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Results for “Natural Cytotoxicity Triggering Receptor 3”

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At least 19 recordsLinked to original sources

PubMed2005

LST1 and NCR3 expression in autoimmune inflammation and in response to IFN-gamma, LPS and microbial infection.

Many genes in the central region of the major histocompatibility complex (MHC) encode proteins involved in immune and inflammatory responses. In this study, we have further characterized two genes in the MHC class IV region, leucocyte-specific transcript (LST) 1 and natural cytotoxicity-triggering receptor 3 (NCR3) (also known as 1C7 and natural killer (NK)p30). The specific function of LST1 is not known, although expression analysis and functional data suggest an immunomodulatory role. The LST1 gene undergoes extensive alternative splicing, giving rise to both membrane-bound (encoded by exon 3) and soluble isoforms. The NCR3 protein is involved in NK-mediated cytotoxicity and plays a role in NK/dendritic cell crosstalk. Expression of these genes was examined, by real-time reverse transcriptase-polymerase chain reaction, in autoimmune-induced inflammation, specifically rheumatoid-arthritis-affected blood and synovium, and in response to stimulation with inflammatory mediators and bacterial agents. The expression of LST1, specifically splice variants encoding soluble isoforms and NCR3, was increased in rheumatoid-arthritis-affected blood and synovium and was associated with more severe inflammation in the synovium. Furthermore, both genes were significantly up-regulated in response to lipopolysaccharide, interferon (IFN)-gamma and bacterial infection. These findings suggest that NCR3 and soluble isoforms of LST1 may play a role in inflammatory and infectious diseases.

Arthritis, Rheumatoid↗

PubMed2005

The Eighth Human Leucocyte Differentiation Antigen (HLDA8) Workshop: natural killer cell section report.

Monoclonal antibodies submitted to the natural killer (NK) cell section of the Eighth International Workshop on Human Leucocyte Differentiation Antigens (HLDA8) comprised those to known clusters of differentiation (CD), those to well-characterised molecules without a CD nomenclature, and those to unknown molecules. From the HLDA8 workshop, the seven well-characterised molecules in the NK cell panel were assigned a CD classification. These were NKG2D (CD314), LAIR-1 (CD305), NKp46 (CD335), NKp44 (CD336), NKp30 (CD337), CRACC (CD319), and NKG2C (CD159c).

Antibodies, Monoclonal↗

PubMed2003

Transforming growth factor beta 1 inhibits expression of NKp30 and NKG2D receptors: consequences for the NK-mediated killing of dendritic cells.

The surface density of the triggering receptors responsible for the natural killer (NK)-mediated cytotoxicity is crucial for the ability of NK cells to kill susceptible target cells. In this study, we show that transforming growth factor beta1 (TGFbeta1) down-regulates the surface expression of NKp30 and in part of NKG2D but not that of other triggering receptors such as NKp46. The TGFbeta1-mediated inhibition of NKp30 surface expression reflects gene regulation at the transcriptional level. NKp30 has been shown to represent the major receptor involved in the NK-mediated killing of dendritic cells. Accordingly, the TGFbeta1-dependent down-regulation of NKp30 expression profoundly inhibited the NK-mediated killing of dendritic cells. On the contrary, killing of different NK-susceptible tumor cell lines was variably affected, reflecting the differential usage of NKp30 and/or NKG2D in the lysis of such tumors. Our present data suggest a possible mechanism by which TGFbeta1-producing dendritic cells may acquire resistance to the NK-mediated attack.

Antigens, CD↗

PubMed2005

Ligands for natural killer cell-activating receptors are expressed upon the maturation of normal myelomonocytic cells but at low levels in acute myeloid leukemias.

