RESUMO
Cancer is a leading cause of mortality worldwide, with around 10 million deaths every year. Despite huge advances due to immunotherapy, the majority of cancer patients present primary or secondary resistance to these treatments. In this Found in Translation, we focus on the approaches developed to harness the anti-tumor function of NK cells, suggesting promising strategies to complete the therapeutic arsenal of cancer immunotherapies.
Assuntos
Células Matadoras Naturais , Neoplasias , Humanos , Fatores Imunológicos , Imunoterapia , Células Matadoras Naturais/patologia , Neoplasias/patologia , Neoplasias/terapiaRESUMO
Because of their potent antitumor activity and their proinflammatory role, natural killer (NK) cells are at the forefront of efforts to develop immuno-oncologic treatments. NK cells participate in immune responses to tumors by killing target cells and producing cytokines. However, in the immunosuppressive tumor microenvironment, NK cells become dysfunctional through exposure to inhibitory molecules produced by cancer cells, leading to tumor escape. We provide an overview of what is known about NK tumor infiltration and surveillance and about the mechanisms by which NK cells become dysfunctional. SIGNIFICANCE: The functions of tumor-infiltrating NK cells may be impaired. This review aims to describe the various mechanisms by which tumors alter NK-cell functions.
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Células Matadoras Naturais/imunologia , Microambiente Tumoral/imunologia , HumanosRESUMO
Arginine metabolism plays a significant role in regulating cell function, affecting tumor growth and metastatization. To study the effect of the arginine-catabolizing enzyme Arginase1 (ARG1) on tumor microenvironment, we generated a mouse model of mammary carcinogenesis by crossbreeding a transgenic mouse line overexpressing ARG1 in macrophages (FVBArg+/+) with the MMTV-Neu mouse line (FVBNeu+/+). This double transgenic line (FVBArg+/-;Neu+/+) showed a significant shortening in mammary tumor latency, and an increase in the number of mammary nodules. Transfer of tumor cells from FVBNeu+/+ into either FVB wild type or FVBArg+/+ mice resulted in increase regulatory T cells in the tumor infiltrate, suggestive of an impaired antitumor immune response. However, we also found increased frequency of tumor stem cells in tumors from FVBArg+/-;Neu+/+ transgenic compared with FVBNeu+/+ mice, suggesting that increased arginine metabolism in mammary tumor microenvironment may supports the cancer stem cells niche. We provide in vivo evidence of a novel, yet unexploited, mechanism through which ARG1 may contribute to tumor development.
Assuntos
Arginase/metabolismo , Transformação Celular Neoplásica/patologia , Neoplasias Mamárias Experimentais/patologia , Microambiente Tumoral/imunologia , Animais , Apoptose , Arginase/genética , Proliferação de Células , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/metabolismo , Feminino , Humanos , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/metabolismo , Camundongos , Camundongos Transgênicos , Células Tumorais CultivadasRESUMO
Innate lymphoid cells (ILCs) represent a heterogeneous group of cells lacking genetically rearranged antigen receptors that derive from common lymphoid progenitors. Five major groups of ILCs have been defined based on their cytokine production pattern and developmental transcription factor requirements: namely, natural killer (NK) cells, ILC1s, ILC2s, ILC3s, and lymphoid tissue-inducer (LTi) cells. ILC1s, ILC2s, and ILC3s mirror the corresponding T helper subsets (Th1, Th2, and Th17, respectively) and produce cytokines involved in defense against pathogens, lymphoid organogenesis, and tissue remodeling. During the first trimester of pregnancy, decidual tissues contain high proportion of decidual NK (dNK) cells, representing up to 50% of decidual lymphocytes, and ILC3s. They release peculiar cytokines and chemokines that contribute to successful pregnancy. Recent studies revealed that ILCs display a high degree of plasticity allowing their prompt adaptation to environmental changes. Decidual NK cells may derive from peripheral blood NK cells migrated when pregnancy establishes or from in situ differentiation of hematopoietic precursors. Previous studies showed that human and murine decidua contain dNK cells, tissue resident NK cells, and ILC3s, all characterized by unique phenotypic and functional properties, most likely induced by decidual microenvironment to favor the establishment and the maintenance of pregnancy. Thus, during the early phase of pregnancy, the simultaneous presence of different ILC subsets further underscores the complexity of the cellular components of decidual tissues as well as the role of decidual microenvironment in shaping the plasticity and the function of ILCs.
Assuntos
Decídua/citologia , Heterogeneidade Genética , Imunidade Inata , Células Matadoras Naturais/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Citocinas/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Camundongos , Fenótipo , Gravidez , Primeiro Trimestre da Gravidez/genética , Primeiro Trimestre da Gravidez/imunologiaRESUMO
Determining the function of uterine lymphocytes is challenging because of the dynamic changes in response to sex hormones and, during pregnancy, to the invading foetal trophoblast cells. Here we provide a genome-wide transcriptome atlas of mouse uterine group 1 innate lymphoid cells (ILCs) at mid-gestation. Tissue-resident Eomes+CD49a+ NK cells (trNK), which resemble human uterine NK cells, are most abundant during early pregnancy, and have gene signatures associated with TGF-ß responses and interactions with trophoblast, epithelial, endothelial, smooth muscle cells, leucocytes and extracellular matrix. Conventional NK cells expand late in gestation and may engage in crosstalk with trNK cells involving IL-18 and IFN-γ. Eomes-CD49a+ ILC1s dominate before puberty, and specifically expand in second pregnancies when the expression of the memory cell marker CXCR6 is upregulated. These results identify trNK cells as the cellular hub of uterine group 1 ILCs, and mark CXCR6+ ILC1s as potential memory cells of pregnancy.
Assuntos
Imunidade Inata , Linfócitos/citologia , Linfócitos/metabolismo , Útero/citologia , Animais , Feminino , Perfilação da Expressão Gênica , Genoma , Humanos , Memória Imunológica , Interleucinas/metabolismo , Camundongos Endogâmicos C57BL , Modelos Biológicos , Gravidez , Receptores CXCR6/metabolismo , Proteínas com Domínio T/metabolismo , Transcriptoma/genética , Interleucina 22RESUMO
In Box 1 in the originally published version of this article, three key references referring to mouse and human killer inhibitory receptors were mistakenly deleted during revision of the article. These references have now been added to the corrected version of the article.
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Immuno-oncology is an emerging field that has revolutionized cancer treatment. Most immunomodulatory strategies focus on enhancing T cell responses, but there has been a recent surge of interest in harnessing the relatively underexplored natural killer (NK) cell compartment for therapeutic interventions. NK cells show cytotoxic activity against diverse tumour cell types, and some of the clinical approaches originally developed to increase T cell cytotoxicity may also activate NK cells. Moreover, increasing numbers of studies have identified novel methods for increasing NK cell antitumour immunity and expanding NK cell populations ex vivo, thereby paving the way for a new generation of anticancer immunotherapies. The role of other innate lymphoid cells (group 1 innate lymphoid cell (ILC1), ILC2 and ILC3 subsets) in tumours is also being actively explored. This Review provides an overview of the field and summarizes current immunotherapeutic approaches for solid tumours and haematological malignancies.
Assuntos
Citocinas/uso terapêutico , Imunoterapia Adotiva/métodos , Células Matadoras Naturais/transplante , Neoplasias , Linfócitos T Citotóxicos/transplante , Humanos , Imunidade Inata/imunologia , Células Matadoras Naturais/imunologia , Ativação Linfocitária , Neoplasias/imunologia , Neoplasias/prevenção & controle , Neoplasias/terapia , Linfócitos T Citotóxicos/imunologiaRESUMO
After many years of research, recent advances shed a new light on the role of the immune system in cancer. New therapeutic antibodies, such as anti-PD-1/L1, that block the interactions of inhibitory receptors (immune checkpoint inhibitors, ICI) with their ligands, have revolutionized the management of cancer patients. Nevertheless, they only affect a small part of the patient population. The main current challenge for immuno-oncology is to overcome these resistances by targeting new control points and new immune cells, combining these new immunotherapies with one another and with other standard treatments. Monalizumab is a novel antibody that simultaneously stimulates the anti-tumor action of NK and T cells by blocking one of their inhibitory receptors: NKG2A. NKG2A is present on the surface of both cell types and its ligand, HLA-E, and is very frequently overexpressed by human tumors, opening a wide therapeutic window to monalizumab.
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Oncologia/métodos , Oncologia/tendências , Neoplasias/terapia , Animais , Bioengenharia/métodos , Bioengenharia/tendências , Humanos , Imunoterapia/métodos , Imunoterapia/tendências , Células Matadoras Naturais/fisiologia , Células Matadoras Naturais/transplante , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , Subfamília C de Receptores Semelhantes a Lectina de Células NK/antagonistas & inibidores , Subfamília C de Receptores Semelhantes a Lectina de Células NK/imunologia , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Receptores KIR/antagonistas & inibidores , Receptores KIR/imunologiaRESUMO
After many years of research, recent advances have shed new light on the role of the immune system in advanced-stage cancer. Various types of immune cells may be useful for therapeutic purposes, along with chemical molecules and engineered monoclonal antibodies. The immune effectors suitable for manipulation for adoptive transfer or drug targeting in vivo include natural killer (NK) cells. These cells are of particular interest because they are tightly regulated by an array of inhibitory and activating receptors, enabling them to kill tumor cells while sparing normal cells. New therapeutic antibodies blocking the interactions of inhibitory receptors (immune checkpoint inhibitors, ICI) with their ligands have been developed and can potentiate NK cell functions in vivo.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Imunoterapia/métodos , Células Matadoras Naturais/imunologia , Neoplasias/terapia , Transferência Adotiva , Animais , Receptores Coestimuladores e Inibidores de Linfócitos T/imunologia , Citotoxicidade Imunológica , Engenharia Genética , Humanos , Células Matadoras Naturais/transplante , Neoplasias/imunologiaRESUMO
In this issue of JEM, Taylor et al. (https://doi.org/10.1084/jem.20161653) describe PD-1 as a critical negative regulator of group 2 innate lymphoid cells (ILC-2s). PD-1 intrinsically controls proliferation and cytokine production of both mouse and human ILC-2s. PD-1 signaling inhibits STAT5 phosphorylation and the removal of this brake by knocking down PD-1 expression or by using anti-PD-1 blocking antibodies, translated in vivo into better clearance of helminth worm infection in mice.
Assuntos
Imunidade Inata , Linfócitos/citologia , Linfócitos/imunologia , Animais , Humanos , Camundongos , Modelos Biológicos , Receptores Imunológicos/metabolismoRESUMO
Mesenchymal stromal cells (MSCs) support hematopoiesis and exert immunoregulatory activities. Here, we analyzed the functional outcome of the interactions between MSCs and monocytes/macrophages. We showed that MSCs supported the survival of monocytes that underwent differentiation into macrophages, in the presence of macrophage colony-stimulating factor. However, MSCs skewed their polarization toward a peculiar M2-like functional phenotype (M(MSC) ), through a prostaglandin E2-dependent mechanism. M(MSC) were characterized by high expression of scavenger receptors, increased phagocytic capacity, and high production of interleukin (IL)-10 and transforming growth factor-ß. These cytokines contributed to the immunoregulatory properties of M(MSC) , which differed from those of typical IL-4-induced macrophages (M2). In particular, interacting with activated natural killer (NK) cells, M(MSC) inhibited both the expression of activating molecules such as NKp44, CD69, and CD25 and the production of IFNγ, while M2 affected only IFNγ production. Moreover, M(MSC) inhibited the proliferation of CD8(+) T cells in response to allogeneic stimuli and induced the expansion of regulatory T cells (Tregs). Toll-like receptor engagement reverted the phenotypic and functional features of M(MSC) to those of M1 immunostimulatory/proinflammatory macrophages. Overall our data show that MSCs induce the generation of a novel type of alternatively activated macrophages capable of suppressing both innate and adaptive immune responses. These findings may help to better understand the role of MSCs in healthy tissues and inflammatory diseases including cancer, and provide clues for novel therapeutic approaches. Stem Cells 2016;34:1909-1921.
Assuntos
Imunidade Adaptativa , Imunidade Inata , Ativação de Macrófagos , Macrófagos/citologia , Células-Tronco Mesenquimais/citologia , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular , Linhagem Celular , Proliferação de Células , Sobrevivência Celular , Criança , Humanos , Imunomodulação , Interferon gama/metabolismo , Células Matadoras Naturais/metabolismo , Macrófagos/metabolismo , Monócitos/citologia , Linfócitos T ReguladoresRESUMO
Murine NK cells can be divided by the expression of two cell surface markers, CD27 and Mac-1 (a.k.a. CD11b), into four separate subsets. These subsets suggest a linear development model: CD27(-) Mac-1(-) â CD27(+) Mac-1(-) â CD27(+) Mac-1(+) â CD27(-) Mac-1(+) . Here, we used a combination of BrdU labeling experiments and mathematical modeling to gain insights regarding NK-cell development in mouse bone marrow (BM), spleen and liver. The modeling results that best fit the experimental data show that the majority of NK cells already express CD27 upon entering the NK-cell developmental pathway. Additionally, only a small fraction of NK cells exit the BM to other sites, suggesting that peripheral NK-cell populations originate from site-specific immature NK cells more than from BM-derived mature NK cells.
Assuntos
Células da Medula Óssea/imunologia , Células Matadoras Naturais/fisiologia , Fígado/imunologia , Baço/imunologia , Animais , Células da Medula Óssea/fisiologia , Antígeno CD11b/imunologia , Diferenciação Celular , Células Cultivadas , Simulação por Computador , Células Matadoras Naturais/imunologia , Fígado/fisiologia , Camundongos , Modelos Teóricos , Baço/fisiologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismoRESUMO
Decidual and uterine natural killer (NK) cells have been shown to contribute to the successful pregnancy both in humans and mice. NK cells represent "cytotoxic" group 1 innate lymphoid cells (ILCs) and are distinct from the recently described "helper" ILC1. Here, we show that both in humans and mice the majority of group 1 ILC in endometrium/uterus and decidua express Eomesodermin (Eomes), thus suggesting that they are developmentally related to conventional NK cells. However, they differ from peripheral NK cells. In humans, Eomes(+) decidual NK (dNK) cells express CD49a and other markers of tissue residency, including CD103, integrin ß7, CD9, and CD69. The expression of CD103 allows the identification of different subsets of IFNγ-producing Eomes(+) NK cells. We show that TGFß can sustain/induce CD103 and CD9 expression in dNK cells and decidual CD34-derived NK cells, indicating that the decidual microenvironment can instruct the phenotype of Eomes(+) NK cells. In murine decidua and uterus, Eomes(+) cells include CD49a(-)CD49b(+) conventional NK cells and CD49a(+) cells. Notably, Eomes(+)CD49a(+) cells are absent in spleen and liver. Decidual and uterine Eomes(+)CD49a(+) cells can be dissected in two peculiar cell subsets according to CD49b expression. CD49a(+)CD49b ((-)) and CD49a(+)CD49b(+) cells are enriched in immature CD11b(low)CD27(high) cells, while CD49a(-)CD49b(+) cells contain higher percentages of mature CD11b(high)CD27(low) cells, both in uterus and decidua. Moreover, Eomes(+)CD49a(+)CD49b(-) cells decrease during gestation, thus suggesting that this peculiar subset may be required in early pregnancy rather than on later phases. Conversely, a minor Eomes(-)CD49a(+) ILC1 population present in decidua and uterus increases during pregnancy. CD49b(-)Eomes(±) cells produce mainly TNF, while CD49a(-)CD49b(+) conventional NK cells and CD49a(+)CD49b(+) cells produce both IFNγ and TNF. Thus, human and murine decidua contains unique subsets of group 1 ILCs, including Eomes(+) and Eomes(-) cells, with peculiar phenotypic and functional features. Our study contributes to re-examination of the complexity of uterine and decidual ILC subsets in humans and mice and highlights the role of the decidual microenvironment in shaping the features of these cells.
RESUMO
Decidual natural killer cells accumulate at the fetal-maternal interface and play a key role in a successful pregnancy. However, their origin is still unknown. Do they derive from peripheral natural killer cells recruited in decidua or do they represent a distinct population that originates in situ? Here, we identified natural killer precursors in decidua and uterus of pregnant mice. These precursors underwent rapid in situ differentiation and large proportions of proliferating immature natural killer cells were present in decidua and uterus as early as gestation day 4.5. Here, we investigated the origin of decidua- and uterus-natural killer cells by performing transfer experiments of peripheral mature natural killer cells or precursors from EGFP(+) mice. Results showed that mature natural killer cells did not migrate into decidua and uterus, while precursors were recruited in these organs and differentiated towards natural killer cells. Moreover, decidua- and uterus-natural killer cells displayed unique phenotypic and functional features. They expressed high levels of the activating Ly49D receptor in spite of their immature phenotype. In addition, decidua- and uterus-natural killer cells were poorly cytolytic and produced low amounts of IFN-γ, while they released factors (GM-CSF, VEGF, IP-10) involved in neo-angiogenesis and tissue remodeling. Our data reveal in situ generation of decidual natural killer cells and provide an important correlation between mouse and human decidual natural killer cells, allowing further studies to be carried out on their role in pregnancy-related diseases.
Assuntos
Diferenciação Celular , Decídua/citologia , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Células Matadoras Naturais/citologia , Células Matadoras Naturais/metabolismo , Animais , Antígenos de Superfície/metabolismo , Proliferação de Células , Citotoxicidade Imunológica , Decídua/imunologia , Decídua/metabolismo , Feminino , Hematopoese , Imunomodulação , Imunofenotipagem , Células Matadoras Naturais/imunologia , Camundongos , Camundongos Transgênicos , Subfamília A de Receptores Semelhantes a Lectina de Células NK/metabolismo , Gravidez , Útero/citologia , Útero/imunologiaRESUMO
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition due to the association of an infectious agent with lymphocyte cytotoxicity defects, either of congenital genetic origin in children or presumably acquired in adults. In HLH patients, an excess of lymphocyte or macrophage cytokines, such as IFN-γ and TNFα is present in serum. In animal models of the disease, IFN-γ and TNF-α have been shown to play a central pathogenic role. In humans, unusually high concentrations of IL-18, an inducer of IFN-γ, and TNF-α have been reported, and are associated with an imbalance between IL-18 and its natural inhibitor IL-18 binding protein (IL-18BP) resulting in an excess of free IL-18. Here we studied whether IL-18BP could reduce disease severity in an animal model of HLH. Mouse cytomegalovirus infection in perforin-1 knock-out mice induced a lethal condition similar to human HLH characterized by cytopenia with marked inflammatory lesions in the liver and spleen as well as the presence of hemophagocytosis in bone marrow. IL-18BP treatment decreased hemophagocytosis and reversed liver as well as spleen damage. IL-18BP treatment also reduced both IFN-γ and TNF-α production by CD8(+) T and NK cells, as well as Fas ligand expression on NK cell surface. These data suggest that IL-18BP is beneficial in an animal model of HLH and in combination with anti-infectious therapy may be a promising strategy to treat HLH patients.
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Over the last decade, several studies have extensively reported that activated natural killer (NK) cells can kill autologous immature dendritic cells (DCs) in vitro, whereas they spare fully activated DCs. This led to the proposal that activated NK cells might select a more immunogenic subset of DCs during a protective immune response. However, there is no demonstration that autologous DC killing by NK cells is an event occurring in vivo and, consequently, the functional relevance of this killing remains elusive. Here we report that a significant decrease of CD11c(+) DCs was observed in draining lymph nodes of mice inoculated with MHC-devoid cells as NK cell targets able to induce NK cell activation. This in vivo DC editing by NK cells was perforin-dependent and it was functionally relevant, since residual lymph node DCs displayed an improved capability to induce T cell proliferation. In addition, in a model of anti-cancer vaccination, the administration of MHC-devoid cells together with tumor cells increased the number of tumor-specific CTLs and resulted in a significant increase in survival of mice upon challenge with a lethal dose of tumor cells. Depletion of NK cells or the use of perforin knockout mice strongly decreased the tumor-specific CTL expansion and its protective role against tumor cell challenge. As a whole, our data support the hypothesis that NK cell-mediated DC killing takes place in vivo and is able to promote expansion of cancer-specific CTLs. Our results also indicate that cancer vaccines could be improved by strategies aimed at activating NK cells.
Assuntos
Células Dendríticas/imunologia , Células Matadoras Naturais/imunologia , Neoplasias/imunologia , Animais , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer , Linhagem Celular Tumoral , Citotoxicidade Imunológica , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Epitopos/imunologia , Feminino , Linfonodos/imunologia , Linfonodos/metabolismo , Ativação Linfocitária/imunologia , Complexo Principal de Histocompatibilidade/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neoplasias/terapia , Perforina/imunologia , Perforina/metabolismo , Linfócitos T Citotóxicos , Linfócitos T Auxiliares-Indutores/imunologiaRESUMO
The use of fetal bovine serum (FBS) for the culture and expansion of mesenchymal stromal cells (MSCs) limits their possible clinical applications. Although some recent studies recommended substituting FBS with human platelet lysate (HPL) for the expansion of MSCs for clinical use, the functional capacity of the expanded cells has only been partially explored. 10% FBS and two other commercial FBS-containing media (MesenCult and MesenPro) were compared with 10% HPL-containing medium for their ability to support MSCs expansion and immunomodulation. We demonstrate that HPL sustained MSC proliferation and expansion in vitro. However, the cumulative cell numbers recovered were comparable with those obtained in MesenPro medium. Moreover, we show that HPL alters the expression of some relevant MSC surface molecules, namely the DNAM-1 ligands PVR and Nectin-2, the NKG2D ligand ULBP3, the adhesion molecules CD49d and αvß3 and the fibroblast-associated protein. In addition, MSCs cultured in HPL displayed impaired inhibitory capacity on T-cell proliferation to alloantigen and NK-cell proliferation and cytotoxicity. Finally, they showed decreased constitutive PGE2 production while IL-6, IL-8 and RANTES secretion were upregulated. These results imply some limitations in the use of HPL for the expansion of MSCs to be used as immunomodulators in clinical applications.
Assuntos
Plaquetas/química , Técnicas de Cultura de Células/métodos , Proliferação de Células/efeitos dos fármacos , Meios de Cultura/farmacologia , Células-Tronco Mesenquimais/citologia , Plaquetas/metabolismo , Diferenciação Celular/efeitos dos fármacos , Separação Celular , Células Cultivadas , Citometria de Fluxo , Humanos , Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Teste de Cultura Mista de Linfócitos , Células-Tronco Mesenquimais/efeitos dos fármacos , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
Surface density of CD27 and CD11b subdivides mouse natural killer (NK) cells into 4 subsets: CD11b(low)CD27(low), CD11b(low)CD27(high), CD11b(high)CD27(high), and CD11b(high)CD27(low). To determine the developmental relationship between these 4 subsets, we used several complementary approaches. First, we took advantage of NDE transgenic mice that express enhanced green fluorescent protein (EGFP) and diphtheria toxin receptor specifically in NK cells. Diphtheria toxin injection leads to a transient depletion of NK cells, allowing the monitoring of the phenotype of developing EGFP+ NK cells after diphtheria toxin injection. Second, we evaluated the overall proximity between NK-cell subsets based on their global gene profile. Third, we compared the proliferative capacity of NK-cell subsets at steady state or during replenishment of the NK-cell pool. Fourth, we performed adoptive transfers of EGFP+ NK cell subsets from NDE mice into unirradiated mice and followed the fate of transferred cells. The results of these various experiments collectively support a 4-stage model of NK-cell maturation CD11b(low)CD27(low) --> CD11b(low)CD27(high) --> CD11b(high)CD27(high) --> CD11b(high)CD27(low). This developmental program appears to be associated with a progressive acquisition of NK-cell effector functions.
Assuntos
Diferenciação Celular/fisiologia , Células Matadoras Naturais/fisiologia , Animais , Antígeno CD11b/metabolismo , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Células Cultivadas , Toxina Diftérica/imunologia , Toxina Diftérica/farmacologia , Perfilação da Expressão Gênica , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Análise de Sequência com Séries de Oligonucleotídeos , Fatores de Tempo , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismoRESUMO
Consistent with their function in immune surveillance, natural killer (NK) cells are distributed throughout lymphoid and nonlymphoid tissues. However, the mechanisms governing the steady-state trafficking of NK cells remain unknown. The lysophospholipid sphingosine 1-phosphate (S1P), by binding to its receptor S1P1, regulates the recirculation of T and B lymphocytes. In contrast, S1P5 is detected in the brain and regulates oligodendrocyte migration and survival in vitro. Here we show that S1P5 was also expressed in NK cells in mice and humans and that S1P5-deficient mice had aberrant NK cell homing during steady-state conditions. In addition, we found that S1P5 was required for the mobilization of NK cells to inflamed organs. Our data emphasize distinct mechanisms regulating the circulation of various lymphocyte subsets and raise the possibility that NK cell trafficking may be manipulated by therapies specifically targeting S1P5.
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Células Matadoras Naturais/fisiologia , Lisofosfolipídeos/metabolismo , Receptores de Lisoesfingolipídeo/fisiologia , Esfingosina/análogos & derivados , Linfócitos T/fisiologia , Animais , Humanos , Subpopulações de Linfócitos/imunologia , Camundongos , Receptores de Lisoesfingolipídeo/genética , Esfingosina/metabolismoRESUMO
Steroids have been shown to inhibit the function of fresh or IL-2-activated natural killer (NK) cells. Since IL-15 plays a key role in NK-cell development and function, we comparatively analyzed the effects of methylprednisolone on IL-2- or IL-15-cultured NK cells. Methylprednisolone inhibited the surface expression of the major activating receptors NKp30 and NKp44 in both conditions, whereas NK-cell proliferation and survival were sharply impaired only in IL-2-cultured NK cells. Accordingly, methylprednisolone inhibited Tyr phosphorylation of STAT1, STAT3, and STAT5 in IL-2-cultured NK cells but only marginally in IL-15-cultured NK cells, whereas JAK3 was inhibited under both conditions. Also, the NK cytotoxicity was similarly impaired in IL-2- or IL-15-cultured NK cells. This effect strictly correlated with the inhibition of ERK1/2 Tyr phosphorylation, perforin release, and cytotoxicity in a redirected killing assay against the FcRgamma(+) P815 target cells upon cross-linking of NKp46, NKG2D, or 2B4 receptors. In contrast, in the case of CD16, inhibition of ERK1/2 Tyr phosphorylation, perforin release, and cytotoxicity were not impaired. Our study suggests a different ability of IL-15-cultured NK cells to survive to steroid treatment, thus offering interesting clues for a correct NK-cell cytokine conditioning in adoptive immunotherapy.