scholarly journals NK Cells in Mucosal Defense against Infection

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Daria Ivanova ◽  
Ryan Krempels ◽  
Jennyfer Ryfe ◽  
Kaitlyn Weitzman ◽  
David Stephenson ◽  
...  
Keyword(s):  
Nk Cells ◽  
Rational Design ◽  
Nk Cell ◽  
The Body ◽  
Parasitic Infections ◽  
Published Data ◽  
Mucosal Tissue ◽  
Rapid Responses ◽  
Mucosal Infection ◽  
Set Up

Conventional natural killer cells (NK cells) provide continual surveillance for cancer and rapid responses to infection. They develop in the bone marrow, emerge as either NK precursor cells, immature, or mature cells, and disperse throughout the body. In the periphery NK cells provide critical defense against pathogens and cancer and are noted to develop features of adaptive immune responses. In the tightly regulated and dynamic mucosal tissues, they set up residency via unknown mechanisms and from sources that are yet to be defined. Once resident, they appear to have the ability to functionally mature dependent on the mucosal tissue microenvironment. Mucosal NK cells play a pivotal role in early protection through their cytolytic function and IFNγproduction against bacteria, fungi, viruses, and parasitic infections. This review presents what is known about NK cell development and phenotypes of mucosal tissue resident conventional NK cells. The question of how they come to reside in their tissues and published data on their function against pathogens during mucosal infection are discussed. Dissecting major questions highlighted in this review will be important to the further understanding of NK cell homing and functional diversity and improve rational design of NK cell based therapies against mucosal infection.

scholarly journals Enhancing network activation in natural killer cells: predictions from in silico modeling

2020 ◽  
Vol 12 (5) ◽  
pp. 109-121
Author(s):  
Sahak Z Makaryan ◽  
Stacey D Finley
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
In Silico ◽  
Intracellular Signaling ◽  
Cell Activation ◽  
Nk Cell ◽  
Mechanistic Model ◽  
Cell Killing ◽  
Published Data ◽  
Network Activation

Abstract Natural killer (NK) cells are part of the innate immune system and are capable of killing diseased cells. As a result, NK cells are being used for adoptive cell therapies for cancer patients. The activation of NK cell stimulatory receptors leads to a cascade of intracellular phosphorylation reactions, which activates key signaling species that facilitate the secretion of cytolytic molecules required for cell killing. Strategies that maximize the activation of such intracellular species can increase the likelihood of NK cell killing upon contact with a cancer cell and thereby improve efficacy of NK cell-based therapies. However, due to the complexity of intracellular signaling, it is difficult to deduce a priori which strategies can enhance species activation. Therefore, we constructed a mechanistic model of the CD16, 2B4 and NKG2D signaling pathways in NK cells to simulate strategies that enhance signaling. The model predictions were fit to published data and validated with a separate dataset. Model simulations demonstrate strong network activation when the CD16 pathway is stimulated. The magnitude of species activation is most sensitive to the receptor’s initial concentration and the rate at which the receptor is activated. Co-stimulation of CD16 and NKG2D in silico required fewer ligands to achieve half-maximal activation than other combinations, suggesting co-stimulating these pathways is most effective in activating the species. We applied the model to predict the effects of perturbing the signaling network and found two strategies that can potently enhance network activation. When the availability of ligands is low, it is more influential to engineer NK cell receptors that are resistant to proteolytic cleavage. In contrast, for high ligand concentrations, inhibiting phosphatase activity leads to sustained species activation. The work presented here establishes a framework for understanding the complex, nonlinear aspects of NK cell signaling and provides detailed strategies for enhancing NK cell activation.

scholarly journals Transient and persistent effects of IL-15 on lymphocyte homeostasis in nonhuman primates

Blood ◽  
2010 ◽  
Vol 116 (17) ◽  
pp. 3238-3248 ◽  
Author(s):  
Enrico Lugli ◽  
Carolyn K. Goldman ◽  
Liyanage P. Perera ◽  
Jeremy Smedley ◽  
Rhonda Pung ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
The Body ◽  
Effector Memory ◽  
Memory Cd8 T Cells

