scholarly journals Cytoskeletal stabilization of inhibitory interactions in immunologic synapses of mature human dendritic cells with natural killer cells

Blood ◽  
2011 ◽  
Vol 118 (25) ◽  
pp. 6487-6498 ◽  
Author(s):  
Rosa Barreira da Silva ◽  
Claudine Graf ◽  
Christian Münz
Keyword(s):  
Dendritic Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Actin Polymerization ◽  
Nk Cell ◽  
Cell Reactivity ◽  
Inhibitory Signaling ◽  
Leukocyte Populations ◽  
Human Dendritic Cells ◽  
Inhibitory Molecules

Abstract Human mature dendritic cells (DCs) can efficiently stimulate natural killer (NK)–cell responses without being targeted by their cytotoxicity. To understand this important regulatory crosstalk, we characterized the development of the immunologic synapse between mature DCs and resting NK cells. Conjugates between these 2 innate leukocyte populations formed rapidly, persisted for prolonged time periods and matured with DC-derived f-actin polymerization at the synapse. Polarization of IL-12 and IL-12R to the synapse coincided with f-actin polymerization, while other activating and inhibitory molecules were enriched at the interface between DCs and NK cells earlier. Functional assays revealed that inhibition of f-actin polymerization in mature synapses led to an increase of IFN-γ secretion and cytotoxicity by NK cells. This elevated NK-cell reactivity resulted from decreased inhibitory signaling in the absence of MHC class I polarization at the interface, which was observed on inhibition of f-actin polymerization in DCs. Thus, inhibitory signaling is stabilized by f-actin at the synapse between mature DCs and resting NK cells.

scholarly journals Human Dendritic Cells Activate Resting Natural Killer (NK) Cells and Are Recognized via the NKp30 Receptor by Activated NK Cells

2002 ◽  
Vol 195 (3) ◽  
pp. 343-351 ◽  
Author(s):  
Guido Ferlazzo ◽  
Ming L. Tsang ◽  
Lorenzo Moretta ◽  
Giovanni Melioli ◽  
Ralph M. Steinman ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Cytolytic Activity ◽  
Innate And Adaptive Immunity ◽  
Leukocyte Antigen ◽  
Histocompatibility Complex ◽  
Ifn Γ ◽  
Human Dendritic Cells

During the innate response to many inflammatory and infectious stimuli, dendritic cells (DCs) undergo a differentiation process termed maturation. Mature DCs activate antigen-specific naive T cells. Here we show that both immature and mature DCs activate resting human natural killer (NK) cells. Within 1 wk the NK cells increase two– to fourfold in numbers, start secreting interferon (IFN)-γ, and acquire cytolytic activity against the classical NK target LCL721.221. The DC-activated NK cells then kill immature DCs efficiently, even though the latter express substantial levels of major histocompatibility complex (MHC) class I. Similar results are seen with interleukin (IL)-2–activated NK cell lines and clones, i.e., these NK cells kill and secrete IFN-γ in response to immature DCs. Mature DCs are protected from activated NK lysis, but lysis takes place if the NK inhibitory signal is blocked by a human histocompatibility leukocyte antigen (HLA)-A,B,C–specific antibody. The NK activating signal mainly involves the NKp30 natural cytotoxicity receptor, and not the NKp46 or NKp44 receptor. However, both immature and mature DCs seem to use a NKp30 independent mechanism to act as potent stimulators for resting NK cells. We suggest that DCs are able to control directly the expansion of NK cells and that the lysis of immature DCs can regulate the afferent limb of innate and adaptive immunity.

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 Characterization of the defective interaction between a subset of natural killer cells and dendritic cells in HIV-1 infection

2006 ◽  
Vol 203 (10) ◽  
pp. 2339-2350 ◽  
Author(s):  
Domenico Mavilio ◽  
Gabriella Lombardo ◽  
Audrey Kinter ◽  
Manuela Fogli ◽  
Andrea La Sala ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Cell Subset ◽  
Interferon Γ ◽  
And Function ◽  
Hiv 1

