Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 122
Filtrar
1.
Cell ; 177(7): 1701-1713.e16, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31155232

RESUMO

Over the last decade, various new therapies have been developed to promote anti-tumor immunity. Despite interesting clinical results in hematological malignancies, the development of bispecific killer-cell-engager antibody formats directed against tumor cells and stimulating anti-tumor T cell immunity has proved challenging, mostly due to toxicity problems. We report here the generation of trifunctional natural killer (NK) cell engagers (NKCEs), targeting two activating receptors, NKp46 and CD16, on NK cells and a tumor antigen on cancer cells. Trifunctional NKCEs were more potent in vitro than clinical therapeutic antibodies targeting the same tumor antigen. They had similar in vivo pharmacokinetics to full IgG antibodies and no off-target effects and efficiently controlled tumor growth in mouse models of solid and invasive tumors. Trifunctional NKCEs thus constitute a new generation of molecules for fighting cancer. VIDEO ABSTRACT.


Assuntos
Anticorpos Biespecíficos , Antígenos Ly/imunologia , Antineoplásicos Imunológicos , Citotoxicidade Imunológica/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Receptor 1 Desencadeador da Citotoxicidade Natural/imunologia , Neoplasias Experimentais , Animais , Anticorpos Biespecíficos/imunologia , Anticorpos Biespecíficos/uso terapêutico , Antineoplásicos Imunológicos/imunologia , Antineoplásicos Imunológicos/farmacologia , Humanos , Imunoglobulina G/imunologia , Imunoglobulina G/farmacologia , Células Matadoras Naturais/patologia , Camundongos , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia
2.
Nat Immunol ; 22(10): 1245-1255, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34556884

RESUMO

Innate lymphoid cells (ILCs) are guardians of mucosal immunity, yet the transcriptional networks that support their function remain poorly understood. We used inducible combinatorial deletion of key transcription factors (TFs) required for ILC development (RORγt, RORα and T-bet) to determine their necessity in maintaining ILC3 identity and function. Both RORγt and RORα were required to preserve optimum effector functions; however, RORα was sufficient to support robust interleukin-22 production among the lymphoid tissue inducer (LTi)-like ILC3 subset, but not natural cytotoxicity receptor (NCR)+ ILC3s. Lymphoid tissue inducer-like ILC3s persisted with only selective loss of phenotype and effector functions even after the loss of both TFs. In contrast, continued RORγt expression was essential to restrain transcriptional networks associated with type 1 immunity within NCR+ ILC3s, which coexpress T-bet. Full differentiation to an ILC1-like population required the additional loss of RORα. Together, these data demonstrate how TF networks integrate within mature ILCs after development to sustain effector functions, imprint phenotype and restrict alternative differentiation programs.


Assuntos
Imunidade Inata/imunologia , Linfócitos/imunologia , Animais , Diferenciação Celular/imunologia , Linhagem da Célula/imunologia , Células Cultivadas , Feminino , Regulação da Expressão Gênica/imunologia , Imunidade nas Mucosas/imunologia , Tecido Linfoide/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptor 1 Desencadeador da Citotoxicidade Natural/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Proteínas com Domínio T/imunologia , Fatores de Transcrição/imunologia
3.
Nat Immunol ; 19(10): 1083-1092, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30224819

RESUMO

The activation of natural killer (NK) cells depends on a change in the balance of signals from inhibitory and activating receptors. The activation threshold values of NK cells are thought to be set by engagement of inhibitory receptors during development. Here, we found that the activating receptor NKG2D specifically set the activation threshold for the activating receptor NCR1 through a process that required the adaptor DAP12. As a result, NKGD2-deficient (Klrk1-/-) mice controlled tumors and cytomegalovirus infection better than wild-type controls through the NCR1-induced production of the cytokine IFN-γ. Expression of NKG2D before the immature NK cell stage increased expression of the adaptor CD3ζ. Reduced expression of CD3ζ in Klrk1-/- mice was associated with enhanced signal transduction through NCR1, and CD3ζ deficiency resulted in hyper-responsiveness to stimulation via NCR1. Thus, an activating receptor developmentally set the activity of another activating receptor on NK cells and determined NK cell reactivity to cellular threats.