Natural killer (NK) cell-mediated cytolytic activity against tumors requires the engagement of activating NK receptors by the tumor-associated ligands. Here, we have studied the role of NKG2D and natural cytotoxicity receptors (NCRs) in the recognition of human leukemia. To detect as-yet-unknown cell-surface molecules recognized by NCRs, we developed soluble forms of NKp30, NKp44, and NKp46 as staining reagents binding the putative cognate ligands. Analysis of UL16-binding protein-1 (ULBP1), ULBP2, and ULBP3 ligands for NKG2D and of potential ligands for NKp30, NKp44, and NKp46 in healthy hematopoietic cells demonstrated the ligand-negative phenotype of bone marrow-derived CD34(+) progenitor cells and the acquisition of cell-surface ligands during the course of myeloid differentiation. In acute myeloid leukemia (AML), leukemic blasts from approximately 80% of patients expressed very low levels of ULBPs and NCR-specific ligands. Treatment with differentiation-promoting myeloid growth factors, together with interferon-gamma, upregulated cell-surface levels of ULBP1 and putative NCR ligands on AML blasts, conferring an increased sensitivity to NK cell-mediated lysis. We conclude that the ligand-negative/low phenotype in AML is a consequence of cell maturation arrest on malignant transformation and that defective expression of ligands for the activating NKG2D and NCR receptors may compromise leukemia recognition by NK cells.

Acute Disease↗

PubMed2007

Reciprocal regulation of human natural killer cells and macrophages associated with distinct immune synapses.

Natural killer (NK) cells directly lyse tumor or viral-infected cells but also an important role for NK cell cytotoxicity in regulating the extent of immune responses is emerging. Here, we show that autologous human macrophages activated NK cell proliferation and cytokine secretion, increased expression of activating receptors, and primed NK cell cytotoxicity against susceptible target cells. Ligation of NK cell 2B4, and not NKp30 (known to be important for DC-mediated NK cell activation), is critical for this macrophage-mediated NK cell activation. Reciprocally, however, NK cells regulated macrophage activity by directly killing macrophages stimulated by high doses of LPS. Cytolysis was triggered by NKG2D recognition of stress-inducible class I major histocompatibility complex (MHC)-like ligands on macrophages: high doses of LPS induced transcription and surface expression of ULBP1, ULBP2, and ULBP3 and surface expression of constitutively transcribed MICA. Thus, these data suggest a new function for NK cell cytotoxicity in eliminating overstimulated macrophages. Additionally, these interactions define, for the first time, 2 distinct activating NK cell synapses: lytic and nonlytic. Triggering NK cell proliferation and cytokine secretion, but not cytolysis, specifically associated with synaptic accumulation of macrophage F-actin and NK cell 2B4, while macrophages were killed when NK cell F-actin and macrophage ICAM-1 accumulated around a central cluster of NK cell NKG2D/DAP10.

Actins↗

PubMed2001

NK cell-mediated lysis of autologous antigen-presenting cells is triggered by the engagement of the phosphatidylinositol 3-kinase upon ligation of the natural cytotoxicity receptors NKp30 and NKp46.

Interleukin-2 (IL-2)-activated polyclonal or clonal NK cells lysed autologous antigen presenting cells (APC) through the engagement of the natural cytotoxicity receptors (NCR) NKp30 and NKp46. NK cell-mediated cytolysis of APC correlated with the surface density of these NCR. Indeed, NK cell clones bearing low amounts of NKp30 and NKp46 did not lyse autologous APC, whereas NK cell clones with bright expression of these NCR efficiently killed autologous APC. Upon masking of NKp30 or NKp46 by specific monoclonal antibodies a strong reduction (by 50%) of APC lysis could be detected and the complete inhibition was achieved by the simultaneous masking of these NCR. Interestingly, NK cell-mediated APC lysis was impaired by the phosphatidylinositol 3-kinase (PI-3 K) inhibitors LY294002 or wortmannin. Similarly, these drugs strongly reduced NK cell activation triggered by NKp30 or NKp46 in a re-directed killing assay as well as the activation of Akt/PKB, substrate of PI-3 K, induced by the engagement of these receptors. Altogether, these findings strongly suggest that NCR are responsible for the killing of autologous APC through the activation of PI-3 K.

Antigen-Presenting Cells↗

PubMed2006

The tryptophan catabolite L-kynurenine inhibits the surface expression of NKp46- and NKG2D-activating receptors and regulates NK-cell function.

