Cytokine-Mediated Activation of NK Cells during Viral Infection

ABSTRACTNatural killer (NK) cells provide a first line of defense against infection via the production of antiviral cytokines and direct lysis of target cells. Cytokines such as interleukin 12 (IL-12) and IL-18 are critical regulators of NK cell activation, but much remains to be learned about how cytokines interact to regulate NK cell function. Here, we have examined cytokine-mediated activation of NK cells during infection with two natural mouse pathogens, lymphocytic choriomeningitis virus (LCMV) and murine cytomegalovirus (MCMV). Using a systematic screen of 1,849 cytokine pairs, we identified the most potent combinations capable of eliciting gamma interferon (IFN-γ) production in NK cells. We observed that NK cell responses to cytokine stimulation were reduced 8 days after acute LCMV infection but recovered to preinfection levels by 60 days postinfection. In contrast, during MCMV infection, NK cell responses to cytokines remained robust at all time points examined. Ly49H-positive (Ly49H+) NK cells recognizing viral ligand m157 showed preferential proliferation during early MCMV infection. A population of these cells was still detected beyond 60 days postinfection, but these divided cells did not demonstrate enhanced IFN-γ production in response to innate cytokine stimulation. Instead, the maturation state of the NK cells (as determined by CD11b or CD27 surface phenotype) was predictive of responsiveness to cytokines, regardless of Ly49H expression. These results help define cytokine interactions that regulate NK cell activation and highlight variations in NK cell function during two unrelated viral infections.IMPORTANCENatural killer cells play an important role in immunity to many viral infections. From an initial screen of 1,849 cytokine pairs, we identified the most stimulatory cytokine combinations capable of inducing IFN-γ production by NK cells. Ly49H+NK cells, which can be directly activated by MCMV protein m157, preferentially proliferated during MCMV infection but did not show enhanced IFN-γ production following directex vivocytokine stimulation. Instead, mature CD11b+and/or CD27+NK cells responded similarly to innate cytokine stimulation regardless of Ly49H expression. Collectively, our data provide a better foundation for understanding cytokine-mediated NK cell activation during viral infection.

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Key features and homing properties of NK cells in the liver are shaped by activated iNKT cells

Scientific Reports ◽

10.1038/s41598-019-52666-9 ◽

2019 ◽

Vol 9 (1) ◽

Author(s):

Stephanie Trittel ◽

Benedict J. Chambers ◽

Ulrike Heise ◽

Carlos A. Guzmán ◽

Peggy Riese

Keyword(s):

Nk Cells ◽

Natural Killer ◽

Cell Activation ◽

Viral Infections ◽

Nk Cell ◽

Infection Model ◽

Inkt Cells ◽

Mcmv Infection ◽

Viral Loads

Abstract The contribution of natural killer (NK) cells to the clearance of hepatic viral infections is well recognized. The recently discovered heterogeneity of NK cell populations renders them interesting targets for immune interventions. Invariant natural killer T (iNKT) cells represent a key interaction partner for hepatic NK cells. The present study addressed whether characteristics of NK cells in the liver can be shaped by targeting iNKT cells. For this, the CD1d-binding pegylated glycolipid αGalCerMPEG was assessed for its ability to modulate the features of NK cells permanently or transiently residing in the liver. In vivo administration resulted in enhanced functionality of educated and highly differentiated CD27+ Mac-1+ NK cells accompanied by an increased proliferation. Improved liver homing was supported by serum-derived and cellular factors. Reduced viral loads in a mCMV infection model confirmed the beneficial effect of NK cells located in the liver upon stimulation with αGalCerMPEG. Thus, targeting iNKT cell-mediated NK cell activation in the liver represents a promising approach for the establishment of liver-directed immune interventions.

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Aberrant anti-viral response of natural killer cells in severe asthma

European Respiratory Journal ◽

10.1183/13993003.02422-2018 ◽

2020 ◽

Vol 55 (5) ◽

pp. 1802422

Author(s):

Justine Devulder ◽

Cécile Chenivesse ◽

Valérie Ledroit ◽

Stéphanie Fry ◽

Pierre-Emmanuel Lobert ◽

...

