined with functional multi-parametric immunophenotyping methods in fifteen NBAS-deficient patients to discover possible alterations in their immune system. Results Our study revealed reduced absolute numbers of mature CD56dim natural killer (NK) cells. Notably, the residual NK cell population in NBAS-deficient patients exerted a lower potential for activation and degranulation in response to K562 target cells, suggesting an NK cell–intrinsic role for NBAS in the release of cytotoxic granules. NBAS-deficient NK cell activation and degranulation was normalized upon pre-activation by IL-2 in vitro, suggesting that functional impairment was reversible. In addition, we observed a reduced number of naïve B cells in the peripheral blood associated with hypogammaglobulinemia. Conclusion In summary, we demonstrate that pathogenic biallelic variants in NBAS are associated with dysfunctional NK cells as well as impaired adaptive humoral immunity.

Toll-Like Receptor-Induced Expression of the NKG2D Ligand MICA on Monocytes Modulates Their Interaction with NK Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2415-2415
Author(s):  
Mercedes Kloss ◽  
Patrice Decker ◽  
Matthias Krusch ◽  
Katrin M. Baltz ◽  
Tina Baessler ◽  
...  
Keyword(s):  
Immune Responses ◽  
Nk Cells ◽  
Nk Cell ◽  
Surface Expression ◽  
Cell Interaction ◽  
Soluble Form ◽  
Blood Monocytes ◽  
Activated Monocytes ◽  
Mica Expression ◽  
Stimulation Of

Abstract Reciprocal interactions of NK cells with Dendritic Cells (DC) have been shown to influence activation of NK cells as well as maturation or lysis of DC and subsequent adaptive immune responses. However, little is known about the interaction of peripheral blood Monocytes with NK cells. Here we report that stimulation of Toll-like receptors (TLR) on Monocytes using LPS, Pam3Cys, R848 and PolyI:C induced mRNA and surface expression of MICA but no relevant changes of the further ligands of the activating immunoreceptor NKG2D, MICB or ULBP1-3. MICA upregulation upon stimulation with TLR ligands correlated with CD80 and HLA-DR upregulation and increased secretion of the pro-inflammatory cytokines IL-6, IL-8 and TNF by Monocytes. Interestingly, high MICA surface expression on activated Monocytes was not accompanied by a release of MICA in soluble form. The LPS-induced MICA upregulation by Monocytes was highly sensitive since it was observed with as little as 4 ng/ml LPS after 15 hours and was associated with IL-6 secretion and inhibition of apoptosis indicating that Monocytes were activated and functional. To determine whether upregulated MICA expression on Monocytes was detected by NK cells we took advantage of the fact that NKG2D is down-regulated after interacting with its ligands. While NKG2D levels on NK cells were not substantially changed in cultures with unstimulated Monocytes, a marked reduction of NKG2D was observed in the presence of activated MICA-expressing Monocytes. The modulation of NKG2D did not occur when NK cells and monocytes were separated by a transwell filter, which demonstrates that the numerous cytokines produced by TLR-activated Monocytes are not responsible for the NKG2D modulation and confirmes the role of MICA in Monocyte-NK cell interaction. Importantly, TLR-induced MICA expression on Monocytes stimulated IFN-γ production of NK cells, which could be reduced by addition of blocking anti-MICA/B F(ab’)2 fragments while isotype control had no effect. This demonstrates that the observed stimulation of NK cells was in fact specifically due to NKG2D-NKG2DL interaction. Our data indicate that NKG2D-MICA interaction provides a mechanism by which NK cells and Monocytes may communicate directly during innate immune responses to infections in humans.

scholarly journals The role of natural killer cell in gastrointestinal cancer: killer or helper

Oncogene ◽  
2020 ◽  
Author(s):  
Feixue Wang ◽  
Jennie Ka Ching Lau ◽  
Jun Yu
Keyword(s):  
Immune System ◽  
Nk Cells ◽  
Natural Killer ◽  
Gastrointestinal Cancer ◽  
Nk Cell ◽  
Checkpoint Inhibitors ◽  
Killer Cell ◽  
Adaptive Immune System ◽  
High Morbidity ◽  
Adaptive Immune