Abstract Interleukin-15 (IL-15) is a cytokine with potential therapeutic application in individuals with cancer or immunodeficiency to promote natural killer (NK)– and T-cell activation and proliferation or in vaccination protocols to generate long-lived memory T cells. Here we report that 10-50 μg/kg IL-15 administered intravenously daily for 12 days to rhesus macaques has both short- and long-lasting effects on T-cell homeostasis. Peripheral blood lymphopenia preceded a dramatic expansion of NK cells and memory CD8 T cells in the circulation, particularly a 4-fold expansion of central memory CD8 T cells and a 6-fold expansion of effector memory CD8 T cells. This expansion is a consequence of their activation in multiple tissues. A concomitant inverted CD4/CD8 T-cell ratio was observed throughout the body at day 13, a result of preferential CD8 expansion. Expanded T- and NK-cell populations declined in the blood soon after IL-15 was stopped, suggesting migration to extralymphoid sites. By day 48, homeostasis appears restored throughout the body, with the exception of the maintenance of an inverted CD4/CD8 ratio in lymph nodes. Thus, IL-15 generates a dramatic expansion of short-lived memory CD8 T cells and NK cells in immunocompetent macaques and has long-term effects on the balance of CD4+ and CD8+ T cells.

Fc-Engineered RANK-Fc Fusion Proteins for Neutralization of Soluble RANKL and Induction of Antibody-Dependent Cellular Cytotoxicity (ADCC) Against Multiple Myeloma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3039-3039
Author(s):  
Benjamin J Schmiedel ◽  
Carolin Scheible ◽  
Tina Baessler ◽  
Constantin M Wende ◽  
Stefan Wirths ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Nk Cells ◽  
Fusion Proteins ◽  
Nk Cell ◽  
Conflicts Of Interest ◽  
Soluble Form ◽  
Target Cells ◽  
Published Data ◽  
Cellular Cytotoxicity ◽  
Antibody Dependent Cellular Cytotoxicity

Abstract Abstract 3039 Bone resorption is commonly associated with aging, but also with certain cancers. Recent studies identified Receptor Activator of NF-κB (RANK) ligand (RANKL) and its receptors RANK and osteoprotegerin as key regulators of bone remodelling. Multiple myeloma (MM) disrupts the balance within this molecule system towards osteoclastogenesis and bone destruction. Neutralization of RANKL by the monoclonal antibody Denosumab (AMG162) is presently being evaluated for treatment of both non-malignant and malignant osteolysis. We found, in line with previously published data, that primary MM cells (9 of 10) express substantial levels of RANKL at the cell surface and that MM cells directly release RANKL in soluble form (sRANKL). Next we evaluated the possibility to combine neutralization of sRANKL with targeting of MM cells for antibody-dependent cellular cytotoxicity (ADCC) of NK cells utilizing RANK-Ig fusion proteins with modified Fc portions. Compared to wildtype RANK-Fc, our mutants (S239D/I332E and E233P/L234V/L235A/DG236/A327G/A330S) displayed highly enhanced (RANK-Fc-ADCC) and abrogated (RANK-Fc-KO) affinity, respectively, to the NK cell FcγRIIIa, but comparable capacity to neutralize RANKL in binding competition and osteoclast formation assays. Analyses with RANKL transfectants and RANKL-negative controls confirmed the high and lacking potential of the RANK-Fc-ADCC and the RANK-Fc-KO to induce NK ADCC, respectively, and ascertained that the RANK-Fc-ADCC specifically induced NK cell lysis of RANKL-expressing but not RANKL-negative target cells. Most notably, in cultures of NK cells with RANKL-expressing primary MM cells RANK-Fc-ADCC potently enhanced NK cell degranulation, cytokine release and MM cells lysis due to enhanced NK reactivity. Thus, our Fc-engineered RANK-Fc-ADCC fusion protein may both neutralize detrimental effects of sRANKL and enhance NK anti-tumor reactivity by targeting RANKL-expressing malignant cells thereby constituting an attractive immunotherapeutic means for treatment of MM. Disclosures: No relevant conflicts of interest to declare.