Assuntos
Antígenos Ly/imunologia , Citotoxicidade Imunológica/imunologia , Células Matadoras Naturais/imunologia , Ativação Linfocitária/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Receptor 1 Desencadeador da Citotoxicidade Natural/imunologia , Animais , Camundongos , Camundongos Knockout
4.
Immunity ; 54(6): 1320-1337.e4, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-33945787

RESUMO

Natural killer (NK) cells and type 1 innate lymphoid cells (ILC1s) are heterogenous innate lymphocytes broadly defined in mice as Lin-NK1.1+NKp46+ cells that express the transcription factor T-BET and produce interferon-γ. The ILC1 definition primarily stems from studies on liver and small intestinal populations. However, NK1.1+NKp46+ cells in the salivary glands, uterus, adipose, and other tissues exhibit nonuniform programs that differ from those of liver or intestinal ILC1s or NK cells. Here, we performed single-cell RNA sequencing on murine NK1.1+NKp46+ cells from blood, spleen, various tissues, and solid tumors. We identified gene expression programs of tissue-specific ILC1s, tissue-specific NK cells, and non-tissue-specific populations in blood, spleen, and other tissues largely corresponding to circulating cells. Moreover, we found that circulating NK cell programs were reshaped in tumor-bearing mice. Core programs of circulating and tumor NK cells paralleled conserved human NK cells signatures, advancing our understanding of the human NK-ILC1 spectrum.


Assuntos
Imunidade Inata/imunologia , Células Matadoras Naturais/imunologia , Linfócitos/imunologia , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Subfamília B de Receptores Semelhantes a Lectina de Células NK/imunologia , Receptor 1 Desencadeador da Citotoxicidade Natural/imunologia , Neoplasias/imunologia , Análise de Célula Única/métodos , Fatores de Transcrição/imunologia
5.
Nat Immunol ; 16(4): 376-85, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25729921

RESUMO

An important cause of obesity-induced insulin resistance is chronic systemic inflammation originating in visceral adipose tissue (VAT). VAT inflammation is associated with the accumulation of proinflammatory macrophages in adipose tissue, but the immunological signals that trigger their accumulation remain unknown. We found that a phenotypically distinct population of tissue-resident natural killer (NK) cells represented a crucial link between obesity-induced adipose stress and VAT inflammation. Obesity drove the upregulation of ligands of the NK cell-activating receptor NCR1 on adipocytes; this stimulated NK cell proliferation and interferon-γ (IFN-γ) production, which in turn triggered the differentiation of proinflammatory macrophages and promoted insulin resistance. Deficiency of NK cells, NCR1 or IFN-γ prevented the accumulation of proinflammatory macrophages in VAT and greatly ameliorated insulin sensitivity. Thus NK cells are key regulators of macrophage polarization and insulin resistance in response to obesity-induced adipocyte stress.


Assuntos
Adipócitos/imunologia , Resistência à Insulina/imunologia , Gordura Intra-Abdominal/imunologia , Células Matadoras Naturais/imunologia , Macrófagos/imunologia , Obesidade/imunologia , Adipócitos/patologia , Animais , Antígenos Ly/genética , Antígenos Ly/imunologia , Diferenciação Celular , Feminino , Regulação da Expressão Gênica , Humanos , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Insulina/imunologia , Interferon gama/biossíntese , Interferon gama/imunologia , Gordura Intra-Abdominal/patologia , Células Matadoras Naturais/patologia , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptor 1 Desencadeador da Citotoxicidade Natural/genética , Receptor 1 Desencadeador da Citotoxicidade Natural/imunologia , Obesidade/genética , Obesidade/patologia , Transdução de Sinais
6.
Proc Natl Acad Sci U S A ; 118(10)2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33649222