AbstractGastrointestinal cancer is one of the leading health problems worldwide, with a high morbidity and mortality. To date, harnessing both the innate and adaptive immune system against cancer provides a selective and effective therapeutic strategy for patients. As a first line defense against cancer, natural killer (NK) cells can swiftly target and lyse tumor cells without prior activation. In addition to its pivotal role in innate immunity, NK cells also play unique roles in the adaptive immune system as it enhance anti-tumor adaptive immune responses through secretion of cytokines and retaining an immunological memory. All these characteristics make NK cell a promising anti-cancer agent for patients. In spite of scarce infiltration and impaired function of NK cells in tumors, and the fact that tumors easily develop resistant mechanisms to evade the attacks from endogenous NK cells, multiple strategies have been developed to boost anti-tumor effect of NK cells and abolish tumor resistance. Some examples include adoptive transfer of NK cells after ex vivo activation and expansion; restoration of NK cell function using immune checkpoint inhibitors, and monoclonal antibody or cytokine treatment. Preclinical data have shown encouraging results, suggesting that NK cells hold great potential in cancer therapy. In this review, we discuss NK cells’ cytotoxicity and modulation function in GI cancer and the current application in clinical therapy.

scholarly journals GSK-3α Inhibition in Drug-Resistant CML Cells Promotes Susceptibility to NK Cell-Mediated Lysis in an NKG2D- and NKp30-Dependent Manner

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1802
Author(s):  
Nayoung Kim ◽  
Mi Yeon Kim ◽  
Woo Seon Choi ◽  
Eunbi Yi ◽  
Hyo Jung Lee ◽  
...  
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Negative Regulator ◽  
Target Cells ◽  
Dependent Manner ◽  
Cell Functions ◽  
Cell Based Therapy ◽  
Activating Receptors ◽  
Gsk 3Β

Natural killer (NK) cells are innate cytotoxic lymphocytes that provide early protection against cancer. NK cell cytotoxicity against cancer cells is triggered by multiple activating receptors that recognize specific ligands expressed on target cells. We previously demonstrated that glycogen synthase kinase (GSK)-3β, but not GSK-3α, is a negative regulator of NK cell functions via diverse activating receptors, including NKG2D and NKp30. However, the role of GSK-3 isoforms in the regulation of specific ligands on target cells is poorly understood, which remains a challenge limiting GSK-3 targeting for NK cell-based therapy. Here, we demonstrate that GSK-3α rather than GSK-3β is the primary isoform restraining the expression of NKG2D ligands, particularly ULBP2/5/6, on tumor cells, thereby regulating their susceptibility to NK cells. GSK-3α also regulated the expression of the NKp30 ligand B7-H6, but not the DNAM-1 ligands PVR or nectin-2. This regulation occurred independently of BCR-ABL1 mutation that confers tyrosine kinase inhibitor (TKI) resistance. Mechanistically, an increase in PI3K/Akt signaling in concert with c-Myc was required for ligand upregulation in response to GSK-3α inhibition. Importantly, GSK-3α inhibition improved cancer surveillance by human NK cells in vivo. Collectively, our results highlight the distinct role of GSK-3 isoforms in the regulation of NK cell reactivity against target cells and suggest that GSK-3α modulation could be used to enhance tumor cell susceptibility to NK cells in an NKG2D- and NKp30-dependent manner.

scholarly journals Direct Binding of Human NK Cell Natural Cytotoxicity Receptor NKp44 to the Surfaces of Mycobacteria and Other Bacteria

2008 ◽  
Vol 76 (4) ◽  
pp. 1719-1727 ◽  
Author(s):  
Semih Esin ◽  
Giovanna Batoni ◽  
Claudio Counoupas ◽  
Annarita Stringaro ◽  
Franca Lisa Brancatisano ◽  
...  
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Cell Subset ◽  
Surface Expression ◽  
Binding Assays ◽  
Igg Antibody ◽  
Direct Stimulation ◽  
Activating Receptors ◽  
Accessory Cells