In this study, we demonstrate that the in vitro interactions between a CD56neg/CD16pos (CD56neg) subset of natural killer (NK) cells and autologous dendritic cells (DCs) from HIV-1–infected viremic but not aviremic individuals are markedly impaired and likely interfere with the development of an effective immune response. Among the defective interactions are abnormalities in the process of reciprocal NK–DC activation and maturation as well as a defect in the NK cell–mediated editing or elimination of immature DCs (iDCs). Notably, the lysis of mature DCs (mDCs) by autologous NK cells was highly impaired even after the complete masking of major histocompatibility complex I molecules, suggesting that the defective elimination of autologous iDCs is at the level of activating NK cell receptors. In this regard, the markedly impaired expression/secretion and function of NKp30 and TNF-related apoptosis-inducing ligand, particularly among the CD56neg NK cell subset, largely accounts for the highly defective NK cell–mediated lysis of autologous iDCs. Moreover, mDCs generated from HIV-1 viremic but not aviremic patients are substantially impaired in their ability to secrete interleukin (IL)-10 and -12 and to prime the proliferation of neighboring autologous NK cells, which, in turn, fail to secrete adequate amounts of interferon-γ.

scholarly journals Virally infected and matured human dendritic cells activate natural killer cells via cooperative activity of plasma membrane-bound TNF and IL-15

Blood ◽  
2010 ◽  
Vol 116 (4) ◽  
pp. 575-583 ◽  
Author(s):  
Lazar Vujanovic ◽  
David E. Szymkowski ◽  
Sean Alber ◽  
Simon C. Watkins ◽  
Nikola L. Vujanovic ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Activation ◽  
Nk Cell ◽  
Recombinant Adenovirus ◽  
Interferon Γ ◽  
Cell Contact ◽  
Immune Functions ◽  
Cd69 Expression

Abstract Recombinant adenovirus-engineered dendritic cells (Ad.DCs) are potent immunologic adjuvants of antiviral and anticancer vaccines. The effectiveness of Ad.DC-based vaccines may depend on the ability of Ad.DCs to crosstalk with natural killer (NK) cells and to activate, polarize, and bridge innate and adaptive immunity. We investigated, for the first time, whether and how human Ad.DCs activate NK cells, and compared the Ad.DC function with that of immature DCs and matured DCs (mDCs). We found that adenovirus transduction and lipopolysaccharide/interferon-γ-induced maturation increased expression of transmembrane tumor necrosis factor (TNF) and trans-presented (trans) interleukin-15 (IL-15) on DCs, leading to enhanced NK cell activation without enhancing DC susceptibility to NK cell-mediated killing. This crosstalk enhanced NK cell CD69 expression, interferon-γ secretion, proliferation, and antitumor activities, with Ad.DCs being significantly more effective than immature DCs, but less effective than mDCs. The Ad.DC and mDC crosstalk with NK cells was largely prevented by physical separation of DCs and NK cells, and neutralization of total TNF and IL-15, but not by selective sequestration of soluble TNF. These findings demonstrate that both Ad.DCs and mDCs can efficiently promote innate immune functions by activation of NK cells through the cooperative activities of tmTNF and trans-IL-15 mediated by cell-to-cell contact.

scholarly journals Transmission of Toxoplasma gondii from Infected Dendritic Cells to Natural Killer Cells

2009 ◽  
Vol 77 (3) ◽  
pp. 970-976 ◽  
Author(s):  
Catrine M. Persson ◽  
Henrik Lambert ◽  
Polya P. Vutova ◽  
Isabel Dellacasa-Lindberg ◽  
Joanna Nederby ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Toxoplasma Gondii ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Immune Recognition ◽  
Cell Infection ◽  
Obligate Intracellular ◽  
Rapid Transfer ◽  
Intraperitoneal Inoculation

ABSTRACT The obligate intracellular parasite Toxoplasma gondii can actively infect any nucleated cell type, including cells from the immune system. In the present study, we observed that a large number of natural killer (NK) cells were infected by T. gondii early after intraperitoneal inoculation of parasites into C57BL/6 mice. Interestingly, one mechanism of NK cell infection involved NK cell-mediated targeting of infected dendritic cells (DC). Perforin-dependent killing of infected DC led to active egress of infectious parasites that rapidly infected adjacent effector NK cells. Infected NK cells were not efficiently targeted by other NK cells. These results suggest that rapid transfer of T. gondii from infected DC to effector NK cells may contribute to the parasite's sequestration and shielding from immune recognition shortly after infection.

scholarly journals Neutrophil depletion impairs natural killer cell maturation, function, and homeostasis

2012 ◽  
Vol 209 (3) ◽  
pp. 565-580 ◽  
Author(s):  
Baptiste N. Jaeger ◽  
Jean Donadieu ◽  
Céline Cognet ◽  
Claire Bernat ◽  
Diana Ordoñez-Rueda ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Immature Stage ◽  
Immune Defense ◽  
Cell Reactivity ◽  
Cell Functions

Natural killer (NK) cells are bone marrow (BM)–derived granular lymphocytes involved in immune defense against microbial infections and tumors. In an N-ethyl N-nitrosourea (ENU) mutagenesis strategy, we identified a mouse mutant with impaired NK cell reactivity both in vitro and in vivo. Dissection of this phenotype showed that mature neutrophils were required both in the BM and in the periphery for proper NK cell development. In mice lacking neutrophils, NK cells displayed hyperproliferation and poor survival and were blocked at an immature stage associated with hyporesponsiveness. The role of neutrophils as key regulators of NK cell functions was confirmed in patients with severe congenital neutropenia and autoimmune neutropenia. In addition to their direct antimicrobial activity, mature neutrophils are thus endowed with immunoregulatory functions that are conserved across species. These findings reveal novel types of cooperation between cells of the innate immune system and prompt examination of NK cell functional deficiency in patients suffering from neutropenia-associated diseases.

scholarly journals CD11cloB220+ interferon-producing killer dendritic cells are activated natural killer cells

2007 ◽  
Vol 204 (11) ◽  
pp. 2569-2578 ◽  
Author(s):  
Christian A.J. Vosshenrich ◽  
Sarah Lesjean-Pottier ◽  
Milena Hasan ◽  
Odile Richard-Le Goff ◽  
Erwan Corcuff ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Mhc Class Ii ◽  
Nk Cell ◽  
Phenotypic Differences ◽  
Mhc Ii ◽  
Class Ii Mhc

Interferon-producing killer dendritic cells (IKDCs) are a recently described subset of CD11cloB220+ cells that share phenotypic and functional properties of DCs and natural killer (NK) cells (Chan, C.W., E. Crafton, H.N. Fan, J. Flook, K. Yoshimura, M. Skarica, D. Brockstedt, T.W. Dubensky, M.F. Stins, L.L. Lanier, et al. 2006. Nat. Med. 12:207–213; Taieb, J., N. Chaput, C. Menard, L. Apetoh, E. Ullrich, M. Bonmort, M. Pequignot, N. Casares, M. Terme, C. Flament, et al. 2006. Nat. Med. 12:214–219). IKDC development appears unusual in that cytokines using the interleukin (IL)-2 receptor β (IL-2Rβ) chain but not those using the common γ chain (γc) are necessary for their generation. By directly comparing Rag2−/−γc−/y, Rag2−/−IL-2Rβ−/−, Rag2−/−IL-15−/−, and Rag2−/−IL-2−/− mice, we demonstrate that IKDC development parallels NK cell development in its strict IL-15 dependence. Moreover, IKDCs uniformly express NK-specific Ncr-1 transcripts (encoding NKp46), whereas NKp46+ cells are absent in Ncr1gfp/+γc−/y mice. Distinguishing features of IKDCs (CD11cloB220+MHC-II+) were carefully examined on developing NK cells in the bone marrow and on peripheral NK cells. As B220 expression was heterogeneous, defining B220lo versus B220hi NK1.1+ NK cells could be considered as arbitrary, and few phenotypic differences were noted between NK1.1+ NK cells bearing different levels of B220. CD11c expression did not correlate with B220 or major histocompatibility complex (MHC) class II (MHC-II) expression, and most MHC-II+ NK1.1+ cells did not express B220 and were thus not IKDCs. Finally, CD11c, MHC-II, and B220 levels were up-regulated on NK1.1+ cells upon activation in vitro or in vivo in a proliferation-dependent fashion. Our data suggest that the majority of CD11cloB220+ “IKDC-like” cells represent activated NK cells.