RESUMO

Natural killer (NK) cells are innate effectors armed with cytotoxic and cytokine-secreting capacities whose spontaneous antitumor activity is key to numerous immunotherapeutic strategies. However, current mouse models fail to mirror the extensive immune system variation that exists in the human population which may impact on NK cell-based therapies. We performed a comprehensive profiling of NK cells in the Collaborative Cross (CC), a collection of novel recombinant inbred mouse strains whose genetic diversity matches that of humans, thereby providing a unique and highly diverse small animal model for the study of immune variation. We demonstrate that NK cells from CC strains displayed a breadth of phenotypic and functional variation reminiscent of that reported for humans with regards to cell numbers, key marker expression, and functional capacities. We took advantage of the vast genetic diversity of the CC and identified nine genomic loci through quantitative trait locus mapping driving these phenotypic variations. SNP haplotype patterns and variant effect analyses identified candidate genes associated with lung NK cell numbers, frequencies of CD94+ NK cells, and expression levels of NKp46. Thus, we demonstrate that the CC represents an outstanding resource to study NK cell diversity and its regulation by host genetics.


Assuntos
Antígenos Ly , Regulação da Expressão Gênica/imunologia , Células Matadoras Naturais/imunologia , Subfamília D de Receptores Semelhantes a Lectina de Células NK , Receptor 1 Desencadeador da Citotoxicidade Natural , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/imunologia , Animais , Antígenos Ly/genética , Antígenos Ly/imunologia , Cruzamentos Genéticos , Camundongos , Camundongos Endogâmicos , Subfamília D de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília D de Receptores Semelhantes a Lectina de Células NK/imunologia , Receptor 1 Desencadeador da Citotoxicidade Natural/genética , Receptor 1 Desencadeador da Citotoxicidade Natural/imunologia
7.
Immunity ; 40(6): 861-2, 2014 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-24950208

RESUMO

In this issue of Immunity, Crouse et al., (2014) and Xu et al., (2014), show that by modulating the expression of natural killer (NK) cell receptor ligands, type I interferons protect responding T cells against culling by NK cells.


Assuntos
Antígenos Ly/imunologia , Linfócitos T CD8-Positivos/imunologia , Citotoxicidade Imunológica , Interferon Tipo I/imunologia , Células Matadoras Naturais/imunologia , Coriomeningite Linfocítica/imunologia , Receptor 1 Desencadeador da Citotoxicidade Natural/imunologia , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/imunologia , Animais
8.
Immunity ; 40(6): 961-73, 2014 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-24909889

RESUMO

Direct type I interferon (IFN) signaling on T cells is necessary for the proper expansion, differentiation, and survival of responding T cells following infection with viruses prominently inducing type I IFN. The reasons for the abortive response of T cells lacking the type I IFN receptor (Ifnar1(-/-)) remain unclear. We report here that Ifnar1(-/-) T cells were highly susceptible to natural killer (NK) cell-mediated killing in a perforin-dependent manner. Depletion of NK cells prior to lymphocytic choriomeningitis virus (LCMV) infection completely restored the early expansion of Ifnar1(-/-) T cells. Ifnar1(-/-) T cells had elevated expression of natural cytotoxicity triggering receptor 1 (NCR1) ligands upon infection, rendering them targets for NCR1 mediated NK cell attack. Thus, direct sensing of type I IFNs by T cells protects them from NK cell killing by regulating the expression of NCR1 ligands, thereby revealing a mechanism by which T cells can evade the potent cytotoxic activity of NK cells.


Assuntos
Antígenos Ly/imunologia , Citotoxicidade Imunológica , Interferon Tipo I/imunologia , Células Matadoras Naturais/imunologia , Coriomeningite Linfocítica/imunologia , Receptor 1 Desencadeador da Citotoxicidade Natural/imunologia , Receptor de Interferon alfa e beta/genética , Transferência Adotiva , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Cultivadas , Imunidade Inata , Ativação Linfocitária/imunologia , Coriomeningite Linfocítica/virologia , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Perforina/biossíntese , Infecções por Rhabdoviridae/imunologia , Transdução de Sinais/imunologia , Vesiculovirus/genética , Vesiculovirus/imunologia , Replicação Viral/imunologia
9.
PLoS Pathog ; 16(2): e1008279, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32023327

