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1.
Cell Rep ; 7(6): 1809-14, 2014 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-24882008

RESUMO

Hematopoietic stem cell transplantation (HSCT) is often the only curative treatment for a wide variety of hematologic malignancies. Donor selection in these diseases is crucial, given that transplanted cells can mediate not only the desired graft-versus-leukemia effect but also graft-versus-host disease (GVHD). Here, we demonstrate that in the absence of NKp46, a major killer receptor expressed by human and mouse natural killer (NK) cells, GVHD is greatly exacerbated, resulting in rapid mortality of the transplanted animals because of infection with commensal bacteria. Furthermore, we demonstrate that the exacerbated GVHD is the result of an altered ability of immune cells to respond to stimulation by immature dendritic cells. Because high and low expression of NKp46 on NK cells is observed in different individuals, our data indicate that choosing NKp46-high donors for the treatment of different hematologic malignancies might lead to better tumor eradication while minimizing GVHD.


Assuntos
Antígenos Ly/imunologia , Doença Enxerto-Hospedeiro/imunologia , Células Matadoras Naturais/imunologia , Receptor 1 Desencadeador da Citotoxicidade Natural/imunologia , Animais , Transplante de Células-Tronco Hematopoéticas/métodos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
2.
Eur J Immunol ; 43(11): 3006-16, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23878025

RESUMO

Natural killer (NK) cells are cytotoxic cells that are able to rapidly kill viruses, tumor cells, parasites, bacteria, and even cells considered "self". The activity of NK cells is controlled by a fine balance of inhibitory and activating signals mediated by a complex set of different receptors. However, the function of NK cells is not restricted only to the killing of target cells, NK cells also possess other properties such as the secretion of proangiogenic factors during pregnancy. Here, we demonstrate another unique NK-cell activity, namely the regulation of T-cell mediated allergic responses, which is dependent on the NK-cell specific receptor NKp46 (Ncr1 in mice). Using mice in which the Ncr1 gene has been replaced with a green fluorescent protein, we demonstrate reduced delayed-type hypersensitivity and airway hypersensitivity. Interestingly, we show that this reduction in airway hypersensitivity is due to differences in the stimulation of T cells resulting in an altered cytokine profile.


Assuntos
Antígenos Ly/imunologia , Hipersensibilidade Tardia/imunologia , Células Matadoras Naturais/imunologia , Receptor 1 Desencadeador da Citotoxicidade Natural/imunologia , Hipersensibilidade Respiratória/imunologia , Animais , Antígenos Ly/genética , Citotoxicidade Imunológica/imunologia , Células Dendríticas/imunologia , Proteínas de Fluorescência Verde/genética , Inflamação/imunologia , Interferon gama/biossíntese , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Receptor 1 Desencadeador da Citotoxicidade Natural/genética , Ovalbumina , Linfócitos T/imunologia
3.
PLoS Pathog ; 9(3): e1003226, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23555244

RESUMO

Both NK cells and CTLs kill virus-infected and tumor cells. However, the ways by which these killer cells recognize the infected or the tumorigenic cells are different, in fact almost opposite. CTLs are activated through the interaction of the TCR with MHC class I proteins. In contrast, NK cells are inhibited by MHC class I molecules. The inhibitory NK receptors recognize mainly MHC class I proteins and in this regard practically all of the HLA-C proteins are recognized by inhibitory NK cell receptors, while only certain HLA-A and HLA-B proteins interact with these receptors. Sophisticated viruses developed mechanisms to avoid the attack of both NK cells and CTLs through, for example, down regulation of HLA-A and HLA-B molecules to avoid CTL recognition, leaving HLA-C proteins on the cell surface to inhibit NK cell response. Here we provide the first example of a virus that through specific down regulation of HLA-C, harness the NK cells for its own benefit. We initially demonstrated that none of the tested HSV-2 derived microRNAs affect NK cell activity. Then we show that surprisingly upon HSV-2 infection, HLA-C proteins are specifically down regulated, rendering the infected cells susceptible to NK cell attack. We identified a motif in the tail of HLA-C that is responsible for the HSV-2-meduiated HLA-C down regulation and we show that the HLA-C down regulation is mediated by the viral protein ICP47. Finally we show that HLA-C proteins are down regulated from the surface of HSV-2 infected dendritic cells (DCs) and that this leads to the killing of DC by NK cells. Thus, we propose that HSV-2 had developed this unique and surprising NK cell-mediated killing strategy of infected DC to prevent the activation of the adaptive immunity.