Tryptophan (Trp) catabolism mediated by indoleamine 2,3-dioxygenase (IDO) plays a central role in the regulation of T-cell-mediated immune responses. In this study, we also demonstrate that natural killer (NK)-cell function can be influenced by IDO. Indeed, l-kynurenine, a Trp-derived catabolite resulting from IDO activity, was found to prevent the cytokine-mediated up-regulation of the expression and function of specific triggering receptors responsible for the induction of NK-cell-mediated killing. The effect of l-kynurenine appears to be restricted to NKp46 and NKG2D, while it does not affect other surface receptors such as NKp30 or CD16. As a consequence, l-kynurenine-treated NK cells display impaired ability to kill target cells recognized via NKp46 and NKG2D. Instead, they maintain the ability to kill targets, such as dendritic cells (DCs), that are mainly recognized via the NKp30 receptor. The effect of l-kynurenine, which is effective at both the transcriptional and the protein level, can be reverted, since NK cells were found to recover their functional competence after washing.

Antigens, CD↗

PubMed2006

Recognition of vaccinia virus-infected cells by human natural killer cells depends on natural cytotoxicity receptors.

Natural Killer (NK) cells are important in the immune response to a number of viruses; however, the mechanisms used by NK cells to discriminate between healthy and virus-infected cells are only beginning to be understood. Infection with vaccinia virus provokes a marked increase in the susceptibility of target cells to lysis by NK cells, and we show that recognition of the changes in the target cell induced by vaccinia virus infection depends on the natural cytotoxicity receptors NKp30, NKp44, and NKp46. Vaccinia virus infection does not induce expression of ligands for the activating NKG2D receptor, nor does downregulation of major histocompatibility complex class I molecules appear to be of critical importance for altered target cell susceptibility to NK cell lysis. The increased susceptibility to lysis by NK cells triggered upon poxvirus infection depends on a viral gene, or genes, transcribed early in the viral life cycle and present in multiple distinct orthopoxviruses. The more general implications of these data for the processes of innate immune recognition are discussed.

Cell Line↗

PubMed2006

Human congenital infection with Trypanosoma cruzi induces phenotypic and functional modifications of cord blood NK cells.

We studied the phenotype and activity of cord blood natural killer (NK) cells in newborns congenitally infected with Trypanosoma cruzi. We found that the proportion of CD56(bright) NK cells was significantly decreased in cord blood from these newborns, suggesting they may have been recruited to secondary lymphoid organs. The remaining CD56(bright) NK cells exhibited a defective ability in the production of interferon (IFN)-gamma following in vitro activation with interleukin (IL)-12 + IL-2 or IL-12 + IL-15 cytokines, as compared with NK cells from uninfected newborns. In addition, cord blood NK cells from congenitally infected newborns stimulated with cytokines have a decreased release of granzyme B (GrB) when incubated with K562 target cells. This defect in cytotoxic effector function is associated with a reduced surface expression of activating NK receptors (NKp30, NKp46, and NKG2D) on CD56(dim) NK cells compared with uninfected newborns. These alterations of fetal NK cells from congenitally infected newborns may reflect a down-regulation of the NK cell response after an initial peak of activation and could also be the result of T. cruzi modulating the immune response.

Animals↗

PubMed2004

Molecular classification of human endometrial cycle stages by transcriptional profiling.

Endometrium is a dynamic tissue that undergoes cyclic changes each month, under the overall control of estrogen and progesterone. The aims of this study were to investigate the changing global gene expression profile of human endometrium during the menstrual cycle using microarray technology and to determine the correlation between histopathological evaluation and molecular profile of the samples. Standard two-colour cDNA microarrays were performed on the 43 samples against a common reference, using a 10.5 K cDNA glass slide microarray. The results were validated using real-time PCR. Analysis of expression data was carried out using parametric analysis of variance with Benjamini-Hochberg correction. Hierarchical clustering reveals a strong relationship between histopathology and transcriptional profile of the samples. The study identified 1452 genes that showed significant changes in expression (P< or =0.05) across the menstrual cycle, with 425 genes having changes that are at least 2-fold. The data were also independently analysed by a CSIRO algorithm called GeneRaVE that identified a small subset of genes whose expression profiles could be used to classify nearly all the biopsies into their correct cycle stage. We also identified and validated three genes [(natural cytotoxicity triggering receptor (NCR)3, fucosyl transferase (FUT)4 and Fyn-binding protein (FYB)] that had not been shown to have significant cyclic changes in the human endometrium, previously. We have shown for the first time that endometrial cycle stage prediction is possible based on global gene expression profile.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Interaction between human NK cells and bone marrow stromal cells induces NK cell triggering: role of NKp30 and NKG2D receptors.