RESUMO

IFN-γ is an enigmatic cytokine that shows direct anti-viral effects, confers upregulation of MHC-II and other components relevant for antigen presentation, and that adjusts the composition and balance of complex cytokine responses. It is produced during immune responses by innate as well as adaptive immune cells and can critically affect the course and outcome of infectious diseases, autoimmunity, and cancer. To selectively analyze the function of innate immune cell-derived IFN-γ, we generated conditional IFN-γOFF mice, in which endogenous IFN-γ expression is disrupted by a loxP flanked gene trap cassette inserted into the first intron of the IFN-γ gene. IFN-γOFF mice were intercrossed with Ncr1-Cre or CD4-Cre mice that express Cre mainly in NK cells (IFN-γNcr1-ON mice) or T cells (IFN-γCD4-ON mice), respectively. Rosa26RFP reporter mice intercrossed with Ncr1-Cre mice showed selective RFP expression in more than 80% of the NK cells, while upon intercrossing with CD4-Cre mice abundant RFP expression was detected in T cells, but also to a minor extent in other immune cell subsets. Previous studies showed that IFN-γ expression is needed to promote survival of vaccinia virus (VACV) infection. Interestingly, during VACV infection of wild type and IFN-γCD4-ON mice two waves of serum IFN-γ were induced that peaked on day 1 and day 3/4 after infection. Similarly, VACV infected IFN-γNcr1-ON mice mounted two waves of IFN-γ responses, of which the first one was moderately and the second one profoundly reduced when compared with WT mice. Furthermore, IFN-γNcr1-ON as well as IFN-γCD4-ON mice survived VACV infection, whereas IFN-γOFF mice did not. As expected, ex vivo analysis of splenocytes derived from VACV infected IFN-γNcr1-ON mice showed IFN-γ expression in NK cells, but not T cells, whereas IFN-γOFF mice showed IFN-γ expression neither in NK cells nor T cells. VACV infected IFN-γNcr1-ON mice mounted normal cytokine responses, restored neutrophil accumulation, and showed normal myeloid cell distribution in blood and spleen. Additionally, in these mice normal MHC-II expression was detected on peripheral macrophages, whereas IFN-γOFF mice did not show MHC-II expression on such cells. In conclusion, upon VACV infection Ncr1 positive cells including NK cells mount two waves of early IFN-γ responses that are sufficient to promote the induction of protective anti-viral immunity.


Assuntos
Antígenos Ly/imunologia , Regulação da Expressão Gênica/imunologia , Interferon gama/imunologia , Células Matadoras Naturais/imunologia , Receptor 1 Desencadeador da Citotoxicidade Natural/imunologia , Vaccinia virus/imunologia , Vacínia/imunologia , Animais , Antígenos Ly/genética , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Interferon gama/genética , Células Matadoras Naturais/patologia , Camundongos , Camundongos Transgênicos , Receptor 1 Desencadeador da Citotoxicidade Natural/genética , Linfócitos T/imunologia , Linfócitos T/patologia , Vacínia/genética , Vacínia/patologia , Vaccinia virus/genética
10.
Nat Immunol ; 11(11): 1030-8, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20935648

RESUMO

The potent tumoricidal activity of interleukin 12 (IL-12) is thought to be mediated by the activation and polarization of natural killer (NK) cells and T helper type 1 (T(H)1) cells, respectively. By systematic analysis of the IL-12-induced immune response to subcutaneous melanoma (B16), we found that tumor suppression was mediated independently of T lymphocytes or NK cells. IL-12 initiated local antitumor immunity by stimulating a subset of NKp46(+) lymphoid tissue-inducer (LTi) cells dependent on the transcription factor RORγt. The presence of these NKp46(+) LTi cells induced upregulation of adhesion molecules in the tumor vasculature and resulted in more leukocyte invasion. Thus, this innate cell type is responsive to IL-12 and is a powerful mediator of tumor suppression.