Keyword(s):

Nk Cells ◽

Natural Killer ◽

Severe Asthma ◽

Cell Activation ◽

Mononuclear Cells ◽

Nk Cell ◽

Peripheral Blood Mononuclear ◽

Healthy Donors ◽

Asthma Patients ◽

Ifn Γ

Rhinovirus infections are the main cause of asthma exacerbations. As natural killer (NK) cells are important actors of the antiviral innate response, we aimed at evaluating the functions of NK cells from severe asthma patients in response to rhinovirus-like molecules or rhinoviruses.Peripheral blood mononuclear cells from patients with severe asthma and healthy donors were stimulated with pathogen-like molecules or with the rhinoviruses (RV)-A9 and RV-2. NK cell activation, degranulation and interferon (IFN)-γ expression were analysed.NK cells from severe asthma patients were less cytotoxic than those from healthy donors in response to toll-like receptor (TLR)3, TLR7/8 or RV-A9 but not in response to RV-2 stimulation. Furthermore, when cultured with interleukin (IL)-12+IL-15, cytokines which are produced during viral infections, NK cells from patients with severe asthma were less cytotoxic and expressed less IFN-γ than NK cells from healthy donors. NK cells from severe asthmatics exhibited an exhausted phenotype, with an increased expression of the checkpoint molecule Tim-3.Together, our findings indicate that the activation of NK cells from patients with severe asthma may be insufficient during some but not all respiratory infections. The exhausted phenotype may participate in NK cell impairment and aggravation of viral-induced asthma exacerbation in these patients.

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Contribution of Natural Killer Cells to Inhibition of Angiogenesis by Interleukin-12

Blood ◽

10.1182/blood.v93.5.1612 ◽

1999 ◽

Vol 93 (5) ◽

pp. 1612-1621 ◽

Cited By ~ 127

Author(s):

Lei Yao ◽

Cecilia Sgadari ◽

Keizo Furuke ◽

Eda T. Bloom ◽

Julie Teruya-Feldstein ◽

...

Keyword(s):

Endothelial Cells ◽

Nk Cells ◽

Natural Killer ◽

Cell Function ◽

Nk Cell ◽

Primary Cultures ◽

Interleukin 12 ◽

Ifn Γ

Abstract Interleukin-12 (IL-12) inhibits angiogenesis in vivo by inducing interferon-γ (IFN-γ) and other downstream mediators. Here, we report that neutralization of natural killer (NK) cell function with antibodies to either asialo GM1 or NK 1.1 reversed IL-12 inhibition of basic fibroblast growth factor (bFGF)-induced angiogenesis in athymic mice. By immunohistochemistry, those sites where bFGF-induced neovascularization was inhibited by IL-12 displayed accumulation of NK cells and the presence of IP-10–positive cells. Based on expression of the cytolytic mediators perforin and granzyme B, the NK cells were locally activated. Experimental Burkitt lymphomas treated locally with IL-12 displayed tumor tissue necrosis, vascular damage, and NK-cell infiltration surrounding small vessels. After activation in vitro with IL-12, NK cells from nude mice became strongly cytotoxic for primary cultures of syngeneic aortic endothelial cells. Cytotoxicity was neutralized by antibodies to IFN-γ. These results document that NK cells are required mediators of angiogenesis inhibition by IL-12, and provide evidence that NK-cell cytotoxicity of endothelial cells is a potential mechanism by which IL-12 can suppress neovascularization.

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Natural-killer cells and dendritic cells: “l'union fait la force”

Blood ◽

10.1182/blood-2005-03-1154 ◽

2005 ◽

Vol 106 (7) ◽

pp. 2252-2258 ◽

Cited By ~ 386

Author(s):

Thierry Walzer ◽

Marc Dalod ◽

Scott H. Robbins ◽

Laurence Zitvogel ◽

Eric Vivier

Keyword(s):

Dendritic Cells ◽

Nk Cells ◽

Natural Killer ◽

Cell Activation ◽

Nk Cell ◽

Interleukin 12 ◽

Cell Contact ◽

Ifn Γ

AbstractSeveral recent publications have focused on the newly described interactions between natural-killer (NK) cells and dendritic cells (DCs). Activated NK cells induce DC maturation either directly or in synergy with suboptimal levels of microbial signals. Immature DCs appear susceptible to autologous NK-cell-mediated cytolysis while mature DCs are protected. NK-cell-induced DC activation is dependent on both tumor necrosis factor-α (TNF-α)/interferon-γ (IFN-γ) secretion and a cell-cell contact involving NKp30. In vitro, interleukin-12 (IL-12)/IL-18, IL-15, and IFN-α/β production by activated DCs enhance, in turn, NK-cell IFN-γ production, proliferation, and cytotoxic potential, respectively. In vivo, NK-cell/DC interactions may occur in lymphoid organs as well as in nonlymphoid tissues, and their consequences are multiple. By inducing DC activation, NK-cell activation induced by tumor cells can indirectly promote antitumoral T-cell responses. Reciprocally, DCs activated through Toll-like receptors (TLRs) induce potent NK-cell activation in antiviral responses. Thus, DCs and NK cells are equipped with complementary sets of receptors that allow the recognition of various pathogenic agents, emphasizing the role of NK-cell/DC crosstalk in the coordination of innate and adaptive immune responses.

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Tim-3, a Novel Immune Receptor, Is Constitutively Expressed on Human Natural Killer Cells and Functions as An Activating Coreceptor

Blood ◽

10.1182/blood.v116.21.106.106 ◽

2010 ◽

Vol 116 (21) ◽

pp. 106-106

Author(s):

Michelle Gleason ◽

Todd Lenvik ◽

Valarie McCullar ◽

Sarah Cooley ◽

Michael Verneris ◽

...

Keyword(s):

Nk Cells ◽

Board Of Directors ◽

Cell Activation ◽

Low Dose ◽

Cell Function ◽

Nk Cell ◽

Effector Function ◽

Advisory Committees ◽

Immune Receptor ◽

Ifn Γ

Abstract Abstract 106 NK cells are an attractive option for immunotherapy as they do not require pre-sensitization for anti-tumor activity and do not induce graft versus host disease (GvHD) in an allogeneic transplant setting. The potential of NK cells in controlling human hematological malignancies has been increasingly recognized in recent years, as the adoptive transfer of alloreactive NK cells in hematopoietic cell transplantation (HCT) clinical trials have demonstrated therapeutic anti-leukemia effects. NK cell function is regulated by the integration of antagonist signals received from cell surface activating and inhibitory receptors. Tim-3 is a novel immune receptor that is a member of the T cell immunoglobulin and mucin-containing domain (TIM) family of glycoproteins. While its role in T cells and antigen presenting cells has been described, little is known about its function in human NK cells. While Tim-3 is present on a variety of immune cells, resting NK cells constitutively express Tim-3 compared to other lymphocyte populations (NK: 73±3%; NKT: 6±1%; T: 1±1%; n=14) and we hypothesized that Tim-3 may be important in mediating NK cell function. The unique subset of cytokine producing CD56Bright NK cells exhibited significantly lower resting Tim-3 expression compared to CD56Dim NK cells (53±3% vs. 75±3%; p<0.001, n=14). Distinct Tim-3 expression patterns were found on resting CD56Dim NK cells and activation with low dose IL-12 (1ng/mL) and IL-18 (10ng/mL), intended to more closely mimic physiologic conditions, resulted in further differentiation of this unique expression pattern dividing NK cells into 4 distinct populations: Tim-3 was homogeneously up-regulated on all CD56Bright NK cells after activation while CD56Dim NK cells were further stratified into 3 defined populations with Tim-3hi, Tim-3lo and Tim-3neg expression. The only identified ligand of Tim-3 is galectin-9 (Gal-9), a β-galactoside binding lectin, which is expressed on a wide range of healthy and malignant cells. To investigate the potential function of Tim-3, an expression vector containing human Gal-9 was transduced into K562 and Raji cells, both without endogenous Gal-9 expression. Resting NK cytotoxicity (51Cr release) was found to be increased in the presence of Gal-9 compared to the non-Gal-9 expressing targets [E:T=0.7:1, K562 vs. K562-Gal-9: 25±3% vs. 33±3% (n=8, p<0.05); E:T=20:1, Raji vs. Raji-Gal-9: 8±1% vs. 17±2% (n=4, p<0.05)]. Analysis of CD107a degranulation showed that resting Tim-3+ CD56Bright cells were more functional against Gal-9 expressing targets than Tim-3− CD56Bright cells, suggesting that Tim-3 might also play a role in IFN-γ production. To further investigate this, resting NK cells were activated with low-dose IL-12/IL-18 overnight and IFN-γ levels were measured in response to soluble rhGal-9 (0, 2.5, 5, 10 and 20nM). Exposure to soluble rhGal-9 alone without IL-12/IL-18 did not induce IFN-γ production. For both the CD56Bright and CD56Dim IL-12/IL-18 activated NK populations, only Tim-3+ NK cells displayed a dose dependent increase in IFN-γ production upon exposure to soluble rhGal-9 compared to Tim-3− NK cells. To understand the relevance of the distinct Tim-3 populations circulating in resting blood, CD56Bright, CD56Dim/Tim-3hi, CD56Dim/Tim-3lo and CD56Dim/Tim-3neg populations were sorted, cultured overnight in IL-12/IL-18 and exposed to soluble rhGal-9. Results showed the Tim-3 expressing populations contain the predominant IFN-γ producing cells that were responsive to rhGal-9 (results for the sorted CD56Dim/Tim-3lo population shown in the figure below). This increase in IFN-γ production within the Tim-3 expressing NK cell populations was abrogated by the addition of β-lactose, a β-galactoside that binds and blocks Gal-9 activity. Lastly, Western blot and immunohistochemistry analysis of human primary acute leukemia blasts revealed high Gal-9 expression. As the presence of ligands for NK cell activating receptors on tumors provide an important prerequisite for NK cell activation and effector function, we show a novel functional role for the receptor Tim-3 in human NK cell biology in the presence of its ligand Gal-9. We, therefore, propose a model where constitutively expressed Tim-3 is up-regulated by NK cell activation and effector function is enhanced by Tim-3/Gal-9 interaction, which may potentiate the elimination of Gal-9 positive tumors by NK cells. Disclosures: Niki: GalPharma: Membership on an entity's Board of Directors or advisory committees. Hirashima:GalPharma: Membership on an entity's Board of Directors or advisory committees.

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AFM13 Is the Most Advanced Bispecific NK-Cell Engaging Antibody in Clinical Development Substantially Enhancing NK-Cell Effector Function and Proliferation

Blood ◽

10.1182/blood.v128.22.1764.1764 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1764-1764 ◽

Cited By ~ 1

Author(s):

Jens Pahl ◽

Uwe Reusch ◽

Thorsten Gantke ◽

Anne Kerber ◽

Joachim Koch ◽

...

Keyword(s):

Nk Cells ◽

Cell Activation ◽

Nk Cell ◽

Target Cells ◽

Cell Cytotoxicity ◽

Cell Receptors ◽

Cell Responses ◽

Nk Cell Receptors ◽

Ifn Γ ◽

Nk Cell Cytotoxicity

Abstract Introduction: AFM13 is an NK-cell engaging CD30/CD16A bispecific tetravalent TandAb antibody currently in phase 2 clinical development in Hodgkin lymphoma (HL) and other CD30+ malignancies. It engages NK-cells through CD16A with high affinity and specificity and confers significantly stronger NK-cell activation compared to other therapeutic antibodies. We have previously shown synergistic efficacy when NK-cell activation by AFM13 is combined with check-point modulation such as anti-PD-1 treatment, which is known to unleash T cell and NK-cell activity. The goal of this study was to identify further candidates for combination treatments and biomarkers that potentially indicate NK-cell responses to AFM13 treatment. Methods: AFM13-mediated NK-cell cytotoxicity and IFN-γ production after 4-hour interaction with HL cell lines was measured by 51Cr release assays and flow cytometry, respectively. Expression of NK-cell receptors, NK-cell proliferation (CFSE dilution) and expansion (absolute cell counts) was analyzed by flow cytometry. Results: The interaction of NK-cells with AFM13-coated tumor cells up-regulated the expression of NK-cell receptors such as CD25, CD69, CD137/4-1BB as well as molecules that may serve as NK-cell check-points when compared with the unrelated NK-cell binding TandAb AFM12 that does not bind to target cells. Importantly, CD16A engagement by AFM13 enhanced the proliferation and expansion potential of NK-cells when subsequently incubated with IL-15 or with particularly low doses of IL-2. NK-cell cytotoxicity and IFN-γ production was substantially increased towards CD30+ tumor cells in the presence of AFM13. Even target cells resistant to naïve and IL-2/IL-15-activated NK-cells were susceptible to AFM13-induced NK-cell cytotoxicity. AFM13 concentrations of as low as 10-2 µg/mL resulted in maximal activity while AFM13 was significantly more potent than native anti-CD30 IgG1 antibody. NK-cell activation by IL-2 or IL-15 had a synergistic effect on AFM13-mediated cytotoxicity. Conclusion: AFM13 specifically enhances the cytotoxic, proliferative and cytokine-producing potential of NK-cells. Our data indicate that the distinctive modulation of NK-cell receptors can be utilized to monitor NK-cell responses during AFM13 therapy and provides candidates for therapeutic combination strategies. Moreover, the combination with low doses of IL-2 or with IL-15 may expand the quantity of tumor-reactive NK-cells after AFM13 treatment and promote NK-cell functionality in the tumor microenvironment in cancer patients. Disclosures Reusch: Affimed: Employment, Patents & Royalties: Patents. Gantke:Affimed GmbH: Employment. Kerber:Affimed: Employment. Koch:Affimed: Employment. Treder:Affimed: Employment. Cerwenka:Affimed: Research Funding.