In this study we have analyzed the interaction between in vitro cultured bone marrow stromal cells (BMSC) and NK cells. Ex vivo-isolated NK cells neoexpressed the activation Ag CD69 and released IFN-gamma and TNF-alpha upon binding with BMSC. Production of these proinflammatory cytokines was dependent on ligation of ICAM1 expressed on BMSC and its receptor LFA1 on NK cells. Furthermore, the NKp30, among natural cytotoxicity receptors, appeared to be primarily involved in triggering NK cells upon interaction with BMSC. Unexpectedly, autologous IL-2-activated NK cells killed BMSC. Again, LFA1/ICAM1 interaction plays a key role in NK/BMSC interaction; this interaction is followed by a strong intracellular calcium increase in NK cells. More importantly, NKG2D/MHC-I-related stress-inducible molecule A and/or NKG2D/UL-16 binding protein 3 engagement is responsible for the delivery of a lethal hit. It appears that HLA-I molecules do not protect BMSC from NK cell-mediated injury. Thus, NK cells, activated upon binding with BMSC, may regulate BMSC survival.

Antigens, CD↗

PubMed2006

Association analyses of NCR3 polymorphisms with P. falciparum mild malaria.

Plasmodium falciparum malaria is a major cause of morbidity and mortality in many developing countries especially in sub-Saharan Africa. A susceptibility locus for mild malaria has been mapped to the MHC region, and TNF polymorphisms have been associated with mild malaria. The Natural Cytotoxicity-triggering Receptor 3 (NCR3) gene is located in the peak region of linkage, and is 15kb distal to TNF. In this study, we considered NCR3 as a candidate gene, and we genotyped ten NCR3 single nucleotide polymorphisms (SNPs). Here, we report evidence of an association between mild malaria and NCR3 -412G>C polymorphism located within the promoter. Population-based association analysis showed that NCR3 -412C carriers had more frequent mild malaria attacks than NCR3 -412GG individuals (P=0.001). Using the family-based association test (FBAT) program and its phenotype (PBAT) option, we further found that NCR3 -412C (P=0.0009) and a haplotype containing NCR3 -412C (P=0.008) were significantly associated with increased risk of mild malaria, and that the association was not due to the association of TNF with mild malaria. These observations suggest that there are at least two genes located on the central region of MHC involved in genetic control of human malaria. The association of NCR3 with malaria should provide new insights into the role of Natural Killer cells in this common disease.

Adolescent↗

PubMed2004

Dysregulated NK receptor expression in patients with lymphoproliferative disease of granular lymphocytes.

The natural killer (NK) type of lymphoproliferative disease of granular lymphocytes (LDGL) is associated with the expansion of CD3(-), CD16(+), and/or CD56(+) lymphocytes. We have examined the repertoire of NK receptors expressed on these cells and delineated the functional activity. We found skewed NK receptor expression on patient NK cells. Reactivity to a single anti-killer cell immunoglobulin-like receptor (anti-KIR) antibody was noted in 7 of 13 patients. LDGL patients variably expressed NKp30, NKp44, and NKp46 RNA. In contrast, CD94 and its inhibitory heterodimerization partner NKG2A were homogeneously expressed at high levels on these NK cells. Interestingly, these patients expressed a large number of activating KIR receptors by genotype analysis. Semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) demonstrated that lower than normal levels of RNA of the inhibitory KIR was present in some patients in contrast to normal NK cells. Consistent with a high level of activating receptors, we found the NK-LDGL cells have potent cytolytic function in both direct and redirected cytotoxicity assays. These results demonstrate that patients with NK-LDGL have an increased activating-to-inhibitory KIR ratio. This altered ratio might induce inappropriate lysis or cytokine production and impact the disease pathogenesis.