Assuntos
Interleucina-12/imunologia , Tecido Linfoide/imunologia , Melanoma/imunologia , Receptor 1 Desencadeador da Citotoxicidade Natural/imunologia , Animais , Linhagem Celular Tumoral , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Células Tumorais Cultivadas
11.
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
12.
Immunity ; 38(2): 322-35, 2013 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-23352232

RESUMO

Dendritic cells (DCs) are crucial for mounting allergic airway inflammation, but it is unclear which subset of DCs performs this task. By using CD64 and MAR-1 staining, we reliably separated CD11b(+) monocyte-derived DCs (moDCs) from conventional DCs (cDCs) and studied antigen uptake, migration, and presentation assays of lung and lymph node (LN) DCs in response to inhaled house dust mite (HDM). Mainly CD11b(+) cDCs but not CD103(+) cDCs induced T helper 2 (Th2) cell immunity in HDM-specific T cells in vitro and asthma in vivo. Studies in Flt3l(-/-) mice, lacking all cDCs, revealed that moDCs were also sufficient to induce Th2 cell-mediated immunity but only when high-dose HDM was given. The main function of moDCs was the production of proinflammatory chemokines and allergen presentation in the lung during challenge. Thus, we have identified migratory CD11b(+) cDCs as the principal subset inducing Th2 cell-mediated immunity in the LN, whereas moDCs orchestrate allergic inflammation in the lung.


Assuntos
Alérgenos/imunologia , Antígenos de Dermatophagoides/imunologia , Asma/imunologia , Células Dendríticas/imunologia , Imunidade Celular , Pyroglyphidae/imunologia , Células Th2/imunologia , Administração por Inalação , Transferência Adotiva , Alérgenos/isolamento & purificação , Animais , Antígenos de Dermatophagoides/administração & dosagem , Antígenos de Dermatophagoides/isolamento & purificação , Antígenos Ly/genética , Antígenos Ly/imunologia , Asma/patologia , Antígeno CD11b/genética , Antígeno CD11b/imunologia , Movimento Celular , Proliferação de Células , Células Dendríticas/transplante , Expressão Gênica , Inflamação/imunologia , Inflamação/patologia , Pulmão/imunologia , Pulmão/patologia , Linfonodos/imunologia , Linfonodos/patologia , Camundongos , Camundongos Transgênicos , Monócitos/imunologia , Monócitos/transplante , Receptor 1 Desencadeador da Citotoxicidade Natural/genética , Receptor 1 Desencadeador da Citotoxicidade Natural/imunologia , Especificidade de Órgãos , Receptores de IgG/genética , Receptores de IgG/imunologia
13.
Eur J Immunol ; 50(12): 1952-1958, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32734619

RESUMO

NK1.1+ cells found in salivary glands (SG) represent a unique cell population of innate lymphoid cells (ILC) with characteristics of both conventional NK cells and ILC1. Here, we demonstrate that these NK1.1+  cells limit the accumulation and differentiation of virus-specific tissue-resident memory CD8+ T cells (TRM  cells) in SG of mice infected with lymphocytic choriomeningitis virus (LCMV). The negative regulation of LCMV-specific CD8+ TRM  cells by NK1.1+  cells in SG is independent of NKG2D, NKp46, TRAIL, and perforin. Moreover, analysis of NKp46iCre+ Eomesfl/fl mice revealed that Eomes-dependent conventional NK cells are dispensable for negative regulation. Since the SG are prone to autoimmune reactions, regulation of TRM  cells by tissue-resident ILC may be particularly important to prevent immunopathology in this organ.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Imunidade Inata/imunologia , Memória Imunológica/imunologia , Células Matadoras Naturais/imunologia , Glândulas Salivares/imunologia , Animais , Diferenciação Celular/imunologia , Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Receptor 1 Desencadeador da Citotoxicidade Natural/imunologia , Perforina/imunologia , Ligante Indutor de Apoptose Relacionado a TNF/imunologia
14.
Eur J Immunol ; 50(5): 656-665, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32027754

RESUMO

Natural Killer (NK) cell responses are regulated by a variety of different surface receptors. While we can determine the overall positive or negative effect of a given receptor on NK cell functions, investigating NK cell regulation in a quantitative way is challenging. To quantitatively investigate individual receptors for their effect on NK cell activation, we chose to functionalize latex beads that have approximately the same size as lymphocytes with defined amounts of specific antibodies directed against distinct activating receptors. This enabled us to investigate NK cell reactivity in a defined, clean, and controllable system. Only CD16 and NKp30 could activate the degranulation of resting human NK cells. CD16, NKG2D, NKp30, NKp44, and NKp46 were able to activate cultured NK cells. NK cell activation resulted in the induction of polyfunctional cells that degranulated and produced IFN-γ and MIP-1ß. Interestingly, polyfunctional NK cells were only induced by triggering ITAM-coupled receptors. NKp44 showed a very sensitive response pattern, where a small increase in receptor stimulation caused maximal NK cell activity. In contrast, stimulation of 2B4 induced very little NK cell degranulation, while providing sufficient signal for NK cell adhesion. Our data demonstrate that activating receptors differ in their effectiveness to stimulate NK cells.