Cytokine Activation Induces CD25 Expression and a Signaling-Competent High-Affinity IL-2 Receptor On CD56dim Human NK Cells.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2159-2159
Author(s):  
Julie M Chase ◽  
Jeffrey W Leong ◽  
Rizwan Romee ◽  
Todd A. Fehniger
Keyword(s):  
Flow Cytometry ◽  
Nk Cells ◽  
Low Dose ◽  
Nk Cell ◽  
Surface Expression ◽  
Receptor Expression ◽  
Published Data ◽  
High Affinity ◽  
Cd25 Expression ◽  
Cytokine Activation

Abstract Abstract 2159 Introduction. NK cells are innate immune lymphocytes important for host defense against infection, and also mediate anti-tumor responses. NK cell effector functions are triggered by ligand-mediated engagement of activating receptors and by cytokine stimulation. Human NK cells may be divided into developmental and functional CD56bright and CD56dim subsets with distinct biology. Both NK subsets have constitutive expression of CD122 (IL-2/15Rβ) and CD132 (γc), allowing for responsiveness to IL-15 and high doses (1 nM) of IL-2. The high affinity heterotrimeric IL-2 receptor is formed by CD122, CD132, and CD25 (IL-2Rα), allowing for responses to very low (10 pM) concentrations of IL-2. Previous studies demonstrated that resting CD56bright, but not CD56dim, NK cells constitutively express a functional high-affinity IL-2Rαβγ, as picomolar concentrations of IL-2 result in proliferation and co-stimulate IFN-γ production. We hypothesized that cytokine activation, which occurs at the site of an inflammatory response or interaction with a priming dendritic cell, may induce the expression of CD25 on CD56dimNK cells, allowing for enhanced responsiveness to IL-2. Methods. Purified normal donor NK cells (>95% CD56+CD3-) were cultured for 16h in media containing various cytokines, including IL-15 (100ng/mL) + IL-18 (50ng/mL), IL-15 (100ng/mL) + IL-12 (10ng/mL) or low dose IL-15 (1ng/mL) as a control (to support survival). Following stimulation, cells were washed and analyzed for surface expression of CD25 by antibody staining and flow cytometry. To assess the functional capacity of an induced IL-2Rα chain, NK cells were purified and treated with cytokines as above, washed extensively and replated in media devoid of all cytokines. At 3d after initial stimulation, cultures were briefly (15min) stimulated with IL-2 (10pM, 100pM and 1nM) or IL-15 (100ng/mL) to induce phosphorylation of STAT5. Cells were immediately fixed, permeablized, and assessed for intracellular phosphoSTAT5 by flow cytometry. Results. Pretreatment with IL-15 + IL-18 or IL-12 + IL-18, but no single cytokine, induced marked upregulation of CD25 on both CD56bright as well as CD56dim NK cells, with 93.6 ±1.9% of CD56bright and 97.7 ±1.2% (n=4) of CD56dim NK cells positive for CD25 expression immediately following the initial 16h stimulation with IL-15+18, compared to 20.7 ±6.8 and 3.6 ±1.4% for control treated (low dose IL-15) CD56bright and CD56dim NK. In preliminary experiments, CD25 appears to be markedly upregulated at the mRNA level, following treatment with IL-15+18. While kinetic analyses revealed that the absolute surface receptor expression was maximal at time points early after stimulation, 75.8 ±4.1% of CD56bright and 84.9 ±5.7% (n=4) of CD56dimNK cells pretreated with IL-15+18 retained CD25 surface expression at 7d post-stimulation. Importantly, CD25 induced on both CD56dim and CD56bright NK cells resulted in a signaling-competent high affinity IL-2 receptor, as stimulation with low dose IL-2 at 3d following initial cytokine pre-activation revealed increased production of phosphoSTAT5, versus control treated NK cells. The greatest enhancement was noted in CD56dim NK cells, showing an 8-fold increase in responsiveness to low dose (10pM) IL-2 stimulation (48.2±7.9% pSTAT5+ in IL-15+18 pretreated cells vs. 5.8±2.4% in control treated cells, p<0.02). Cytokine-pretreated CD56bright NK cells demonstrated no enhancement in phosphoSTAT5 following stimulation with low dose IL-2 (10pM) (27.6 ±8.3% in IL-15+18 pretreated vs. 26.0 ±6.4% in control) at this time-point. However, these results are in agreement with published data, which describe expression of CD25 on resting CD56bright but not CD56dimNK cells. Conclusions. Here, we report the induction of CD25, and a signal-competent high-affinity component of the IL-2 receptor, on CD56dim human NK cells, following cytokine pre-activation. These results have implications for the function of both CD56bright and CD56dim NK cells in the context of inflammation and potential for cross-talk with IL-2-producing T cells during an adaptive immune response. In addition, since rhIL-2 is clinically available and used following NK cell adoptive transfer in leukemia patients, these data provides a rationale for low dose IL-2 following allogeneic NK cell pre-activation with combinations of IL-15, IL-12, and IL-18. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Role of Natural Killer Cells in Modulating Dendritic Cell Responses to Leishmania amazonensis Infection

