RESUMEN
Many emerging cancer treatments are immunotherapies that modulate Natural Killer- (NK) or T cell activation, posing a challenge to develop immunoengineering nanomaterials that improve on the performance of molecular reagents. In physiological activation, multiple immunoreceptors signal in consort; however, current biomaterials do not replicate this. Here, NK cells are created for the first time, activating bionanomaterials that stimulate >2 immunoreceptors. Nanoclusters of monoclonal antibodies (mAb), templated by nanoscale graphene oxide sheets (NGO) (≈75 nm size), are exploited. To inform nanoreagent design, a model system of planar substrates with anchored mAb is first investigated. Combining mAb that stimulates three NK cell activating receptors (αNKP46 + αNKG2D + αDNAM-1), activated NK cells act more potently than any single receptor or pair. Applying this insight, an NGO-mAb nanocluster combining three distinct mAb: NGO-mAb(αNKP46 + αNKG2D + αDNAM-1) is created. This construct is potent and outperforms single-receptor-simulating nanoclusters, activating nearly twice as many NK cells as NGO-mAb(αNKP46) at a similar mAb dose or delivering similar activation at 10× lower dosage. Further, NGO-mAb are more potent than planar substrates for both single- and triple-mAb stimulation. These results imply a new concept for immunoengineering biomaterials: both nanoclustering and multi-receptor stimulation should be incorporated for maximum effect.
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Citotoxicidad Inmunológica , Células Asesinas Naturales , Activación de LinfocitosRESUMEN
Treating colorectal cancer (CRC) is a major challenge due to the heterogeneous immunological, clinical and pathological landscapes. Immunotherapy has so far only proven effective in a very limited subgroup of CRC patients. To better define the immune landscape, we examined the immune gene expression profile in various subsets of CRC patients and used a mouse model of intestinal tumors to dissect immune functions. We found that the NK cell receptor, natural-killer group 2 member D (NKG2D, encoded by KLRK1) and NKG2D ligand gene expression is elevated in the most immunogenic subset of CRC patients. High level of KLRK1 positively correlated with the mRNA expression of IFNG and associated with a poor survival of CRC patients. We further show that NKG2D deficiency in the Apcmin/+ mouse model of intestinal tumorigenesis led to reduced intratumoral IFNγ production, reduced tumorigenesis and enhanced survival, suggesting that the high levels of IFNγ observed in the tumors of CRC patients may be a consequence of NKG2D engagement. The mechanisms governing the contribution of NKG2D to CRC progression highlighted in this study will fuel discussions about (i) the benefit of targeting NKG2D in CRC patients and (ii) the need to define the predictive value of NKG2D and NKG2D ligand expression across tumor types.
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γδT cells are unconventional T cells particularly abundant in mucosal tissues that play an important role in tissue surveillance, homeostasis, and cancer. γδT cells recognize stressed cells or cancer cells through the NKG2D receptor to kill these cells and maintain normality. Contrary to the well-established anti-tumor function of these NKG2D-expressing γδT cells, we show here that, in mice, NKG2D regulates a population of pro-tumor γδT cells capable of producing IL-17A. Germline deletion of Klrk1, the gene encoding NKG2D, reduced the frequency of γδT cells in the tumor microenvironment and delayed tumor progression. We further show that blocking NKG2D reduced the capability of γδT cells to produce IL-17A in the pre-metastatic lung and that co-culture of lung T cells with NKG2D ligand-expressing tumor cells specifically increased the frequency of γδT cells. Together, these data support the hypothesis that, in a tumor microenvironment where NKG2D ligands are constitutively expressed, γδT cells accumulate in an NKG2D-dependent manner and drive tumor progression by secreting pro-inflammatory cytokines, such as IL-17A.