Antigens, CD↗

PubMed2001

Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis.

Natural killer cells can discriminate between normal cells and cells that do not express adequate amounts of major histocompatibility complex (MHC) class I molecules. The discovery, both in mouse and in human, of MHC-specific inhibitory receptors clarified the molecular basis of this important NK cell function. However, the triggering receptors responsible for positive NK cell stimulation remained elusive until recently. Some of these receptors have now been identified in humans, thus shedding some light on the molecular mechanisms involved in NK cell activation during the process of natural cytotoxicity. Three novel, NK-specific, triggering surface molecules (NKp46, NKp30, and NKp44) have been identified. They represent the first members of a novel emerging group of receptors collectively termed natural cytotoxicity receptors (NCR). Monoclonal antibodies (mAbs) to NCR block to differing extents the NK-mediated lysis of various tumors. Moreover, lysis of certain tumors can be virtually abrogated by the simultaneous masking of the three NCRs. There is a coordinated surface expression of the three NCRs, their surface density varying in different individuals and also in the NK cells isolated from a given individual. A direct correlation exists between the surface density of NCR and the ability of NK cells to kill various tumors. NKp46 is the only NCR involved in human NK-mediated killing of murine target cells. Accordingly, a homologue of NKp46 has been detected in mouse. Molecular cloning of NCR revealed novel members of the Ig superfamily displaying a low degree of similarity to each other and to known human molecules. NCRs are coupled to different signal transducing adaptor proteins, including CD3 zeta, Fc epsilon RI gamma, and KARAP/DAP12. Another triggering NK receptor is NKG2D. It appears to play either a complementary or a synergistic role with NCRs. Thus, the triggering of NK cells in the process of tumor cell lysis may often depend on the concerted action of NCR and NKG2D. In some instances, however, it may uniquely depend upon the activity of NCR or NKG2D only. Strict NKG2D-dependency can be appreciated using clones that, in spite of their NCR(dull) phenotype, efficiently lyse certain epithelial tumors or leukemic cell lines. Other triggering surface molecules including 2B4 and the novel NKp80 appear to function as coreceptors rather than as true receptors. Indeed, they can induce natural cytotoxicity only when co-engaged with a triggering receptor. While an altered expression or function of NCR or NKG2D is being explored as a possible cause of immunological disorders, 2B4 dysfunction has already been associated with a severe form of immunodeficiency. Indeed, in patients with the X-linked lymphoproliferative disease, the inability to control Epstein-Barr virus infections may be consequent to a major dysfunction of 2B4 that exerts inhibitory instead of activating functions.

Adaptor Proteins, Signal Transducing↗

PubMed2006

IL-21 down-regulates NKG2D/DAP10 expression on human NK and CD8+ T cells.

IL-21 is a recently described cytokine, produced by activated Th cells, that shares significant homology with members of the IL-2 family of cytokines. IL-21 mediates its biological effects via the IL-21R in conjunction with the common receptor gamma-chain that is also shared by members of the IL-2 family. We report that culture of human primary NK and CD8+ T cells with IL-21 in combination with IL-2 results in significant reduction of the cell surface expression of NKG2D, compared with that in cells treated with IL-2 alone. The reduced expression of NKG2D after IL-21 culture had functional consequences for NK cell function, as assessed by NKG2D-mediated redirected lysis assays and degranulation assays, compared with NK cells treated with IL-2 alone. IL-21-mediated NKG2D down-regulation in human NK cells correlated with a marked reduction of DNAX-activating protein of 10 kDa (DAP10) transcription in cells treated with IL-2 in combination with IL-21 compared with cells stimulated with only IL-2. This was attributed to a dramatic reduction in DAP10 promoter activity, as assessed by a DAP10 luciferase reporter construct. In contrast to NKG2D expression, IL-21 was able to induce the expression of the NK activation receptors NKp30 and 2B4 as well as the costimulatory receptor CD28 on CD8+ T cells. These data indicate that IL-21 is able to channel NK and CD8+ T cell function by altering the expression pattern of activation/costimulatory receptors.