2008 ◽  
Vol 76 (11) ◽  
pp. 5100-5109 ◽  
Author(s):  
Mayra X. Hernandez Sanabria ◽  
Diego A. Vargas-Inchaustegui ◽  
Lijun Xin ◽  
Lynn Soong
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
T Cell Activation ◽  
Cell Activation ◽  
Nk Cell ◽  
Parasitic Infection ◽  
Leishmania Amazonensis ◽  
Parasitic Infections ◽  
Cell Contact

ABSTRACT The importance of the interaction between natural killer (NK) cells and dendritic cells (DCs) in the expansion of antiviral and antitumor immune responses is well-documented; however, limited information on DC-NK cell interaction during parasitic infections is available. Given that some Leishmania parasites are known to prevent or suppress DC activation, we developed a DC-NK cell coculture system to examine the role of NK cells in modulating the functions of Leishmania-infected DCs. We found that the addition of freshly isolated, resting NK cells significantly promoted the activation of DCs that were preinfected with Leishmania amazonensis promastigotes and that these activated DCs, in turn, stimulated NK cell activation mostly via cell contact-dependent mechanisms. Notably, L. amazonensis amastigote infection failed to activate DCs, and this lack of DC activation could be partially reversed by the addition of preactivated NK (ANK) cells but not resting NK cells. Moreover, the adoptive transfer of ANK cells into L. amazonensis-infected mice markedly increased DC and T-cell activation and reduced tissue parasite loads at 1 and 3 weeks postinfection. These results suggest differential roles of DC-NK cell cross talk at different stages of Leishmania infection and provide new insight into the interplay of components of the innate immune system during parasitic infection.

scholarly journals Natural Killer Cells from Allergic Donors Are Defective in Their Response to CCL18 Chemokine

2021 ◽  
Vol 22 (8) ◽  
pp. 3879
Author(s):  
Latiffa Amniai ◽  
Coline Ple ◽  
Mathieu Barrier ◽  
Patricia de Nadai ◽  
Philippe Marquillies ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
G Protein ◽  
Transmembrane Domain ◽  
Nk Cell ◽  
Allergic Diseases ◽  
The Body ◽  
Dependent Manner ◽  
Effector Cells ◽  
Cell Functions