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Natural killer (NK) cell responses depend on the balance of signals from inhibitory and activating receptors. However, how the integration of antagonistic signals occurs upon NK cell-target cell interaction is not fully understood. Here we provide evidence that NK cell inhibition via the inhibitory receptor Ly49A is dependent on its relative colocalization at the nanometer scale with the activating receptor NKG2D upon immune synapse (IS) formation. NKG2D and Ly49A signal integration and colocalization were studied using NKG2D-GFP and Ly49A-RFP-expressing primary NK cells, forming ISs with NIH3T3 target cells, with or without the expression of single-chain trimer (SCT) H2-Dd and an extended form of SCT H2-Dd-CD4 MHC-I molecules. Nanoscale colocalization was assessed by Förster resonance energy transfer between NKG2D-GFP and Ly49A-RFP and measured for each synapse. In the presence of their respective cognate ligands, NKG2D and Ly49A colocalize at the nanometer scale, leading to NK cell inhibition. However, increasing the size of the Ly49A ligand reduced the nanoscale colocalization with NKG2D, consequently impairing Ly49A-mediated inhibition. Thus, our data shows that NK cell signal integration is critically dependent on the dimensions of NK cell ligand-receptor pairs by affecting their relative nanometer-scale colocalization at the IS. Our results together suggest that the balance of NK cell signals and NK cell responses is determined by the relative nanoscale colocalization of activating and inhibitory receptors in the immune synapse.
Asunto(s)
Subfamilia A de Receptores Similares a Lectina de Células NK , Subfamilia K de Receptores Similares a Lectina de Células NK , Animales , Proteínas Portadoras/metabolismo , Antígenos H-2 , Antígeno de Histocompatibilidad H-2D/metabolismo , Células Asesinas Naturales , Lectinas Tipo C/metabolismo , Ligandos , Ratones , Células 3T3 NIH , Subfamilia A de Receptores Similares a Lectina de Células NK/metabolismo , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismo , Receptores Similares a Lectina de Células NK/metabolismo , Receptores de Células Asesinas Naturales/metabolismoRESUMEN
BACKGROUND & AIMS: The NKG2D system is a potent immunosurveillance mechanism in cancer, wherein the activating NK cell receptor (NKG2D) on immune cells recognises its cognate ligands on tumour cells. Herein, we evaluated the expression of NKG2D ligands in hepatocellular carcinoma (HCC), in both humans and mice, taking the genomic features of HCC tumours into account. METHODS: The expression of NKG2D ligands (MICA, MICB, ULBP1 and ULBP2) was analysed in large human HCC datasets by Fluidigm TaqMan and RNA-seq methods, and in 2 mouse models (mRNA and protein levels) reproducing the features of both major groups of human tumours. RESULTS: We provide compelling evidence that expression of the MICA and MICB ligands in human HCC is associated with tumour aggressiveness and poor patient outcome. We also found that the expression of ULBP1 and ULBP2 was associated with poor patient outcome, and was downregulated in CTNNB1-mutated HCCs displaying low levels of inflammation and associated with a better prognosis. We also found an inverse correlation between ULBP1/2 expression levels and the expression of ß-catenin target genes in patients with HCC, suggesting a role for ß-catenin signalling in inhibiting expression. We showed in HCC mouse models that ß-catenin signalling downregulated the expression of Rae-1 NKG2D ligands, orthologs of ULBPs, through TCF4 binding. CONCLUSIONS: We demonstrate that the expression of NKG2D ligands is associated with aggressive liver tumorigenesis and that the downregulation of these ligands by ß-catenin signalling may account for the less aggressive phenotype of CTNNB1-mutated HCC tumours. LAY SUMMARY: The NKG2D system is a potent immunosurveillance mechanism in cancer. However, its role in hepatocellular carcinoma development has not been widely investigated. Herein, we should that the expression of NKG2D ligands by tumour cells is associated with a more aggressive tumour subtype.