Assuntos
Citotoxicidade Imunológica , Células Dendríticas/imunologia , Antígenos HLA-C/metabolismo , Infecções por Herpesviridae/imunologia , Herpesvirus Humano 2/imunologia , Proteínas Imediatamente Precoces/imunologia , Células Matadoras Naturais/imunologia , Imunidade Adaptativa , Sobrevivência Celular , Clonagem Molecular , Células Dendríticas/virologia , Regulação para Baixo , Regulação Viral da Expressão Gênica , Infecções por Herpesviridae/metabolismo , Infecções por Herpesviridae/virologia , Herpesvirus Humano 2/genética , Humanos , Proteínas Imediatamente Precoces/genética , Proteínas Imediatamente Precoces/metabolismo , Células Matadoras Naturais/metabolismo , Ativação Linfocitária/imunologia
4.
PLoS Pathog ; 8(3): e1002601, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22457623

RESUMO

Periodontitis is a common human chronic inflammatory disease that results in the destruction of the tooth attachment apparatus and tooth loss. Although infections with periopathogenic bacteria such as Porphyromonas gingivalis (P. gingivalis) and Fusobacterium nucleatum (F. nucleatum) are essential for inducing periodontitis, the nature and magnitude of the disease is determined by the host's immune response. Here, we investigate the role played by the NK killer receptor NKp46 (NCR1 in mice), in the pathogenesis of periodontitis. Using an oral infection periodontitis model we demonstrate that following F. nucleatum infection no alveolar bone loss is observed in mice deficient for NCR1 expression, whereas around 20% bone loss is observed in wild type mice and in mice infected with P. gingivalis. By using subcutaneous chambers inoculated with F. nucleatum we demonstrate that immune cells, including NK cells, rapidly accumulate in the chambers and that this leads to a fast and transient, NCR1-dependant TNF-α secretion. We further show that both the mouse NCR1 and the human NKp46 bind directly to F. nucleatum and we demonstrate that this binding is sensitive to heat, to proteinase K and to pronase treatments. Finally, we show in vitro that the interaction of NK cells with F. nucleatum leads to an NCR1-dependent secretion of TNF-α. Thus, the present study provides the first evidence that NCR1 and NKp46 directly recognize a periodontal pathogen and that this interaction influences the outcome of F. nucleatum-mediated periodontitis.


Assuntos
Antígenos Ly/imunologia , Fusobacterium nucleatum/imunologia , Células Matadoras Naturais/imunologia , Receptor 1 Desencadeador da Citotoxicidade Natural/imunologia , Periodontite/imunologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Interações Hospedeiro-Patógeno , Células Matadoras Naturais/metabolismo , Camundongos , Camundongos Knockout , Periodontite/patologia , Fator de Necrose Tumoral alfa/metabolismo
5.
J Immunol ; 184(10): 5637-44, 2010 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-20404273

RESUMO

NK cells interact with a wide variety of hazardous cells including pathogen-infected and tumor cells. NKp46 is a specific NK killer receptor that recognizes various influenza hemagglutinins and unknown tumor ligands. It was recently shown that NKp46 plays a significant role in the in vivo eradication of tumor cells; however, the role played by NKp46 in vivo with regard to tumor development is still unclear. In this study, we used the 3-methylcholanthrene (MCA)-induced fibrosarcoma model in NKp46-deficient mice to test the NKp46 recognition of carcinogen-induced tumors. We show that although the rate of MCA-induced tumor formation was similar in the presence and in the absence of NKp46, the expression of its unknown ligands was NKp46 dependent. The unknown NKp46 ligands were nearly absent in tumors that originated in wild-type mice, whereas they were detected in tumors that originated in the NKp46-deficient mice. We demonstrate that the interactions between NKp46 and its MCA tumor-derived ligands lead to the secretion of IFN-gamma but not to the elimination of the MCA-derived tumor cells. In addition, we show that the in vivo growth of MCA-derived tumor cells expressing high levels of the NKp46 ligands is NKp46 and IFN-gamma dependent. Thus, we present in this study a novel NKp46-mediated mechanism of tumor editing.


Assuntos
Antígenos Ly/fisiologia , Fibrossarcoma/imunologia , Fibrossarcoma/metabolismo , Vigilância Imunológica , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Receptor 1 Desencadeador da Citotoxicidade Natural/fisiologia , Animais , Antígenos Ly/genética , Antígenos Ly/metabolismo , Células COS , Linhagem Celular Tumoral , Células Cultivadas , Chlorocebus aethiops , Técnicas de Cocultura , Fibrossarcoma/induzido quimicamente , Fibrossarcoma/patologia , Interferon gama/metabolismo , Células Matadoras Naturais/patologia , Ligantes , Metilcolantreno/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptor 1 Desencadeador da Citotoxicidade Natural/deficiência , Receptor 1 Desencadeador da Citotoxicidade Natural/genética , Receptor 1 Desencadeador da Citotoxicidade Natural/metabolismo , Evasão Tumoral/imunologia
6.
J Immunol ; 184(6): 2761-8, 2010 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-20164429