Natural killer (NK) cells were originally described as cytolytic effector cells, but since then have been recognized to possess regulatory functions on immune responses. Chemokines locate NK cells throughout the body in homeostatic and pathological conditions. They may also directly stimulate immune cells. CCL18 is a constitutive and inducible chemokine involved in allergic diseases. The aim of this study was to evaluate CCL18’s effect on NK cells from allergic and nonallergic donors in terms of both chemotactic and immune effects. Results showed that CCL18 was able to induce migration of NK cells from nonallergic donors in a G-protein-dependent manner, suggesting the involvement of a classical chemokine receptor from the family of seven-transmembrane domain G-protein-coupled receptors. In contrast, NK cells from allergic patients were unresponsive. Similarly, CCL18 was able to induce NK cell cytotoxicity only in nonallergic subjects. Purified NK cells did not express CCR8, one of the receptors described to be involved in CCL18 functions. Finally, the defect in CCL18 response by NK cells from allergic patients was unrelated to a defect in CCL18 binding to NK cells. Overall, our results suggest that some NK cell functions may be defective in allergic diseases.

scholarly journals Enhancing network activation in Natural Killer cells: Predictions from in silico modeling

2018 ◽  
Author(s):  
Sahak Z. Makaryan ◽  
Stacey D. Finley
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
In Silico ◽  
Intracellular Signaling ◽  
Cell Activation ◽  
Nk Cell ◽  
Mechanistic Model ◽  
Published Data ◽  
Cell Therapies ◽  
Network Activation

ABSTRACTNatural killer (NK) cells are part of the innate immune system and are capable of killing diseased cells. As a result, NK cells are being used for adoptive cell therapies for cancer patients. The activation of NK cell stimulatory receptors leads to a cascade of intracellular phosphorylation reactions, which activates key signaling species that facilitate the secretion of cytolytic molecules required for cell killing. Strategies that maximize the activation of such intracellular species can increase the likelihood of NK cell activation upon contact with a cancer cell, and thereby improve efficacy of NK cell-based therapies. However, due to the complexity of intracellular signaling, it is difficult to deduce a priori which strategies can enhance species activation. Therefore, we constructed a mechanistic model of the CD16, 2B4 and NKG2D signaling pathways in NK cells to simulate strategies that enhance signaling. The model predictions were fit to published data and validated with a separate dataset. Model simulations demonstrate strong network activation when the CD16 pathway is stimulated. The magnitude of species activation is most sensitive to the receptor concentration and the rate at which the receptor is deactivated. Co-stimulation of CD16 and NKG2D in silico required fewer ligands to achieve half-maximal activation than other combinations, suggesting co-stimulating these pathways is most effective in activating the species. We applied the model to predict the effects of perturbing the signaling network and found two strategies that can potently enhance network activation. When the availability of ligands is low, it is more influential to engineer NK cell receptors that are resistant to proteolytic cleavage. In contrast, for high ligand concentrations, inhibiting phosphatase activity leads to more activation. The work presented here establishes a framework for understanding the complex, nonlinear aspects of NK cell signaling and provides detailed strategies for enhancing NK cell activation.

scholarly journals IL-15Rα chaperones IL-15 to stable dendritic cell membrane complexes that activate NK cells via trans presentation

2008 ◽  
Vol 205 (5) ◽  
pp. 1213-1225 ◽  
Author(s):  
Erwan Mortier ◽  
Tammy Woo ◽  
Rommel Advincula ◽  
Sara Gozalo ◽  
Averil Ma
Keyword(s):  
Nk Cells ◽  
Biosynthetic Pathway ◽  
Cell Activation ◽  
Nk Cell ◽  
Cell Contact ◽  
Rapid Responses ◽  
Direct Cell ◽  
Membrane Bound