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Carcinoma Hepatocelular/metabolismo , Regulación hacia Abajo/genética , Regulación Neoplásica de la Expresión Génica , Antígenos de Histocompatibilidad Clase I/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Neoplasias Hepáticas/metabolismo , Transducción de Señal/genética , beta Catenina/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Carcinogénesis/genética , Carcinogénesis/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Estudios de Cohortes , Modelos Animales de Enfermedad , Femenino , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/metabolismo , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Pronóstico , Adulto JovenRESUMEN
Inflammation can support or restrain cancer progression and the response to therapy. Here, we searched for primary regulators of cancer-inhibitory inflammation through deep profiling of inflammatory tumor microenvironments (TMEs) linked to immune-dependent control in mice. We found that early intratumoral accumulation of interferon gamma (IFN-γ)-producing natural killer (NK) cells induced a profound remodeling of the TME and unleashed cytotoxic T cell (CTL)-mediated tumor eradication. Mechanistically, tumor-derived prostaglandin E2 (PGE2) acted selectively on EP2 and EP4 receptors on NK cells, hampered the TME switch, and enabled immune evasion. Analysis of patient datasets across human cancers revealed distinct inflammatory TME phenotypes resembling those associated with cancer immune control versus escape in mice. This allowed us to generate a gene-expression signature that integrated opposing inflammatory factors and predicted patient survival and response to immune checkpoint blockade. Our findings identify features of the tumor inflammatory milieu associated with immune control of cancer and establish a strategy to predict immunotherapy outcomes.
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Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inflamación/inmunología , Neoplasias/inmunología , Escape del Tumor/inmunología , Animales , Dinoprostona/metabolismo , Humanos , Inmunoterapia , Inflamación/genética , Interferón gamma/metabolismo , Células Asesinas Naturales/inmunología , Ratones , Neoplasias/terapia , Fenotipo , Pronóstico , Prostaglandina-Endoperóxido Sintasas/genética , Subtipo EP2 de Receptores de Prostaglandina E/metabolismo , Subtipo EP4 de Receptores de Prostaglandina E/metabolismo , Linfocitos T Citotóxicos/inmunología , Microambiente Tumoral/inmunologíaRESUMEN
Hepatocellular carcinoma (HCC) is the third most frequent cause of cancer-related death. The immune-rich contexture of the HCC microenvironment makes this tumour an appealing target for immune-based therapies. Here, we discuss how the functional characteristics of the liver microenvironment can potentially be harnessed for the treatment of HCC. We will review the evidence supporting a therapeutic role for vaccines, cell-based therapies and immune-checkpoint inhibitors and discuss the potential for patient stratification in an attempt to overcome the series of failures that has characterised drug development in this disease area.
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Carcinoma Hepatocelular/terapia , Inmunoterapia , Neoplasias Hepáticas/terapia , Microambiente Tumoral/inmunología , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/uso terapéutico , Carcinoma Hepatocelular/inmunología , Tratamiento Basado en Trasplante de Células y Tejidos/tendencias , Humanos , Hígado/inmunología , Neoplasias Hepáticas/inmunologíaRESUMEN
The activating receptor NKG2D and its ligands are recognized as a potent immune axis that controls tumor growth and microbial infections. With regards to cancer surveillance, various studies have demonstrated the antitumor function mediated by NKG2D on natural killer cells and on conventional and unconventional T cells. The use of NKG2D-deficient mice established the importance of NKG2D in delaying tumor development in transgenic mouse models of cancer. However, we recently demonstrated an unexpected, flip side to this coin, the ability for NKG2D to contribute to tumor growth in a model of inflammation-driven liver cancer. With a focus on the liver, here, we review current knowledge of NKG2D-mediated tumor surveillance and discuss evidence supporting a dual role for NKG2D in cancer immunity. We postulate that in certain advanced cancers, expression of ligands for NKG2D can drive cancer progression rather than rejection. We propose that the nature of the microenvironment within and surrounding tumors impacts the outcome of NKG2D activation. In a form of autoimmune attack, NKG2D promotes tissue damage, mostly in the inflamed tissue adjacent to the tumor, facilitating tumor progression while being ineffective at rejecting transformed cells in the tumor bed.
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Inmunidad , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismo , Neoplasias/etiología , Neoplasias/metabolismo , Animales , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Progresión de la Enfermedad , Hepatitis/complicaciones , Humanos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Ligandos , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Subfamilia K de Receptores Similares a Lectina de Células NK/genética , Neoplasias/patología , Unión Proteica , Linfocitos T/inmunología , Linfocitos T/metabolismo , Microambiente Tumoral/inmunologíaRESUMEN
TRAIL is an apoptosis-inducing ligand constitutively expressed on liver-resident type 1 innate lymphoid cells (ILC1s) and a subset of natural killer (NK) cells, where it contributes to NK cell anti-tumor, anti-viral, and immunoregulatory functions. However, the intrinsic pathways involved in TRAIL expression in ILCs remain unclear. Here, we demonstrate that the murine natural cytotoxic receptor mNKp46/NCR1, expressed on ILC1s and NK cells, controls TRAIL protein expression. Using NKp46-deficient mice, we show that ILC1s lack constitutive expression of TRAIL protein and that NK cells activated in vitro and in vivo fail to upregulate cell surface TRAIL in the absence of NKp46. We show that NKp46 regulates TRAIL expression in a dose-dependent manner and that the reintroduction of NKp46 in mature NK cells deficient for NKp46 is sufficient to restore TRAIL surface expression. These studies uncover a link between NKp46 and TRAIL expression in ILCs with potential implications in pathologies involving NKp46-expressing cells.
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Antígenos Ly/metabolismo , Células Asesinas Naturales/metabolismo , Linfocitos/metabolismo , Receptor 1 Gatillante de la Citotoxidad Natural/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/biosíntesis , Animales , Antígenos Ly/inmunología , Células Asesinas Naturales/inmunología , Hígado/citología , Hígado/inmunología , Hígado/metabolismo , Linfocitos/inmunología , Ratones , Ratones Transgénicos , Receptor 1 Gatillante de la Citotoxidad Natural/inmunología , Ligando Inductor de Apoptosis Relacionado con TNF/inmunología , Regulación hacia ArribaRESUMEN
Inflammation is recognized as one of the drivers of cancer. Yet, the individual immune components that possess pro- and anti-tumorigenic functions in individual cancers remain largely unknown. NKG2D is a potent activating immunoreceptor that has emerged as an important player in inflammatory disorders besides its well-established function as tumour suppressor. Here, we provide genetic evidence of an unexpected tumour-promoting effect of NKG2D in a model of inflammation-driven liver cancer. Compared to NKG2D-deficient mice, NKG2D-sufficient mice display accelerated tumour growth associated with, an increased recruitment of memory CD8+T cells to the liver and exacerbated pro-inflammatory milieu. In addition, we show that NKG2D contributes to liver damage and consequent hepatocyte proliferation known to favour tumorigenesis. Thus, the NKG2D/NKG2D-ligand pathway provides an additional mechanism linking chronic inflammation to tumour development in hepatocellular carcinoma. Our findings expose the need to selectively target the types of cancer that could benefit from NKG2D-based immunotherapy.
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Carcinoma Hepatocelular/patología , Neoplasias Hepáticas Experimentales/patología , Neoplasias Hepáticas/patología , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Animales , Antineoplásicos Inmunológicos/farmacología , Antineoplásicos Inmunológicos/uso terapéutico , Carcinogénesis/efectos de los fármacos , Carcinogénesis/patología , Carcinoma Hepatocelular/inducido químicamente , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/inmunología , Proliferación Celular/efectos de los fármacos , Dietilnitrosamina/toxicidad , Progresión de la Enfermedad , Hepatocitos/inmunología , Hepatocitos/patología , Humanos , Inmunoterapia/métodos , Ligandos , Hígado/citología , Hígado/patología , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas Experimentales/inducido químicamente , Neoplasias Hepáticas Experimentales/tratamiento farmacológico , Neoplasias Hepáticas Experimentales/inmunología , Masculino , Ratones , Ratones Noqueados , Subfamilia K de Receptores Similares a Lectina de Células NK/genética , Subfamilia K de Receptores Similares a Lectina de Células NK/inmunología , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/inmunologíaRESUMEN
Rhenium (I)-diselenother (Re-diselenoether) is a water soluble metal-based compound, combining one atom of rhenium and two atoms of selenium. This compound has been reported to exhibit marked activities against several solid tumor cell lines. We now disclose an improved synthesis of this complex. The Re-diselenoether showed a potent inhibitory effect on MDA-MB231 cell division in vitro, which lasted when the complex was no longer present in the culture. Re-diselenoether induced a remarkable reduction of the volume of the primitive breast tumors and of the pulmonary metastases without clinical signs of toxicity, in mice-bearing a MDA-MB231 Luc+ tumor, orthotopically transplanted, after a daily oral administration at the dose of 10 mg/kg/d. Interestingly, an antagonism was observed when cisplatin was administered as a single i.p. injection 1 week after the end of the Re-diselenoether administration. In an effort to gain insight of the mechanisms of action of Re-diselenoether complex, interaction with 9-methylguanine as a nucleic acid base model was studied. We have shown that Re-diselenoether gave both mono- and bis-guanine Re adducts, the species assumed to be responsible for the DNA intrastrand lesions.
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Antineoplásicos/uso terapéutico , Complejos de Coordinación/uso terapéutico , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Renio/uso terapéutico , Selenio/uso terapéutico , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/farmacología , Femenino , Guanina/análogos & derivados , Guanina/metabolismo , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundario , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Ratones Desnudos , Renio/farmacología , Selenio/farmacología , Distribución Tisular , Carga Tumoral/efectos de los fármacosRESUMEN
Fluorescence lifetime imaging (FLIM) has previously been shown to provide contrast between normal and diseased tissue. Here we present progress towards clinical and preclinical FLIM endoscopy of tissue autofluorescence, demonstrating a flexible wide-field endoscope that utilised a low average power blue picosecond laser diode excitation source and was able to acquire â¼mm-scale spatial maps of autofluorescence lifetimes from fresh ex vivo diseased human larynx biopsies in â¼8 seconds using an average excitation power of â¼0.5 mW at the specimen. To illustrate its potential for FLIM at higher acquisition rates, a higher power mode-locked frequency doubled Ti:Sapphire laser was used to demonstrate FLIM of ex vivo mouse bowel at up to 2.5 Hz using 10 mW of average excitation power at the specimen.
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Endoscopios , Luz , Imagen Óptica/instrumentación , Animales , Color , Colorantes Fluorescentes/metabolismo , Humanos , Neoplasias Intestinales/patología , Laringe/citología , Laringe/metabolismo , RatonesRESUMEN
BACKGROUND: The diverse roles of innate immune cells in the pathogenesis of asthma remain to be fully defined. Natural killer (NK) cells are innate lymphocytes that can regulate adaptive immune responses. NK cells are activated in asthma; however, their role in allergic airway inflammation is not fully understood. OBJECTIVE: We investigated the importance of NK cells in house dust mite (HDM)-triggered allergic pulmonary inflammation. Specifically, we aimed to determine the role of the major NK-cell activating receptor NKG2D and NK-cell effector functions mediated by granzyme B. METHODS: Allergic airway inflammation was induced in the airways of mice by repeated intranasal HDM extract administration and responses in wild-type and NKG2D-deficient mice were compared. Adoptive transfer studies were used to identify the cells and mechanisms involved. RESULTS: Mice that lacked NKG2D were resistant to the induction of allergic inflammation and showed little pulmonary eosinophilia, few airway TH2 cells, and no rise in serum IgE after multiple HDM-allergen exposures. However, NKG2D was not required for pulmonary inflammation after a single inoculation of allergen. NKG2D-deficient mice showed no alteration in responses to respiratory virus infection. Transfer of wild-type NK cells (but not CD3(+) cells) into NKG2D-deficient mice restored allergic inflammatory responses only if the NK cells expressed granzyme B. CONCLUSIONS: These studies established a pivotal role for NK-cell NKG2D and granzyme B in the pathogenesis of HDM-induced allergic lung disease, and identified novel therapeutic targets for the prevention and treatment of asthma.
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Asma/etiología , Granzimas/fisiología , Células Asesinas Naturales/inmunología , Subfamilia K de Receptores Similares a Lectina de Células NK/fisiología , Neumonía/etiología , Animales , Asma/inmunología , Femenino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Neumonía/inmunología , Pyroglyphidae/inmunologíaRESUMEN
The non-destructive ex vivo determination of haemoglobin (Hgb) concentration offers the capability to conduct multiple red blood cell haematological measurements on a single sample, an advantage that current optical techniques are unable to offer. Here, a microwave method and device for the accurate and non-destructive determination of Hgb concentration in microlitre blood samples are described. Using broadband microwave spectroscopy, a relationship is established between the dielectric properties of murine blood and Hgb concentration that is utilized to create a technique for the determination of Hgb concentration. Subsequently, a microwave dielectric resonator-microfluidic system is implemented in the analysis of 52 murine samples with microlitre volumes and Hgb concentrations ranging from 0 to 17 g dL(-1) . Using the characterized relationship, independent and minimally invasive Hgb measurements are made on nine healthy mice as well as seven with mutations in the Adenomatous polyposis coli (APC) gene that leads to colorectal cancer and consequently anaemia.
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Eritrocitos/química , Hemoglobinas/análisis , Microondas , Animales , Proteínas Sanguíneas/análisis , Proteínas Sanguíneas/química , Espectroscopía Dieléctrica , Electrólitos/sangre , Electrólitos/química , Eritrocitos/efectos de la radiación , Ratones , Suero/química , Suero/efectos de la radiaciónRESUMEN
The NKG2D activating receptor has been implicated in numerous autoimmune diseases. We tested the role of NKG2D in models of autoimmunity and inflammation using NKG2D knockout mice and antibody blockade experiments. The severity of experimental autoimmune encephalitis (EAE) was decreased in NKG2D-deficient mice when the disease was induced with a limiting antigen dose, but unchanged with an optimal antigen dose. Surprisingly, however, NKG2D deficiency had no detectable effect in several other models, including two models of type 1 diabetes, and a model of intestinal inflammation induced by poly(I:C). NKG2D antibody blockade in normal mice also failed to inhibit disease in the NOD diabetes model or the intestinal inflammation model. Published evidence using NKG2D knockout mice demonstrated a role for NKG2D in mouse models of atherosclerosis and liver inflammation, as well as in chronic obstructive pulmonary disease. Therefore, our results suggest that NKG2D plays selective roles in inflammatory diseases.
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Diabetes Mellitus Tipo 1/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Enfermedades Inflamatorias del Intestino/inmunología , Células Asesinas Naturales/inmunología , Subfamilia K de Receptores Similares a Lectina de Células NK/inmunología , Secuencia de Aminoácidos , Animales , Anticuerpos Neutralizantes/farmacología , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patología , Encefalomielitis Autoinmune Experimental/inducido químicamente , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/patología , Femenino , Expresión Génica , Enfermedades Inflamatorias del Intestino/inducido químicamente , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/patología , Células Asesinas Naturales/patología , Masculino , Ratones , Ratones Endogámicos NOD , Ratones Noqueados , Datos de Secuencia Molecular , Glicoproteína Mielina-Oligodendrócito , Subfamilia K de Receptores Similares a Lectina de Células NK/deficiencia , Subfamilia K de Receptores Similares a Lectina de Células NK/genética , Fragmentos de Péptidos , Poli I-C , Índice de Severidad de la EnfermedadRESUMEN
The immunoreceptors NKG2D and NKp46 are known for their capacity to activate natural killer (NK) cell cytotoxicity and secretory responses in the contexts of tumors and infections, yet their roles in NK cell education remain unclear. Here, we provide the first characterization of mice deficient for both NKG2D and NKp46 receptors to address the relevance of their concomitant absence during NK cell development and function. Our findings reveal that NK cells develop normally in double-mutant (DKO) mice. Mice lacking NKG2D but not NKp46 showed subtle differences in the percentages of NK cells expressing inhibitory Ly49 receptors and the adhesion molecule DNAM-1. A slightly increased percentage of terminally differentiated NK cells and functional response to in vitro stimuli was observed in some experiments. These alterations were modest and did not affect NK cell function in vivo in response to mouse cytomegalovirus infection. NKp46 deficiency alone, or in combination with NKG2D deficiency, had no effect on frequency or function of NK cells.
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Antígenos Ly/inmunología , Células Asesinas Naturales/inmunología , Subgrupos Linfocitarios/inmunología , Subfamilia K de Receptores Similares a Lectina de Células NK/inmunología , Receptor 1 Gatillante de la Citotoxidad Natural/inmunología , Animales , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Subfamilia K de Receptores Similares a Lectina de Células NK/deficiencia , Receptor 1 Gatillante de la Citotoxidad Natural/deficienciaRESUMEN
BACKGROUND: The interplay between the immune system and abnormal metabolic conditions sustains and propagates a vicious feedback cycle of chronic inflammation and metabolic dysfunction that is critical for atherosclerotic progression. It is well established that abnormal metabolic conditions, such as dyslipidemia and hyperglycemia, cause various cellular stress responses that induce tissue inflammation and immune cell activation, which in turn exacerbate the metabolic dysfunction. However, molecular events linking these processes are not well understood. METHODS AND RESULTS: Tissues and organs of humans and mice with hyperglycemia and hyperlipidemia were examined for expression of ligands for NKG2D, a potent immune-activating receptor expressed by several types of immune cells, and the role of NKG2D in atherosclerosis and metabolic diseases was probed with the use of mice lacking NKG2D or by blocking NKG2D with monoclonal antibodies. NKG2D ligands were upregulated in multiple organs, particularly atherosclerotic aortas and inflamed livers. Ligand upregulation was induced in vitro by abnormal metabolites associated with metabolic dysfunctions. Using apolipoprotein E-deficient mouse models, we demonstrated that preventing NKG2D functions resulted in a dramatic reduction in plaque formation, suppressed systemic and organ inflammation mediated by multiple immune cell types, and alleviated abnormal metabolic conditions. CONCLUSIONS: The NKG2D/ligand interaction is a critical molecular link in the vicious cycle of chronic inflammation and metabolic dysfunction that promotes atherosclerosis and might be a useful target for therapeutic intervention in the disease.
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Aterosclerosis/inmunología , Diabetes Mellitus Experimental/inmunología , Síndrome Metabólico/inmunología , Subfamilia K de Receptores Similares a Lectina de Células NK/inmunología , Animales , Anticuerpos Bloqueadores/farmacología , Anticuerpos Monoclonales/farmacología , Apolipoproteínas E/genética , Aterosclerosis/genética , Aterosclerosis/metabolismo , Biomarcadores/metabolismo , Citocinas/metabolismo , Diabetes Mellitus Experimental/metabolismo , Hepatitis/inmunología , Hepatitis/metabolismo , Humanos , Sistema Inmunológico/inmunología , Ligandos , Masculino , Síndrome Metabólico/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismo , Regulación hacia Arriba/inmunologíaRESUMEN
A growing body of research is addressing how pathways that are dysregulated during tumorigenesis are linked to innate immune responses, which can contribute to immune surveillance of cancer. Components of the innate immune system that are localized in tissues are thought to eliminate early neoplastic cells, thereby preventing or delaying the establishment of advanced tumours. This Review addresses our current understanding of the mechanisms that detect cellular stresses that are associated with tumorigenesis and that culminate in the recognition and, in some cases, the elimination of the tumour cells by natural killer cells and other lymphocytes that express natural killer cell receptors.