Antigens, CD↗

PubMed2005

TLR7/8-mediated activation of human NK cells results in accessory cell-dependent IFN-gamma production.

NK cells express receptors that allow them to recognize pathogens and activate effector functions such as cytotoxicity and cytokine production. Among these receptors are the recently identified TLRs that recognize conserved pathogen structures and initiate innate immune responses. We demonstrate that human NK cells express TLR3, TLR7, and TLR8 and that these receptors are functional. TLR3 is expressed at the cell surface where it functions as a receptor for polyinosinic acid:cytidylic acid (poly(I:C)) in a lysosomal-independent manner. TLR7/8 signaling is sensitive to chloroquine inhibition, indicating a requirement for lysosomal signaling as for other cell types. Both R848, an agonist of human TLR7 and TLR8, and poly(I:C) activate NK cell cytotoxicity against Daudi target cells. However, IFN-gamma production is differentially regulated by these TLR agonists. In contrast to poly(I:C), R848 stimulates significant IFN-gamma production by NK cells. This is accessory cell dependent and is inhibited by addition of a neutralizing anti-IL-12 Ab. Moreover, stimulation of purified monocyte populations with R848 results in IL-12 production, and reconstitution of purified NK cells with monocytes results in increased IFN-gamma production in response to R848. In addition, we demonstrate that while resting NK cells do not transduce signals directly in response to R848, they can be primed to do so by prior exposure to either IL-2 or IFN-alpha. Therefore, although NK cells can be directly activated by TLRs, accessory cells play an important and sometimes essential role in the activation of effector functions such as IFN-gamma production and cytotoxicity.

Antigen-Presenting Cells↗

PubMed2005

Tumor-induced apoptosis of human IL-2-activated NK cells: role of natural cytotoxicity receptors.

We provide evidence that tumor cells can induce apoptosis of NK cells by engaging the natural cytotoxicity receptors (NCR) NKp30, NKp44, and NKp46. Indeed, the binding between NCR on NK cells and their putative ligands on tumor target cells led to NK cell apoptosis, and this event was abolished by blocking NCR/NCR-ligand interaction by anti-NCR-specific mAbs. The engagement of NCR induced up-regulation of Fas ligand (FasL) mRNA, FasL protein synthesis, and release. In turn, FasL interacting with Fas at NK cell surface causes NK cell suicide, as apoptosis of NK cells was inhibited by blocking FasL/Fas interaction with specific mAbs. Interestingly, NK cell apoptosis, but not killing of tumor target cells, is inhibited by cyclosporin A, suggesting that apoptosis and cytolysis are regulated by different biochemical pathways. These findings indicate that NCR are not only triggering molecules essential for antitumor activity, but also surface receptors involved in NK cell suicide.

Antibodies, Monoclonal↗

PubMed2003

The impaired NK cell cytolytic function in viremic HIV-1 infection is associated with a reduced surface expression of natural cytotoxicity receptors (NKp46, NKp30 and NKp44).

Signals leading to NK cell triggering are primarily mediated by natural cytotoxicity receptors (NCR) upon binding to as-yet-undefined cell surface ligand(s) on normal hematopoietic cells, pathogen-infected cells or tumor cells. In this study we tried to determine whether the decreased NK cell cytolytic function that is observed in HIV-1-infected patients may be related to a decreased expression of NCR. In HIV-1-infected patients, freshly drawn, purified NK cells expressed significantly decreased surface densities of NKp46 and NKp30 NCR. The low surface density of NKp46, NKp30 and NKp44 was also confirmed in in-vitro-activated NK cell populations and NK cell clones derived from HIV-1 patients compared with uninfected donors. This defective NCR expression in HIV-1 patients was associated with a parallel decrease of NCR-mediated killing of different tumor target cells. Thus, the present study indicates that the defective expression of NCR represents at least one of the possible mechanisms leading to the impaired NK cell function in HIV-1 infection and it can contribute to explain the relatively high frequency of opportunistic tumors reported in cohorts of untreated patients before the occurrence of profound immunosuppression (<200 CD4(+) cells/mm(3)).

Down-Regulation↗