RESUMO

The killing activity of NK cells is carried out by several activating NK receptors, which includes NKp46, NKp44, NKp30, NKp80, NKG2D, and 2B4. The ligands of these receptors are either self-derived, pathogen-derived, stress-induced ligands or tumor ligands. Importantly, none of these killer ligands are expressed on NK cells and thus self-killing of NK cells is prevented. A notable exception with this regard, is the ligand of the 2B4 receptor. This unusual receptor can exert both activating and inhibiting signals; however, in human NK cells, it serves mainly as an activating receptor. The ligand of 2B4 is CD48 and in contrast to the ligands of all the other NK activating receptors, CD48 is also present on NK cells. Thus, NK cells might be at risk for self-killing that is mediated via the 2B4-CD48 interaction. In this study, we identify a novel mechanism that prevents this self-killing as we show that the association of the MHC class I proteins with the 2B4 receptor, both present on NK cells, results in the attenuation of the 2B4-mediated self-killing of NK cells.


Assuntos
Antígenos CD/metabolismo , Testes Imunológicos de Citotoxicidade , Regulação para Baixo/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Receptores Imunológicos/metabolismo , Animais , Antígenos CD/imunologia , Antígenos CD/fisiologia , Antígeno CD48 , Linhagem Celular Transformada , Linhagem Celular Tumoral , Inibidores do Crescimento/antagonistas & inibidores , Inibidores do Crescimento/metabolismo , Inibidores do Crescimento/fisiologia , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/fisiologia , Humanos , Células Matadoras Naturais/citologia , Ligantes , Camundongos , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/fisiologia , Transdução de Sinais/imunologia , Família de Moléculas de Sinalização da Ativação Linfocitária
7.
Nat Immunol ; 11(2): 121-8, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20023661

RESUMO

The mechanism of action of natural killer (NK) cells in type 1 diabetes is still unknown. Here we show that the activating receptor NKp46 recognizes mouse and human ligands on pancreatic beta cells. NK cells appeared in the pancreas when insulitis progressed to type 1 diabetes, and NKp46 engagement by beta cells led to degranulation of NK cells. NKp46-deficient mice had less development of type 1 diabetes induced by injection of a low dose of streptozotocin. Injection of soluble NKp46 proteins into nonobese diabetic mice during the early phase of insulitis and the prediabetic stage prevented the development of type 1 diabetes. Our findings demonstrate that NKp46 is essential for the development of type 1 diabetes and highlight potential new therapeutic modalities for this disease.


Assuntos
Autoantígenos/imunologia , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Tipo 1/imunologia , Receptor 1 Desencadeador da Citotoxicidade Natural/imunologia , Animais , Antígenos Ly/genética , Antígenos Ly/imunologia , Antígenos Ly/metabolismo , Autoantígenos/genética , Autoantígenos/metabolismo , Degranulação Celular/imunologia , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/metabolismo , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Imunofluorescência , Humanos , Imuno-Histoquímica , Células Secretoras de Insulina/imunologia , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Receptor 1 Desencadeador da Citotoxicidade Natural/genética , Receptor 1 Desencadeador da Citotoxicidade Natural/metabolismo
8.
J Immunol ; 182(4): 2221-30, 2009 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-19201876

RESUMO

The in vitro elimination of virus-infected and tumor cells by NK cells is regulated by a balance between signals conveyed via specific inhibitory and activating receptors. Whether NK cells and specifically the NK-activating receptor NKp46 (NCR1 in mice) are directly involved in tumor eradication in vivo is still largely unknown. Since the NKp46/NCR1 tumor ligands have not been identified yet, we use a screening technique to identify functional ligands for NKp46/NCR1 which is based on a cell reporter assay and discover a NCR1 ligand in the PD1.6 lymphoma line. To study whether NKp46/NCR1 is important for the eradication of PD1.6 lymphoma in vivo, we used the Ncr1 knockout Ncr1(gfp/gfp) mice generated by our group. Strikingly, all Ncr1 knockout mice developed growing PD1.6 tumors, whereas initial tumor growth was observed in the wild-type mice and tumors were completely rejected as time progressed. The growth of other lymphoma cell lines such as B10 and EL4 was equivalent between the Ncr1 knockout and wild-type mice. Finally, we show that PD1.6 lymphoma cells are less killed both in vitro and in vivo in the absence of NKp46/NCR1. Our results therefore reveal a crucial role for NKp46/NCR1 in the in vivo eradication of some lymphoma cells.


Assuntos
Antígenos Ly/imunologia , Citotoxicidade Imunológica/imunologia , Células Matadoras Naturais/imunologia , Linfoma/imunologia , Receptor 1 Desencadeador da Citotoxicidade Natural/imunologia , Animais , Antígenos Ly/genética , Citometria de Fluxo , Técnicas In Vitro , Linfoma/genética , Camundongos , Camundongos Knockout , Receptor 1 Desencadeador da Citotoxicidade Natural/genética
9.
Nat Immunol ; 9(9): 1065-73, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18677316

RESUMO

MICA and MICB are stress-induced ligands recognized by the activating receptor NKG2D. A microRNA encoded by human cytomegalovirus downregulates MICB expression by targeting a specific site in the MICB 3' untranslated region. As this site is conserved among different MICB alleles and a similar site exists in the MICA 3' untranslated region, we speculated that these sites are targeted by cellular microRNAs. Here we identified microRNAs that bound to these MICA and MICB 3' untranslated region sequences and obtained data suggesting that these microRNAs maintain expression of MICA and MICB protein under a certain threshold and facilitate acute upregulation of MICA and MICB during cellular stress. These microRNAs were overexpressed in various tumors and we demonstrate here that they aided tumor avoidance of immune recognition.


Assuntos
Antígenos de Histocompatibilidade Classe I/metabolismo , MicroRNAs/fisiologia , Receptores Imunológicos/metabolismo , Estresse Fisiológico/imunologia , Antígenos de Superfície/metabolismo , Linhagem Celular , Vetores Genéticos , Antígenos de Histocompatibilidade Classe I/química , Humanos , MicroRNAs/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK , Receptores de Células Matadoras Naturais , Estresse Fisiológico/genética , Estresse Fisiológico/metabolismo
10.
Blood ; 109(10): 4306-12, 2007 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-17255357

RESUMO

Griscelli syndrome (GS) type 2 is an autosomal recessive disorder represented by pigment dilution and impaired cytotoxic T lymphocyte (CTL) activity. NK activity has been scarcely investigated in GS patients. Here, we describe a new patient, possessing a hemophagocytic syndrome with a homozygous Q118X nonsense RAB27A mutation. Single specific primer-polymerase chain reaction (SSP-PCR) was developed based on this mutation and is currently used in prenatal genetic analysis. As expected, CTLs in the patient are not functional and NK cytotoxicity against K562 or 721.221 cells is diminished. Surprisingly, however, we demonstrate that CD16-mediated killing is intact in this patient and is therefore RAB27A independent, whereas NKp30-mediated killing is impaired and is therefore RAB27A dependent. We further analyzed the signaling pathways of these 2 receptors and demonstrated phosphorylation of Vav1 after CD16 activation but not after NKp30 engagement. Thus, we identify a novel homozygous mutation in the RAB27A gene of a new GS patient, observe for the first time that some activating NK receptors function in GS patients, and demonstrate a functional dichotomy in the killing mediated by these human NK-activating receptors.


Assuntos
Antígenos CD/fisiologia , Citotoxicidade Imunológica , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Células Matadoras Naturais/imunologia , Receptores de IgG/fisiologia , Receptores Imunológicos/fisiologia , Sequência de Aminoácidos , Citotoxicidade Celular Dependente de Anticorpos/genética , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Sequência de Bases , Células Cultivadas , Análise Mutacional de DNA , Feminino , Proteínas Ligadas por GPI , Humanos , Lactente , Células K562 , Mutação , Receptor 3 Desencadeador da Citotoxicidade Natural , Proteínas rab de Ligação ao GTP/genética , Proteínas rab27 de Ligação ao GTP
11.
Nat Immunol ; 7(5): 517-23, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16565719

RESUMO

The elimination of viruses and tumors by natural killer cells is mediated by specific natural killer cell receptors. To study the in vivo function of a principal activating natural killer cell receptor, NCR1 (NKp46 in humans), we replaced the gene encoding this receptor (Ncr1) with a green fluorescent protein reporter cassette. There was enhanced spread of certain tumors in 129/Sv but not C57BL/6 Ncr1(gfp/gfp) mice, and influenza virus infection was lethal in both 129/Sv and C57BL/6 Ncr1(gfp/gfp) mice. We noted accumulation of natural killer cells at the site of influenza infection by tracking the green fluorescent protein. Our results demonstrate a critical function for Ncr1 in the in vivo eradication of influenza virus.


Assuntos
Vírus da Influenza A/imunologia , Células Matadoras Naturais/imunologia , Infecções por Orthomyxoviridae/imunologia , Receptores Imunológicos/genética , Animais , Linhagem Celular , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Imunidade Inata/imunologia , Células Matadoras Naturais/metabolismo , Camundongos , Camundongos Knockout , Receptor 1 Desencadeador da Citotoxicidade Natural , Receptores Imunológicos/deficiência , Receptores Imunológicos/metabolismo , Especificidade da Espécie , Taxa de Sobrevida
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