ABSTRACT Our previous studies demonstrated that Mycobacterium bovis bacillus Calmette-Guérin (BCG) can directly interact with human NK cells and induce the proliferation, gamma interferon production, and cytotoxic activity of such cells without the need for accessory cells. Thus, the aim of the present study was to identify the putative receptor(s) responsible for the recognition of BCG by human NK cells and potentially involved in the activation of NK cells. To this end, we first investigated the surface expression of three NK cell-activating receptors belonging to the natural cytoxicity receptor (NCR) family on highly purified human NK cells upon in vitro direct stimulation with BCG. An induction of the surface expression of NKp44, but not of NKp30 or NKp46, was observed after 3 and 4 days of in vitro stimulation with live BCG. The NKp44 induction involved mainly a particular NK cell subset expressing the CD56 marker at high density, CD56bright. In order to establish whether NKp44 could directly bind to BCG, whole BCG cells were stained with soluble forms of the three NCRs chimeric for the human immunoglobulin G (IgG) Fc fragment (NKp30-Fc, NKp44-Fc, NKp46-Fc), followed by incubation with a phycoerythrin (PE)-conjugated goat anti-human IgG antibody. Analysis by flow cytometry of the complexes revealed a higher PE fluorescence intensity for BCG incubated with NKp44-Fc than for BCG incubated with NKp30-Fc, NKp46-Fc, or negative controls. The binding of NKp44-Fc to the BCG surface was confirmed with immunogold labeling using transmission electron microscopy, suggesting the presence of a putative ligand(s) for human NKp44 on the BCG cell wall. Similar binding assays performed on a number of gram-positive and gram-negative bacteria revealed a pattern of NKp44-Fc binding restricted to members of the genus Mycobacterium, to the mycobacterium-related species Nocardia farcinica, and to Pseudomonas aeruginosa. Altogether, the results obtained indicate, for the first time, that at least one member of the NCR family (NKp44) may be involved in the direct recognition of bacterial pathogens by human NK cells.

Impact of β2 integrin deficiency on mouse natural killer cell development and function

Blood ◽  
2011 ◽  
Vol 117 (10) ◽  
pp. 2874-2882 ◽  
Author(s):  
Karine Crozat ◽  
Céline Eidenschenk ◽  
Baptiste N. Jaeger ◽  
Philippe Krebs ◽  
Sophie Guia ◽  
...  
Keyword(s):  
Cell Surface ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Surface Expression ◽  
Cell Maturation ◽  
Cell Surface Expression ◽  
Mcmv Infection ◽  
Β2 Integrin

Abstract Natural killer (NK) cells are innate immune cells that express members of the leukocyte β2 integrin family in humans and mice. These CD11/CD18 heterodimers play critical roles in leukocyte trafficking, immune synapse formation, and costimulation. The cell-surface expression of one of these integrins, CD11b/CD18, is also recognized as a major marker of mouse NK-cell maturation, but its function on NK cells has been largely ignored. Using N-ethyl-N-nitrosourea (ENU) mutagenesis, we generated a mouse carrying an A → T transverse mutation in the Itgb2 gene, resulting in a mutation that prevented the cell-surface expression of CD18 and its associated CD11a, CD11b, and CD11c proteins. We show that β2 integrin–deficient NK cells have a hyporesponsive phenotype in vitro, and present an alteration of their in vivo developmental program characterized by a selective accumulation of c-kit+ cells. NK-cell missing-self recognition was partially altered in vivo, whereas the early immune response to mouse cytomegalovirus (MCMV) infection occurred normally in CD18-deficient mice. Therefore, β2 integrins are required for optimal NK-cell maturation, but this deficiency is partial and can be bypassed during MCMV infection, highlighting the robustness of antiviral protective responses.

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