Natural killer (NK) cells are innate immune effectors that mediate rapid responses to viral antigens. Interleukin (IL)-15 and its high affinity IL-15 receptor, IL-15Rα, support NK cell homeostasis in resting animals via a novel trans presentation mechanism. To better understand how IL-15 and IL-15Rα support NK cell activation during immune responses, we have used sensitive assays for detecting native IL-15 and IL-15Rα proteins and developed an assay for detecting complexes of these proteins. We find that IL-15 and IL-15Rα are preassembled in complexes within the endoplasmic reticulum/Golgi of stimulated dendritic cells (DCs) before being released from cells. IL-15Rα is required for IL-15 production by DCs, and IL-15 that emerges onto the cell surface of matured DCs does not bind to neighboring cells expressing IL-15Rα. We also find that soluble IL-15–IL-15Rα complexes are induced during inflammation, but membrane-bound IL-15–IL-15Rα complexes, rather than soluble complexes, support NK cell activation in vitro and in vivo. Finally, we provide in vivo evidence that expression of IL-15Rα specifically on DCs is critical for trans presenting IL-15 and activating NK cells. These studies define an unprecedented cytokine–receptor biosynthetic pathway in which IL-15Rα serves as a chaperone for IL-15, after which membrane-bound IL-15Rα–IL-15 complexes activate NK cells via direct cell–cell contact.

scholarly journals Polysaccharide from Codium fragile Induces Anti-Cancer Immunity by Activating Natural Killer Cells

Marine Drugs ◽  
2020 ◽  
Vol 18 (12) ◽  
pp. 626
Author(s):  
Hae-Bin Park ◽  
Juyoung Hwang ◽  
Wei Zhang ◽  
Seulgi Go ◽  
Jihoe Kim ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Activation ◽  
Nk Cell ◽  
The Body ◽  
Cell Infiltration ◽  
Codium Fragile ◽  
Cancer Immunity ◽  
Anti Cancer ◽  
Ifn Γ

Natural polysaccharides exhibit beneficial immune modulatory effects, including immune stimulatory and anti-cancer activities. In this study, we examined the effect of Codium fragile polysaccharide (CFP) on natural killer (NK) cell activation, and its effect on tumor-bearing mice. Intravenous CFP treatment of C57BL/6 mice resulted in the upregulation of CD69, which is a marker associated with NK cell activation. In addition, intracellular levels of interferon (IFN)-γ and the cytotoxic mediators perforin and granzyme B were markedly increased in response to the CFP treatment of splenic NK cells. IFN-γ production by NK cells was directly induced by CFP, whereas the upregulation of CD69 and cytotoxic mediators required IL-12. Finally, intraperitoneal treatment with CFP prevented CT-26 (murine carcinoma) tumor cell infiltration in the lungs, without significantly reducing the body weight. In addition, treatment with CFP prevented B16 melanoma cell infiltration in the lung of C57BL/6 mice. Moreover, the anti-tumor effect was diminished by the depletion of NK cells. Therefore, these data suggest that CFP may be used as an NK cell stimulator to produce a phenomenon that contributes to anti-cancer immunity.

Natural killer cells and cancer therapy, what we know and where we are going

Immunotherapy ◽  
2019 ◽  
Vol 11 (14) ◽  
pp. 1231-1251 ◽  
Author(s):  
Faezeh Ghaemdoust ◽  
Mahsa Keshavarz-Fathi ◽  
Nima Rezaei
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
The Body ◽  
Innate Immune ◽  
Regulatory Function ◽  
Therapeutic Approaches ◽  
Cell Immunotherapy ◽  
And Function ◽  
Cancer Immunosurveillance

Natural killer (NK) cells are among the significant components of innate immune system and they have come to the first line of defense against tumor cells developing inside the body. CD56lo/CD16+NK cells are highly cytotoxic and CD56hi NK cells can produce cytokines and perform a regulatory function. Specific features of NK cells have made them a unique choice for cancer immunotherapy. Simple interventions like cytokine-injection to boost the internal NK cells were the first trials to target these cells. Nowadays, many other types of intervention are under investigation, such as adoptive NK cell immunotherapy. In this paper, we will discuss the biology and function of NK cells in cancer immunosurveillance and therapeutic approaches against cancer via using NK cells.

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