scholarly journals Natural killer cells in the human lung tumor microenvironment display immune inhibitory functions

2020 ◽  
Vol 8 (2) ◽  
pp. e001054
Author(s):  
Jules Russick ◽  
Pierre-Emmanuel Joubert ◽  
Mélanie Gillard-Bocquet ◽  
Carine Torset ◽  
Maxime Meylan ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Nk Cells ◽  
Natural Killer ◽  
Chemokine Receptor ◽  
Human Lung ◽  
Nk Cell ◽  
Lung Tumor ◽  
Human Lung Tumor ◽  
Cell Dysfunction ◽  
Inhibitory Molecules

BackgroundNatural killer (NK) cells play a crucial role in tumor immunosurveillance through their cytotoxic effector functions and their capacity to interact with other immune cells to build a coordinated antitumor immune response. Emerging data reveal NK cell dysfunction within the tumor microenvironment (TME) through checkpoint inhibitory molecules associated with a regulatory phenotype.ObjectiveWe aimed at analyzing the gene expression profile of intratumoral NK cells compared with non-tumorous NK cells, and to characterize their inhibitory function in the TME.MethodsNK cells were sorted from human lung tumor tissue and compared with non- tumoral distant lungs.ResultsIn the current study, we identify a unique gene signature of NK cell dysfunction in human non-small cell lung carcinoma (NSCLC). First, transcriptomic analysis reveals significant changes related to migratory pattern with a downregulation of sphingosine-1-phosphate receptor 1 (S1PR1) and CX3C chemokine receptor 1 (CX3CR1) and overexpression of C-X-C chemokine receptor type 5 (CXCR5) and C-X-C chemokine receptor type 6 (CXCR6). Second, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and killer cell lectin like receptor (KLRC1) inhibitory molecules were increased in intratumoral NK cells, and CTLA-4 blockade could partially restore MHC class II level on dendritic cell (DC) that was impaired during the DCs/NK cell cross talk. Finally, NK cell density impacts the positive prognostic value of CD8+ T cells in NSCLC.ConclusionsThese findings demonstrate novel molecular cues associated with NK cell inhibitory functions in NSCLC.

scholarly journals A Chimeric IL-15/IL-15Rα Molecule Expressed on NFκB-Activated Dendritic Cells Supports Their Capability to Activate Natural Killer Cells

2021 ◽  
Vol 22 (19) ◽  
pp. 10227
Author(s):  
Naomi C. Bosch ◽  
Lena-Marie Martin ◽  
Caroline J. Voskens ◽  
Carola Berking ◽  
Barbara Seliger ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Immune System ◽  
Nk Cells ◽  
Natural Killer ◽  
Cellular Response ◽  
Nk Cell ◽  
Ex Vivo ◽  
Therapeutic Vaccine ◽  
Chimeric Protein ◽  
Hla Class I

Natural killer (NK) cells, members of the innate immune system, play an important role in the rejection of HLA class I negative tumor cells. Hence, a therapeutic vaccine, which can activate NK cells in addition to cells of the adaptive immune system might induce a more comprehensive cellular response, which could lead to increased tumor elimination. Dendritic cells (DCs) are capable of activating and expanding NK cells, especially when the NFκB pathway is activated in the DCs thereby leading to the secretion of the cytokine IL-12. Another prominent NK cell activator is IL-15, which can be bound by the IL-15 receptor alpha-chain (IL-15Rα) to be transpresented to the NK cells. However, monocyte-derived DCs do neither secrete IL-15, nor express the IL-15Rα. Hence, we designed a chimeric protein consisting of IL-15 and the IL-15Rα. Upon mRNA electroporation, the fusion protein was detectable on the surface of the DCs, and increased the potential of NFκB-activated, IL-12-producing DC to activate NK cells in an autologous cell culture system with ex vivo-generated cells from healthy donors. These data show that a chimeric IL-15/IL-15Rα molecule can be expressed by monocyte-derived DCs, is trafficked to the cell surface, and is functional regarding the activation of NK cells. These data represent an initial proof-of-concept for an additional possibility of further improving cellular DC-based immunotherapies of cancer.

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