Assuntos
Anticorpos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Células Matadoras Naturais/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Anticorpos/química , Adesão Celular/efeitos dos fármacos , Degranulação Celular/efeitos dos fármacos , Células Cultivadas , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/imunologia , Humanos , Interferon gama/genética , Interferon gama/imunologia , Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Microesferas , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Receptor 1 Desencadeador da Citotoxicidade Natural/genética , Receptor 1 Desencadeador da Citotoxicidade Natural/imunologia , Receptor 2 Desencadeador da Citotoxicidade Natural/genética , Receptor 2 Desencadeador da Citotoxicidade Natural/imunologia , Receptor 3 Desencadeador da Citotoxicidade Natural/genética , Receptor 3 Desencadeador da Citotoxicidade Natural/imunologia , Ligação Proteica , Receptores de IgG/genética , Receptores de IgG/imunologia , Transdução de Sinais
15.
PLoS Pathog ; 15(6): e1007797, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31220194

RESUMO

During viral infection, tight regulation of CD8+ T-cell functions determines the outcome of the disease. Recently, others and we determined that the natural killer (NK) cells kill hyperproliferative CD8+ T cells in the context of viral infection, but molecules that are involved in shaping the regulatory capability of NK cells remain virtually unknown. Here we used mice lacking the Fc-receptor common gamma chain (FcRγ, FcεRIγ, Fcer1g-/- mice) to determine the role of Fc-receptor and NK-receptor signaling in the process of CD8+ T-cell regulation. We found that the lack of FcRγ on NK cells limits their ability to restrain virus-specific CD8+ T cells and that the lack of FcRγ in Fcer1g-/- mice leads to enhanced CD8+ T-cell responses and rapid control of the chronic docile strain of the lymphocytic choriomeningitis virus (LCMV). Mechanistically, FcRγ stabilized the expression of NKp46 but not that of other killer cell-activating receptors on NK cells. Although FcRγ did not influence the development or activation of NK cell during LCMV infection, it specifically limited their ability to modulate CD8+ T-cell functions. In conclusion, we determined that FcRγ plays an important role in regulating CD8+ T-cell functions during chronic LCMV infection.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Ativação Linfocitária , Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Receptores Fc/imunologia , Doença Aguda , Animais , Antígenos Ly/genética , Antígenos Ly/imunologia , Linfócitos T CD8-Positivos/patologia , Doença Crônica , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Coriomeningite Linfocítica/genética , Coriomeningite Linfocítica/patologia , Camundongos , Camundongos Knockout , Receptor 1 Desencadeador da Citotoxicidade Natural/genética , Receptor 1 Desencadeador da Citotoxicidade Natural/imunologia , Receptores Fc/genética
16.
Nat Immunol ; 10(1): 83-91, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19029903

RESUMO

The mucosal immune system of the intestine is separated from a vast array of microbes by a single layer of epithelial cells. Cues from the commensal microflora are needed to maintain epithelial homeostasis, but the molecular and cellular identities of these cues are unclear. Here we provide evidence that signals from the commensal microflora contribute to the differentiation of a lymphocyte population coexpressing stimulatory natural killer cell receptors and the transcription factor RORgammat that produced interleukin 22 (IL-22). The emergence of these IL-22-producing RORgammathiNKp46+NK1.1(int) cells depended on RORgammat expression, which indicated that these cells may have been derived from lymphoid tissue-inducer cells. IL-22 released by these cells promoted the production of antimicrobial molecules important in the maintenance of mucosal homeostasis.


