scholarly journals A Contribution of Mouse Dendritic Cell–Derived IL-2 for NK Cell Activation

2004 ◽  
Vol 200 (3) ◽  
pp. 287-295 ◽  
Author(s):  
Francesca Granucci ◽  
Ivan Zanoni ◽  
Norman Pavelka ◽  
Serani L.H. van Dommelen ◽  
Christopher E. Andoniou ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Nk Cell ◽  
Type I Interferons ◽  
Efficient Production ◽  
Type I ◽  
New Information

Dendritic cells (DCs) play a predominant role in activation of natural killer (NK) cells that exert their functions against pathogen-infected and tumor cells. Here, we used a murine model to investigate the molecular mechanisms responsible for this process. Two soluble molecules produced by bacterially activated myeloid DCs are required for optimal priming of NK cells. Type I interferons (IFNs) promote the cytotoxic functions of NK cells. IL-2 is necessary both in vitro and in vivo for the efficient production of IFNγ, which has an important antimetastatic and antibacterial function. These findings provide new information about the mechanisms that mediate DC–NK cell interactions and define a novel and fundamental role for IL-2 in innate immunity.

scholarly journals P03.24 Calreticulin exposure on malignant blasts correlates with improved NK cell-mediated cytotoxicity in AML patients

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A32.1-A32
Author(s):  
I Truxova ◽  
L Kasikova ◽  
C Salek ◽  
M Hensler ◽  
D Lysak ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
Type I ◽  
Danger Signals ◽  
Hla Dr ◽  
Patient Prognosis ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

In some settings, cancer cells responding to treatment undergo an immunogenic form of cell death that is associated with the abundant emission of danger signals in the form of damage-associated molecular patterns. Accumulating preclinical and clinical evidence indicates that danger signals play a crucial role in the (re-)activation of antitumor immune responses in vivo, thus having a major impact on patient prognosis. We have previously demonstrated that the presence of calreticulin on the surface of malignant blasts is a positive prognostic biomarker for patients with acute myeloid leukemia (AML). Calreticulin exposure not only correlated with enhanced T-cell-dependent antitumor immunity in this setting but also affected the number of circulating natural killer (NK) cells upon restoration of normal hematopoiesis. Here, we report that calreticulin exposure on malignant blasts is associated with enhanced NK cell cytotoxic and secretory functions, both in AML patients and in vivo in mice. The ability of calreticulin to stimulate NK-cells relies on CD11c+CD14high cells that, upon exposure to CRT, express higher levels of IL-15Rα, maturation markers (CD86 and HLA- DR) and CCR7. CRT exposure on malignant blasts also correlates with the upregulation of genes coding for type I interferon. This suggests that CD11c+CD14high cells have increased capacity to migrate to secondary lymphoid organs, where can efficiently deliver stimulatory signals (IL-15Rα/IL- 15) to NK cells. These findings delineate a multipronged, clinically relevant mechanism whereby surface-exposed calreticulin favors NK-cell activation in AML patients.Disclosure InformationI. Truxova: None. L. Kasikova: None. C. Salek: None. M. Hensler: None. D. Lysak: None. P. Holicek: None. P. Bilkova: None. M. Holubova: None. X. Chen: None. R. Mikyskova: None. M. Reinis: None. M. Kovar: None. B. Tomalova: None. J.P. Kline: None. L. Galluzzi: None. R. Spisek: None. J. Fucikova: None.

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

Blood ◽  
2005 ◽  
Vol 106 (7) ◽  
pp. 2252-2258 ◽  
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.

scholarly journals Type I Interferon-mediated Stimulation of T Cells by CpG DNA

1998 ◽  
Vol 188 (12) ◽  
pp. 2335-2342 ◽  
Author(s):  
Siquan Sun ◽  
Xiaohong Zhang ◽  
David F. Tough ◽  
Jonathan Sprent
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Type I Interferons ◽  
Type I ◽  
Cpg Dna ◽  
Stimulation Of

Immunostimulatory DNA and oligodeoxynucleotides containing unmethylated CpG motifs (CpG DNA) are strongly stimulatory for B cells and antigen-presenting cells (APCs). We report here that, as manifested by CD69 and B7-2 upregulation, CpG DNA also induces partial activation of T cells, including naive-phenotype T cells, both in vivo and in vitro. Under in vitro conditions, CpG DNA caused activation of T cells in spleen cell suspensions but failed to stimulate highly purified T cells unless these cells were supplemented with APCs. Three lines of evidence suggested that APC-dependent stimulation of T cells by CpG DNA was mediated by type I interferons (IFN-I). First, T cell activation by CpG DNA was undetectable in IFN-IR−/− mice. Second, in contrast to normal T cells, the failure of purified IFN-IR−/− T cells to respond to CpG DNA could not be overcome by adding normal IFN-IR+ APCs. Third, IFN-I (but not IFN-γ) caused the same pattern of partial T cell activation as CpG DNA. Significantly, T cell activation by IFN-I was APC independent. Thus, CpG DNA appeared to stimulate T cells by inducing APCs to synthesize IFN-I, which then acted directly on T cells via IFN-IR. Functional studies suggested that activation of T cells by IFN-I was inhibitory. Thus, exposing normal (but not IFN-IR−/−) T cells to CpG DNA in vivo led to reduced T proliferative responses after TCR ligation in vitro.

scholarly journals Pro-apoptotic caspase deficiency reveals a cell-extrinsic mechanism of NK cell regulation

2021 ◽  
Author(s):  
Tayla M. Olsen ◽  
Wei Hong Tan ◽  
Arne C. Knudsen ◽  
Anthony Rongvaux
Keyword(s):  
Cell Death ◽  
Nk Cells ◽  
Nk Cell ◽  
Apoptotic Cell ◽  
Type I ◽  
Dependent Manner ◽  
Apoptosis Pathway ◽  
A Cell

AbstractRegulated cell death is essential for the maintenance of cellular and tissue homeostasis. In the hematopoietic system, genetic defects in apoptotic cell death generally produce the accumulation of immune cells, inflammation and autoimmunity. In contrast, we found that genetic deletion of caspases of the mitochondrial apoptosis pathway reduces natural killer (NK) cell numbers and makes NK cells functionally defective in vivo and in vitro. Caspase deficiency results in constitutive activation of a type I interferon (IFN) response, due to leakage of mitochondrial DNA and activation of the cGAS/STING pathway. The NK cell defect in caspase-deficient mice is independent of the type I IFN response, but the phenotype is partially rescued by cGAS or STING deficiency. Finally, caspase deficiency alters NK cells in a cell-extrinsic manner. Type I IFNs and NK cells are two essential effectors of antiviral immunity, and our results demonstrate that they are both regulated in a caspase-dependent manner. Beyond caspase-deficient animals, our observations may have implications in infections that trigger mitochondrial stress and caspase-dependent cell death.

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

Marine Drugs ◽  
2019 ◽  
Vol 17 (4) ◽  
pp. 197 ◽  
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.

Abstract 49: Over-activation Of Natural Killer Cells Due To Dysfunction Of Cd16-mediated Signaling In Adamts13-deficient Ttp Patients With A History Of Relapse

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
FANG ZHOU ◽  
Darise Farris
Keyword(s):  
Nk Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
K562 Cells ◽  
Antibody Treatment ◽  
History Of ◽  
Relapse Group

Thrombotic thrombocytopenic purpura (TTP) is a rare life-threaten vascular autoimmune disease. There is no effective method to treat it in clinical trials since pathogenesis of TTP has not been fully elucidated. Here we investigate the role of NK cells in relapse development of TTP. Our results showed that the frequencies of CD3 − CD56 dim CD16 − and CD3 − CD56 bri CD16 − NK cells are increased in TTP patients with a history of relapse. Expression of CD107a, granzyme A and IFN-γ by CD3 − CD56 dim NK cells following in vitro stimulation with PMA/ionomycin / monensin is improved in the relapse group, compared with those on NK cells derived from TTP patients without relapse development. NK cells isolated from TTP patients with a history of relapse indicated stronger cytotoxicity to target K562 cells than those of NK cells derived from TTP patients without relapse development, suggesting prior activation of NK cells in vivo . Treatment with anti-human CD16 antibody up-regulates cytotoxicity of NK cells derived from TTP patients without relapse development. However, Anti-human CD16 antibody treatment does not affect cytotoxicity of NK cells isolated from TTP patients with a history of relapse, suggesting inability of CD16-mediated signaling in NK cells derived from TTP patients with relapse development. These data provide evidence of altered NK cell activation and/or licensing in TTP patients with a history of relapse modulated by CD16-mediated signaling and a new avenue of investigation into mechanisms of TTP immunopathogenesis.

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 Activation of ADAM17 by IL-15 Limits Human NK Cell Proliferation

2021 ◽  
Vol 12 ◽  
Author(s):  
Hemant K. Mishra ◽  
Kate J. Dixon ◽  
Nabendu Pore ◽  
Martin Felices ◽  
Jeffrey S. Miller ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Nk Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
Feedback System ◽  
Cytotoxic Lymphocytes ◽  
Cell Therapies ◽  
Surface Receptors

Natural killer (NK) cells are innate cytotoxic lymphocytes that can recognize assorted determinants on tumor cells and rapidly kill these cells. Due to their anti-tumor effector functions and potential for allogeneic use, various NK cell platforms are being examined for adoptive cell therapies. However, their limited in vivo persistence is a current challenge. Cytokine-mediated activation of these cells is under extensive investigation and interleukin-15 (IL-15) is a particular focus since it drives their activation and proliferation. IL-15 efficacy though is limited in part by its induction of regulatory checkpoints. A disintegrin and metalloproteinase-17 (ADAM17) is broadly expressed by leukocytes, including NK cells, and it plays a central role in cleaving cell surface receptors, a process that regulates cell activation and cell-cell interactions. We report that ADAM17 blockade with a monoclonal antibody markedly increased human NK cell proliferation by IL-15 both in vitro and in a xenograft mouse model. Blocking ADAM17 resulted in a significant increase in surface levels of the homing receptor CD62L on proliferating NK cells. We show that NK cell proliferation in vivo by IL-15 and the augmentation of this process upon blocking ADAM17 are dependent on CD62L. Hence, our findings reveal for the first time that ADAM17 activation in NK cells by IL-15 limits their proliferation, presumably functioning as a feedback system, and that its substrate CD62L has a key role in this process in vivo. ADAM17 blockade in combination with IL-15 may provide a new approach to improve NK cell persistence and function in cancer patients.

scholarly journals Viral infection modulates Qa-1b in infected and bystander cells to properly direct NK cell killing

2021 ◽  
Vol 218 (5) ◽  
Author(s):  
Maria Ferez ◽  
Cory J. Knudson ◽  
Avital Lev ◽  
Eric B. Wong ◽  
Pedro Alves-Peixoto ◽  
...  
Keyword(s):  
Viral Infection ◽  
Nk Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
Inhibitory Receptors ◽  
Inflammatory Monocytes ◽  
Activating Receptors ◽  
Infected Cells

Natural killer (NK) cell activation depends on the signaling balance of activating and inhibitory receptors. CD94 forms inhibitory receptors with NKG2A and activating receptors with NKG2E or NKG2C. We previously demonstrated that CD94-NKG2 on NK cells and its ligand Qa-1b are important for the resistance of C57BL/6 mice to lethal ectromelia virus (ECTV) infection. We now show that NKG2C or NKG2E deficiency does not increase susceptibility to lethal ECTV infection, but overexpression of Qa-1b in infected cells does. We also demonstrate that Qa-1b is down-regulated in infected and up-regulated in bystander inflammatory monocytes and B cells. Moreover, NK cells activated by ECTV infection kill Qa-1b–deficient cells in vitro and in vivo. Thus, during viral infection, recognition of Qa-1b by activating CD94/NKG2 receptors is not critical. Instead, the levels of Qa-1b expression are down-regulated in infected cells but increased in some bystander immune cells to respectively promote or inhibit their killing by activated NK cells.

Role of fractalkine (CX3CL1) rich neuroblastoma microenvironments for ganglioside GD2 directed immunotherapy

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 9521-9521
Author(s):  
H. N. Lode ◽  
Y. Zeng ◽  
S. Fest ◽  
G. Gaedicke
Keyword(s):  
T Cell ◽  
Nk Cells ◽  
Therapeutic Effect ◽  
Cell Activation ◽  
Nk Cell ◽  
Ganglioside Gd2 ◽  
Ifn Γ

9521 Background: Fractalkine (FKN) is a unique CX3C chemokine (CX3CL1) known to induce adhesion and migration of leukocytes mediated by a membrane-bound and a soluble form. Methods: We found that FKN is expressed in >90% of 68 neuroblastoma (NB) samples as determined by cDNA microarray analysis. FKN expression was inversely correlated with MYCN amplification, suggesting a higher expression of FKN in MYCN non amplified tumors. We characterized the effect of FKN in the neuroblastoma microenvironment in a mouse model. We demonstrate that FKN released from NB cells mediate migration and adhesion of CD4+-, CD8+- and NK- cells and subsequent secretion of IFN-γ, in vitro and in vivo. However, the presence of FKN in NB microenvironments did not result in significant anti-NB activity. Results: Targeting of IL-2 into the NB microenvironment using anti-ganglioside GD2 antibody cytokine fusion proteins (ch14.18-IL-2) is currently under clinical evaluation. We investigated a the role of FKN in this context. For this purpose, IL-2 was targeted to GD2 positive NB microenvironments secreting FKN. Only mice bearing FKN and IL2 enriched NB microenvironments exhibited a reduction in primary tumor growth and a complete eradication of experimental liver metastases, in contrast to controls with only FKN or IL-2 enriched NB. This effect was specific since a non-specific antibody-IL-2 fusion protein ch225-IL-2 was ineffective. The mechanisms involved included NK-cell activation by targeted IL-2 into FKN rich NB as indicated by the enhancement of NK-cell mediated lysis using YAC-1 cells as targeted cells. The depletion of NK cells in vivo inhibited the therapeutic effect. Furthermore, co-culture of NXS2-FKN cells and NK cells in vitro induced the expression of IFN-γ by NK cells. However, the depletion of CD8+ T-cells in vivo abrogated the therapeutic effect, and these effector cells showed the highest cytolytic activity against NXS2 target cells in vitro. Finally, only the FKN and IL-2 enriched NB microenvironment resulted in T-cell activation and the release of proinflammatory cytokines. Conclusions: In conclusion our data suggest that targeted IL-2 therapy of FKN rich NB associated with MYCN non-amplified tumors may result in T-cell mediated immune responses. No significant financial relationships to disclose.

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