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Mononuclear myeloid-derived “suppressor” cells express RAE-1 and activate natural killer cells

Blood ◽

10.1182/blood-2008-03-143776 ◽

2008 ◽

Vol 112 (10) ◽

pp. 4080-4089 ◽

Cited By ~ 99

Author(s):

Norman Nausch ◽

Ioanna E. Galani ◽

Eva Schlecker ◽

Adelheid Cerwenka

Keyword(s):

Nk Cells ◽

Natural Killer ◽

T Cell Activation ◽

Cell Activation ◽

Cell Function ◽

Nk Cell ◽

Suppressor Cells ◽

Myeloid Derived Suppressor Cells ◽

Tumor Bearing

Abstract Myeloid-derived suppressor cells (MDSCs) accumulate in cancer patients and tumor-bearing mice and potently suppress T-cell activation. In this study, we investigated whether MDSCs regu-late natural killer (NK)–cell function. We discovered that mononuclear Gr-1+CD11b+F4/80+ MDSCs isolated from RMA-S tumor-bearing mice do not suppress, but activate NK cells to produce high amounts of IFN-γ. Gr-1+CD11b+F4/80+ MDSCs isolated from tumor-bearing mice, but not myeloid cells from naive mice, expressed the ligand for the activating receptor NKG2D, RAE-1. NK-cell activation by MDSCs depended partially on the interaction of NKG2D on NK cells with RAE-1 on MDSCs. NK cells eliminated Gr-1+CD11b+F4/80+ MDSCs in vitro and upon adoptive transfer in vivo. Finally, depletion of Gr-1+ cells that comprise MDSCs confirmed their protective role against the NK-sensitive RMA-S lymphoma in vivo. Our study reveals that MDSCs do not suppress all aspects of antitumor immune responses and defines a novel, unexpected activating role of MDSCs on NK cells. Thus, our results have great impact on the design of immune therapies against cancer aiming at the manipulation of MDSCs.

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DC-like cell-dependent activation of human natural killer cells by the bisphosphonate zoledronic acid is regulated by γδ T lymphocytes

Blood ◽

10.1182/blood-2011-01-328526 ◽

2011 ◽

Vol 118 (10) ◽

pp. 2743-2751 ◽

Cited By ~ 53

Author(s):

Oliver Nussbaumer ◽

Georg Gruenbacher ◽

Hubert Gander ◽

Martin Thurnher

Keyword(s):

T Cell ◽

Zoledronic Acid ◽

T Lymphocytes ◽

Nk Cells ◽

Natural Killer ◽

Cell Activation ◽

Nk Cell ◽

Γδ T Cell ◽

Caspase 1 ◽

Ifn Γ

Abstract Bisphosphonates are mainly used for the inhibition of osteoclast-mediated bone resorption but also have been shown to induce γδ T-cell activation. Using IL-2–primed cultures of CD56+ peripheral blood mononuclear cells, we show here that zoledronic acid (zoledronate) could induce IFN-γ production not only in γδ T lymphocytes but, surprisingly, also in natural killer (NK) cells in a manner that depended on antigen-presenting cells, which share properties of inflammatory monocytes and dendritic cells (DCs; here referred to as DC-like cells). In the presence of γδ T lymphocytes, DC-like cells were rapidly eliminated, and NK cell IFN-γ production was silenced. Conversely, in the absence of γδ T lymphocytes, DC-like cells were spared, allowing NK cell IFN-γ production to proceed. γδ T cell–independent NK cell activation in response to zoledronate was because of downstream depletion of endogenous prenyl pyrophosphates and subsequent caspase-1 activation in DC-like cells, which then provide mature IL-18 and IL-1β for the activation of IL-2–primed NK cells. Pharmacologic inhibition of caspase-1 almost abolished IFN-γ production in NK cells and γδ T lymphocytes, indicating that caspase-1–mediated cytokine maturation is the crucial mechanism underlying innate lymphocyte activation in response to zoledronate.

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Sars-Cov-2 Spike 1 protein control Natural killer cells activation via HLA-E/NKG2A pathway.

10.21203/rs.3.rs-31860/v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Daria Bortolotti ◽

Valentina Gentili ◽

Sabrina Rizzo ◽

Antonella Rotola ◽

Roberta Rizzo

Keyword(s):

Epithelial Cells ◽

Nk Cells ◽

Natural Killer ◽

Cell Activation ◽

Viral Infections ◽

Nk Cell ◽

Lung Epithelial Cells ◽

Lung Epithelial ◽

Spike Proteins

Abstract Natural killer (NK) cells are important in the control of viral infections. However, the role of NK cells during Sars-Cov-2 infection has previously not been identified. Peripheral blood NK cells from Sars-Cov and Sars-Cov-2 naïve subjects were evaluated for their activation, degranulation, interferon-gamma expression in the presence of Sars-Cov and Sars-Cov-2 spike proteins. K562 and lung epithelial cells were transfected with spike proteins and co-cultured with NK cells. The analysis was performed by flow cytometry and immune-fluorescence. Sars-Cov and Sars-Cov-2 spike proteins did not alter NK cell activation in K562 in vitro model. On the contrary, Sars-Cov-2 spike 1 protein (SP1) intracellular expression by lung epithelial cells resulted in NK cell reduced degranulation. Further experiments revealed a concomitant induction of HLA-E expression on the surface of lung epithelial cells and the recognition of a SP1-derived HLA-E-binding peptide. Simultaneously, there was the up-modulation of the inhibitory receptor NKG2A/CD94 on NK cells when SP1 is expressed in lung epithelial cells. We ruled out GATA3 transcription factor as responsible for HLA-E increased levels and HLA-E/NKG2A interaction as implicate in NK cells exhaustion. We show for the first time that NK cells are affected by SP1 expression in lung epithelial cells via HLA-E/NKG2A interaction. The resulting NK cells exhaustion might contribute to immunopathogenesis in Sars-Cov-2 infection.

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Ascophyllan Induces Activation of Natural Killer Cells in Mice In Vivo and In Vitro

Marine Drugs ◽

10.3390/md17040197 ◽

2019 ◽

Vol 17 (4) ◽

pp. 197 ◽

Cited By ~ 5

Author(s):

Wei Zhang ◽

Takasi Okimura ◽

Tatsuya Oda ◽

Jun-O Jin

Keyword(s):

Nk Cells ◽

Natural Killer ◽

Cell Activation ◽

Nk Cell ◽

Promote Cell Proliferation ◽

Ifn Γ ◽

Human And Mouse ◽

Marine Polysaccharide

Natural marine polysaccharides have demonstrated immune stimulatory effects in both mice and humans. Our previous study compared the ability of ascophyllan and fucoidan to activate human and mouse dendritic cells (DCs). In this study, we further examined the effect of ascophyllan on the activation of mouse natural killer (NK) cells in vivo and in vitro and compared it to that of fucoidan, a well-studied natural marine polysaccharide. Specifically, administration of ascophyllan to C57BL/6 mice increased the number of NK cells in the spleen when compared to the number in PBS-treated mice. Moreover, the number of IFN-γ-producing NK cells and expression of CD69 were markedly upregulated by ascophyllan treatment. Ascophyllan treatment also induced IFN-γ production and CD69 upregulation in isolated NK cells, but did not promote cell proliferation. Finally, ascophyllan treatment increased the cytotoxicity of NK cells against Yac-1 cells. The effects of ascophyllan on NK cell activation were considerably stronger than those of fucoidan. These data demonstrated that ascophyllan promotes NK cell activation both in mice and in vitro, and its stimulatory effect on NK cells is stronger than that of fucoidan.

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