Assuntos
Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Células T Matadoras Naturais/imunologia , Receptores do Ácido Retinoico/fisiologia , Receptores dos Hormônios Tireóideos/fisiologia , Fatores de Transcrição/fisiologia , Animais , Antígenos Ly/imunologia , Bactérias/imunologia , Diferenciação Celular , Homeostase/imunologia , Interleucinas/biossíntese , Camundongos , Camundongos Knockout , Receptor 1 Desencadeador da Citotoxicidade Natural/imunologia , Células T Matadoras Naturais/citologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares , Nódulos Linfáticos Agregados/imunologia , Receptores do Ácido Retinoico/genética , Receptores dos Hormônios Tireóideos/genética , Interleucina 22
17.
Nat Immunol ; 10(1): 75-82, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19029904

RESUMO

NKp46+CD3- natural killer lymphocytes isolated from blood, lymphoid organs, lung, liver and uterus can produce granule-dependent cytotoxicity and interferon-gamma. Here we identify in dermis, gut lamina propria and cryptopatches distinct populations of NKp46+CD3- cells with a diminished capacity to degranulate and produce interferon-gamma. In the gut, expression of the transcription factor RORgammat, which is involved in the development of lymphoid tissue-inducer cells, defined a previously unknown subset of NKp46+CD3- lymphocytes. Unlike RORgammat- lamina propria and dermis natural killer cells, gut RORgammat+NKp46+ cells produced interleukin 22. Our data show that lymphoid tissue-inducer cells and natural killer cells shared unanticipated similarities and emphasize the heterogeneity of NKp46+CD3- cells in innate immunity, lymphoid organization and local tissue repair.


Assuntos
Derme/imunologia , Mucosa Intestinal/imunologia , Células T Matadoras Naturais/imunologia , Receptores do Ácido Retinoico/fisiologia , Receptores dos Hormônios Tireóideos/fisiologia , Fatores de Transcrição/fisiologia , Animais , Complexo CD3/metabolismo , Divisão Celular , Humanos , Interferon gama/biossíntese , Interleucinas/biossíntese , Ativação Linfocitária/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Receptor 1 Desencadeador da Citotoxicidade Natural/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares , Nódulos Linfáticos Agregados/imunologia , Receptores do Ácido Retinoico/genética , Receptores dos Hormônios Tireóideos/genética , Fatores de Transcrição/genética , Interleucina 22
18.
PLoS Biol ; 16(4): e2004867, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29702643

RESUMO

NKp46, a natural killer (NK) cell-activating receptor, is involved in NK cell cytotoxicity against virus-infected cells or tumor cells. However, the role of NKp46 in other NKp46+ non-NK innate lymphoid cell (ILC) populations has not yet been characterized. Here, an NKp46 deficiency model of natural cytotoxicity receptor 1 (Ncr1)gfp/gfp and Ncr1gfp/+ mice, i.e., homozygous and heterozygous knockout (KO), was used to explore the role of NKp46 in regulating the development of the NKp46+ ILCs. Surprisingly, our studies demonstrated that homozygous NKp46 deficiency resulted in a nearly complete depletion of the ILC1 subset (ILC1) of group 1 ILCs, and heterozygote KO decreased the number of cells in the ILC1 subset. Moreover, transplantation studies confirmed that ILC1 development depends on NKp46 and that the dependency is cell intrinsic. Interestingly, however, the cell depletion specifically occurred in the ILC1 subset but not in the other ILCs, including ILC2s, ILC3s, and NK cells. Thus, our studies reveal that NKp46 selectively participates in the regulation of ILC1 development.


Assuntos
Antígenos Ly/genética , Linhagem da Célula/imunologia , Regulação da Expressão Gênica no Desenvolvimento/imunologia , Células Matadoras Naturais/imunologia , Receptor 1 Desencadeador da Citotoxicidade Natural/genética , Animais , Antígenos Ly/imunologia , Células da Medula Óssea/citologia , Células da Medula Óssea/imunologia , Linhagem da Célula/genética , Genes Reporter , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/imunologia , Heterozigoto , Homozigoto , Imunidade Inata , Imunofenotipagem , Integrina alfa2/genética , Integrina alfa2/imunologia , Células Matadoras Naturais/citologia , Fígado/citologia , Fígado/imunologia , Camundongos , Camundongos Knockout , Receptor 1 Desencadeador da Citotoxicidade Natural/deficiência , Receptor 1 Desencadeador da Citotoxicidade Natural/imunologia , Baço/citologia , Baço/imunologia , Ligante Indutor de Apoptose Relacionado a TNF/deficiência , Ligante Indutor de Apoptose Relacionado a TNF/genética , Ligante Indutor de Apoptose Relacionado a TNF/imunologia
19.
J Immunol ; 203(7): 1981-1988, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31444264

