scholarly journals Role of the NK Cell-Activating Receptor CRACC in Periodontitis

2012 ◽  
Vol 81 (3) ◽  
pp. 690-696 ◽  
Author(s):  
Benjamin Krämer ◽  
Moritz Kebschull ◽  
Michael Nowak ◽  
Ryan T. Demmer ◽  
Manuela Haupt ◽  
...  
Keyword(s):  
Nk Cells ◽  
Chronic Periodontitis ◽  
Cell Activation ◽  
Nk Cell ◽  
Aggressive Periodontitis ◽  
Interleukin 12 ◽  
Rapid Progression ◽  
Periodontal Tissue ◽  
Tissue Destruction ◽  
Content Type

ABSTRACTPeriodontitis is a highly prevalent, biofilm-mediated chronic inflammatory disease that results in the loss of the tooth-supporting tissues. It features two major clinical entities: chronic periodontitis, which is more common, and aggressive periodontitis, which usually has an early onset and a rapid progression. Natural killer (NK) cells are a distinct subgroup of lymphocytes that play a major role in the ability of the innate immune system to steer immune responses. NK cells are abundant in periodontitis lesions, and NK cell activation has been causally linked to periodontal tissue destruction. However, the exact mechanisms of their activation and their role in the pathophysiology of periodontitis are elusive. Here, we show that the predominant NK cell-activating molecule in periodontitis is CD2-like receptor activating cytotoxic cells (CRACC). We show that CRACC induction was significantly more pronounced in aggressive than chronic periodontitis and correlated positively with periodontal disease severity, subgingival levels of specific periodontal pathogens, and NK cell activationin vivo. We delineate howAggregatibacter actinomycetemcomitans, an oral pathogen that is causally associated with aggressive periodontitis, indirectly induces CRACC on NK cells via activation of dendritic cells and subsequent interleukin 12 (IL-12) signaling. In contrast, we demonstrate that fimbriae fromPorphyromonas gingivalis, a principal pathogen in chronic periodontitis, actively attenuate CRACC induction on NK cells. Our data suggest an involvement of CRACC-mediated NK cell activation in periodontal tissue destruction and point to a plausible distinction in the pathobiology of aggressive and chronic periodontitis that may help explain the accelerated tissue destruction in aggressive periodontitis.

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 Activation of Human NK Cells by Staphylococci and Lactobacilli Requires Cell Contact-Dependent Costimulation by Autologous Monocytes

2002 ◽  
Vol 9 (3) ◽  
pp. 649-657 ◽  
Author(s):  
D. Haller ◽  
P. Serrant ◽  
D. Granato ◽  
E. J. Schiffrin ◽  
S. Blum
Keyword(s):  
Nk Cells ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Nk Cell ◽  
Interleukin 12 ◽  
Accessory Cell ◽  
Cell Contact ◽  
Gram Positive ◽  
Gram Positive Bacteria ◽  
Ifn Γ

ABSTRACT NK cells are instrumental in innate immune responses, in particular for the early production of gamma interferon (IFN-γ) and other cytokines necessary to control certain bacterial, parasitic, and viral infections. NK cell-mediated effector functions are controlled by a fine balance between distinct receptors mediating activating and inhibitory signals; however, little is known about activating receptors on NK cells and their corresponding ligands. Several studies have shown that commensal lactobacilli isolated from the human gastrointestinal tract activate human mononuclear cells and are potent inducers of IFN-γ and monocyte-derived interleukin 12 (IL-12). NK cell activation was shown for Lactobacillus johnsonii La1. In this study the cellular mechanisms of in vitro NK cell activation by gram-positive bacteria were analyzed. Staphylococcus aureus- and L. johnsonii La1-mediated activation of CD3− CD16+ CD56+ human peripheral blood NK cells, including expression of the activation antigen CD69 and secretion of IFN-γ, required cell contact-dependent costimulation by autologous monocytes. S. aureus- and L. johnsonii-preactivated monocytes retained their capacity to induce NK cell activation. In contrast, cytokine-primed monocytes completely failed to induce NK cell activation unless bacteria were present. This suggests that phagocytosis of bacteria provided additional coactivation signals on accessory cells that may differ from those induced by tumor necrosis factor and IFN-γ. Blocking of costimulatory molecules by B7.1, B7.2, and IL-12 but not CD14 monoclonal antibodies inhibited S. aureus- and L. johnsonii-induced effector function of NK cells. Our data suggest an important role for accessory cell-derived signals in the process of NK cell activation by gram-positive bacteria.

scholarly journals Distinct and complementary functions of MDA5 and TLR3 in poly(I:C)-mediated activation of mouse NK cells

2009 ◽  
Vol 206 (13) ◽  
pp. 2967-2976 ◽  
Author(s):  
Stephen McCartney ◽  
William Vermi ◽  
Susan Gilfillan ◽  
Marina Cella ◽  
Theresa L. Murphy ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
Poly I:C ◽  
Interleukin 12 ◽  
Interferon Α ◽  
Accessory Cells ◽  
A Minor ◽  
Bone Marrow Chimeras

The double-stranded RNA (dsRNA) analogue poly(I:C) is a promising adjuvant for cancer vaccines because it activates both dendritic cells (DCs) and natural killer (NK) cells, concurrently promoting adaptive and innate anticancer responses. Poly(I:C) acts through two dsRNA sensors, Toll-like receptor 3 (TLR3) and melanoma differentiation-associated protein-5 (MDA5). Here, we investigated the relative contributions of MDA5 and TLR3 to poly(I:C)-mediated NK cell activation using MDA5−/−, TLR3−/−, and MDA5−/−TLR3−/− mice. MDA5 was crucial for NK cell activation, whereas TLR3 had a minor impact most evident in the absence of MDA5. MDA5 and TLR3 activated NK cells indirectly through accessory cells and induced the distinct stimulatory cytokines interferon-α and interleukin-12, respectively. To identify the relevant accessory cells in vivo, we generated bone marrow chimeras between either wild-type (WT) and MDA5−/− or WT and TLR3−/− mice. Interestingly, multiple accessory cells were implicated, with MDA5 acting primarily in stromal cells and TLR3 predominantly in hematopoietic cells. Furthermore, poly(I:C)-mediated NK cell activation was not notably impaired in mice lacking CD8α DCs, providing further evidence that poly(I:C) acts through diverse accessory cells rather than solely through DCs. These results demonstrate distinct yet complementary roles for MDA5 and TLR3 in poly(I:C)-mediated NK cell activation.

scholarly journals Variation in Adenovirus Transgene Expression between BALB/c and C57BL/6 Mice Is Associated with Differences in Interleukin-12 and Gamma Interferon Production and NK Cell Activation

2001 ◽  
Vol 75 (10) ◽  
pp. 4540-4550 ◽  
Author(s):  
YuFeng Peng ◽  
Erik Falck-Pedersen ◽  
Keith B. Elkon
Keyword(s):  
Nk Cells ◽  
Transgene Expression ◽  
Cell Activation ◽  
Cell Function ◽  
Nk Cell ◽  
Gamma Interferon ◽  
Innate Immune ◽  
Interleukin 12 ◽  
Mouse Strains ◽  
Innate Immune Responses

ABSTRACT The innate immune response against replication-defective adenoviruses (Ad) is poorly defined. We and others have previously observed striking differences in the rate at which the Ad vector itself or the virus encoding a variety of transgenes is eliminated in different mouse strains. Here, we report that Ad infection of BALB/ mice is associated with sixfold-higher levels of serum alanine aminotransferase and that Ad transgenes induce two- to threefold-higher levels of intrahepatic NK cells and NK activity compared to C57BL/6 mice. The increase in NK activation in BALB/c mice was associated with ∼4-fold higher level of mRNA expression of a newly described NKG2 receptor activator, H-60, as well as increased expression of interleukin-12 and gamma interferon mRNAs in BALB/c mice compared to C57BL/6 mice. NK depletion in BALB/c mice or defective NK function in C3H beige mice extended transgene expression compared to their appropriate controls, and attenuation of NK together with CD8 T-cell function had a synergistic effect. These findings indicate that there are intrinsic differences in the innate immune responses of different mouse strains to Ad and Ad transgenes and that NK cells, in cooperation with CD8 T cells, play a pivotal role in the early extinction of transgene expression in BALB/c mice.

Candida Species-Dependent Release of IL-12 by Dendritic Cells Induces Different Levels of NK Cell Stimulation

2020 ◽  
Vol 221 (12) ◽  
pp. 2060-2071 ◽  
Author(s):  
Alessandra Marolda ◽  
Kerstin Hünniger ◽  
Sarah Böttcher ◽  
Wolfgang Vivas ◽  
Jürgen Löffler ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Nk Cells ◽  
Human Blood ◽  
Candida Species ◽  
Cell Activation ◽  
Nk Cell ◽  
Ex Vivo ◽  
Death Receptor ◽  
Bloodstream Infections ◽  
Interleukin 12

Abstract Background Candida albicans and Candida glabrata are the 2 most prevalent Candida species causing bloodstream infections. Patterns of innate immune activation triggered by the 2 fungi differ considerably. Methods To analyze human natural killer (NK) cell activation by both species, we performed ex vivo whole-blood infection assays and confrontation assays with primary human NK cells. Results C. albicans was a stronger activator for isolated human NK cells than C. glabrata. In contrast, activation of blood NK cells, characterized by an upregulated surface exposure of early activation antigen CD69 and death receptor ligand TRAIL, as well as interferon-γ (IFN-γ) secretion, was more pronounced during C. glabrata infection. NK cell activation in blood is mediated by humoral mediators released by other immune cells and does not depend on direct activation by fungal cells. Cross-talk between Candida-confronted monocyte-derived dendritic cells (moDC) and NK cells resulted in the same NK activation phenotype as NK cells in human blood. Blocking experiments and cytokine substitution identified interleukin-12 as a critical mediator in regulation of primary NK cells by moDC. Conclusions Activation of human NK cells in response to Candida in human blood mainly occurs indirectly by mediators released from monocytic cells.

Abstract 57: Natural Killer Cells Drive Angiotensin II-Induced Vascular Dysfunction Dependent on the T-bet/IFN-gamma Axis

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Sabine Kossmann ◽  
Melanie Schwenk ◽  
Michael Hausding ◽  
Hanhan Hu ◽  
Maria I Schmidgen ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Activation ◽  
Vascular Tissue ◽  
Nk Cell ◽  
Vascular Dysfunction ◽  
Interleukin 12 ◽  
Monocyte Chemoattractant Protein 1 ◽  
Ifn Γ

Rationale Immune cells contribute to angiotensin II (ATII) induced vascular dysfunction and inflammation. However, the mechanisms of recruitment and immune effector pathways remain incompletely understood. Objective We tested the hypothesis that interferon-gamma (IFN-γ) and natural killer (NK) cells play a pivotal role in ATII-driven vascular inflammation. Methods and results IFN-γ -/- and Tbx21 -/- mice were partially protected from ATII-induced vascular endothelial and smooth muscle dysfunction, whereas mice overexpressing IFN-γ showed constitutive vascular dysfunction. Absence of T-bet, the IFN-γ transcription factor encoded by Tbx21, reduced vascular superoxide and peroxynitrite formation and attenuated expression of NADPH oxidase subunits as well as inducible NO synthase, monocyte chemoattractant protein 1 and interleukin 12 in aortas of ATII-infused mice. Compared to controls, IFN-γ -/- and Tbx21 -/- mice were characterized by reduced ATII-mediated vascular recruitment of both NK1.1 + NK-cells as the major producers of IFN-γ and CD11b + Gr-1 low IL-12 secreting monocytes. Selective depletion and adoptive transfer experiments identified NK-cells as essential contributors to vascular dysfunction and showed that T-bet + LysM + myelomonocytic cells were required for NK-cell recruitment into vascular tissue and local IFN-γ production. Conclusion We provide first evidence that NK-cells play an essential role in ATII-induced vascular dysfunction. In addition, we disclose the T-bet-IFN-γ pathway and mutual monocyte-NK-cell activation as potential therapeutic targets in cardiovascular disease.

NK cell activation by dendritic cells (DCs) requires the formation of a synapse leading to IL-12 polarization in DCs

Blood ◽  
2004 ◽  
Vol 104 (10) ◽  
pp. 3267-3275 ◽  
Author(s):  
Christophe Borg ◽  
Abdelali Jalil ◽  
Diego Laderach ◽  
Kouji Maruyama ◽  
Hiro Wakasugi ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Nk Cells ◽  
Neutralizing Antibodies ◽  
Cell Activation ◽  
Nk Cell ◽  
Critical Role ◽  
Interleukin 12 ◽  
Loss Of Function ◽  
Knock Out ◽  
Ifn Γ

Abstract Mature dendritic cells (mDCs) can trigger the effector functions of natural killer (NK) cells. Knock-out, small-interfering RNA or neutralizing antibodies targeting interleukin 12 (IL-12) subunits revealed a critical role for IL-12 in NK cell interferon γ (IFN-γ) secretion promoted by mDCs. However, NK cell activation by DCs also required direct cell-to-cell contacts. DC-mediated NK cell activation involved the formation of stimulatory synapses between DCs and NK cells. The formation of DC/NK cell conjugates depended on cytoskeleton remodeling and lipid raft mobilization in DCs. Moreover, the disruption of the DC cytoskeleton using pharmacologic agents or the loss-of-function mutation of the Wiskott-Aldrich syndrome protein abolished the DC-mediated NK cell activation. Synapse formation promoted the polarized secretion of preassembled stores of IL-12 by DCs toward the NK cell. The synaptic delivery of IL-12 by DCs was required for IFN-γ secretion by NK cells, as assessed using inhibitors of cytoskeleton rearrangements and transwell experiments. Therefore, the cross-talk between DCs and NK cells is dictated by functional synapses. (Blood. 2004;104:3267-3275)

scholarly journals Suppression of Staphylococcus aureus Superantigen-Independent Interferon Gamma Response by a Probiotic Polysaccharide

2020 ◽  
Vol 88 (4) ◽  
Author(s):  
Wonbeom Paik ◽  
Francis Alonzo ◽  
Katherine L. Knight
Keyword(s):  
Staphylococcus Aureus ◽  
Bloodstream Infection ◽  
Interferon Gamma ◽  
T Cell Activation ◽  
Cell Activation ◽  
Nk Cell ◽  
Interleukin 12 ◽  
Dependent Manner ◽  
Content Type ◽  
Ifn Γ

ABSTRACT Staphylococcus aureus is a Gram-positive opportunistic pathogen that causes a variety of diseases. Bloodstream infection is the most severe, with mortality rates reaching 20 to 50%. Exopolysaccharide (EPS) from the probiotic Bacillus subtilis reduces bacterial burden and inflammation during S. aureus bloodstream infection in mice. Protection is due, in part, to hybrid macrophages that restrict S. aureus growth through reactive oxygen species and to limiting superantigen-induced T cell activation and interferon gamma (IFN-γ) production during infection. A decrease in IFN-γ production was observed within 24 h after infection, and here, we investigated how EPS abrogates its production. We discovered that S. aureus uses a rapid, superantigen-independent mechanism to induce host IFN-γ and that this is mediated by interleukin-12 (IL-12) activation of NK cells. Furthermore, we found that EPS limits IFN-γ production by modulating host immunity in a Toll-like receptor 4 (TLR4)-dependent manner, a signaling pathway that is required for EPS-mediated protection from S. aureus infection in vivo. We conclude that EPS protects hosts from acute bloodstream S. aureus infection not only by inducing macrophages that restrict S. aureus growth and inhibit superantigen-activated T cells but also by limiting NK cell production of IFN-γ after S. aureus infection in a TLR4-dependent manner.

scholarly journals Regulation and Function of T-Cell-Mediated Immunity during Toxoplasma gondii Infection

1998 ◽  
Vol 11 (4) ◽  
pp. 569-588 ◽  
Author(s):  
Eric Y. Denkers ◽  
Ricardo T. Gazzinelli
Keyword(s):  
T Cell ◽  
Toxoplasma Gondii ◽  
Inflammatory Cytokine ◽  
Cell Activation ◽  
Nk Cell ◽  
Clinical Manifestations ◽  
Interleukin 12 ◽  
Cell Mediated Immunity ◽  
Tissue Destruction ◽  
Ifn Γ

SUMMARY The intracellular protozoan Toxoplasma gondii is a widespread opportunistic parasite of humans and animals. Normally, T. gondii establishes itself within brain and skeletal muscle tissues, persisting for the life of the host. Initiating and sustaining strong T-cell-mediated immunity is crucial in preventing the emergence of T. gondii as a serious pathogen. The parasite induces high levels of gamma interferon (IFN-γ) during initial infection as a result of early T-cell as well as natural killer (NK) cell activation. Induction of interleukin-12 by macrophages is a major mechanism driving early IFN-γ synthesis. The latter cytokine, in addition to promoting the differentiation of Th1 effectors, is important in macrophage activation and acquisition of microbicidal functions, such as nitric oxide release. During chronic infection, parasite-specific T lymphocytes release high levels of IFN-γ, which is required to prevent cyst reactivation. T-cell-mediated cytolytic activity against infected cells, while easily demonstrable, plays a secondary role to inflammatory cytokine production. While part of the clinical manifestations of toxoplasmosis results from direct tissue destruction by the parasite, inflammatory cytokine-mediated immunopathologic changes may also contribute to disease progression.

scholarly journals Optimizing the Procedure to Manufacture Clinical-Grade NK Cells for Adoptive Immunotherapy

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 577
Author(s):  
Adrián Fernández ◽  
Alfonso Navarro-Zapata ◽  
Adela Escudero ◽  
Nerea Matamala ◽  
Beatriz Ruz-Caracuel ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Nk Cell ◽  
Fold Increase ◽  
Clinical Grade ◽  
Transcriptome Profile ◽  
Expansion Process ◽  
Peripheral Blood Mononuclear ◽  
Activation Status

Natural killer (NK) cells represent promising tools for cancer immunotherapy. We report the optimization of an NK cell activation–expansion process and its validation on clinical-scale. Methods: RPMI-1640, stem cell growth medium (SCGM), NK MACS and TexMACS were used as culture mediums. Activated and expanded NK cells (NKAE) were obtained by coculturing total peripheral blood mononuclear cells (PBMC) or CD45RA+ cells with irradiated K562mbIL15-41BBL or K562mbIL21-41BBL. Fold increase, NK cell purity, activation status, cytotoxicity and transcriptome profile were analyzed. Clinical-grade NKAE cells were manufactured in CliniMACS Prodigy. Results: NK MACS and TexMACs achieved the highest NK cell purity and lowest T cell contamination. Obtaining NKAE cells from CD45RA+ cells was feasible although PBMC yielded higher total cell numbers and NK cell purity than CD45RA+ cells. The highest fold expansion and NK purity were achieved by using PBMC and K562mbIL21-41BBL cells. However, no differences in activation and cytotoxicity were found when using either NK cell source or activating cell line. Transcriptome profile showed to be different between basal NK cells and NKAE cells expanded with K562mbIL21-41BBL or K562mbIL15-41BBL. Clinical-grade manufactured NKAE cells complied with the specifications from the Spanish Regulatory Agency. Conclusions: GMP-grade NK cells for clinical use can be obtained by using different starting cells and aAPC.

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