RESUMO

NK cells can recognize target cells such as virus-infected and tumor cells through integration of activation and inhibitory receptors. Recognition by NK cells can lead to direct lysis of the target cell and production of the signature cytokine IFN-γ. However, it is unclear whether stimulation through activation receptors alone is sufficient for IFN-γ production. In this study, we show that NK activation receptor engagement requires additional signals for optimal IFN-γ production, which could be provided by IFN-ß or IL-12. Stimulation of murine NK cells with soluble Abs directed against NK1.1, Ly49H, Ly49D, or NKp46 required additional stimulation with cytokines, indicating that a range of activation receptors with distinct adaptor molecules require additional stimulation for IFN-γ production. The requirement for multiple signals extends to stimulation with primary m157-transgenic target cells, which triggers the activation receptor Ly49H, suggesting that NK cells do require multiple signals for IFN-γ production in the context of target cell recognition. Using quantitative PCR and RNA flow cytometry, we found that cytokines, not activating ligands, act on NK cells to express Ifng transcripts. Ly49H engagement is required for IFN-γ translational initiation. Results using inhibitors suggest that the proteasome-ubiquitin-IKK-TPL2-MNK1 axis was required during activation receptor engagement. Thus, this study indicates that activation receptor-dependent IFN-γ production is regulated on the transcriptional and translational levels.


Assuntos
Interferon gama/imunologia , Células Matadoras Naturais/imunologia , Complexo de Endopeptidases do Proteassoma/imunologia , Biossíntese de Proteínas/imunologia , Transdução de Sinais/imunologia , Transcrição Gênica/imunologia , Animais , Antígenos Ly/genética , Antígenos Ly/imunologia , Interferon gama/genética , Células Matadoras Naturais/citologia , Camundongos , Camundongos Knockout , Subfamília A de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília A de Receptores Semelhantes a Lectina de Células NK/imunologia , Subfamília B de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília B de Receptores Semelhantes a Lectina de Células NK/imunologia , Receptor 1 Desencadeador da Citotoxicidade Natural/genética , Receptor 1 Desencadeador da Citotoxicidade Natural/imunologia , Complexo de Endopeptidases do Proteassoma/genética , Transdução de Sinais/genética
20.
Proc Natl Acad Sci U S A ; 115(46): 11808-11813, 2018 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-30381460

RESUMO

Natural killer (NK) cells play a critical role in controlling malignancies. Susceptibility or resistance to lung cancer, for example, specifically depends on NK cell function. Nevertheless, intrinsic factors that control NK cell-mediated clearance of lung cancer are unknown. Here we report that NK cells exposed to exogenous major histocompatibility class I (MHCI) provide a significant immunologic barrier to the growth and progression of malignancy. Clearance of lung cancer is facilitated by up-regulation of NKG2D, NKp46, and other activating receptors upon exposure to environmental MHCI. Surface expression of the inhibitory receptor Ly49C/I, on the other hand, is down-regulated upon exposure to tumor-bearing tissue. We thus demonstrate that NK cells exhibit dynamic plasticity in surface expression of both activating and inhibitory receptors based on the environmental context. Our data suggest that altering the activation state of NK cells may contribute to immunologic control of lung and possibly other cancers.


Assuntos
Antígenos Ly/imunologia , Células Matadoras Naturais/imunologia , Neoplasias Pulmonares/imunologia , Subfamília A de Receptores Semelhantes a Lectina de Células NK/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Receptor 1 Desencadeador da Citotoxicidade Natural/imunologia , Receptores Imunológicos/imunologia , Receptores de Células Matadoras Naturais/metabolismo , Animais , Citotoxicidade Imunológica , Regulação para Baixo , Antígenos de Histocompatibilidade Classe I/metabolismo , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Regulação para Cima
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA