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Sample records for 18ffdg-labeled natural killer

  1. Natural Killer Cell Memory

    PubMed Central

    O’Sullivan, Timothy E.; Sun, Joseph C.; Lanier, Lewis L.

    2015-01-01

    Natural killer (NK) cells have historically been considered short-lived cytolytic cells that can rapidly respond against pathogens and tumors in an antigen-independent manner, and then undergo cell death. Recently, however, NK cells have been shown to possess traits of adaptive immunity, and can acquire immunological memory in a similar manner to T and B cells. In this review, we discuss evidence for NK cell memory and the mechanisms involved in the generation and survival of these innate lymphocytes. PMID:26488815

  2. Natural Killer Cell Memory.

    PubMed

    O'Sullivan, Timothy E; Sun, Joseph C; Lanier, Lewis L

    2015-10-20

    Natural killer (NK) cells have historically been considered short-lived cytolytic cells that can rapidly respond against pathogens and tumors in an antigen-independent manner and then undergo cell death. Recently, however, NK cells have been shown to possess traits of adaptive immunity and can acquire immunological memory in a manner similar to that of T and B cells. In this review, we discuss evidence of NK cell memory and the mechanisms involved in the generation and survival of these innate lymphocytes.

  3. Natural killer cell deficiency.

    PubMed

    Orange, Jordan S

    2013-09-01

    Natural killer (NK) cells are part of the innate immune defense against infection and cancer and are especially useful in combating certain viral pathogens. The utility of NK cells in human health has been underscored by a growing number of persons who are deficient in NK cells and/or their functions. This can be in the context of a broader genetically defined congenital immunodeficiency, of which there are more than 40 presently known to impair NK cells. However, the abnormality of NK cells in certain cases represents the majority immunologic defect. In aggregate, these conditions are termed NK cell deficiency. Recent advances have added clarity to this diagnosis and identified defects in 3 genes that can cause NK cell deficiency, as well as some of the underlying biology. Appropriate consideration of these diagnoses and patients raises the potential for rational therapeutic options and further innovation.

  4. Immunobiology of natural killer cells

    SciTech Connect

    Lotzova, E.; Herberman, R.B.

    1986-01-01

    This book combines research from many disciplines into a review of natural killer (NK) cell-mediated immunity in humans and experimental animal system. Topics for the volumes include: Volume I: Assays for NK Cell Cytotoxicity; Their Values and Pitfalls. Separation and Characterization of Phenotypically Distinct Subsets of NK Cells. Ultrastructure and Cytochemistry of the Human Large Granular Lymphocytes. Phylogeny and Ontogeny of NK Cells. Tissue and Organ distribution of NK Cells. Genetic Control of NK Cell Activity in Rodents. Phenotype, Functional Heterogeneity, and Lineage of Natural Killer Cells. Target Cell Structures, Recognition Sites, and the Mechanism of NK Cytotoxicity. Natural Killer Cytotoxic Factors (NKCF) Role in Cell-Mediated Cytotoxicity. Characteristics of Cultured NK Cells. Lectin-Dependent Killer Cells. MLC-Induced Cytotoxicity as a Model for the Development and Regulation of NK Cytotoxicity. LGL Lymphoproliferative Diseases in Man and Experimental Animals: The Characteristics of These Cells and Their Potential Experimental Uses. Index.

  5. Natural killer cell leukaemia.

    PubMed

    Gandhi, Jamish

    2009-01-01

    A 42-year-old white woman, who was a general practitioner referral to the medical team, presented with a 3-day history of left upper quadrant pain; an urgent private ultrasound scan had showed splenomegaly. She was initially admitted with sepsis without an obvious cause but with a differential diagnosis of a haematological malignancy. Her admission blood tests showed a mildly reduced white cell count and low platelets. Her symptoms progressed and she developed right upper quadrant pain. Her blood counts deteriorated showing a disseminated intravascular coagulation (DIC) picture and mildly deranged liver function tests. Blood films were non-diagnostic. A CT scan of the abdomen/pelvis showed splenomegaly and also hepatomegaly and ascites, not seen in her initial ultrasound scan. Multiple cultures of blood/urine/ascites and infective serology were unremarkable.She was transferred to a larger tertiary centre under the care of the surgeons with presumed abdominal sepsis and underwent an open laparotomy, which showed a big firm liver and spleen but no obvious cause for sepsis. The infectious disease team were unable to find a cause, and haematology became involved to investigate the possibility of a haematological malignancy. The patient underwent two bone marrow biopsies, a percutaneous liver biopsy and had flow cytometry of her ascitic fluid, which revealed the diagnosis of a natural killer cell leukaemia. After some slight improvement on steroids, the patient was given cyclophosphamide, doxorubicin, vincristine, prednisone, rituximab (CHOP-R) chemotherapy. The patient had an initial response to chemotherapy, with reduction in ascitic volume and hepatosplenomegaly, and normalisation of her coagulation. This was accompanied by an overall improvement in her physical condition. She had a second cycle of CHOP-R, but unfortunately approximately 2 weeks after that, she deteriorated rapidly. She was too weak for salvage chemotherapy, so she was put on comfort care. She died

  6. Natural killer cells: remembrances of things past.

    PubMed

    Raulet, David H

    2009-04-14

    Recent work has revealed that natural killer cells exhibit a form of memory, previously considered an exclusive property of adaptive immunity. While protective, natural killer cell memory is probably hazier and more fleeting than T cell memory.

  7. Deficient natural killer cell function in preeclampsia

    SciTech Connect

    Alanen, A.; Lassila, O.

    1982-11-01

    Natural killer cell activity of peripheral blood lymphocytes was measured against K-562 target cells with a 4-hour /sup 51/Cr release assay in 15 primigravid women with preeclamptic symptoms. Nineteen primigravid women with an uncomplicated pregnancy and 18 nonpregnant women served as controls. The natural killer cell activity of preeclamptic women was observed to be significantly lower than that of both control groups. Natural killer cells in preeclamptic women responded normally to augmentation caused by interferon. These findings give further evidence for the participation of the maternal immune system in this pregnancy disorder.

  8. Human natural killer cell development.

    PubMed

    Freud, Aharon G; Caligiuri, Michael A

    2006-12-01

    Our understanding of human natural killer (NK) cell development lags far behind that of human B- or T-cell development. Much of our recent knowledge of this incomplete picture comes from experimental animal models that have aided in identifying fundamental in vivo processes, including those controlling NK cell homeostasis, self-tolerance, and the generation of a diverse NK cell repertoire. However, it has been difficult to fully understand the mechanistic details of NK cell development in humans, primarily because the in vivo cellular intermediates and microenvironments of this developmental pathway have remained elusive. Although there is general consensus that NK cell development occurs primarily within the bone marrow (BM), recent data implicate secondary lymphoid tissues as principal sites of NK cell development in humans. The strongest evidence stems from the observation that the newly described stages of human NK cell development are naturally and selectively enriched within lymph nodes and tonsils compared with blood and BM. In the current review, we provide an overview of these recent findings and discuss these in the context of existing tenets in the field of lymphocyte development.

  9. Natural Killer Cells: Remembrances of things past

    PubMed Central

    Raulet, David H.

    2010-01-01

    Natural killer (NK) cells exhibit a form of memory, previously considered an exclusive property of adaptive immunity. While protective, NK memory is probably hazier and more fleeting than T cell memory. PMID:19368874

  10. Evolutionary vignettes of natural killer cell receptors.

    PubMed

    Sambrook, Jennifer G; Beck, Stephan

    2007-10-01

    The discovery of novel immune receptors has led to a recent renaissance of research into the innate immune system, following decades of intense research of the adaptive immune system. Of particular interest has been the discovery of the natural killer (NK) cell receptors which, depending on type, interact with classical or non-classical MHC class I antigens of the adaptive immune system, thus functioning at the interface of innate and adaptive immunity. Here, we review recent progress with respect to two such families of NK receptors, the killer immunoglobulin-like receptors (KIRs) and the killer cell lectin-like receptors (KLRs), and attempt to trace their evolution across vertebrates.

  11. Natural killer cell regulation - beyond the receptors

    PubMed Central

    Urlaub, Doris; Fasbender, Frank; Claus, Maren

    2014-01-01

    Natural killer (NK) cells are lymphocytes that are important for early and effective immune responses against infections and cancer. In the last 40 years, many receptors, their corresponding ligands and signaling pathways that regulate NK cell functions have been identified. However, we now know that additional processes, such as NK cell education, differentiation and also the formation of NK cell memory, have a great impact on the reactivity of these cells. Here, we summarize the current knowledge about these modulatory processes. PMID:25374665

  12. The Human Natural Killer Cell Immune Synapse

    NASA Astrophysics Data System (ADS)

    Davis, Daniel M.; Chiu, Isaac; Fassett, Marlys; Cohen, George B.; Mandelboim, Ofer; Strominger, Jack L.

    1999-12-01

    Inhibitory killer Ig-like receptors (KIR) at the surface of natural killer (NK) cells induced clustering of HLA-C at the contacting surface of target cells. In this manner, inhibitory immune synapses were formed as human NK cells surveyed target cells. At target/NK cell synapses, HLA-C/KIR distributed into rings around central patches of intercellular adhesion molecule-1/lymphocyte function-associated antigen-1, the opposite orientation to mature murine T cell-activating synapses. This organization of protein was stable for at least 20 min. Cells could support multiple synapses simultaneously, and clusters of HLA-C moved as NK cells crawled over target cells. Clustering required a divalent metal cation, explaining how metal chelators inhibit KIR function. Surprisingly, however, formation of inhibitory synapses was unaffected by ATP depletion and the cytoskeletal inhibitors, colchicine and cytochalsins B and D. Clearly, supramolecular organization within plasma membranes is critical for NK cell immunosurveillance.

  13. Natural killer cells in hepatitis B virus infection.

    PubMed

    Wu, Shao-fei; Wang, Wen-jing; Gao, Yue-qiu

    2015-01-01

    Natural killer cells are a unique type of lymphocytes with cytotoxic capacity, and play important roles against tumors and infections. Recently, natural killer cells have been increasingly valued in their effects in hepatitis B virus infection. Since hepatitis B virus is not cytopathic, the subsequent antiviral immune responses of the host are responsible for sustaining the liver injury, which may result in cirrhosis and even hepatocellular carcinoma. Many studies have confirmed that natural killer cells participate in anti-hepatitis B virus responses both in the early phase after infection and in the chronic phase via cytolysis, degranulation, and cytokine secretion. However, natural killer cells play dichotomic roles: they exert antiviral and immunoregulatory functions whilst contribute to the pathogenesis of liver injury. Here, we review the roles of natural killer cells in hepatitis B virus infection, introducing novel therapeutic strategies for controlling hepatitis B virus infection via the modulation of natural killer cells.

  14. Natural Killer Cell Reduction and Uteroplacental Vasculopathy.

    PubMed

    Golic, Michaela; Haase, Nadine; Herse, Florian; Wehner, Anika; Vercruysse, Lisbeth; Pijnenborg, Robert; Balogh, Andras; Saether, Per Christian; Dissen, Erik; Luft, Friedrich C; Przybyl, Lukasz; Park, Joon-Keun; Alnaes-Katjavivi, Patji; Staff, Anne Cathrine; Verlohren, Stefan; Henrich, Wolfgang; Muller, Dominik N; Dechend, Ralf

    2016-10-01

    Uterine natural killer cells are important for uteroplacental development and pregnancy maintenance. Their role in pregnancy disorders, such as preeclampsia, is unknown. We reduced the number of natural killer cells by administering rabbit anti-asialo GM1 antiserum in an established rat preeclamptic model (female human angiotensinogen×male human renin) and evaluated the effects at the end of pregnancy (day 21), compared with preeclamptic control rats receiving normal rabbit serum. In 100% of the antiserum-treated, preeclamptic rats (7/7), we observed highly degenerated vessel cross sections in the mesometrial triangle at the end of pregnancy. This maternal uterine vasculopathy was characterized by a total absence of nucleated/living cells in the vessel wall and perivascularly and prominent presence of fibrosis. Furthermore, there were no endovascular trophoblast cells within the vessel lumen. In the control, normal rabbit serum-treated, preeclamptic rats, only 20% (1/5) of the animals displayed such vasculopathy. We confirmed the results in healthy pregnant wild-type rats: after anti-asialo GM1 treatment, 67% of maternal rats displayed vasculopathy at the end of pregnancy compared with 0% in rabbit serum-treated control rats. This vasculopathy was associated with a significantly lower fetal weight in wild-type rats and deterioration of fetal brain/liver weight ratio in preeclamptic rats. Anti-asialo GM1 application had no influence on maternal hypertension and albuminuria during pregnancy. Our results show a new role of natural killer cells during hypertensive pregnancy in maintaining vascular integrity. In normotensive pregnancy, this integrity seems important for fetal growth. © 2016 American Heart Association, Inc.

  15. Viral Evasion of Natural Killer Cell Activation.

    PubMed

    Ma, Yi; Li, Xiaojuan; Kuang, Ersheng

    2016-04-12

    Natural killer (NK) cells play a key role in antiviral innate defenses because of their abilities to kill infected cells and secrete regulatory cytokines. Additionally, NK cells exhibit adaptive memory-like antigen-specific responses, which represent a novel antiviral NK cell defense mechanism. Viruses have evolved various strategies to evade the recognition and destruction by NK cells through the downregulation of the NK cell activating receptors. Here, we review the recent findings on viral evasion of NK cells via the impairment of NK cell-activating receptors and ligands, which provide new insights on the relationship between NK cells and viral actions during persistent viral infections.

  16. Modeling Natural Killer Cell Targeted Immunotherapies

    PubMed Central

    Lopez-Lastra, Silvia; Di Santo, James P.

    2017-01-01

    Animal models have extensively contributed to our understanding of human immunobiology and to uncover the underlying pathological mechanisms occurring in the development of diseases. However, mouse models do not reproduce the genetic and molecular complexity inherent in human disease conditions. Human immune system (HIS) mouse models that are susceptible to human pathogens and can recapitulate human hematopoiesis and tumor immunobiology provide one means to bridge the interspecies gap. Natural killer cells are the founding member of the innate lymphoid cell family. They exert a rapid and strong immune response against tumor and pathogen-infected cells. Their antitumor features have long been exploited for therapeutic purposes in the context of cancer. In this review, we detail the development of highly immunodeficient mouse strains and the models currently used in cancer research. We summarize the latest improvements in adoptive natural killer (NK) cell therapies and the development of novel NK cell sources. Finally, we discuss the advantages of HIS mice to study the interactions between human NK cells and human cancers and to develop new therapeutic strategies. PMID:28405194

  17. Natural killer cells in inflammatory heart disease.

    PubMed

    Ong, SuFey; Rose, Noel R; Čiháková, Daniela

    2017-02-01

    Despite of a multitude of excellent studies, the regulatory role of natural killer (NK) cells in the pathogenesis of inflammatory cardiac disease is greatly underappreciated. Clinical abnormalities in the numbers and functions of NK cells are observed in myocarditis and inflammatory dilated cardiomyopathy (DCMi) as well as in cardiac transplant rejection [1-6]. Because treatment of these disorders remains largely symptomatic in nature, patients have little options for targeted therapies [7,8]. However, blockade of NK cells and their receptors can protect against inflammation and damage in animal models of cardiac injury and inflammation. In these models, NK cells suppress the maturation and trafficking of inflammatory cells, alter the local cytokine and chemokine environments, and induce apoptosis in nearby resident and hematopoietic cells [1,9,10]. This review will dissect each protective mechanism employed by NK cells and explore how their properties might be exploited for their therapeutic potential.

  18. Immunobiology of natural killer cells. Volume II

    SciTech Connect

    Lotzova, E.; Herberman, R.B.

    1986-01-01

    This book provides a review of natural killer (NK) cell-mediated immunity in humans and experimental animal system. Topics for the volume include: In vivo activities of NK cells against primary and metastatic tumors in experimental animals; involvement of NK cells in human malignant disease; impaired NK cell profile in leukemia patients; in vivo modulation of NK activity in cancer patients; implications of aberrant NK cell activity in nonmalignant, chronic diseases; NK cell role in regulation of the growth and functions of hemopoietic and lymphoid cells; NK cells active against viral, bacterial, protozoan, and fungal infections; cytokine secretion and noncytotoxic functions of human large granular lymphocytes; augmentation of NK activity; regulation of NK cell activity by suppressor cells; NK cell cloning technology and characteristics of NK cell clones; comparison of antibody-dependent cellular cytotoxicity (ADCC) and NK activity, and index.

  19. Natural killer T cell based Immunotherapy

    PubMed Central

    Subrahmanyam, Priyanka B.; Sun, Wenji; East, James E.; Li, Junxin; Webb, Tonya J.

    2013-01-01

    Natural killer T (NKT) cells play an important immunoregulatory role and are thought to bridge the innate and adaptive immune responses. Following activation through cognate interactions with lipid antigen presented in the context of CD1d molecules, NKT cells rapidly produce a plethora of cytokines and can also mediate cytotoxicity. Due to their potent effector functions, extensive research has been performed to increase our understanding on how to effectively modulate these cells. In fact, NKT cell agonists have been used as vaccine adjuvants to enhance antigen specific T and B cell responses to infections and malignancy. In this review, we will focus on recent advances in NKT cell-based vaccination strategies. Given the role that NKT cells play in autoimmune disease, infectious diseases, cancer, transplant immunology and dermatology, it is important to understand how to effectively guide their effector functions in order to develop novel immunotherapeutic strategies. PMID:24089657

  20. Regulation of murine natural killer cell commitment

    PubMed Central

    Huntington, Nicholas D.; Nutt, Stephen L.; Carotta, Sebastian

    2013-01-01

    Natural killer (NK) cells can derive from the same precursors as B and T cells, however, to achieve lineage specificity, several transcription factors need to be activated or annulled. While a few important transcription factors have been identified for NK genesis the mechanisms of how this is achieved is far from resolved. Adding to the complexity of this, NK cells are found and potentially develop in diverse locations in vivo and it remains to be addressed if a common NK cell precursor seeds diverse niches and how transcription factors may differentially regulate NK cell commitment in distinct microenvironments. Here we will summarize some recent findings in NK cell commitment and discuss how a NK cell transcriptional network might be organized, while addressing some misconceptions and anomalies along the way. PMID:23386852

  1. Natural killer cells, ageing and cancer.

    PubMed

    Naumova, Elissaveta; Pawelec, Graham; Mihaylova, Anastasiya

    2016-04-01

    Natural killer (NK) cells are key components of innate immunity and substantially contribute to anti-tumor immune responses. The role of NK cells in immune surveillance is linked to many aspects of NK cell biology, but the age of the animal being studied or the human under treatment is rarely taken into account. The solicited reviews constituting a collection of papers presented here as a "Symposium-in-Writing" on the topic of NK cells, ageing and cancer were inspired by the increasing knowledge of NK cell biology and genetics, and emerging data on their impact in the clinic (disease associations and therapies), together with the realization that older individuals also differ from younger ones regarding innate as well as adaptive immunity.

  2. Natural killer cells: In health and disease.

    PubMed

    Mandal, Arundhati; Viswanathan, Chandra

    2015-06-01

    Natural killer (NK) cells constitute our bodies' frontline defense system, guarding against tumors and launching attacks against infections. The activities of NK cells are regulated by the interaction of various receptors expressed on their surfaces with cell surface ligands. While the role of NK cells in controlling tumor activity is relatively clear, the fact that they are also linked to various other disease conditions is now being highlighted. Here, we present an overview of the role of NK cells during normal body state as well as under diseased state. We discuss the possible utilization of these powerful cells as immunotherapeutic agents in combating diseases such as asthma, autoimmune diseases, and HIV-AIDS. This review also outlines current challenges in NK cell therapy.

  3. Natural killer cells in human autoimmune disorders

    PubMed Central

    2013-01-01

    Natural killer (NK) cells are innate lymphocytes that play a critical role in early host defense against viruses. Through their cytolytic capacity and generation of cytokines and chemokines, NK cells modulate the activity of other components of the innate and adaptive immune systems and have been implicated in the initiation or maintenance of autoimmune responses. This review focuses on recent research elucidating a potential immunoregulatory role for NK cells in T-cell and B-cell-mediated autoimmune disorders in humans, with a particular focus on multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematous. A better understanding of the contributions of NK cells to the development of autoimmunity may lead to novel therapeutic targets in these diseases. PMID:23856014

  4. The role of natural killer cells in periodontitis.

    PubMed

    Wilensky, Asaf; Chaushu, Stella; Shapira, Lior

    2015-10-01

    Periodontitis is the most common chronic inflammatory disease of humans. The microbial etiology of the disease is well documented, as is the major role of the host response in disease pathogenesis. As natural killer cells are one of the most important components of innate immunity against bacteria and viruses, they can be expected to act as major players in the development of the disease. Through direct interaction with periodontal pathogens, natural killer cells produce pro-inflammatory cytokines that subsequently may lead to tissue destruction. Indeed, using a murine periodontitis model, such mechanisms have been shown to be involved in bacterial-induced alveolar bone loss. In the present review we document the available literature and evidence base regarding the origin, biology and characteristics of natural killer cells, and their interactions with periodontal pathogens. The potential role of natural killer cells in periodontal pathogenesis and the mechanisms involved are discussed.

  5. Regulation of Murine Natural Killer Cell Development

    PubMed Central

    Goh, Wilford; Huntington, Nicholas D.

    2017-01-01

    Natural killer (NK) cells are effector lymphocytes of the innate immune system that are known for their ability to kill transformed and virus-infected cells. NK cells originate from hematopoietic stem cells in the bone marrow, and studies on mouse models have revealed that NK cell development is a complex, yet tightly regulated process, which is dependent on both intrinsic and extrinsic factors. The development of NK cells can be broadly categorized into two phases: lineage commitment and maturation. Efforts to better define the developmental framework of NK cells have led to the identification of several murine NK progenitor populations and mature NK cell subsets, each defined by a varied set of cell surface markers. Nevertheless, the relationship between some of these NK cell subsets remains to be determined. The classical approach to studying both NK cell development and function is to identify the transcription factors involved and elucidate the mechanistic action of each transcription factor. In this regard, recent studies have provided further insight into the mechanisms by which transcription factors, such as ID2, FOXO1, Kruppel-like factor 2, and GATA-binding protein 3 regulate various aspects of NK cell biology. It is also becoming evident that the biology of NK cells is not only transcriptionally regulated but also determined by epigenetic alterations and posttranscriptional regulation of gene expression by microRNAs. This review summarizes recent progress made in NK development, focusing primarily on transcriptional regulators and their mechanistic actions. PMID:28261203

  6. The evolution of natural killer cell receptors.

    PubMed

    Carrillo-Bustamante, Paola; Keşmir, Can; de Boer, Rob J

    2016-01-01

    Natural killer (NK) cells are immune cells that play a crucial role against viral infections and tumors. To be tolerant against healthy tissue and simultaneously attack infected cells, the activity of NK cells is tightly regulated by a sophisticated array of germline-encoded activating and inhibiting receptors. The best characterized mechanism of NK cell activation is "missing self" detection, i.e., the recognition of virally infected or transformed cells that reduce their MHC expression to evade cytotoxic T cells. To monitor the expression of MHC-I on target cells, NK cells have monomorphic inhibitory receptors which interact with conserved MHC molecules. However, there are other NK cell receptors (NKRs) encoded by gene families showing a remarkable genetic diversity. Thus, NKR haplotypes contain several genes encoding for receptors with activating and inhibiting signaling, and that vary in gene content and allelic polymorphism. But if missing-self detection can be achieved by a monomorphic NKR system why have these polygenic and polymorphic receptors evolved? Here, we review the expansion of NKR receptor families in different mammal species, and we discuss several hypotheses that possibly underlie the diversification of the NK cell receptor complex, including the evolution of viral decoys, peptide sensitivity, and selective MHC-downregulation.

  7. Manufacturing Natural Killer Cells as Medicinal Products.

    PubMed

    Chabannon, Christian; Mfarrej, Bechara; Guia, Sophie; Ugolini, Sophie; Devillier, Raynier; Blaise, Didier; Vivier, Eric; Calmels, Boris

    2016-01-01

    Natural Killer (NK) cells are innate lymphoid cells (ILC) with cytotoxic and regulatory properties. Their functions are tightly regulated by an array of inhibitory and activating receptors, and their mechanisms of activation strongly differ from antigen recognition in the context of human leukocyte antigen presentation as needed for T-cell activation. NK cells thus offer unique opportunities for new and improved therapeutic manipulation, either in vivo or in vitro, in a variety of human diseases, including cancers. NK cell activity can possibly be modulated in vivo through direct or indirect actions exerted by small molecules or monoclonal antibodies. NK cells can also be adoptively transferred following more or less substantial modifications through cell and gene manufacturing, in order to empower them with new or improved functions and ensure their controlled persistence and activity in the recipient. In the present review, we will focus on the technological and regulatory challenges of NK cell manufacturing and discuss conditions in which these innovative cellular therapies can be brought to the clinic.

  8. Manufacturing Natural Killer Cells as Medicinal Products

    PubMed Central

    Chabannon, Christian; Mfarrej, Bechara; Guia, Sophie; Ugolini, Sophie; Devillier, Raynier; Blaise, Didier; Vivier, Eric; Calmels, Boris

    2016-01-01

    Natural Killer (NK) cells are innate lymphoid cells (ILC) with cytotoxic and regulatory properties. Their functions are tightly regulated by an array of inhibitory and activating receptors, and their mechanisms of activation strongly differ from antigen recognition in the context of human leukocyte antigen presentation as needed for T-cell activation. NK cells thus offer unique opportunities for new and improved therapeutic manipulation, either in vivo or in vitro, in a variety of human diseases, including cancers. NK cell activity can possibly be modulated in vivo through direct or indirect actions exerted by small molecules or monoclonal antibodies. NK cells can also be adoptively transferred following more or less substantial modifications through cell and gene manufacturing, in order to empower them with new or improved functions and ensure their controlled persistence and activity in the recipient. In the present review, we will focus on the technological and regulatory challenges of NK cell manufacturing and discuss conditions in which these innovative cellular therapies can be brought to the clinic. PMID:27895646

  9. Compromised natural killer cells in pulmonary embolism

    PubMed Central

    Zhang, Xiaoyu; Wang, Qiang; Shen, Yuqin; Song, Haoming; Gong, Zhu; Wang, Lemin

    2015-01-01

    Objective: The high morbidity, mortality and misdiagnosis rate render pulmonary embolism (PE) as a worldwide health problem. However, the etiology and pathogenesis of this disease have not been well characterized. Increasing studies indicate infection and immunity play a crucial role in PE. Natural killer (NK) cells act as a bridge between the innate immune and acquired immune. This study aimed to investigate the possible function of NK cells in PE. Methods: Human cDNA microarray analysis was employed to detect genes associated with NK cells in peripheral blood mononuclear cells (PBMCs). Random variance model corrected t-test was used for statistical analysis of differential gene expression. Flow cytometry was performed to detect the CD16+CD56+ NK cells. Results: In the present study, based on gene expression microarray analysis, we showed four inhibitory receptors (KLRB1, KLRD1, KLRF1, KLRG1) and four activating receptors (KLRC1, KLRC3, KLRK1 and NCR1) on NK cells were remarkably down-regulated and the cytological experiment demonstrated the proportion of CD16+CD56+ NK cells among PBMCs decreased in the PE group. Conclusions: We confirmed the presence of reduced expression of critical activating as well as inhibitory NK cell receptors and low proportion of CD16+CD56+ NK cells in PE. The consistence between genomic and cytological examination suggests compromised NK cells may contribute to the pathogenesis of PE. PMID:26339393

  10. Targeting natural killer cells and natural killer T cells in cancer

    PubMed Central

    Vivier, Eric; Ugolini, Sophie; Blaise, Didier; Chabannon, Christian; Brossay, Laurent

    2016-01-01

    Preface text Natural killer (NK) and NKT cells are subsets of lymphocytes that share some phenotypic and functional similarities. Both cell types can rapidly respond to the presence of tumour cells and participate in antitumour immune responses. This has prompted interest in the development of innovative anticancer therapies that are based on the manipulation of NK and NKT cells. Recent studies have highlighted how the immune reactivity of NK and NKT cells is shaped by the environment in which they develop. The rationale use of these cells for cancer immunotherapies awaits a better understanding of their effector functions, migratory patterns and survival properties in humans. PMID:22437937

  11. The role of natural killer cells in chronic myeloid leukemia

    PubMed Central

    Danier, Anna Carolyna Araújo; de Melo, Ricardo Pereira; Napimoga, Marcelo Henrique; Laguna-Abreu, Maria Theresa Cerávolo

    2011-01-01

    Chronic myeloid leukemia is a neoplasia resulting from a translocation between chromosomes 9 and 22 producing the BCR-ABL hybrid known as the Philadelphia chromosome (Ph). In chronic myeloid leukemia a proliferation of malignant myeloid cells occurs in the bone marrow due to excessive tyrosine kinase activity. In order to maintain homeostasis, natural killer cells, by means of receptors, identify the major histocompatibility complex on the surface of tumor cells and subsequently induce apoptosis. The NKG2D receptor in the natural killer cells recognizes the transmembrane proteins related to major histocompatibility complex class I chain-related genes A and B (MICA and MICB), and it is by the interaction between NKG2D and MICA that natural killer cells exert cytotoxic activity against chronic myeloid leukemia tumor cells. However, in the case of chronic exposure of the NKG2D receptor, the MICA ligand releases soluble proteins called sMICA from the tumor cell surface, which negatively modulate NKG2D and enable the tumor cells to avoid lysis mediated by the natural killer cells. Blocking the formation of sMICA may be an important antitumor strategy. Treatment using tyrosine kinase inhibitors induces modulation of NKG2DL expression, which could favor the activity of the natural killer cells. However this mechanism has not been fully described in chronic myeloid leukemia. In the present study, we analyze the role of natural killer cells to reduce proliferation and in the cellular death of tumor cells in chronic myeloid leukemia. PMID:23049299

  12. Natural killer cells and their receptors in multiple sclerosis

    PubMed Central

    Kaur, Gurman; Trowsdale, John

    2013-01-01

    The immune system has crucial roles in the pathogenesis of multiple sclerosis. While the adaptive immune cell subsets, T and B cells, have been the main focus of immunological research in multiple sclerosis, it is now important to realize that the innate immune system also has a key involvement in regulating autoimmune responses in the central nervous system. Natural killer cells are innate lymphocytes that play vital roles in a diverse range of infections. There is evidence that they influence a number of autoimmune conditions. Recent studies in multiple sclerosis and its murine model, experimental autoimmune encephalomyelitis, are starting to provide some understanding of the role of natural killer cells in regulating inflammation in the central nervous system. Natural killer cells express a diverse range of polymorphic cell surface receptors, which interact with polymorphic ligands; this interaction controls the function and the activation status of the natural killer cell. In this review, we discuss evidence for the role of natural killer cells in multiple sclerosis and experimental autoimmune encephalomyelitis. We consider how a change in the balance of signals received by the natural killer cell influences its involvement in the ensuing immune response, in relation to multiple sclerosis. PMID:22734127

  13. Natural killer cells and their receptors in multiple sclerosis.

    PubMed

    Kaur, Gurman; Trowsdale, John; Fugger, Lars

    2013-09-01

    The immune system has crucial roles in the pathogenesis of multiple sclerosis. While the adaptive immune cell subsets, T and B cells, have been the main focus of immunological research in multiple sclerosis, it is now important to realize that the innate immune system also has a key involvement in regulating autoimmune responses in the central nervous system. Natural killer cells are innate lymphocytes that play vital roles in a diverse range of infections. There is evidence that they influence a number of autoimmune conditions. Recent studies in multiple sclerosis and its murine model, experimental autoimmune encephalomyelitis, are starting to provide some understanding of the role of natural killer cells in regulating inflammation in the central nervous system. Natural killer cells express a diverse range of polymorphic cell surface receptors, which interact with polymorphic ligands; this interaction controls the function and the activation status of the natural killer cell. In this review, we discuss evidence for the role of natural killer cells in multiple sclerosis and experimental autoimmune encephalomyelitis. We consider how a change in the balance of signals received by the natural killer cell influences its involvement in the ensuing immune response, in relation to multiple sclerosis.

  14. Radiosensitivity of human natural killer cells: Binding and cytotoxic activities of natural killer cell subsets

    SciTech Connect

    Rana, R.; Vitale, M.; Mazzotti, G.; Manzoli, L.; Papa, S. )

    1990-10-01

    The sensitivity of human natural killer (NK) cell activities (both binding and killing) after exposure of peripheral blood mononuclear cells to different doses of gamma radiation was studied. A panel of monoclonal antibodies was used to identify the NK and T-lymphocyte subsets and to evaluate their radiosensitivity. Peripheral blood mononuclear cells were irradiated with low (2-6 Gy) and high (10-30 Gy) doses and NK cell binding and cytotoxic activity against K562 target cells were studied after 3 h and 48 h in culture. The primary damage to NK cell activity was identified at the postbinding level and affected mainly the lytic machinery. After 48 h culture postirradiation, an overall depression of cytotoxic activity was observed, but ionizing radiation produced either a selection of the more cytotoxic NK cell subsets, which therefore might be considered more resistant to radiation damage than the less cytotoxic NK cells, or a long-term stimulation of cytotoxic activity in surviving cells.

  15. Suppression of newborn natural killer cell activity by prostaglandin E2

    SciTech Connect

    Milch, P.O.; Salvatore, W.; Luft, B.; Baker, D.A.

    1988-10-01

    The effect of prostaglandin E2 on natural killer cell activity of cord blood was examined. Natural killer cell activity, determined by chromium 51 release, was significantly reduced after prostaglandin E2 (1 microgram/ml) treatment. Prostaglandin E2 has been found to enhance the cellular spread of herpesvirus. Thus prostaglandins may enhance viral infections indirectly by suppressing natural killer cell activity.

  16. In vivo generation of decidual natural killer cells from resident hematopoietic progenitors.

    PubMed

    Chiossone, Laura; Vacca, Paola; Orecchia, Paola; Croxatto, Daniele; Damonte, Patrizia; Astigiano, Simonetta; Barbieri, Ottavia; Bottino, Cristina; Moretta, Lorenzo; Mingari, Maria Cristina

    2014-03-01

    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.

  17. In vivo generation of decidual natural killer cells from resident hematopoietic progenitors

    PubMed Central

    Chiossone, Laura; Vacca, Paola; Orecchia, Paola; Croxatto, Daniele; Damonte, Patrizia; Astigiano, Simonetta; Barbieri, Ottavia; Bottino, Cristina; Moretta, Lorenzo; Mingari, Maria Cristina

    2014-01-01

    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. PMID:24179150

  18. Natural killer cells, killer immunoglobulin-like receptors and human leucocyte antigen class I in disease

    PubMed Central

    Boyton, R J; Altmann, D M

    2007-01-01

    Natural killer cells constitute a potent, rapid part of the innate immune response to infection or transformation, and also generate a link to priming of adaptive immunity. Their function can encompass direct cytotoxicity as well as the release of cytokines and chemokines. In humans, a major component of natural killer (NK) cell target recognition depends mainly on the surveillance of human leucocyte antigen (HLA) class I molecules by killer immunoglobulin-like receptors (KIR). Different KIR can transmit inhibitory or activatory signals to the cell, and effector function is considered to result from the balance of these contributing signals. The regulation of NK cell responses depends on a number of variables: KIR genotype, HLA genotype, heterozygosity versus homozygosity for these, whether there is cognate recognition between the HLA and KIR products carried by an individual, clonal variation between individual NK cells in KIR expression, and the specific modulation of HLA expression by infection, transformation or peptide binding. Different HLA/KIR genotypes can impart different thresholds of activation to the NK cell repertoire and such genotypic variation has been found to confer altered risk in a number of diseases including human immunodeficiency virus (HIV) susceptibility and progression, hepatitis C virus clearance, idiopathic bronchiectasis, autoimmunity and cancer. PMID:17521317

  19. Uterine natural killer cell partnerships in early mouse decidua basalis.

    PubMed

    Felker, Allison M; Croy, B Anne

    2016-10-01

    The decidua basalis of developing mouse implantation sites is highly enriched in CD45(+) leukocytes. In intact, syngeneically mated C57BL/6 decidua basalis examined at gestation day 8.5 by whole-mount in situ immunohistochemistry, leukocyte, but not trophoblast, conjugations were reported. Nothing is known regarding time course, frequency, composition, or importance of physiologic decidual CD45(+) cell pairing. In this study, we confirmed the presence of anti-CD54(+)/anti-CD11a(+) immune synapses in CD45(+) decidual cell conjugates and characterized their cellular heterogeneity. Conjugated cell pairs were virtually absent before implantation (virgin and gestation days 3.5 and 4.5), were infrequent at gestation day 5.5, but involved 19% of all CD45(+) cells by gestation day 8.5, then declined. By gestation day 8.5, almost all CD45(+) cells coexpressed CD31, and 2 CD45(+)CD31(+) cells composed most conjugates. Conjugation partners were defined for 2 nonoverlapping uterine natural killer cell subsets (Ly49C/I (+)/Dolichos biflorus agglutinin lectin(-) and Ly49C/I(-)/Dolichos biflorus agglutinin lectin(+)). Ly49C/I(+) uterine natural killer cells were the major subset from before mating up to gestation day 6.5. At gestation day 5.5/6.5, uterine natural killer cell conjugates involving Ly49C/I (+) cells were more abundant. By gestation day 8.5/9.5, Dolichos biflorus agglutinin lectin(+) uterine natural killer cells were the dominant subset with Dolichos biflorus agglutinin lectin(+)/Dolichos biflorus agglutinin lectin(+) homologous conjugates and Dolichos biflorus agglutinin lectin(+)/Dolichos biflorus agglutinin lectin(-) heterologous conjugates dominating uterine natural killer cell pairings. At gestation day 6.5, both Ly49C/I(+)/CD45(+) and Dolichos biflorus agglutinin lectin(+)/CD45(+) heterologous conjugate pairs strongly engaged antigen-presenting cells (CD11c(+), CD68(+), or major histocompatibility complex class II(+)). By gestation day 8.5, dominant partners of

  20. Impaired cytotoxicity associated with defective natural killer cell differentiation in myelodysplastic syndromes.

    PubMed

    Hejazi, Maryam; Manser, Angela R; Fröbel, Julia; Kündgen, Andrea; Zhao, Xiaoyi; Schönberg, Kathrin; Germing, Ulrich; Haas, Rainer; Gattermann, Norbert; Uhrberg, Markus

    2015-05-01

    Natural killer cells are well known to mediate anti-leukemic responses in myeloid leukemia but their role in myelodysplastic syndromes is not well understood. Here, in a cohort of newly diagnosed patients (n=75), widespread structural and functional natural killer cell defects were identified. One subgroup of patients (13%) had a selective deficiency of peripheral natural killer cells (count <10/mm(3) blood) with normal frequencies of T and natural killer-like T cells. Natural killer cell-deficient patients were predominantly found in high-risk subgroups and deficiency of these cells was significantly associated with poor prognosis. In the second subgroup, comprising the majority of patients (76%), natural killer cells were present but exhibited poor cytotoxicity. The defect was strongly associated with reduced levels of perforin and granzyme B. Notably, natural killer cell function and arming of cytotoxic granules could be fully reconstituted by in vitro stimulation. Further phenotypic analysis of these patients revealed an immature natural killer cell compartment that was biased towards CD56(bright) cells. The residual CD56(dim) cells exhibited a significant increase of the unlicensed NKG2A(-)KIR(-) subset and a striking reduction in complexity of the repertoire of killer cell immunoglobulin-like receptors. Taken together, these results suggest that the widespread defects in natural killer cell function occurring in patients with myelodysplastic syndromes are mostly due to either unsuccessful or inefficient generation of mature, functionally competent natural killer cells, which might contribute to disease progression through impaired immune surveillance.

  1. Killer clays! Natural antibacterial clay minerals

    USGS Publications Warehouse

    Williams, L.B.; Holland, M.; Eberl, D.D.; Brunet, T.; De Courrsou, L. B.

    2004-01-01

    The clay chemical properties that may be important in medicine were investigated. It was found that natural clay minerals can have striking and very specific effects on microbial populations. The effects can range from potentially enhanced microbial growth to complete sterilization. This paper presents evidence that natural clay minerals can be effective antimicrobial agents.

  2. Interferon induces natural killer cell blastogenesis in vivo

    NASA Technical Reports Server (NTRS)

    Biron, C. A.; Sonnenfeld, G.; Welsh, R. M.

    1984-01-01

    Interferon (IFN), types beta and gamma, and IFN inducers polyinosinic-polycytidylic acid and lymphocytic choriomeningitis virus, all stimulated the generation of blast-natural killer (NK) cells in mouse spleens, Blast-NK cells were characterized on the basis of size, 3H-thymidine uptake, and NK cell markers These data indicate that in addition to augmenting NK cell-mediated lysis, IFN may regulate NK cell proliferation in vivo.

  3. Interferon induces natural killer cell blastogenesis in vivo

    NASA Technical Reports Server (NTRS)

    Biron, C. A.; Sonnenfeld, G.; Welsh, R. M.

    1984-01-01

    Interferon (IFN), types beta and gamma, and IFN inducers polyinosinic-polycytidylic acid and lymphocytic choriomeningitis virus, all stimulated the generation of blast-natural killer (NK) cells in mouse spleens, Blast-NK cells were characterized on the basis of size, 3H-thymidine uptake, and NK cell markers These data indicate that in addition to augmenting NK cell-mediated lysis, IFN may regulate NK cell proliferation in vivo.

  4. Immunosurveillance of senescent cancer cells by natural killer cells

    PubMed Central

    Iannello, Alexandre; Raulet, David H

    2014-01-01

    We recently dissected how senescent tumors can trigger complementing signaling pathways that mobilize natural killer (NK) cells to eliminate malignant cells. In addition to cell-intrinsic effects on proliferation, senescence induces the production of chemokine (C-C motif) ligand 2 (CCL2), which recruits NK cells to mediate direct tumoricidal effects. Hence, senescence activates a cancer cell-extrinsic oncosuppression program. PMID:24800169

  5. Natural Killer Cells to the Attack: Combination Therapy against Neuroblastoma.

    PubMed

    Zenarruzabeitia, Olatz; Vitallé, Joana; Astigarraga, Itziar; Borrego, Francisco

    2017-02-01

    TGFβ in the tumor microenvironment diminishes natural killer (NK) cell-mediated anti-disialoganglioside (anti-GD2) mAb elimination of neuroblastoma cells. Consequently, blockade of TGFβ signaling with galunisertib in combination with the anti-GD2 mAb dinutuximab plus adoptively transferred NK cells is a promising tool for the treatment of neuroblastoma. Clin Cancer Res; 23(3); 615-7. ©2016 AACRSee related article by Tran et al., p. 804.

  6. Effect of spaceflight on natural killer cell activity

    NASA Technical Reports Server (NTRS)

    Rykova, Marina P.; Sonnenfeld, Gerald; Lesniak, A. T.; Taylor, Gerald R.; Meshkov, Dimitrii O.; Mandel, Adrian D.; Medvedev, Andrei E.; Berry, Wallace D.; Fuchs, Boris B.; Konstantinova, Irina V.

    1992-01-01

    The effects of spaceflight on immune cell function were determined in rats flown on Cosmos 2044. Control groups included vivarium, synchronous, and antiorthostatically suspended rats. The ability of natural killer cells to lyse two different target cell lines was determined. Spleen and bone marrow cells obtained from flight rats showed significantly inhibited cytotoxicity for YAC-1 target cells compared with cells from synchronous control rats. This could have been due to exposure of the rats to microgravity. Antiorthostatic suspension did not affect the level of cytotoxicity from spleen cells of suspended rats for YAC-1 cells. On the other hand, cells from rats flown in space showed no significant differences from vivarium and synchronous control rats in cytotoxicity for K-562 target cells. Binding of natural killer cells to K-562 target cells was unaffected by spaceflight. Antiorthostatic suspension resulted in higher levels of cytotoxicity from spleen cells for Cr-51-labeled K-562 cells. The results indicate differential effects of spaceflight on function of natural killer cells. This shows that spaceflight has selective effects on the immune response.

  7. Effect of spaceflight on natural killer cell activity

    NASA Technical Reports Server (NTRS)

    Rykova, Marina P.; Sonnenfeld, Gerald; Lesniak, A. T.; Taylor, Gerald R.; Meshkov, Dimitrii O.; Mandel, Adrian D.; Medvedev, Andrei E.; Berry, Wallace D.; Fuchs, Boris B.; Konstantinova, Irina V.

    1992-01-01

    The effects of spaceflight on immune cell function were determined in rats flown on Cosmos 2044. Control groups included vivarium, synchronous, and antiorthostatically suspended rats. The ability of natural killer cells to lyse two different target cell lines was determined. Spleen and bone marrow cells obtained from flight rats showed significantly inhibited cytotoxicity for YAC-1 target cells compared with cells from synchronous control rats. This could have been due to exposure of the rats to microgravity. Antiorthostatic suspension did not affect the level of cytotoxicity from spleen cells of suspended rats for YAC-1 cells. On the other hand, cells from rats flown in space showed no significant differences from vivarium and synchronous control rats in cytotoxicity for K-562 target cells. Binding of natural killer cells to K-562 target cells was unaffected by spaceflight. Antiorthostatic suspension resulted in higher levels of cytotoxicity from spleen cells for Cr-51-labeled K-562 cells. The results indicate differential effects of spaceflight on function of natural killer cells. This shows that spaceflight has selective effects on the immune response.

  8. Natural Killer Cells Differentiate Human Adipose-Derived Stem Cells and Modulate Their Adipogenic Potential.

    PubMed

    Rezzadeh, Kameron S; Hokugo, Akishige; Jewett, Anahid; Kozlowska, Anna; Segovia, Luis Andres; Zuk, Patricia; Jarrahy, Reza

    2015-09-01

    Natural killer cells are thought to represent more than 30 percent of all lymphocytes within the stromal vascular fraction of lipoaspirates. However, their physiologic interaction with adipocytes and their precursors has never been specifically examined. The authors hypothesized that natural killer cells, by means of cytokine secretion, are capable of promoting the differentiation of adipose-derived stem cells. Human natural killer cells purified from healthy donors' peripheral blood mononuclear cells were activated with a combination of interleukin-2 and anti-CD16 monoclonal antibody; natural killer cell supernatant was collected. Adipose-derived stem cells isolated from raw human lipoaspirates from healthy patients were treated with growth media, growth media with natural killer cell supernatant, adipogenic media, and adipogenic media with natural killer cells supernatant. Flow cytometric analysis was performed on cells using antibodies against B7H1, CD36, CD44, CD34, CD29, and MHC-1. Adipogenic-related gene expression (PPAR-γ, LPL, GPD-1, and aP2) was assessed. Oil Red O staining was performed as a functional assay of adipocyte differentiation and adipogenesis. Adipose-derived stem cells maintained in growth media with natural killer cell supernatant lost markers of "stemness," including CD44, CD34, and CD29; and expressed markers of differentiation, including B7H1 and MHC-1. Adipose-derived stem cells treated with natural killer cell supernatant accumulated small amounts of lipid after 10 days of natural killer cell supernatant treatment. Adipose-derived stem cells treated with natural killer cell supernatant showed altered expression of adipogenesis-associated genes compared with cells maintained in growth media. Adipose-derived stem cells maintained in adipogenic media with natural killer cell supernatant accumulated less lipid than those cells in adipogenic media alone. The authors demonstrate that, through secreted factors, natural killer cells are capable

  9. Revving up Natural Killer Cells and Cytokine-Induced Killer Cells Against Hematological Malignancies

    PubMed Central

    Pittari, Gianfranco; Filippini, Perla; Gentilcore, Giusy; Grivel, Jean-Charles; Rutella, Sergio

    2015-01-01

    Natural killer (NK) cells belong to innate immunity and exhibit cytolytic activity against infectious pathogens and tumor cells. NK-cell function is finely tuned by receptors that transduce inhibitory or activating signals, such as killer immunoglobulin-like receptors, NK Group 2 member D (NKG2D), NKG2A/CD94, NKp46, and others, and recognize both foreign and self-antigens expressed by NK-susceptible targets. Recent insights into NK-cell developmental intermediates have translated into a more accurate definition of culture conditions for the in vitro generation and propagation of human NK cells. In this respect, interleukin (IL)-15 and IL-21 are instrumental in driving NK-cell differentiation and maturation, and hold great promise for the design of optimal NK-cell culture protocols. Cytokine-induced killer (CIK) cells possess phenotypic and functional hallmarks of both T cells and NK cells. Similar to T cells, they express CD3 and are expandable in culture, while not requiring functional priming for in vivo activity, like NK cells. CIK cells may offer some advantages over other cell therapy products, including ease of in vitro propagation and no need for exogenous administration of IL-2 for in vivo priming. NK cells and CIK cells can be expanded using a variety of clinical-grade approaches, before their infusion into patients with cancer. Herein, we discuss GMP-compliant strategies to isolate and expand human NK and CIK cells for immunotherapy purposes, focusing on clinical trials of adoptive transfer to patients with hematological malignancies. PMID:26029215

  10. Revving up Natural Killer Cells and Cytokine-Induced Killer Cells Against Hematological Malignancies.

    PubMed

    Pittari, Gianfranco; Filippini, Perla; Gentilcore, Giusy; Grivel, Jean-Charles; Rutella, Sergio

    2015-01-01

    Natural killer (NK) cells belong to innate immunity and exhibit cytolytic activity against infectious pathogens and tumor cells. NK-cell function is finely tuned by receptors that transduce inhibitory or activating signals, such as killer immunoglobulin-like receptors, NK Group 2 member D (NKG2D), NKG2A/CD94, NKp46, and others, and recognize both foreign and self-antigens expressed by NK-susceptible targets. Recent insights into NK-cell developmental intermediates have translated into a more accurate definition of culture conditions for the in vitro generation and propagation of human NK cells. In this respect, interleukin (IL)-15 and IL-21 are instrumental in driving NK-cell differentiation and maturation, and hold great promise for the design of optimal NK-cell culture protocols. Cytokine-induced killer (CIK) cells possess phenotypic and functional hallmarks of both T cells and NK cells. Similar to T cells, they express CD3 and are expandable in culture, while not requiring functional priming for in vivo activity, like NK cells. CIK cells may offer some advantages over other cell therapy products, including ease of in vitro propagation and no need for exogenous administration of IL-2 for in vivo priming. NK cells and CIK cells can be expanded using a variety of clinical-grade approaches, before their infusion into patients with cancer. Herein, we discuss GMP-compliant strategies to isolate and expand human NK and CIK cells for immunotherapy purposes, focusing on clinical trials of adoptive transfer to patients with hematological malignancies.

  11. In vivo functions of natural killer cells

    SciTech Connect

    Pollack, S.B.

    1983-01-01

    This review focuses on recent experiments in which the natural killed (NK) compartment has been directly manipulated in vivo either by passive transfer of NK-enriched cell populations or by selection depletion of NK cells. These data have provided direct evidence for the role of NK cells in vivo. It is evident that even these experiments have inherent limitations due to the complexity of in vivo interactions. In the aggregate, however, these data build a compelling case for the in vivo activity of NK cells and for their biologic importance. Most of the experiments were carried out in mice. Although there is heterogeneity among NK cells, these studies deal mainly with classical NK cells defined as bone marrow-derived, non-B (Ig/sup -/), non-T (Lyt 1/sup -/2/sup -/) lymphocytes that are nonadherent and bear the NK-associated antigens NK-1 and asialo-GMl. A natural model which has been exploited to study NK cells in the intact host is also discussed.

  12. Restoration of Immune Surveillance in Lung Cancer by Natural Killer Cells

    DTIC Science & Technology

    2016-10-01

    AWARD NUMBER: W81XWH-15-1-0400 TITLE: Restoration of Immune Surveillance in Lung Cancer by Natural Killer Cells PRINCIPAL INVESTIGATOR...related to natural killer (NK) cells . The goal of this application is to uncover how a microRNA, namely miR183, can disrupt the expression of a critical...molecule, DAP12, that controls tumoricidal function in human Natural Killer (NK) Cells and to understand how nicotine, contained in tobacco smoke

  13. Natural Killer Cell Lymphoma: A Case with Classification Dilemma.

    PubMed

    Jitani, Ankit Kumar; Khonglah, Yookarin; Kumar, Ritesh; Gogoi, Bidyut Bikash; Jajodia, Ekta

    2016-02-01

    Non-Hodgkins lymphoma of the Natural Killer (NK) cell type is rare. World Health Organisation recognises 3 NK-cell phenotypic entities; extranodal NK/T cell lymphoma, nasal type (ENK/TL); aggressive NK cell leukaemia (ANKL); and chronic lymphoproliferative disorders of NK cells (CLPD-NK) which is classified as a provisional entity. Though specific clinical, morphological and immunophenotypic criteria have been laid down to diagnose these conditions there may however, be considerable variations in the clinical presentation making diagnosis difficult. We present a case with contrasting clinical and haematopathological findings posing difficulty in its diagnosis and classification, and despite the aggressive presentation showing favourable response to treatment.

  14. Natural Killer Cell Lymphoma: A Case with Classification Dilemma

    PubMed Central

    Jitani, Ankit Kumar; Kumar, Ritesh; Gogoi, Bidyut Bikash; Jajodia, Ekta

    2016-01-01

    Non-Hodgkins lymphoma of the Natural Killer (NK) cell type is rare. World Health Organisation recognises 3 NK-cell phenotypic entities; extranodal NK/T cell lymphoma, nasal type (ENK/TL); aggressive NK cell leukaemia (ANKL); and chronic lymphoproliferative disorders of NK cells (CLPD-NK) which is classified as a provisional entity. Though specific clinical, morphological and immunophenotypic criteria have been laid down to diagnose these conditions there may however, be considerable variations in the clinical presentation making diagnosis difficult. We present a case with contrasting clinical and haematopathological findings posing difficulty in its diagnosis and classification, and despite the aggressive presentation showing favourable response to treatment. PMID:27042473

  15. Natural Killer Cells in the Orchestration of Chronic Inflammatory Diseases

    PubMed Central

    Bassani, Barbara; Tremolati, Marco; Gini, Elisabetta; Farronato, Giampietro; Bruno, Antonino

    2017-01-01

    Inflammation, altered immune cell phenotype, and functions are key features shared by diverse chronic diseases, including cardiovascular, neurodegenerative diseases, diabetes, metabolic syndrome, and cancer. Natural killer cells are innate lymphoid cells primarily involved in the immune system response to non-self-components but their plasticity is largely influenced by the pathological microenvironment. Altered NK phenotype and function have been reported in several pathological conditions, basically related to impaired or enhanced toxicity. Here we reviewed and discussed the role of NKs in selected, different, and “distant” chronic diseases, cancer, diabetes, periodontitis, and atherosclerosis, placing NK cells as crucial orchestrator of these pathologic conditions. PMID:28428965

  16. Location and cellular stages of natural killer cell development.

    PubMed

    Yu, Jianhua; Freud, Aharon G; Caligiuri, Michael A

    2013-12-01

    The identification of distinct tissue-specific natural killer (NK) cell populations that apparently mature from local precursor populations has brought new insight into the diversity and developmental regulation of this important lymphoid subset. NK cells provide a necessary link between the early (innate) and late (adaptive) immune responses to infection. Gaining a better understanding of the processes that govern NK cell development should allow us to harness better NK cell functions in multiple clinical settings, as well as to gain further insight into how these cells undergo malignant transformation. In this review, we summarize recent advances in understanding sites and cellular stages of NK cell development in humans and mice.

  17. Primate-Specific Regulation of Natural Killer Cells

    PubMed Central

    Parham, Peter; Abi-Rached, Laurent; Matevosyan, Lilit; Moesta, Achim K.; Norman, Paul J.; Aguilar, Anastazia M. Older; Guethlein, Lisbeth A.

    2010-01-01

    Summary Natural killer (NK) cells are circulating lymphocytes that function in innate immunity and placental reproduction. Regulating both development and function of NK cells is an array of variable and conserved receptors that interact with major histocompatibility complex (MHC) class I molecules. Families of lectin-like and immunoglobulin-like receptors are determined by genes in the natural killer (NKC) and leukocyte receptor (LRC) complexes, respectively. As a consequence of the strong, varying pressures on the immune and reproductive systems, NK cell receptors and their MHC class I ligands evolve rapidly, are highly diverse, and exhibit dramatic species-specific differences. The variable, polymorphic family of killer cell immunoglobulin-like receptors (KIR) that regulate human NK cell development and function evolved recently, from a single-copy gene during the evolution of simian primates. Our studies of KIR and MHC class I genes in representative species show how these two unlinked but functionally intertwined genetic complexes have co-evolved. In humans, combinations of KIR and HLA class I factors are associated with infectious diseases, including HIV/AIDS, autoimmunity, reproductive success and the outcome of therapeutic transplantation. The extraordinary, and unanticipated, divergence of human NK cell receptors and MHC class I ligands from their mouse counterparts can in part explain the difficulties experienced in finding informative mouse models for human diseases. Non-human primate models have far greater potential, but to realize their promise will first require more complete definition of the genetics and function of KIR and MHC variation in non-human primate species, at a level comparable to that achieved for the human species. PMID:20618586

  18. The occurrence of killer activity in yeasts isolated from natural habitats.

    PubMed

    Wójcik, Monika; Kordowska-Wiater, Monika

    2015-01-01

    Yeast's ability to restrict the growth and kill other yeasts, fungi and bacteria has been known for over 50 years. Killer activity was detected in yeasts deposited in the world collections or isolated from natural habitats. In this study, isolates from the forest environment, leaves of fruit trees, flower petals, cereals and frozen fruit have been screened in terms of their killer activities. Killer activity was tested on strains belonging to six yeast species: Candida, Rhodotorula, Pichia, Pachysolen, Yarrowia, Trichosporon. The reference strains were Kluyveromyces lactis Y-6682 and Kluyveromyces marxinanus Y-8281, well-known to be sensitive to yeast killer toxins. Among one hundred and two tested strains, 24 (23.5% of isolates) showed positive killer action, and 10 (9.8% of the isolates) a weak killer action against at least one sensitive reference strain. The highest killer activity was observed among isolates from forest soil and flowers.

  19. Immunosuppression of pulmonary natural killer activity by exposure to ozone

    SciTech Connect

    Burleson, G.R.; Keyes, L.L.; Stutzman, J.D. )

    1989-01-01

    Ozone is an oxidant gas and an ubiquitous oxidant air pollutant with the potential to adversely affect pulmonary immune function with a consequent increase in disease susceptibility. Pulmonary natural killer (NK) activity was measured in order to assess the pulmonary immunotoxicity of continuous ozone exposure. Continuous ozone exposures at 1.0 ppm were performed for 23.5 hours per day for either 1, 5, 7, or 10 consecutive days. Pulmonary immune function was assessed by measuring natural killer (NK) activity from whole-lung homogenates of male Fischer-344 rats. Results of this study indicated that continuous ozone exposure for 1, 5, or 7 days resulted in a significant decrease in pulmonary NK activity. This suppressed pulmonary NK activity returned to control levels after continuous exposure to ozone for 10 days. The suppressed pulmonary NK response was thus attenuated and returned to normal values in the continued presence of ozone gas. This attenuation process is dynamic, complex, and doubtless involves several cell types and/or products of these cells. Pulmonary NK activity was also suppressed at 0.5 ppm ozone, but not at 0.1 ppm ozone, following 23.5 hours of exposure. NK activity is important for defense against viral, bacterial, and neoplastic disease. The depressed NK activity resulting from continuous ozone exposure could therefore result in a compromised ability to defend against pulmonary diseases.

  20. Effects of antimalarial drugs on human natural killer cell activity.

    PubMed

    Chaicumpa, W; Roca, R V; Atthasishtha, N; Chongsuphajaisiddhi, T

    1983-09-01

    Separation of null cell fraction from the other cellular components of human peripheral blood obtained from normal healthy individuals was effected through the Ficoll-Hypaque density gradient centrifugation, carbonyl iron phagocytosis-magnet application, E-rosette forming and binding to 19S-EAC respectively. The null cells were used as effector cells in the cytotoxic assay. The spontaneous cell-mediated cytotoxicity assay was employed and the highly NK-sensitive K562 labelled with Na251 CrO4 were used as targets. The null cell fraction was divided into several portions to allow for normal control, diluent control and tests. The test portions were those exposed to the various antimalarial drugs employed. It was observed that the T cell, B cells and null cell fractions accounted for 72%, 18% and 10% of the total lymphocyte population respectively. The mean cytotoxicity generated by the natural killer subset was 63%. The antimalarial drugs/drug combination used were chloroquine, quinine, pyrimethamine and sulfadoxine/pyrimethamine combination. Concentrations used were their respective minimal inhibitory concentration (MIC) and corresponding 5 X MIC. The inhibitory effects on natural killer cell activity of these drugs were observed. The possible reasons for these observations are discussed.

  1. Use of natural killer cells as immunotherapy for leukaemia

    PubMed Central

    Grzywacz, Bartosz; Miller, Jeffrey S.; Verneris, Michael R.

    2008-01-01

    Natural killer (NK) cells potentially play a significant role in eradicating residual disease following allogeneic haematopoietic cell transplantation, and have been explored as tools for adoptive immunotherapy for chemotherapy-refractory patients. NK cell cytotoxicity is modulated by multiple activating and inhibitory receptors that maintain a balance between self-tolerance and providing surveillance against pathogens and malignant transformation. The functional characteristics of NK cells are dictated by the strength of inhibitory receptor signalling. Major histocompatibility complex (MHC)-specific inhibitory receptor acquisition occurs sequentially during NK cell development, and is determined by the nature of immunological reconstitution after allogeneic haematopoietic cell transplantation. Polymorphisms of inhibitory receptors [killer immunoglobulin-like receptors (KIRs)] and their ligands (MHC) contribute to interindividual variability. As a result, the functional NK cell repertoire of individual donors has variable potential for graft-vs-leukaemia reactions. Models predicting NK cell alloreactivity, including KIR ligand mismatch and missing KIR ligand strategies, are discussed as algorithms for optimal NK cell donor selection. Future modifications to improve NK cell adoptive immunotherapy by means of increasing target recognition and reducing inhibitory signalling are being explored. PMID:18790450

  2. Effect of different levels of alcohol consumption on natural killer and lymphokine activated killer cells

    SciTech Connect

    Klassen, L.W.; DeVasure, J.M.; Lemley-Gillespie, S.D.; Thiele, G.M. Omaha VA Hospital, NE )

    1991-03-11

    The effect of alcohol consumption on natural killer (NK) cell activity is controversial as both increased and decreased levels have been reported. It was the purpose of this study to determine the effects of feeding BDF1 mice different levels of alcohol on NK and lymphokine activated killer (LAK) cell activity. After four-six weeks of chronic alcohol feeding, mice were sacrificed, spleen cells obtained and assayed for NK and IL-2 boosted NK activity against YAC-1 cells in a traditional {sup 51}chromium release assay. Cells were also cultured in the presence of IL-2 for five days and tested for cytolytic activity using P815 cells as targets. Cells from each group were passed over a nylon wool column and the adherent (AD) and nonadherent (NAD) populations collected and tested as above. Increased NK, 24 hour IL-2 boosted NK and 5 day LAK activity were observed only in the spleen cells obtained from mice on 20% alcohol. Also, NAD populations had a 2-4 fold higher lytic unit values (LU{sub 20}) at all levels of alcohol consumption and in all assays, as compared with the unseparated spleen cells. Analysis of cell surface markers on these three populations of cells show that there were differences in MAC-2, Asialo GM-1, Thy 1.2, B220 and NK 1.1 that may correlate with the differences observed in the cytolytic assays. These data suggest that different levels of alcohol affect the cytolytic activity of NK and LAK cells and may result from alterations in the cell subset populations.

  3. Natural killer cells: role in local tumor growth and metastasis

    PubMed Central

    Langers, Inge; Renoux, Virginie M; Thiry, Marc; Delvenne, Philippe; Jacobs, Nathalie

    2012-01-01

    Historically, the name of natural killer (NK) cells came from their natural ability to kill tumor cells in vitro. From the 1970s to date, accumulating data highlighted the importance of NK cells in host immune response against cancer and in therapy-induced antitumor response. The recognition and the lysis of tumor cells by NK cells are regulated by a complex balance of inhibitory and activating signals. This review summarizes NK cell mechanisms to kill cancer cells, their role in host immune responses against tumor growth or metastasis, and their implications in antitumor immunotherapies via cytokines, antibodies, or in combination with other therapies. The regulatory role of NK cells in autoimmunity is also discussed. PMID:22532775

  4. [Natural killer cells: adaptation and memory in innate immunity].

    PubMed

    Narni-Mancinelli, Emilie; Ugolini, Sophie; Vivier, Eric

    2013-04-01

    Natural killer (NK) cells are lymphocytes of the innate immune system that can kill tumor and infected cells. NK cells also secrete cytokines that participate in the shaping of the adaptive immune response. During the past few years, several studies have shown that the threshold of NK cell responsiveness is more adaptable than originally thought. NK cell reactivity is tuned by the environment and depends on the time of exposure of NK cells to their microenvironment. The impact of the NK cell response on immunity also depends on the intensity and the nature of the tumor or infections assaults. We review here how the local context impacts on NK cell responsiveness and shapes the outcome of NK cell activation. © 2013 médecine/sciences – Inserm / SRMS.

  5. Role of cytolytic impairment of natural killer and natural killer T-cell populations in rheumatoid arthritis.

    PubMed

    Aggarwal, Ashish; Sharma, Aman; Bhatnagar, Archana

    2014-08-01

    Innate immunity has been widely accepted as one of the major cause for the alteration of immune system and progression of autoimmune diseases. Natural killer (NK) cells and natural killer T (NKT) cells have not been explored in clinical studies for their cytolytic components in association with rheumatoid arthritis (RA). The literature available for these potential candidates is controversial in terms of their protective or pathogenic role in disease severity of RA. Present study explained the role of NK and NKT cell populations and intracellular expression of caspases, perforin, granzymes A and B in the pathogenesis of RA in patients. DAS28 score was measured as the disease severity. Immunochemical parameters were studied by using monoclonal antibodies (mAbs) against different cell types in flow cytometry. Results indicated that that whatsoever is the change in percentage cell populations, ratio of NK and NKT cell populations always remained poised even in the disease state. Reactive oxygen species (ROS) levels were elevated with increased intracellular active caspase-3, perforin and granzyme expression in RA patients. Their elevated expressions were positively correlated with DAS28 suggesting the pathogenic role in RA. The expressions of pro-inflammatory cytokines were enhanced while the anti-inflammatory cytokine expressions were diminished in the patients. Present study may point towards futuristic therapeutic targets which can fascinate the pharmaceutical industries to selectively target these molecules in designing the therapeutic strategy of RA patients.

  6. Recycling and target binding capacity of human natural killer cells

    PubMed Central

    1981-01-01

    By combining a newly established single-cell cytotoxicity assay in agarose (16) with estimations of the maximum natural killer (NK) potential (Vmax) by 51Cr release that percentage of target-binding cells (TBC), the fraction of active killers among TBC, the kinetics of single-cell cytotoxicity, and the recycling of effector cells was studied. Using nylon wool-passed peripheral lymphocytes, approximately 10% of the cells will bind to NK- susceptible target cell lines. Most of these have receptors for IgG. Some 50% will go on to kill T cell targets and some 20% to kill the standard target cell K-562. As the individual NK cell is shown to have the capacity to recycle, i.e., to kill more than one target cell in the 3-h test period, and as recycling seems to vary between individuals, there is no consistent correlation between the number of TBC and 51Cr-release values. It seems as if the single-cell cytotoxicity assay, as presently performed in agarose, is a valuable complement to Vmax determinations by 51Cr-release to study the different steps involved in the cytolytic process: recognition, enzyme activation, and effector cell recycling. The discrimination between these steps will probably be necessary to define mechanisms influencing NK cells in different disease states as well as in learning more about the normal function and regulation of the human NK system. PMID:7252409

  7. Cord Blood as a Source of Natural Killer Cells

    PubMed Central

    Mehta, Rohtesh S.; Shpall, Elizabeth J.; Rezvani, Katayoun

    2016-01-01

    Cord blood (CB) offers several unique advantages as a graft source for hematopoietic stem cell transplantation (HSCT). The risk of relapse and graft vs. host disease after cord blood transplantation (CBT) is lower than what is typically observed after other graft sources with a similar degree of human leukocyte antigen mismatch. Natural killer (NK) cells have a well-defined role in both innate and adaptive immunity and as the first lymphocytes to reconstitute after HSCT and CBT, and they play a significant role in protection against early relapse. In this article, we highlight the uses of CB NK cells in transplantation and adoptive immunotherapy. First, we will describe differences in the phenotype and functional characteristics of NK cells in CB as compared with peripheral blood. Then, we will review some of the obstacles we face in using resting CB NK cells for adoptive immunotherapy, and discuss methods to overcome them. We will review the current literature on killer-cell immunoglobulin-like receptors ligand mismatch and outcomes after CBT. Finally, we will touch on current strategies for the use of CB NK cells in cellular immunotherapy. PMID:26779484

  8. Glucocorticoid receptor mediated suppression of natural killer cell activity: identification of associated deacetylase and corepressor molecules.

    PubMed

    Bush, Kristin A; Krukowski, Karen; Eddy, Justin L; Janusek, Linda Witek; Mathews, Herbert L

    2012-01-01

    Physical and psychological stressors reduce natural killer cell function. This reduction in cellular function results from stress-induced release of glucocorticoids. Glucocorticoids act upon natural killer cells to deacetylate and transrepress immune response genes through epigenetic processes. However, other than the glucocorticoid receptor, the proteins that participate in this process are not well described in natural killer cells. The purpose of this study was to identify the proteins associated with the glucocorticoid receptor that are likely epigenetic participants in this process. Treatment of natural killer cells with the synthetic glucocorticoid, dexamethasone, produced a significant time dependent reduction in natural killer cell activity as early as 8h post treatment. This reduction in natural killer cell activity was preceded by nuclear localization of the glucocorticoid receptor with histone deacetylase 1 and the corepressor, SMRT. Other class I histone deacetylases were not associated with the glucocorticoid receptor nor was the corepressor NCoR. These results demonstrate histone deacetylase 1 and SMRT to associate with the ligand activated glucocorticoid receptor within the nuclei of natural killer cells and to be the likely participants in the histone deacetylation and transrepression that accompanies glucocorticoid mediated reductions in natural killer cell function. Copyright © 2012 Elsevier Inc. All rights reserved.

  9. Clearance of Giardia muris infection in mice deficient in natural killer cells.

    PubMed Central

    Heyworth, M F; Kung, J E; Eriksson, E C

    1986-01-01

    Immunocompetent C57BL/6J mice and beige mice (which are deficient in natural killer cells) were infected with Giardia muris. Both types of mice cleared G. muris infection at similar rates. This observation suggests that clearance of G. muris parasites from the mouse intestine is not mediated by natural killer cells. PMID:3781631

  10. Transcription factor Runx3 regulates interleukin-15-dependent natural killer cell activation.

    PubMed

    Levanon, Ditsa; Negreanu, Varda; Lotem, Joseph; Bone, Karen Rae; Brenner, Ori; Leshkowitz, Dena; Groner, Yoram

    2014-03-01

    Natural killer cells belong to the family of innate lymphoid cells comprising the frontline defense against infected and transformed cells. Development and activation of natural killer cells is highly dependent on interleukin-15 signaling. However, very little is known about the transcription program driving this process. The transcription factor Runx3 is highly expressed in natural killer cells, but its function in these cells is largely unknown. We show that loss of Runx3 impaired interleukin-15-dependent accumulation of mature natural killer cells in vivo and under culture conditions and pregnant Runx3(-/-) mice completely lack the unique population of interleukin-15-dependent uterine natural killer cells. Combined chromatin immunoprecipitation sequencing and differential gene expression analysis of wild-type versus Runx3-deficient in vivo activated splenic natural killer cells revealed that Runx3 cooperates with ETS and T-box transcription factors to drive the interleukin-15-mediated transcription program during activation of these cells. Runx3 functions as a nuclear regulator during interleukin-15-dependent activation of natural killer cells by regulating the expression of genes involved in proliferation, maturation, and migration. Similar studies with additional transcription factors will allow the construction of a more detailed transcriptional network that controls natural killer cell development and function.

  11. Ex Vivo Generated Natural Killer Cells Acquire Typical Natural Killer Receptors and Display a Cytotoxic Gene Expression Profile Similar to Peripheral Blood Natural Killer Cells

    PubMed Central

    Lehmann, Dorit; Spanholtz, Jan; Osl, Markus; Tordoir, Marleen; Lipnik, Karoline; Bilban, Martin; Schlechta, Bernhard; Dolstra, Harry

    2012-01-01

    Ex vivo differentiation systems of natural killer (NK) cells from CD34+ hematopoietic stem cells are of potential importance for adjuvant immunotherapy of cancer. Here, we analyzed ex vivo differentiation of NK cells from cord blood-derived CD34+ stem cells by gene expression profiling, real-time RT-PCR, flow cytometry, and functional analysis. Additionally, we compared the identified characteristics to peripheral blood (PB) CD56bright and CD56dim NK cells. The data show sequential expression of CD56 and the CD94 and NKG2 receptor chains during ex vivo NK cell development, resulting finally in the expression of a range of genes with partial characteristics of CD56bright and CD56dim NK cells from PB. Expression of characteristic NK cell receptors and cytotoxic genes was mainly found within the predominant ex vivo generated population of NKG2A+ NK cells, indicating the importance of NKG2A expression during NK cell differentiation and maturation. Furthermore, despite distinct phenotypic characteristics, the detailed analysis of cytolytic genes expressed within the ex vivo differentiated NK cells revealed a pattern close to CD56dim NK cells. In line with this finding, ex vivo generated NK cells displayed potent cytotoxicity. This supports that the ex vivo differentiation system faithfully reproduces major steps of the differentiation of NK cells from their progenitors, constitutes an excellent model to study NK cell differentiation, and is valuable to generate large-scale NK cells appropriate for immunotherapy. PMID:22571679

  12. Ex vivo generated natural killer cells acquire typical natural killer receptors and display a cytotoxic gene expression profile similar to peripheral blood natural killer cells.

    PubMed

    Lehmann, Dorit; Spanholtz, Jan; Osl, Markus; Tordoir, Marleen; Lipnik, Karoline; Bilban, Martin; Schlechta, Bernhard; Dolstra, Harry; Hofer, Erhard

    2012-11-01

    Ex vivo differentiation systems of natural killer (NK) cells from CD34+ hematopoietic stem cells are of potential importance for adjuvant immunotherapy of cancer. Here, we analyzed ex vivo differentiation of NK cells from cord blood-derived CD34+ stem cells by gene expression profiling, real-time RT-PCR, flow cytometry, and functional analysis. Additionally, we compared the identified characteristics to peripheral blood (PB) CD56(bright) and CD56(dim) NK cells. The data show sequential expression of CD56 and the CD94 and NKG2 receptor chains during ex vivo NK cell development, resulting finally in the expression of a range of genes with partial characteristics of CD56(bright) and CD56(dim) NK cells from PB. Expression of characteristic NK cell receptors and cytotoxic genes was mainly found within the predominant ex vivo generated population of NKG2A+ NK cells, indicating the importance of NKG2A expression during NK cell differentiation and maturation. Furthermore, despite distinct phenotypic characteristics, the detailed analysis of cytolytic genes expressed within the ex vivo differentiated NK cells revealed a pattern close to CD56(dim) NK cells. In line with this finding, ex vivo generated NK cells displayed potent cytotoxicity. This supports that the ex vivo differentiation system faithfully reproduces major steps of the differentiation of NK cells from their progenitors, constitutes an excellent model to study NK cell differentiation, and is valuable to generate large-scale NK cells appropriate for immunotherapy.

  13. Fasting enhances TRAIL-mediated liver natural killer cell activity via HSP70 upregulation.

    PubMed

    Dang, Vu T A; Tanabe, Kazuaki; Tanaka, Yuka; Tokumoto, Noriaki; Misumi, Toshihiro; Saeki, Yoshihiro; Fujikuni, Nobuaki; Ohdan, Hideki

    2014-01-01

    Acute starvation, which is frequently observed in clinical practice, sometimes augments the cytolytic activity of natural killer cells against neoplastic cells. In this study, we investigated the molecular mechanisms underlying the enhancement of natural killer cell function by fasting in mice. The total number of liver resident natural killer cells in a unit weight of liver tissue obtained from C57BL/6J mice did not change after a 3-day fast, while the proportions of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)+ and CD69+ natural killer cells were significantly elevated (n = 7, p <0.01), as determined by flow cytometric analysis. Furthermore, we found that TRAIL- natural killer cells that were adoptively transferred into Rag-2-/- γ chain-/- mice could convert into TRAIL+ natural killer cells in fasted mice at a higher proportion than in fed mice. Liver natural killer cells also showed high TRAIL-mediated antitumor function in response to 3-day fasting. Since these fasted mice highly expressed heat shock protein 70 (n = 7, p <0.05) in liver tissues, as determined by western blot, the role of this protein in natural killer cell activation was investigated. Treatment of liver lymphocytes with 50 µg/mL of recombinant heat shock protein 70 led to the upregulation of both TRAIL and CD69 in liver natural killer cells (n = 6, p <0.05). In addition, HSP70 neutralization by intraperitoneally injecting an anti- heat shock protein 70 monoclonal antibody into mice prior to fasting led to the downregulation of TRAIL expression (n = 6, p <0.05). These findings indicate that acute fasting enhances TRAIL-mediated liver natural killer cell activity against neoplastic cells through upregulation of heat shock protein 70.

  14. Liver natural killer cells: subsets and roles in liver immunity

    PubMed Central

    Peng, Hui; Wisse, Eddie; Tian, Zhigang

    2016-01-01

    The liver represents a frontline immune organ that is constantly exposed to a variety of gut-derived antigens as a result of its unique location and blood supply. With a predominant role in innate immunity, the liver is enriched with various innate immune cells, among which natural killer (NK) cells play important roles in host defense and in maintaining immune balance. Hepatic NK cells were first described as ‘pit cells' in the rat liver in the 1970s. Recent studies of NK cells in mouse and human livers have shown that two distinct NK cell subsets, liver-resident NK cells and conventional NK (cNK) cells, are present in this organ. Here, we review liver NK cell subsets in different species, revisiting rat hepatic pit cells and highlighting recent progress related to resident NK cells in mouse and human livers, and also discuss the dual roles of NK cells in liver immunity. PMID:26639736

  15. Memory-like Responses of Natural Killer Cells

    PubMed Central

    Cooper, Megan A.; Yokoyama, Wayne M.

    2010-01-01

    Summary Natural killer (NK) cells are lymphocytes with the capacity to produce cytokines and kill target cells upon activation. NK cells have long been categorized as members of the innate immune system and as such have been thought to follow the ‘rules’ of innate immunity, including the principle that they have no immunologic memory, a property thought to be strictly limited to adaptive immunity. However, recent studies have suggested that NK cells have the capacity to alter their behavior based on prior activation. This property is analogous to adaptive immune memory; however, some NK cell memory-like functions are not strictly antigen-dependent and can be demonstrated following cytokine stimulation. Here we discuss the recent evidence that NK cells can exhibit properties of immunologic memory, focusing on the ability of cytokines to non-specifically induce memory-like NK cells with enhanced responses to restimulation. PMID:20536571

  16. Regulatory Functions of Natural Killer Cells in Multiple Sclerosis

    PubMed Central

    Gross, Catharina C.; Schulte-Mecklenbeck, Andreas; Wiendl, Heinz; Marcenaro, Emanuela; Kerlero de Rosbo, Nicole; Uccelli, Antonio; Laroni, Alice

    2016-01-01

    There is increasing evidence that natural killer (NK) cells exhibit regulatory features. Among them, CD56bright NK cells have been suggested to play a major role in controlling T cell responses and maintaining homeostasis. Dysfunction in NK cell-mediated regulatory features has been recently described in untreated multiple sclerosis (MS), suggesting a contribution to MS pathogenesis. Moreover, biological disease-modifying treatments effective in MS apparently enhance the frequencies and/or regulatory function of NK cells, further pointing toward an immunoprotective role of NK cells in MS. Here, we summarize the current knowledge on the regulatory functions of NK cells, based on their interactions with other cells belonging to the innate compartment, as well as with adaptive effector cells. We review the more recent data reporting disruption of NK cell/T cell interactions in MS and discuss how disease-modifying treatments for MS affect NK cells. PMID:28066417

  17. Novel targets for natural killer/T-cell lymphoma immunotherapy.

    PubMed

    Kumai, Takumi; Kobayashi, Hiroya; Harabuchi, Yasuaki

    2016-01-01

    Extranodal natural killer/T-cell lymphoma, nasal type (NKTL) is a rare but highly aggressive Epstein-Barr virus-related malignancy, which mainly occurs in nasopharyngeal and nasal/paranasal areas. In addition to its high prevalence in Asian, Central American and South American populations, its incidence rate has been gradually increasing in Western countries. The current mainstay of treatment is a combination of multiple chemotherapies and irradiation. Although chemoradiotherapy can cure NKTL, it often causes severe and fatal adverse events. Because a growing body of evidence suggests that immunotherapy is effective against hematological malignancies, this treatment could provide an alternative to chemoradiotherapy for treatment of NKTL. In this review, we focus on how recent findings could be used to develop efficient immunotherapies against NKTL.

  18. On The Role of Natural Killer Cells in Neurodegenerative Diseases

    PubMed Central

    Maghazachi, Azzam A.

    2013-01-01

    Natural killer (NK) cells exert important immunoregulatory functions by releasing several inflammatory molecules, such as IFN-γ and members of chemokines, which include CCL3/MIP-1α and CCL4/MIP-1β. These cells also express heptahelical receptors, which are coupled to heterotrimeric G proteins that guide them into inflamed and injured tissues. NK cells have been shown to recognize and destroy transformed cells and virally-infected cells, but their roles in neurodegenerative diseases have not been examined in detail. In this review, I will summarize the effects of NK cells in two neurodegenerative diseases, namely multiple sclerosis and globoid cell leukodystrophy. It is hoped that the knowledge obtained from these diseases may facilitate building rational protocols for treating these and other neurodegenerative or autoimmune diseases using NK cells and drugs that activate them as therapeutic tools. PMID:23430541

  19. Adenovirus vector delivery stimulates natural killer cell recognition

    PubMed Central

    Tomasec, Peter; Wang, Eddie C. Y.; Groh, Veronika; Spies, Thomas; McSharry, Brian P.; Aicheler, Rebecca J.; Stanton, Richard J.; Wilkinson, Gavin W. G.

    2007-01-01

    We report that delivery of first-generation replication-deficient adenovirus (RDAd) vectors into primary human fibroblasts is associated with the induction of natural killer (NK) cell-mediated cytolysis in vitro. RDAd vector delivery induced cytolysis by a range of NK cell populations including the NK cell clone NKL, primary polyclonal NK lines and a proportion of NK clones (36 %) in autologous HLA-matched assays. Adenovirus-induced cytolysis was inhibited by antibody blocking of the NK-activating receptor NKG2D, implicating this receptor in this function. NKG2D is ubiquitously expressed on NK cells and CD8+ T cells. Significantly, γ-irradiation of the vector eliminated the effect, suggesting that breakthrough expression from the vector induces at least some of the pro-inflammatory responses of unknown aetiology following the application of RDAd vectors during in vivo gene delivery. PMID:17374753

  20. Subsets of human natural killer cells and their regulatory effects

    PubMed Central

    Fu, Binqing; Tian, Zhigang; Wei, Haiming

    2014-01-01

    Human natural killer (NK) cells have distinct functions as NKtolerant, NKcytotoxic and NKregulatory cells and can be divided into different subsets based on the relative expression of the surface markers CD27 and CD11b. CD27+ NK cells, which are abundant cytokine producers, are numerically in the minority in human peripheral blood but constitute the large population of NK cells in cord blood, spleen, tonsil and decidua tissues. Recent data suggest that these NK cells may have immunoregulatory properties under certain conditions. In this review, we will focus on these new NK cell subsets and discuss how regulatory NK cells may serve as rheostats or sentinels in controlling inflammation and maintaining immune homeostasis in various organs. PMID:24303897

  1. Natural killer cells in the innate immunity network of atherosclerosis.

    PubMed

    Bonaccorsi, Irene; De Pasquale, Claudia; Campana, Stefania; Barberi, Chiara; Cavaliere, Riccardo; Benedetto, Filippo; Ferlazzo, Guido

    2015-11-01

    Natural killer (NK) cells are innate lymphocytes which have recently been proposed to play an immunoregulatory role in the pathogenesis and progression of atherosclerosis. Although several studies have evaluated the frequency and the functions of NK cells both in human and in experimental animal models of atherosclerosis, it is yet not clear whether NK cells might behave as protective or pro-atherogenic effectors. Here, we review current knowledge regarding the role of NK cells in atherosclerosis and discuss the potential interactions that might occur in atherosclerotic lesions between NK cells and antigen presenting cells, such as macrophages and dendritic cells. A clearer depiction of the innate immune cell network operating in atherosclerosis might pave the way to novel interesting approaches for the prevention and treatment of this disease. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. Role of natural killer cells in antibacterial immunity.

    PubMed

    Schmidt, Stanislaw; Ullrich, Evelyn; Bochennek, Konrad; Zimmermann, Stefanie-Yvonne; Lehrnbecher, Thomas

    2016-12-01

    Bacteria are a significant cause of infectious complications, in particular in immunocompromised patients. There is an increasing understanding that Natural Killer (NK) cells not only exhibit direct activity against bacteria, but also exert indirect antibacterial activity through interaction with other immune cells via cytokines and interferons. Areas covered: This review seeks to give a global overview of in vitro and in vivo data how NK cells interact with bacteria. In this regard, the review describes how NK cells directly damage and kill bacteria by soluble factors such as perforin, the impact of NK cells on other arms of the immune system, as well as how bacteria may inhibit NK cell activities. Expert commentary: A better characterization of the antibacterial effects of NK cells is urgently needed. With a better understanding of the interaction of NK cells and bacteria, NK cells may become a promising tool to prevent or to combat bacterial infections, e.g. by adoptively transferring NK cells to immunocompromised patients.

  3. Innate or adaptive immunity? The example of natural killer cells.

    PubMed

    Vivier, Eric; Raulet, David H; Moretta, Alessandro; Caligiuri, Michael A; Zitvogel, Laurence; Lanier, Lewis L; Yokoyama, Wayne M; Ugolini, Sophie

    2011-01-07

    Natural killer (NK) cells were originally defined as effector lymphocytes of innate immunity endowed with constitutive cytolytic functions. More recently, a more nuanced view of NK cells has emerged. NK cells are now recognized to express a repertoire of activating and inhibitory receptors that is calibrated to ensure self-tolerance while allowing efficacy against assaults such as viral infection and tumor development. Moreover, NK cells do not react in an invariant manner but rather adapt to their environment. Finally, recent studies have unveiled that NK cells can also mount a form of antigen-specific immunologic memory. NK cells thus exert sophisticated biological functions that are attributes of both innate and adaptive immunity, blurring the functional borders between these two arms of the immune response.

  4. Roles of natural killer cells in antiviral immunity.

    PubMed

    Waggoner, Stephen N; Reighard, Seth D; Gyurova, Ivayla E; Cranert, Stacey A; Mahl, Sarah E; Karmele, Erik P; McNally, Jonathan P; Moran, Michael T; Brooks, Taylor R; Yaqoob, Fazeela; Rydyznski, Carolyn E

    2016-02-01

    Natural killer (NK) cells are important in immune defense against virus infections. This is predominantly considered a function of rapid, innate NK-cell killing of virus-infected cells. However, NK cells also prime other immune cells through the release of interferon gamma (IFN-γ) and other cytokines. Additionally, NK cells share features with long-lived adaptive immune cells and can impact disease pathogenesis through the inhibition of adaptive immune responses by virus-specific T and B cells. The relative contributions of these diverse and conflicting functions of NK cells in humans are poorly defined and likely context-dependent, thereby complicating the development of therapeutic interventions. Here we focus on the contributions of NK cells to disease in diverse virus infections germane to human health. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. Liver natural killer cells: subsets and roles in liver immunity.

    PubMed

    Peng, Hui; Wisse, Eddie; Tian, Zhigang

    2016-05-01

    The liver represents a frontline immune organ that is constantly exposed to a variety of gut-derived antigens as a result of its unique location and blood supply. With a predominant role in innate immunity, the liver is enriched with various innate immune cells, among which natural killer (NK) cells play important roles in host defense and in maintaining immune balance. Hepatic NK cells were first described as 'pit cells' in the rat liver in the 1970s. Recent studies of NK cells in mouse and human livers have shown that two distinct NK cell subsets, liver-resident NK cells and conventional NK (cNK) cells, are present in this organ. Here, we review liver NK cell subsets in different species, revisiting rat hepatic pit cells and highlighting recent progress related to resident NK cells in mouse and human livers, and also discuss the dual roles of NK cells in liver immunity.

  6. Alterations of natural killer cells in traumatic brain injury.

    PubMed

    Kong, Xiao-Dong; Bai, Sheng; Chen, Xin; Wei, Hui-Jie; Jin, Wei-Na; Li, Min-Shu; Yan, Yaping; Shi, Fu-Dong

    2014-12-01

    To investigate the relationship between natural killer (NK) cells and traumatic brain injury (TBI), we tracked an established phenotype of circulating NK cells at several time points in patients with different grades of TBI. In serial peripheral blood samples, NK cells were prospectively measured by flow cytometry of CD3(-) CD56(+) lymphocytes. Compared to healthy controls, TBI patients had reductions in both the percentage and the absolute number of NK cells. Furthermore, the magnitude of NK cell reduction correlated with the degree of TBI severity at several time points. That is, NK cell population size was independently associated with lower Glasgow Coma Scale scores. In addition, at some time points, a positive correlation was found between the NK cell counts and Glasgow Outcome Scale scores. Our results indicate that TBI induces a reduction in the number of NK cells, and the magnitude of the reduction appears to parallel the severity of TBI.

  7. Cutaneous presentation of steroid responsive blastoid natural killer cell lymphoma.

    PubMed

    Bower, C P; Standen, G R; Pawade, J; Knechtli, C J; Kennedy, C T

    2000-05-01

    CD56+ lymphomas derived from natural killer (NK) cell lineage are rarely encountered in Western populations and their clinical and pathological features have not been fully defined. The majority of reported cases are lymphomas of the nasal cavity, which are most commonly seen in Asia. A subtype of CD56+ lymphoma has recently been described (blastoid NK-cell lymphoma) which characteristically presents in older patients with cutaneous infiltrates and disease at other nodal and extranodal sites. We describe a case that correlates well with the clinicopathological features of blastoid NK-cell lymphoma. An unusual feature in our patient was that the cutaneous features of the lymphoma showed complete resolution shortly following commencement of oral steroid therapy.

  8. Type I Interferons and Natural Killer Cell Regulation in Cancer

    PubMed Central

    Müller, Lena; Aigner, Petra; Stoiber, Dagmar

    2017-01-01

    Type I interferons (IFNs) are known to mediate antitumor effects against several tumor types and have therefore been commonly used in clinical anticancer treatment. However, how IFN signaling exerts its beneficial effects is only partially understood. The clinically relevant activity of type I IFNs has been mainly attributed to their role in tumor immune surveillance. Different mechanisms have been postulated to explain how type I IFNs stimulate the immune system. On the one hand, they modulate innate immune cell subsets such as natural killer (NK) cells. On the other hand, type I IFNs also influence adaptive immune responses. Here, we review evidence for the impact of type I IFNs on immune surveillance against cancer and highlight the role of NK cells therein. PMID:28408907

  9. Natural killer cells in host defense against veterinary pathogens.

    PubMed

    Shekhar, Sudhanshu; Yang, Xi

    2015-11-15

    Natural Killer (NK) cells constitute a major subset of innate lymphoid cells that do not express the T- and B-cell receptors and play an important role in antimicrobial defense. NK cells not only induce early and rapid innate immune responses, but also communicate with dendritic cells to shape the adaptive immunity, thus bridging innate and adaptive immunity. Although the functional biology of NK cells is well-documented in a variety of infections in humans and mice, their role in protecting domestic animals from infectious agents is only beginning to be understood. In this article, we summarize the current state of knowledge about the contribution of NK cells in pathogen defense in domestic animals, especially cattle and pigs. Understanding the immunobiology of NK cells will translate into strategies to manipulate these cells for preventive and therapeutic purposes.

  10. Natural born killers?: the development of the sexually sadistic serial killer.

    PubMed

    Johnson, B R; Becker, J V

    1997-01-01

    Today's society seems enthralled with serial killers in the news and the media. Forensic psychiatrists often interview serial killers after they have been caught. There are retrospective studies and case reports of individuals who have committed sexually sadistic serial murders. However, there exists a dearth of case reports on adolescents who have expressed serious fantasies about becoming serial killer prior to actualizing their fantasy. This article presents nine clinical cases of 14- to 18-year-olds who have clinically significant fantasies of becoming a serial killer. Similarities exist in these adolescent cases when compared with retrospective studies and case reports of serial killers on the role of sexually sadistic fantasies and actual killings. Since it has been established that sexual paraphilias may develop at a young age, one can surmise that sadistic paraphilias may also develop in some adolescents. The question is posed, can we predict which of these adolescents may go on to actually become serial killers? This article focuses on how the sexually sadistic fantasy can eventually be acted out and possible motives for the act to be repeated multiple times. Finally, recommendations are made about assessing and treating a youngster who expresses violent sexually sadistic killing fantasies so that attempts can be made to interrupt the progression to actual killing.

  11. Putting the natural killer cell in its place

    PubMed Central

    O'Connor, Geraldine M; Hart, Orla M; Gardiner, Clair M

    2006-01-01

    Natural killer (NK) cells were originally described as ‘null’ lymphocytes, but we have increasing evidence of their role in recognizing pathogen, and our knowledge of NK cell receptors continues to expand exponentially. Human NK cells have many receptors for human leucoctye antigen (HLA) class I. These killer immunoglobulin-like receptors (KIRs) and CD94/NKG2 receptors can signal in both positive and negative ways to regulate NK cell functions. The inhibitory receptors are the best characterized, but even in these cases much of their functional biology remains elusive. In this review, some recent advances in terms of the three-immunoglobulin (3Ig)-domain KIRs are discussed. Natural cytotoxicity receptors (NCRs) are among the activatory receptors found on NK cells. While pathogen ligands for these receptors have been described, endogenous ligands remain elusive. NCRs and NKG2D, a receptor for stress-induced antigens, appear to play complementary functional roles in terms of NK cell activation. More recently described on NK cells are the Toll-like receptors. In particular, these receptors of the innate immune system allow NK cells to directly sense pathogen, and their ligation on accessory cells indirectly activates NK cells through cytokine production. It is becoming clear that none of these receptor systems functions in isolation and that it is the sum of the signals (which will reflect the pathogenic situation), in addition to the cytokine milieu, that will direct NK cell activation. The resulting cytotoxicity, cytokine production and direct cell–cell regulatory interactions with other cells of the immune system, for example dendritic cells, ultimately determine the role of the NK cell in the context of an overall immune response. PMID:16423035

  12. Effect of Schlafen 2 on natural killer and T cell development from common T/natural killer progenitors.

    PubMed

    Ahmadi, S; Veinotte, L L

    2011-11-15

    Natural Killer (NK) cells are thought to develop from common lymphoid progenitors in the bone marrow. Even though thymus is not essential for NK cell development, T-cell/natural killer-cell (T/NK) precursors, DN1 (CD44+CD25-) and DN2 (CD44+CD25+) when cultured on an OP9 stroma, give rise to some NK1.1 cells. Genes of the Schlafen (Slfn) family are involved in hematopoietic and immune processes. The contribution of the Slfn genes in NK cell development from Double Negative (DN) cells is unknown. We transduced DN1 and DN2 progenitors prepared from C57BL/6 (B6) mouse thymus with Schlafen 1 (Slfnl) and Schlafen 2 (Slfn2) genes using Mig retroviral vector containing the Green Fluorescent Protein (GFP) gene and cultured those transduced progenitors on OP9 and OP9 stroma expressing the Notch ligand Delta-like 1 (OP9-DL 1) with appropriate cytokines to see if they affect generating NK and T-cells differently. Maturation of both NK and T cells from immature T/NK thymocytes hampered by Slfn1 and Slfn2 transduction but we got a small number of Slfn1 and Slfn2 expressing cells upon culture of transduced DN progenitors on stroma cells. There was no difference between Slfn1 expressing (GFP+) and none expressing T cells regarding CD3 expression but all mature NK cells were from Slfn1 negative population. Slfn2 completely blocked maturation of T cells but there was no difference between Slfn2 expressing and none expressing NK cells. Based on our findings both Slfn1 and Slfn2 interfere with maturation of DN2 progenitors but T cell development is more sensitive to Slfn2 expression than NK cell.

  13. Bronchoalveolar lavage fluid and blood natural killer and natural killer T-like cells in cryptogenic organizing pneumonia.

    PubMed

    Papakosta, Despina; Manika, Katerina; Gounari, Evdoxia; Kyriazis, George; Kontakiotis, Theodore; Spyropoulos, George; Kontakioti, Eirini; Zarogoulidis, Konstantinos

    2014-07-01

    Natural killer (NK) cells appear to be involved in the development of interstitial lung diseases (ILD). The purpose of this study was to investigate the involvement of NK and natural killer T (NKT)-like cells in two recognized cytotoxic ILD with systemic character, hypersensitivity pneumonitis (HP) and cryptogenic organizing pneumonia (COP), compared with idiopathic pulmonary fibrosis (IPF) and controls. Bronchoalveolar lavage fluid (BALF) and peripheral blood (PBL) cells and lymphocyte subsets of 83 patients (26 with COP, 19 with HP and 38 with IPF) and 10 controls were prospectively studied by flow cytometry. The percentage of NK and NKT-like cells was lower in BALF than in PBL in all patient groups and controls. Patients with COP presented with statistically significantly higher NK and NKT-like cell counts in BALF compared with controls (P = 0.044 and P = 0.05 respectively) and IPF (P = 0.049 and P = 0.045 respectively). BALF NKT-like cell count correlated with PBL NKT-like cell count only in COP (r = 0.627, P = 0.002). In addition, a significant positive correlation between BALF NKT-like cell and PBL cytotoxic T CD8+ cell count was observed in COP (r = 0.562, P = 0.006) but not in HP, IPF or controls. Our study provides for the first time evidence for the implication of NKT-like cells in the pathogenesis of COP, as part of both localized and systemic cytotoxicity. © 2014 Asian Pacific Society of Respirology.

  14. Depletion of natural killer cells increases mice susceptibility in a Pseudomonas aeruginosa pneumonia model.

    PubMed

    Broquet, Alexis; Roquilly, Antoine; Jacqueline, Cédric; Potel, Gilles; Caillon, Jocelyne; Asehnoune, Karim

    2014-06-01

    Pseudomonas aeruginosa infection is a clinically relevant infection involved in pneumonia in ICUs. Understanding the type of immune response initiated by the host during pneumonia would help defining new strategies to interfere with the bacteria pathogenicity. In this setting, the role of natural killer cells remains controversial. We assessed the role of systemic natural killer cells in a Pseudomonas aeruginosa mouse pneumonia model. Experimental study. Research laboratory from a university hospital. RjOrl:SWISS and BALB/cJ mice (weight, 20-24 g). Lung injuries were assessed by bacterial load, myeloperoxidase activity, endothelial permeability (pulmonary edema), immune cell infiltrate (histological analysis), proinflammatory cytokine release, and Ly6-G immunohistochemistry. Bacterial loads were assessed in the lungs and spleen. Natural killer cell number and status were assessed in spleen (flow cytometry and quantitative polymerase chain reaction). Depletion of natural killer cells was achieved through an IV anti-asialo-GM1 antibody injection. Pseudomonas aeruginosa tracheal instillation led to an acute pneumonia with a rapid decrease of bacterial load in lungs and with an increase of endothelial permeability, proinflammatory cytokines (tumor necrosis factor-α and interleukin-1β), and myeloperoxidase activity followed by Ly6-G positive cell infiltrate in lungs. Pseudomonas aeruginosa was detected in the spleen. Membrane markers of activation and maturation (CD69 and KLRG1 molecules) were increased in splenic natural killer cells during Pseudomonas aeruginosa infection. Splenic natural killer cells activated upon Pseudomonas aeruginosa infection produced interferon-γ but not interleukin-10. Ultimately, mice depleted of natural killer cells displayed an increased neutrophil numbers in the lungs and an increased mortality rate without bacterial load modifications in the lungs, indicating that mice depleted of natural killer cells were much more susceptible to

  15. Extranodal natural killer/T-cell lymphoma, nasal-type.

    PubMed

    Chorianopoulos, Dimitrios; Samitas, Konstantinos; Vittorakis, Stylianos; Kiriazi, Vasiliki; Rondoyianni, Dimitra; Tsaousis, Georgios; Skoutelis, Athanasios

    2010-01-01

    expressed the cytotoxic proteins T-cell intracellular antigen and granzyme B (Figure 3) They lacked TdT, CD34, CD7, CD8, TCL-1, and CD123. Findings from an in situ hybridization study for Epstein-Barr virus were negative. Give this result, molecular analysis ofT-cell receptor (TCR) gene rearrangements was performed using polymerase chain reaction-based TCR-gamma gene, wit negative results. The morphology and the immunophenotype were consistent with natural killer/T-cell lymphoma, nasal-type. Nasal involvement must be first excluded to proceed to the diagnosis of nasal-type natural killer-cell lymphoma. Indeed, histologic examination of the nasal mass revealed its polypoid nature. Thus, the authors were led to the diagnosis of extranodal extranasal natural killer/T-cell lymphoma, nasal-type, CD56-positive, Ep stein-Barr virus-negative, TCR-negative. The patient received combination chemotherapy and completed 4 cycles of cyclophosphamide, doxorubicin vincristine, and prednisone every 14 days for 2 months. Skin lesions improved, and there was no fever soon after the initiation of therapy. Reevaluatio after the fourth cycle, however, disclosed pulmonary infiltrations as well as leukemic infiltration of the central nervous system. The patient had receive systemic salvage chemotherapy and intrathecal infusions of methotrexate. Although the lung lesions had diminished at that time, the patient develope paraplegia, his clinical course rapidly deteriorated, and he eventually died.

  16. Human natural killer cell development in secondary lymphoid tissues

    PubMed Central

    Freud, Aharon G.; Yu, Jianhua; Caligiuri, Michael A.

    2014-01-01

    For nearly a decade it has been appreciated that critical steps in human natural killer (NK) cell development likely occur outside of the bone marrow and potentially necessitate distinct microenvironments within extramedullary tissues. The latter include the liver and gravid uterus as well as secondary lymphoid tissues such as tonsils and lymph nodes. For as yet unknown reasons these tissues are naturally enriched with NK cell developmental intermediates (NKDI) that span a maturation continuum starting from an oligopotent CD34+CD45RA+ hematopoietic precursor cell to a cytolytic mature NK cell. Indeed despite the detection of NKDI within the aforementioned tissues, relatively little is known about how, why, and when these tissues may be most suited to support NK cell maturation and how this process fits in with other components of the human immune system. With the discovery of other innate lymphoid subsets whose immunophenotypes overlap with those of NKDI, there is also need to revisit and potentially re-characterize the basic immunophenotypes of the stages of the human NK cell developmental pathway in vivo. In this review, we provide an overview of human NK cell development in secondary lymphoid tissues and discuss the many questions that remain to be answered in this exciting field. PMID:24661538

  17. Role of human natural killer cells in health and disease.

    PubMed Central

    Whiteside, T L; Herberman, R B

    1994-01-01

    Natural killer (NK) cells, the CD3- CD56+ CD16+ subset of peripheral blood lymphocytes, have long been known to be involved in non-major histocompatibility complex-restricted natural immunity to virally infected and malignant target cells. The association of abnormalities in NK cell numbers or functions with a broad spectrum of human diseases has been more clearly defined in recent years as a result of the improved knowledge of NK cell physiology and advances in monitoring of NK cell functions in health and disease. The ability to reliably measure changes in NK activity and/or numbers during the course of disease or response to treatment has focused attention on the role of the NK cell in disease pathogenesis. The improved understanding of NK cell deficiency in disease has opened a way for therapies specifically designed to improve NK cell function. The therapeutic use of biologic response modifiers capable of augmenting NK cell activity in vivo and of adoptive transfer of highly enriched, activated autologous NK cells in diseases such as cancer and AIDS is being evaluated. The importance of NK cells in health and the consequences of NK cell deficiency or excess are likely to be more extensively monitored in the future. PMID:7496932

  18. Human natural killer cell development in secondary lymphoid tissues.

    PubMed

    Freud, Aharon G; Yu, Jianhua; Caligiuri, Michael A

    2014-04-01

    For nearly a decade it has been appreciated that critical steps in human natural killer (NK) cell development likely occur outside of the bone marrow and potentially necessitate distinct microenvironments within extramedullary tissues. The latter include the liver and gravid uterus as well as secondary lymphoid tissues such as tonsils and lymph nodes. For as yet unknown reasons these tissues are naturally enriched with NK cell developmental intermediates (NKDI) that span a maturation continuum starting from an oligopotent CD34(+)CD45RA(+) hematopoietic precursor cell to a cytolytic mature NK cell. Indeed despite the detection of NKDI within the aforementioned tissues, relatively little is known about how, why, and when these tissues may be most suited to support NK cell maturation and how this process fits in with other components of the human immune system. With the discovery of other innate lymphoid subsets whose immunophenotypes overlap with those of NKDI, there is also need to revisit and potentially re-characterize the basic immunophenotypes of the stages of the human NK cell developmental pathway in vivo. In this review, we provide an overview of human NK cell development in secondary lymphoid tissues and discuss the many questions that remain to be answered in this exciting field.

  19. Natural killer cells in patients with polycythemia vera.

    PubMed

    Sanchez, Carole; Baier, Céline; Colle, Julien G; Chelbi, Rabie; Rihet, Pascal; Le Treut, Thérèse; Imbert, Jean; Sébahoun, Gérard; Venton, Geoffroy; Costello, Régis T

    2015-09-01

    Natural killer cells (NK) are pivotal cells of innate immunity. They are potent antileukemic cytotoxic effectors. A defect in their cytotoxicity has been described in some hematopoietic malignancies such as acute myeloid leukemia, multiple myeloma and myelodysplastic syndromes. This defect is at least partially linked to a decreased or absent expression of some activating NK cells molecules, more particularly the so-called natural cytotoxicity receptors. In the present study, we more particularly focused our attention on NK cells of polycythemia vera, a myeloproliferative disease characterized by the presence of mutated JAK2 tyrosine kinase. The polymerase chain reaction analysis of NK cells from patients showed that they expressed the mutated form of JAK2. In polycythemia vera the proportion of NK was increased compared to healthy donors. The proliferative and cytotoxic abilities of NK cells from patients were similar to healthy donors. Expression of activating or inhibitory receptors was comparable in patients and donors, with nonetheless an imbalance for the inhibitory form of the CD158a,h couple of receptors in patients. Finally, the transcriptomic profile analysis clearly identified a discriminant signature between NK cells from patients and donors that could putatively be the consequence of abnormal continuous activation of mutated JAK2.

  20. Characterization of Circulating Natural Killer Cells in Neotropical Primates

    PubMed Central

    Carville, Angela; Evans, Tristan I.; Reeves, R. Keith

    2013-01-01

    Despite extensive use of nonhuman primates as models for infectious diseases and reproductive biology, imprecise phenotypic and functional definitions exist for natural killer (NK) cells. This deficit is particularly significant in the burgeoning use of small, less expensive New World primate species. Using polychromatic flow cytometry, we identified peripheral blood NK cells as CD3-negative and expressing a cluster of cell surface molecules characteristic of NK cells (i.e., NKG2A, NKp46, NKp30) in three New World primate species – common marmosets, cotton-top tamarins, and squirrel monkeys. We then assessed subset distribution using the classical NK markers, CD56 and CD16. In all species, similar to Old World primates, only a minor subset of NK cells was CD56+, and the dominant subset was CD56–CD16+. Interestingly, CD56+ NK cells were primarily cytokine-secreting cells, whereas CD56–CD16+ NK cells expressed significantly greater levels of intracellular perforin, suggesting these cells might have greater potential for cytotoxicity. New World primate species, like Old World primates, also had a minor CD56–CD16– NK cell subset that has no obvious counterpart in humans. Herein we present phenotypic profiles of New World primate NK cell subpopulations that are generally analogous to those found in humans. This conservation among species should support the further use of these species for biomedical research. PMID:24244365

  1. Advantages and applications of CAR-expressing natural killer cells

    PubMed Central

    Glienke, Wolfgang; Esser, Ruth; Priesner, Christoph; Suerth, Julia D.; Schambach, Axel; Wels, Winfried S.; Grez, Manuel; Kloess, Stephan; Arseniev, Lubomir; Koehl, Ulrike

    2015-01-01

    In contrast to donor T cells, natural killer (NK) cells are known to mediate anti-cancer effects without the risk of inducing graft-versus-host disease (GvHD). In order to improve cytotoxicity against resistant cancer cells, auspicious efforts have been made with chimeric antigen receptor (CAR) expressing T- and NK cells. These CAR-modified cells express antigen receptors against tumor-associated surface antigens, thus redirecting the effector cells and enhancing tumor-specific immunosurveillance. However, many cancer antigens are also expressed on healthy tissues, potentially leading to off tumor/on target toxicity by CAR-engineered cells. In order to control such potentially severe side effects, the insertion of suicide genes into CAR-modified effectors can provide a means for efficient depletion of these cells. While CAR-expressing T cells have entered successfully clinical trials, experience with CAR-engineered NK cells is mainly restricted to pre-clinical investigations and predominantly to NK cell lines. In this review we summarize the data on CAR expressing NK cells focusing on the possible advantage using these short-lived effector cells and discuss the necessity of suicide switches. Furthermore, we address the compliance of such modified NK cells with regulatory requirements as a new field in cellular immunotherapy. PMID:25729364

  2. Invariant natural killer T infiltration in neuroblastoma with favorable outcome.

    PubMed

    Hishiki, Tomoro; Mise, Naoko; Harada, Kazuaki; Ihara, Fumie; Takami, Mariko; Saito, Takeshi; Terui, Keita; Nakata, Mitsuyuki; Komatsu, Shugo; Yoshida, Hideo; Motohashi, Shinichiro

    2017-10-10

    Tumor immunity has been suggested to play a key role in clinical and biological behavior of neuroblastomas. Given that CD1-restricted invariant natural killer T (iNKT) cells enhance both innate and acquired tumor immunity, we investigated the expression of the iNKT-cell-specific T-cell receptor Vα24-Jα18 in neuroblastoma tissues and its correlation with clinical and biological characteristics. Using real- time quantitative PCR, we quantified the expression of Vα24-Jα18 in untreated tumor samples from 107 neuroblastoma cases followed in our institution and analyzed the correlation between the presence of infiltrated iNKT cells and clinical characteristics or patients' outcome. Vα24-Jα18 receptor was detected in 62 untreated cases (57.9%). The expression was significantly higher in stages 1, 2, 3, or 4S (P = 0.0099), in tumors with low or intermediate risk (P = 0.0050), with high TrkA expression (P = 0.0229), with favorable histology (P = 0.0026), with aneuploidy (P = 0.0348), and in younger patients (P = 0.0036). The overall survival rate was significantly higher in patients with iNKT-cell infiltration (log-rank; P = 0.0089). Since tumor-infiltrating iNKT cells were predominantly observed in neuroblastomas undergoing spontaneous differentiation and/or regression, we suggest that iNKT cells might play a key role in these processes.

  3. Immunotherapeutic strategies targeting natural killer T cell responses in cancer.

    PubMed

    Shissler, Susannah C; Bollino, Dominique R; Tiper, Irina V; Bates, Joshua P; Derakhshandeh, Roshanak; Webb, Tonya J

    2016-08-01

    Natural killer T (NKT) cells are a unique subset of lymphocytes that bridge the innate and adaptive immune system. NKT cells possess a classic αβ T cell receptor (TCR) that is able to recognize self and foreign glycolipid antigens presented by the nonclassical class I major histocompatibility complex (MHC) molecule, CD1d. Type I NKT cells (referred to as invariant NKT cells) express a semi-invariant Vα14Jα18 TCR in mice and Vα24Jα18 TCR in humans. Type II NKT cells are CD1d-restricted T cells that express a more diverse set of TCR α chains. The two types of NKT cells often exert opposing effects especially in tumor immunity, where type II cells generally suppress tumor immunity while type I NKT cells can enhance anti-tumor immune responses. In this review, we focus on the role of NKT cells in cancer. We discuss their effector and suppressive functions, as well as describe preclinical and clinical studies utilizing therapeutic strategies focused on harnessing their potent anti-tumor effector functions, and conclude with a discussion on potential next steps for the utilization of NKT cell-targeted therapies for the treatment of cancer.

  4. MicroRNA regulation of natural killer cells

    PubMed Central

    Sullivan, Ryan P.; Leong, Jeffrey W.; Fehniger, Todd A.

    2013-01-01

    Natural killer (NK) cells are innate immune lymphocytes critical for host defense against viral infection and surveillance against malignant transformation. MicroRNAs (miRNAs) are a family of small, non-coding RNAs that regulate a wide variety of cellular processes. Recent advances have highlighted the importance of miRNA-mediated post-transcriptional regulation in NK cell development, maturation, and function. This review focuses on several facets of this regulatory mechanism in NK cells: (1) the expressed NK cell miRNA transcriptome; (2) the impact of total miRNA deficiency on NK cells; (3) the role of specific miRNAs regulating NK cell development, survival, and maturation; (4) the intrinsic role of miRNAs regulating NK cell function, including cytokine production, proliferation, and cytotoxicity; and (5) the role of NK cell miRNAs in disease. Currently our knowledge of how miRNAs regulate NK cell biology is limited, and thus we also explore key open questions in the field, as well as approaches and techniques to ascertain the role of individual miRNAs as important molecular regulators. PMID:23450173

  5. Immunosuppression of pulmonary natural killer activity by exposure to ozone

    SciTech Connect

    Burleson, G.R.; Keyes, L.L.; Stutzman, J.D.

    1989-01-01

    Ozone is an oxidant gas and an ubiquitous oxidant air pollutant with the potential to adversely affect pulmonary immune function with a subsequent increase in disease susceptibility. Pulmonary natural killer (NK) activity was measured in order to assess the pulmonary immunotoxicity of continuous ozone exposure. Continuous ozone exposures at 1.0 ppm were performed for 23.5 hours per day for either 1, 5, 7, or 10 consecutive days. Pulmonary immune function was assessed by measuring NK activity from whole-lung homogenate of male Fischer-344 rats. Results of the study indicated that continuous ozone exposure for 1, 5, or 7 days resulted in a significant decrease in pulmonary NK activity. This suppressed pulmonary NK activity returned to control levels after continuous exposure to ozone for 10 days. This adaption, or attenuation process, is complex and poorly understood. Pulmonary NK activity was also suppressed at 0.5 ppm ozone, but not at 0.1 ppm ozone, for 23.5 hours. NK activity is important for defense against viral, bacterial, and neoplastic disease.

  6. Natural killer cells in hepatitis C: Current progress.

    PubMed

    Yoon, Joo Chun; Yang, Chang Mo; Song, Youkyong; Lee, Jae Myun

    2016-01-28

    Patients infected with the hepatitis C virus (HCV) are characterized by a high incidence of chronic infection, which results in chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. The functional impairment of HCV-specific T cells is associated with the evolution of an acute infection to chronic hepatitis. While T cells are the important effector cells in adaptive immunity, natural killer (NK) cells are the critical effector cells in innate immunity to virus infections. The findings of recent studies on NK cells in hepatitis C suggest that NK cell responses are indeed important in each phase of HCV infection. In the early phase, NK cells are involved in protective immunity to HCV. The immune evasion strategies used by HCV may target NK cells and might contribute to the progression to chronic hepatitis C. NK cells may control HCV replication and modulate hepatic fibrosis in the chronic phase. Further investigations are, however, needed, because a considerable number of studies observed functional impairment of NK cells in chronic HCV infection. Interestingly, the enhanced NK cell responses during interferon-α-based therapy of chronic hepatitis C indicate successful treatment. In spite of the advances in research on NK cells in hepatitis C, establishment of more physiological HCV infection model systems is needed to settle unsolved controversies over the role and functional status of NK cells in HCV infection.

  7. Extranodal Natural Killer/T-Cell Lymphoma: An Incidental Finding.

    PubMed

    Althoff, Ashley; Bibliowicz, Michael

    2017-05-19

    Extranodal natural killer/T-cell lymphoma (ENKTCL) is a rare form of non-Hodgkin lymphoma. This neoplasm is more prevalent in regions of Asia and Latin America and most commonly involves the sinonasal tract, presenting with signs of nasal obstruction, epistaxis, or sinus infection. It is a locally destructive and angioinvasive neoplasm. The treatment of ENKTCL is dependent on the extent of the tumor. For localized disease, the treatment is chemoradiation. For disseminated disease, treatment is mainly chemotherapy-based. This report describes a case of a 41-year-old Hispanic woman who initially presented with signs of nasal congestion for four weeks and was subsequently diagnosed and treated for chronic sinusitis. The patient underwent endoscopic surgery for persistent chronic sinusitis, with a presumptive diagnosis of allergic fungal rhinosinusitis based on clinical and radiographic presentation. The pathologic exam revealed a diagnosis of ENKTCL. The patient underwent three cycles of chemotherapy comprised of steroid (hydrocortisone), methotrexate, ifosfamide, pre-asparaginase, and etoposide (SMILE) followed by radiation, resulting in clinical and radiographic remission. On review of the literature, ENKTCL is very rare in the United States and diagnosis is commonly delayed due to non-specific signs. We report this case to increase awareness of this disease entity and remind clinicians to include this in the differential diagnosis of nasal obstruction.

  8. Inborn errors of the development of human natural killer cells.

    PubMed

    Jouanguy, Emmanuelle; Gineau, Laure; Cottineau, Julien; Béziat, Vivien; Vivier, Eric; Casanova, Jean-Laurent

    2013-12-01

    Inborn errors of human natural killer (NK) cells may affect the development of these cells, their function, or both. There are two broad categories of genetic defects of NK cell development, depending on whether the deficiency is apparently specific to NK cells or clearly affects multiple hematopoietic lineages. We review here recent progress in the genetic dissection of these NK deficiencies (NKDs). Patients with severe combined immunodeficiencies bearing mutations of adenosine deaminase, adenylate kinase 2, interleukin-2 receptor gamma chain, and Janus kinase 3 genes present NKDs and are prone to a broad range of infections. Patients with GATA binding protein 2 deficiency are susceptible to both mycobacterial and viral infections, and display NKDs and a lack of monocytes. Rare patients with mini chromosomal maintenance 4 deficiency display an apparently selective NKD associated with viral infections, but they also display various nonhematopoietic phenotypes, including adrenal insufficiency and growth retardation. These studies have initiated a genetic dissection of the development of human NK cells. Further studies are warranted, including the search for genetic causes of NKD in particular. This research may lead to the discovery of molecules specifically controlling the development of NK cells and to improvements in our understanding of the hitherto elusive function of these cells in humans.

  9. Role of Distinct Natural Killer Cell Subsets in Anticancer Response

    PubMed Central

    Stabile, Helena; Fionda, Cinzia; Gismondi, Angela; Santoni, Angela

    2017-01-01

    Natural killer (NK) cells, the prototypic member of innate lymphoid cells, are important effectors of anticancer immune response. These cells can survey and control tumor initiation due to their capability to recognize and kill malignant cells and to regulate the adaptive immune response via cytokines and chemokines release. However, several studies have shown that tumor-infiltrating NK cells associated with advanced disease can have profound functional defects and display protumor activity. This evidence indicates that NK cell behavior undergoes crucial alterations during cancer progression. Moreover, a further level of complexity is due to the extensive heterogeneity and plasticity of these lymphocytes, implying that different NK cell subsets, endowed with specific phenotypic and functional features, may be involved and play distinct roles in the tumor context. Accordingly, many studies reported the enrichment of selective NK cell subsets within tumor tissue, whereas the underlying mechanisms are not fully elucidated. A malignant microenvironment can significantly impact NK cell activity, by recruiting specific subpopulations and/or influencing their developmental programming or the acquisition of a mature phenotype; in particular, neoplastic, stroma and immune cells, or tumor-derived factors take part in these processes. In this review, we will summarize and discuss the recently acquired knowledge on the possible contribution of distinct NK cell subsets in the control and/or progression of solid and hematological malignancies. Moreover, we will address emerging evidence regarding the role of different components of tumor microenvironment on shaping NK cell response. PMID:28360915

  10. Natural killer cell activity in cigarette smokers and asbestos workers

    SciTech Connect

    Ginns, L.C.; Ryu, J.H.; Rogol, P.R.; Sprince, N.L.; Oliver, L.C.; Larsson, C.J.

    1985-06-01

    In order to evaluate the effects of cigarette smoking and asbestos exposure on cellular immunity, the authors tested a group of cigarette smokers and asbestos workers for natural killer (NK) activity in the peripheral blood. The mean NK activity in cigarette smokers was lower than in normal subjects (13.7 +/- 1.6 versus 29.0 +/- 3%; p less than 0.05). As a group, the mean NK activity for the asbestos-exposed group was also reduced compared with that of the nonsmoking control group (22.6 +/- 3.2%; p less than 0.05). When divided according to the smoking status, the asbestos workers who were nonsmokers or ex-smokers showed similar decreases in NK activity compared with normal subjects (19.5 +/- 6.2 and 21.2 +/- 4.5%, respectively; p less than 0.05). A subgroup of asbestos-exposed subjects who currently smoked showed no decrease in NK activity. The data show that NK activity is reduced in the peripheral blood of cigarette smokers and asbestos workers. The relatively normal NK activity found in asbestos workers who also smoked is unexplained. Impairment of NK activity is a potential mechanism for the increased incidence of infection and cancer in smokers and neoplasia in asbestos workers.

  11. Analysis of invariant natural killer T cells in human paracoccidioidomycosis.

    PubMed

    Batista, Vanessa Gomes; Moreira-Teixeira, Lúcia; Leite-de-Moraes, Maria C; Benard, Gil

    2011-11-01

    Invariant natural killer T (iNKT) cells are capable of recognizing lipid antigens and secreting Th1/Th2 cytokines. Deficiency in iNKT cell number or function has been partially implicated in susceptibility to some infectious diseases, such as tuberculosis. We evaluated iNKT cells in paracoccidioidomycosis, another chronic granulomatous disease endemic in Latin America. iNKT cells were detected using PBS57-loaded tetramer staining and flow cytometry. Circulating iNKT cell numbers were similar among healthy individuals who had previously been cured of paracoccidioidomycosis (susceptible individuals, n = 7) and healthy Paracoccidioides brasiliensis-infected (n = 5) and non-infected individuals (n = 5). iNKT from all three groups expanded similarly upon α-GalCer and a synthetic analog (OCH) stimulation. IFN-γ was the dominant cytokine produced both by ex vivo and by expanded iNKT cells, followed by IL-4 and IL-10, in the three groups. No deficit in the monocyte expression of CD1d was detected. In conclusion, individuals who had developed paracoccidioidomycosis in the past have no impairment in iNKT number, expansion capacity, and cytokine secretion.

  12. Human natural killer cells: their origin, receptors and function.

    PubMed

    Moretta, Lorenzo; Bottino, Cristina; Pende, Daniela; Mingari, Maria Cristina; Biassoni, Roberto; Moretta, Alessandro

    2002-05-01

    The term of "natural killer" (NK) cells was originally assigned on a merely functional basis to lymphoid cells capable of lysing certain tumors in the absence of prior stimulation. However, both their origin and the molecular mechanism(s) involved in their function remained a mystery for many years 1. Regarding their origin, clear evidence has now been provided both in mouse and in man that NK and T cells may derive from a common precursor 2-5. Thus, mature NK cells can be obtained in vitro from CD34(+) cells isolated from umbilical cord blood, bone marrow (BM) and even human thymus 6 when cultured in the presence of appropriate feeder cells or IL-15. The molecular mechanism allowing NK cells to discriminate between normal and tumor cells, predicted by the "missing self hypothesis" 7, has been clarified only in recent years. Thus, NK cells recognize MHC class I molecules through surface receptors delivering signals that inhibit, rather than activate, NK cells. As a consequence, NK cells lyse target cells that have lost (or express insufficient amounts of) MHC class I molecules, as frequently occurs in tumors and in cells infected by certain viruses.

  13. Communication between natural killer T cells and adipocytes in obesity

    PubMed Central

    Satoh, Masashi; Iwabuchi, Kazuya

    2016-01-01

    ABSTRACT Adipose tissue contains various types of immunocompetent cells, and these cells of innate and adaptive immunity control adipose tissue inflammation that blunts insulin sensitivity. Recent studies have shown that adipocytes express CD1d and present lipid antigen(s) to activate natural killer T (NKT) cells. The function of adipocytes is in turn modulated by cytokines that NKT cells produce to alter the expression of anti-inflammatory adipokine(s) and the production of inflammatory and chemoattractant cytokines. These in vitro studies imply that the interaction between adipocytes and NKT cells might affect the development of not only obesity but also obesity-related diseases. To test the importance of the interaction between NKT cells and adipocytes, we examined whether an adipocyte-specific CD1d deletion affected the development of obesity, which had been demonstrated with B6.CD1d−/− (CD1d KO). We found that the interaction is indeed important to induce adipose tissue inflammation and insulin resistance in response to lipid excess. In this commentary, the advances and controversies on NKT cells and obesity are discussed based on our recent report that NKT cells play a pivotal role in the regulation of adipose tissue by communicating with adipocytes via CD1d. PMID:27994954

  14. Natural killer T cells in adipose tissue prevent insulin resistance

    PubMed Central

    Schipper, Henk S.; Rakhshandehroo, Maryam; van de Graaf, Stan F.J.; Venken, Koen; Koppen, Arjen; Stienstra, Rinke; Prop, Serge; Meerding, Jenny; Hamers, Nicole; Besra, Gurdyal; Boon, Louis; Nieuwenhuis, Edward E.S.; Elewaut, Dirk; Prakken, Berent; Kersten, Sander; Boes, Marianne; Kalkhoven, Eric

    2012-01-01

    Lipid overload and adipocyte dysfunction are key to the development of insulin resistance and can be induced by a high-fat diet. CD1d-restricted invariant natural killer T (iNKT) cells have been proposed as mediators between lipid overload and insulin resistance, but recent studies found decreased iNKT cell numbers and marginal effects of iNKT cell depletion on insulin resistance under high-fat diet conditions. Here, we focused on the role of iNKT cells under normal conditions. We showed that iNKT cell–deficient mice on a low-fat diet, considered a normal diet for mice, displayed a distinctive insulin resistance phenotype without overt adipose tissue inflammation. Insulin resistance was characterized by adipocyte dysfunction, including adipocyte hypertrophy, increased leptin, and decreased adiponectin levels. The lack of liver abnormalities in CD1d-null mice together with the enrichment of CD1d-restricted iNKT cells in both mouse and human adipose tissue indicated a specific role for adipose tissue–resident iNKT cells in the development of insulin resistance. Strikingly, iNKT cell function was directly modulated by adipocytes, which acted as lipid antigen-presenting cells in a CD1d-mediated fashion. Based on these findings, we propose that, especially under low-fat diet conditions, adipose tissue–resident iNKT cells maintain healthy adipose tissue through direct interplay with adipocytes and prevent insulin resistance. PMID:22863618

  15. Natural killer T cells in adipose tissue prevent insulin resistance.

    PubMed

    Schipper, Henk S; Rakhshandehroo, Maryam; van de Graaf, Stan F J; Venken, Koen; Koppen, Arjen; Stienstra, Rinke; Prop, Serge; Meerding, Jenny; Hamers, Nicole; Besra, Gurdyal; Boon, Louis; Nieuwenhuis, Edward E S; Elewaut, Dirk; Prakken, Berent; Kersten, Sander; Boes, Marianne; Kalkhoven, Eric

    2012-09-01

    Lipid overload and adipocyte dysfunction are key to the development of insulin resistance and can be induced by a high-fat diet. CD1d-restricted invariant natural killer T (iNKT) cells have been proposed as mediators between lipid overload and insulin resistance, but recent studies found decreased iNKT cell numbers and marginal effects of iNKT cell depletion on insulin resistance under high-fat diet conditions. Here, we focused on the role of iNKT cells under normal conditions. We showed that iNKT cell-deficient mice on a low-fat diet, considered a normal diet for mice, displayed a distinctive insulin resistance phenotype without overt adipose tissue inflammation. Insulin resistance was characterized by adipocyte dysfunction, including adipocyte hypertrophy, increased leptin, and decreased adiponectin levels. The lack of liver abnormalities in CD1d-null mice together with the enrichment of CD1d-restricted iNKT cells in both mouse and human adipose tissue indicated a specific role for adipose tissue-resident iNKT cells in the development of insulin resistance. Strikingly, iNKT cell function was directly modulated by adipocytes, which acted as lipid antigen-presenting cells in a CD1d-mediated fashion. Based on these findings, we propose that, especially under low-fat diet conditions, adipose tissue-resident iNKT cells maintain healthy adipose tissue through direct interplay with adipocytes and prevent insulin resistance.

  16. Invariant natural killer T cell-based immunotherapy for cancer.

    PubMed

    Motohashi, Shinichiro; Nakayama, Toshinori

    2009-01-01

    Human Valpha24 invariant natural killer T (iNKT) cells are a distinct lymphocyte population, characterized by an invariant T-cell receptor Valpha24 chain paired mainly with Valpha11. Valpha24 iNKT cells are activated by a glycolipid ligand - alpha-galactosylceramide - and produce a large amount of Th1 and Th2 cytokines, thereby modulating the function of other cells. iNKT cells have the capability to control a wide variety of immune responses, including antitumor immunity. Abnormalities in the number and function of Valpha24 iNKT cells have been observed in patients with malignant diseases accompanied with a poor clinical outcome. Therefore, therapeutic strategies that focused on the restoration of Valpha24 iNKT cell population and function would be a reasonable rationale for the treatment of cancer. In this article, the progress to date in the clinical studies of iNKT cell-based immunotherapy is briefly reviewed and the role of Valpha24 iNKT cells in cancer immunotherapy is highlighted.

  17. Antigen specificity of invariant natural killer T-cells.

    PubMed

    Birkholz, Alysia M; Kronenberg, Mitchell

    2015-12-01

    Natural killer T-cells, with an invariant T-cell antigen receptor α-chain (iNKT cells), are unique and conserved subset of lymphocytes capable of altering the immune system through their rapid and potent cytokine responses. They are reactive to lipid antigens presented by the CD1d molecule, an antigen-presenting molecule that is not highly polymorphic. iNKT cell responses frequently involve mixtures of cytokines that work against each other, and therefore attempts are underway to develop synthetic antigens that elicit only strong interferon-gamma (IFNγ) or only strong interleukin-4 responses but not both. Strong IFNγ responses may correlate with tighter binding to CD1d and prolonged stimulation of iNKT cells, and this may be useful for vaccine adjuvants and for stimulating anti-tumor responses. iNKT cells are self-reactive although the structure of the endogenous antigen is controversial. By contrast, bacterial and fungal lipids that engage the T-cell receptor and activate IFNγ from iNKT cells have been identified from both pathogenic and commensal organisms and the responses are in some cases highly protective from pathogens in mice. It is possible that the expanding knowledge of iNKT cell antigens and iNKT cell activation will provide the basis for therapies for patients suffering from infectious and immune diseases and cancer.

  18. Developmental and Functional Control of Natural Killer Cells by Cytokines

    PubMed Central

    Wu, Yang; Tian, Zhigang; Wei, Haiming

    2017-01-01

    Natural killer (NK) cells are effective in combating infections and tumors and as such are tempting for adoptive transfer therapy. However, they are not homogeneous but can be divided into three main subsets, including cytotoxic, tolerant, and regulatory NK cells, with disparate phenotypes and functions in diverse tissues. The development and functions of such NK cells are controlled by various cytokines, such as fms-like tyrosine kinase 3 ligand (FL), kit ligand (KL), interleukin (IL)-3, IL-10, IL-12, IL-18, transforming growth factor-β, and common-γ chain family cytokines, which operate at different stages by regulating distinct signaling pathways. Nevertheless, the specific roles of each cytokine that regulates NK cell development or that shapes different NK cell functions remain unclear. In this review, we attempt to describe the characteristics of each cytokine and the existing protocols to expand NK cells using different combinations of cytokines and feeder cells. A comprehensive understanding of the role of cytokines in NK cell development and function will aid the generation of better efficacy for adoptive NK cell treatment. PMID:28824650

  19. Immune Surveillance of Unhealthy Cells by Natural Killer cells

    PubMed Central

    Iannello, Alexandre; Raulet, David H.

    2014-01-01

    Pathogenic and oncogenic insults result in the induction of intrinsic defense mechanisms such as cell death pathways and senescence, and extrinsic pathways that mobilize immune responses to destroy unhealthy cells. Both protective mechanisms presumably evolved to limit the damage these insults could inflict on the host. After viral infection or malignant transformation, unhealthy cells can be directly sensed by natural killer (NK) and some T cells via the activating receptor NKG2D. All NK cells and subsets of T cells express NKG2D. The NKG2D/ligand system represents a major recognition mechanism for detection and elimination of unhealthy cells. Here we discuss different pathways, including stress pathways, that are responsible for cell surface display of ligands for NKG2D, which are self-proteins that are minimally expressed by normal cells. We also discuss new results indicating that efficient elimination of tumor cells that display NKG2D ligands depends on the recruitment of NK cells and other immune cells to the tumor, which can be regulated by distinct mechanisms, including the p53-dependent production of chemokines by senescent tumors. The cooperative effect of pathways that induce the display NKG2D ligands and distinct pathways that mobilize immune cells provides a higher degree of specificity to the NK cell response. PMID:24135717

  20. Id2 regulates hyporesponsive invariant natural killer T cells

    PubMed Central

    Stradner, Martin H; Cheung, Kitty P; Lasorella, Anna; Goldrath, Ananda W; D’Cruz, Louise M

    2016-01-01

    While the invariant natural killer T (iNKT)-cell response to primary stimulation with the glycolipid, α-galactosylceramide (αGalCer), is robust, the secondary response to this stimulus is muted resulting in a hyporesponsive state characterized by anti-inflammatory interleukin-10 (IL-10) production and high expression of programmed cell death 1 (PD1) and neuropilin 1 (NRP1). The E protein transcription factors and their negative regulators, the Id proteins, have previously been shown to regulate iNKT cell thymic development, subset differentiation and peripheral survival. Here, we provide evidence that the expression of the transcriptional regulator Id2 is downregulated upon stimulation of iNKT cells with their cognate antigen. Moreover, loss of Id2 expression by iNKT cells resulted in a hyporesponsive state, with splenic Id2-deficient iNKT cells expressing low levels of TBET, high levels of PD1 and NRP1 and production of IL-10 upon stimulation. We propose that downregulation of Id2 expression is an essential component of induction of the anti-inflammatory, hyporesponsive state in iNKT cells. PMID:26880074

  1. Natural killer cells in hepatitis C: Current progress

    PubMed Central

    Yoon, Joo Chun; Yang, Chang Mo; Song, Youkyong; Lee, Jae Myun

    2016-01-01

    Patients infected with the hepatitis C virus (HCV) are characterized by a high incidence of chronic infection, which results in chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. The functional impairment of HCV-specific T cells is associated with the evolution of an acute infection to chronic hepatitis. While T cells are the important effector cells in adaptive immunity, natural killer (NK) cells are the critical effector cells in innate immunity to virus infections. The findings of recent studies on NK cells in hepatitis C suggest that NK cell responses are indeed important in each phase of HCV infection. In the early phase, NK cells are involved in protective immunity to HCV. The immune evasion strategies used by HCV may target NK cells and might contribute to the progression to chronic hepatitis C. NK cells may control HCV replication and modulate hepatic fibrosis in the chronic phase. Further investigations are, however, needed, because a considerable number of studies observed functional impairment of NK cells in chronic HCV infection. Interestingly, the enhanced NK cell responses during interferon-α-based therapy of chronic hepatitis C indicate successful treatment. In spite of the advances in research on NK cells in hepatitis C, establishment of more physiological HCV infection model systems is needed to settle unsolved controversies over the role and functional status of NK cells in HCV infection. PMID:26819513

  2. Understanding of molecular mechanisms in natural killer cell therapy

    PubMed Central

    Yoon, Suk Ran; Kim, Tae-Don; Choi, Inpyo

    2015-01-01

    Cancer cells and the immune system are closely related and thus influence each other. Although immune cells can suppress cancer cell growth, cancer cells can evade immune cell attack via immune escape mechanisms. Natural killer (NK) cells kill cancer cells by secreting perforins and granzymes. Upon contact with cancer cells, NK cells form immune synapses to deliver the lethal hit. Mature NK cells are differentiated from hematopoietic stem cells in the bone marrow. They move to lymph nodes, where they are activated through interactions with dendritic cells. Interleukin-15 (IL-15) is a key molecule that activates mature NK cells. The adoptive transfer of NK cells to treat incurable cancer is an attractive approach. A certain number of activated NK cells are required for adoptive NK cell therapy. To prepare these NK cells, mature NK cells can be amplified to obtain sufficient numbers of NK cells. Alternatively, NK cells can be differentiated and amplified from hematopoietic stem cells. In addition, the selection of donors is important to achieve maximal efficacy. In this review, we discuss the overall procedures and strategies of NK cell therapy against cancer. PMID:25676064

  3. Molecular Programming of Immunological Memory in Natural Killer Cells.

    PubMed

    Beaulieu, Aimee M; Madera, Sharline; Sun, Joseph C

    2015-01-01

    Immunological memory is a hallmark of the adaptive immune system. Although natural killer (NK) cells have traditionally been classified as a component of the innate immune system, they have recently been shown in mice and humans to exhibit certain features of immunological memory, including an ability to undergo a clonal-like expansion during virus infection, generate long-lived progeny (i.e. memory cells), and mediate recall responses against previously encountered pathogens--all characteristics previously ascribed only to adaptive immune responses by B and T cells in mammals. To date, the molecular events that govern the generation of NK cell memory are not completely understood. Using a mouse model of cytomegalovirus infection, we demonstrate that individual pro-inflammatory IL-12, IL-18, and type I-IFN signaling pathways are indispensible and play non-redundant roles in the generation of virus-specific NK cell memory. Furthermore, we discovered that antigen-specific proliferation and protection by NK cells is mediated by the transcription factor Zbtb32, which is induced by pro-inflammatory cytokines and promotes a cell cycle program in activated NK cells. A greater understanding of the molecular mechanisms controlling NK cell responses will provide novel strategies for tailoring vaccines to target infectious disease.

  4. Neutrophil depletion impairs natural killer cell maturation, function, and homeostasis

    PubMed Central

    Jaeger, Baptiste N.; Donadieu, Jean; Cognet, Céline; Bernat, Claire; Ordoñez-Rueda, Diana; Barlogis, Vincent; Mahlaoui, Nizar; Fenis, Aurore; Narni-Mancinelli, Emilie; Beaupain, Blandine; Bellanné-Chantelot, Christine; Bajénoff, Marc; Malissen, Bernard; Malissen, Marie

    2012-01-01

    Natural killer (NK) cells are bone marrow (BM)–derived granular lymphocytes involved in immune defense against microbial infections and tumors. In an N-ethyl N-nitrosourea (ENU) mutagenesis strategy, we identified a mouse mutant with impaired NK cell reactivity both in vitro and in vivo. Dissection of this phenotype showed that mature neutrophils were required both in the BM and in the periphery for proper NK cell development. In mice lacking neutrophils, NK cells displayed hyperproliferation and poor survival and were blocked at an immature stage associated with hyporesponsiveness. The role of neutrophils as key regulators of NK cell functions was confirmed in patients with severe congenital neutropenia and autoimmune neutropenia. In addition to their direct antimicrobial activity, mature neutrophils are thus endowed with immunoregulatory functions that are conserved across species. These findings reveal novel types of cooperation between cells of the innate immune system and prompt examination of NK cell functional deficiency in patients suffering from neutropenia-associated diseases. PMID:22393124

  5. The DNA methylation profile of activated human natural killer cells.

    PubMed

    Wiencke, John K; Butler, Rondi; Hsuang, George; Eliot, Melissa; Kim, Stephanie; Sepulveda, Manuel A; Siegel, Derick; Houseman, E Andres; Kelsey, Karl T

    2016-05-03

    Natural killer (NK) cells are now recognized to exhibit characteristics akin to cells of the adaptive immune system. The generation of adaptive memory is linked to epigenetic reprogramming including alterations in DNA methylation. The study herein found reproducible genome wide DNA methylation changes associated with human NK cell activation. Activation led predominately to CpG hypomethylation (81% of significant loci). Bioinformatics analysis confirmed that non-coding and gene-associated differentially methylated sites (DMS) are enriched for immune related functions (i.e., immune cell activation). Known DNA methylation-regulated immune loci were also identified in activated NK cells (e.g., TNFA, LTA, IL13, CSF2). Twenty-one loci were designated high priority and further investigated as potential markers of NK activation. BHLHE40 was identified as a viable candidate for which a droplet digital PCR assay for demethylation was developed. The assay revealed high demethylation in activated NK cells and low demethylation in naïve NK, T- and B-cells. We conclude the NK cell methylome is plastic with potential for remodeling. The differentially methylated region signature of activated NKs revealed similarities with T cell activation, but also provided unique biomarker candidates of NK activation, which could be useful in epigenome-wide association studies to interrogate the role of NK subtypes in global methylation changes associated with exposures and/or disease states.

  6. The DNA methylation profile of activated human natural killer cells

    PubMed Central

    Wiencke, John. K.; Butler, Rondi; Hsuang, George; Eliot, Melissa; Kim, Stephanie; Sepulveda, Manuel A.; Siegel, Derick; Houseman, E. Andres; Kelsey, Karl T.

    2016-01-01

    ABSTRACT Natural killer (NK) cells are now recognized to exhibit characteristics akin to cells of the adaptive immune system. The generation of adaptive memory is linked to epigenetic reprogramming including alterations in DNA methylation. The study herein found reproducible genome wide DNA methylation changes associated with human NK cell activation. Activation led predominately to CpG hypomethylation (81% of significant loci). Bioinformatics analysis confirmed that non-coding and gene-associated differentially methylated sites (DMS) are enriched for immune related functions (i.e., immune cell activation). Known DNA methylation-regulated immune loci were also identified in activated NK cells (e.g., TNFA, LTA, IL13, CSF2). Twenty-one loci were designated high priority and further investigated as potential markers of NK activation. BHLHE40 was identified as a viable candidate for which a droplet digital PCR assay for demethylation was developed. The assay revealed high demethylation in activated NK cells and low demethylation in naïve NK, T- and B-cells. We conclude the NK cell methylome is plastic with potential for remodeling. The differentially methylated region signature of activated NKs revealed similarities with T cell activation, but also provided unique biomarker candidates of NK activation, which could be useful in epigenome-wide association studies to interrogate the role of NK subtypes in global methylation changes associated with exposures and/or disease states. PMID:26967308

  7. Natural killer cells in immunodefense against infective agents.

    PubMed

    Zucchini, Nicolas; Crozat, Karine; Baranek, Thomas; Robbins, Scott H; Altfeld, Marcus; Dalod, Marc

    2008-12-01

    Following the discovery of innate immune receptors, the topics of innate immunity and its role in defense against infective agents have recently blossomed into very active research fields, after several decades of neglect. Among innate immune cells, natural killer (NK) cells are endowed with the unique ability to recognize and kill cells infected with a variety of pathogens, irrespective of prior sensitization to these microbes. NK cells have a number of other functions, including cytokine production and immunoregulatory activities. Major advances have recently been made in the understanding of the role of NK cells in the physiopathology of infectious diseases. The cellular and molecular mechanisms regulating the acquisition of effector functions by NK cells and their triggering upon pathogenic encounters are being unraveled. The possibility that the power of NK cells could be harnessed for the design of innovative treatments against infections is a major incentive for biologists to further explore NK cell subset complexity and to identify the ligands that activate NK cell receptors.

  8. Immunotherapeutic strategies targeting Natural killer T cell responses in cancer

    PubMed Central

    Shissler, Susannah C.; Bollino, Dominique R.; Tiper, Irina V.; Bates, Joshua; Derakhshandeh, Roshanak; Webb, Tonya J.

    2017-01-01

    Natural killer T (NKT) cells are a unique subset of lymphocytes that bridge the innate and adaptive immune system. NKT cells possess a classic αβ T-cell receptor (TCR) that is able to recognize self and foreign glycolipid antigens presented by the nonclassical class I major histocompatibility complex (MHC) molecule, CD1d. Type I NKT cells (referred to as invariant NKT cells) express a semi-invariant Vα14Jα18 TCR in mice and Vα24Jα18 TCR in humans. Type II NKT cells are CD1d-restricted T cells that express a more diverse set of TCR α chains. The two types of NKT cells often exert opposing effects especially in tumor immunity, where Type II cells generally suppress tumor immunity while Type I NKT cells can enhance antitumor immune responses. In this review, we focus on the role of NKT cells in cancer. We discuss their effector and suppressive functions, as well as describe preclinical and clinical studies utilizing therapeutic strategies focused on harnessing their potent anti-tumor effector functions, and conclude with a discussion on potential next steps for the utilization of NKT cell targeted therapies for the treatment of cancer. PMID:27393665

  9. Targeting Cancer Stem Cells with Natural Killer Cell Immunotherapy.

    PubMed

    Luna, Jesus I; Grossenbacher, Steven K; Murphy, William J; Canter, Robert J

    2017-03-01

    Standard cytoreductive cancer therapy, such as chemotherapy and radiotherapy, are frequently resisted by a small portion of cancer cells with 'stem-cell' like properties including quiescence and repopulation. Immunotherapy represents a breakthrough modality for improving oncologic outcomes in cancer patients. Since the success of immunotherapy is not contingent on target cell proliferation, it may also be uniquely suited to address the problem of resistance and repopulation exerted by cancer stem cells (CSCs). Areas covered: Natural killer (NK) cells have long been known for their ability to reject allogeneic hematopoietic stem cells, and there are increasing data demonstrating that NK cells can selectively identify and lyse CSCs. The authors review the current knowledge of CSCs and NK cells and highlight recent studies that support the concept that NK cells are capable of targeting CSC in solid tumors, especially in the context of combination therapy simultaneously targeting non-CSCs and CSCs. Expert opinion: Unlike cytotoxic cancer treatments, NK cells can target and eliminate quiescent/non-proliferating cells such as CSCs, and these enigmatic cells are an important source of relapse and metastasis. NK targeting of CSCs represents a novel and potentially high impact method to capitalize on the intrinsic therapeutic potential of NK cells.

  10. Natural killer cell distribution and trafficking in human tissues

    PubMed Central

    Carrega, Paolo; Ferlazzo, Guido

    2012-01-01

    Few data are available regarding the recirculation of natural killer (NK) cells among human organs. Earlier studies have been often impaired by the use of markers then proved to be either not sufficiently specific for NK cells (e.g., CD57, CD56) or expressed only by subsets of NK cells (e.g., CD16). At the present, available data confirmed that human NK cells populate blood, lymphoid organs, lung, liver, uterus (during pregnancy), and gut. Several studies showed that NK cell homing appears to be subset-specific, as secondary lymphoid organs and probably several solid tissues are preferentially inhabited by CD56brightCD16neg/dull non-cytotoxic NK cells. Similar studies performed in the mouse model showed that lymph node and bone marrow are preferentially populated by CD11bdull NK cells while blood, spleen, and lung by CD27dull NK cells. Therefore, an important topic to be addressed in the human system is the contribution of factors that regulate NK cell tissue homing and egress, such as chemotactic receptors or homeostatic mechanisms. Here, we review the current knowledge on NK cell distribution in peripheral tissues and, based on recent acquisitions, we propose our view regarding the recirculation of NK cells in the human body. PMID:23230434

  11. Advantages and applications of CAR-expressing natural killer cells.

    PubMed

    Glienke, Wolfgang; Esser, Ruth; Priesner, Christoph; Suerth, Julia D; Schambach, Axel; Wels, Winfried S; Grez, Manuel; Kloess, Stephan; Arseniev, Lubomir; Koehl, Ulrike

    2015-01-01

    In contrast to donor T cells, natural killer (NK) cells are known to mediate anti-cancer effects without the risk of inducing graft-versus-host disease (GvHD). In order to improve cytotoxicity against resistant cancer cells, auspicious efforts have been made with chimeric antigen receptor (CAR) expressing T- and NK cells. These CAR-modified cells express antigen receptors against tumor-associated surface antigens, thus redirecting the effector cells and enhancing tumor-specific immunosurveillance. However, many cancer antigens are also expressed on healthy tissues, potentially leading to off tumor/on target toxicity by CAR-engineered cells. In order to control such potentially severe side effects, the insertion of suicide genes into CAR-modified effectors can provide a means for efficient depletion of these cells. While CAR-expressing T cells have entered successfully clinical trials, experience with CAR-engineered NK cells is mainly restricted to pre-clinical investigations and predominantly to NK cell lines. In this review we summarize the data on CAR expressing NK cells focusing on the possible advantage using these short-lived effector cells and discuss the necessity of suicide switches. Furthermore, we address the compliance of such modified NK cells with regulatory requirements as a new field in cellular immunotherapy.

  12. Uterine natural killer cells in patients with idiopathic recurrent miscarriage.

    PubMed

    Kuon, Ruben-J; Weber, Maja; Heger, Julia; Santillán, Isabel; Vomstein, Kilian; Bär, Christin; Strowitzki, Thomas; Markert, Udo R; Toth, Bettina

    2017-10-01

    Uterine natural killer (uNK) cells are major players during implantation and early pregnancy. The aim of our study was to analyze uNK cell concentration in the endometrium of idiopathic recurrent miscarriage (iRM) patients and fertile controls. Out of n=130 couples with ≥3 consecutive, clinical RM screened according to a standardized diagnostic protocol, n=58 patients with iRM were identified. Endometrial biopsies were investigated in patients and n=17 fertile women (controls) via immunohistochemistry. Compared to controls, the concentration of uNK cells was significantly higher in iRM patients (257±212 vs. 148±73 uNK cells/mm², P=.04). IRM patients showed a higher prevalence of >300 uNK cells/mm² than controls (34.5% vs. 5.9%, P=.02). In 88% of controls and 62% of iRM patients, uNK cells were detected within the range of 40-300/mm². Idiopathic recurrent miscarriage patients showed higher uNK cell levels than controls supporting the possible impact of uNK cells in the pathophysiology of miscarriage. Our cutoff levels might help to select RM patients which may benefit from immunomodulatory treatment. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. Mechanism of human natural killer cell activation by Haemophilus ducreyi.

    PubMed

    Li, Wei; Janowicz, Diane M; Fortney, Kate R; Katz, Barry P; Spinola, Stanley M

    2009-08-15

    The role of natural killer (NK) cells in the host response to Haemophilus ducreyi infection is unclear. In pustules obtained from infected human volunteers, there was an enrichment of CD56bright NK cells bearing the activation markers CD69 and HLA-DR, compared with peripheral blood. To study the mechanism by which H. ducreyi activated NK cells, we used peripheral blood mononuclear cells from uninfected volunteers. H. ducreyi activated NK cells only in the presence of antigen-presenting cells. H. ducreyi-infected monocytes and monocyte-derived macrophages activated NK cells in a contact- and interleukin-18 (IL-18)-dependent manner, whereas monocyte-derived dendritic cells induced NK activation through soluble IL-12. More lesional NK cells than peripheral blood NK cells produced IFN-gamma in response to IL-12 and IL-18. We conclude that NK cells are recruited to experimental lesions and likely are activated by infected macrophages and dendritic cells. IFN-gamma produced by lesional NK cells may facilitate phagocytosis of H. ducreyi.

  14. Newtonian cell interactions shape natural killer cell education.

    PubMed

    Goodridge, Jodie P; Önfelt, Björn; Malmberg, Karl-Johan

    2015-09-01

    Newton's third law of motion states that for every action on a physical object there is an equal and opposite reaction. The dynamic change in functional potential of natural killer (NK) cells during education bears many features of such classical mechanics. Cumulative physical interactions between cells, under a constant influence of homeostatic drivers of differentiation, lead to a reactive spectrum that ultimately shapes the functionality of each NK cell. Inhibitory signaling from an array of self-specific receptors appear not only to suppress self-reactivity but also aid in the persistence of effector functions over time, thereby allowing the cell to gradually build up a functional potential. Conversely, the frequent non-cytolytic interactions between normal cells in the absence of such inhibitory signaling result in continuous stimulation of the cells and attenuation of effector function. Although an innate cell, the degree to which the fate of the NK cell is predetermined versus its ability to adapt to its own environment can be revealed through a Newtonian view of NK cell education, one which is both chronological and dynamic. As such, the development of NK cell functional diversity is the product of qualitatively different physical interactions with host cells, rather than simply the sum of their signals or an imprint based on intrinsically different transcriptional programs.

  15. Activation strategies for invariant natural killer T cells.

    PubMed

    Kohlgruber, Ayano C; Donado, Carlos A; LaMarche, Nelson M; Brenner, Michael B; Brennan, Patrick J

    2016-08-01

    Invariant natural killer T (iNKT) cells are a specialized T cell subset that plays an important role in host defense, orchestrating both innate and adaptive immune effector responses against a variety of microbes. Specific microbial lipids and mammalian self lipids displayed by the antigen-presenting molecule CD1d can activate iNKT cells through their semi-invariant αβ T cell receptors (TCRs). iNKT cells also constitutively express receptors for inflammatory cytokines typically secreted by antigen-presenting cells (APCs) after recognition of pathogen-associated molecular patterns (PAMPs), and they can be activated through these cytokine receptors either in combination with TCR signals, or in some cases even in the absence of TCR signaling. During infection, experimental evidence suggests that both TCR-driven and cytokine-driven mechanisms contribute to iNKT cell activation. While the relative contributions of these two signaling mechanisms can vary widely depending on the infectious context, both lipid antigens and PAMPs mediate reciprocal activation of iNKT cells and APCs, leading to downstream activation of multiple other immune cell types to promote pathogen clearance. In this review, we discuss the mechanisms involved in iNKT cell activation during infection, focusing on the central contributions of both lipid antigens and PAMP-induced inflammatory cytokines, and highlight in vivo examples of activation during bacterial, viral, and fungal infections.

  16. Natural killer cells in immunodefense against infective agents

    PubMed Central

    Zucchini, Nicolas; Crozat, Karine; Baranek, Thomas; Robbins, Scott H; Altfeld, Marcus; Dalod, Marc

    2009-01-01

    Following the discovery of innate immune receptors, the topics of innate immunity and its role in defense against infective agents have recently blossomed into very active research fields, after several decades of neglect. Among innate immune cells, natural killer (NK) cells are endowed with the unique ability to recognize and kill cells infected with a variety of pathogens, irrespective of prior sensitization to these microbes. NK cells have a number of other functions, including cytokine production and immunoregulatory activities. Major advances have recently been made in the understanding of the role of NK cells in the physiopathology of infectious diseases. The cellular and molecular mechanisms regulating the acquisition of effector functions by NK cells and their triggering upon pathogenic encounters are being unraveled. The possibility that the power of NK cells could be harnessed for the design of innovative treatments against infections is a major incentive for biologists to further explore NK cell subset complexity and to identify the ligands that activate NK cell receptors. PMID:19053900

  17. Natural killer cell biology: an update and future directions.

    PubMed

    Campbell, Kerry S; Hasegawa, Jun

    2013-09-01

    Natural killer (NK) cells constitute a minor subset of normal lymphocytes that initiate innate immune responses toward tumor and virus-infected cells. They can mediate spontaneous cytotoxicity toward these abnormal cells and rapidly secrete numerous cytokines and chemokines to promote subsequent adaptive immune responses. Significant progress has been made in the past 2 decades to improve our understanding of NK cell biology. Here we review recent discoveries, including a better comprehension of the "education" of NK cells to achieve functional competence during their maturation and the discovery of "memory" responses by NK cells, suggesting that they might also contribute to adaptive immunity. The improved understanding of NK cell biology has forged greater awareness that these cells play integral early roles in immune responses. In addition, several promising clinical therapies have been used to exploit NK cell functions in treating patients with cancer. As our molecular understanding improves, these and future immunotherapies should continue to provide promising strategies to exploit the unique functions of NK cells to treat cancer, infections, and other pathologic conditions.

  18. Natural killer cell mediated cytotoxic responses in the Tasmanian devil.

    PubMed

    Brown, Gabriella K; Kreiss, Alexandre; Lyons, A Bruce; Woods, Gregory M

    2011-01-01

    The Tasmanian devil (Sarcophilus harrisii), the world's largest marsupial carnivore, is under threat of extinction following the emergence of an infectious cancer. Devil facial tumour disease (DFTD) is spread between Tasmanian devils during biting. The disease is consistently fatal and devils succumb without developing a protective immune response. The aim of this study was to determine if Tasmanian devils were capable of forming cytotoxic antitumour responses and develop antibodies against DFTD cells and foreign tumour cells. The two Tasmanian devils immunised with irradiated DFTD cells did not form cytotoxic or humoral responses against DFTD cells, even after multiple immunisations. However, following immunisation with xenogenic K562 cells, devils did produce cytotoxic responses and antibodies against this foreign tumour cell line. The cytotoxicity appeared to occur through the activity of natural killer (NK) cells in an antibody dependent manner. Classical NK cell responses, such as innate killing of DFTD and foreign cancer cells, were not observed. Cells with an NK-like phenotype comprised approximately 4 percent of peripheral blood mononuclear cells. The results of this study suggest that Tasmanian devils have NK cells with functional cytotoxic pathways. Although devil NK cells do not directly recognise DFTD cancer cells, the development of antibody dependent cell-mediated cytotoxicity presents a potential pathway to induce cytotoxic responses against the disease. These findings have positive implications for future DFTD vaccine research.

  19. Natural Killer Cell Mediated Cytotoxic Responses in the Tasmanian Devil

    PubMed Central

    Brown, Gabriella K.; Kreiss, Alexandre; Lyons, A. Bruce; Woods, Gregory M.

    2011-01-01

    The Tasmanian devil (Sarcophilus harrisii), the world's largest marsupial carnivore, is under threat of extinction following the emergence of an infectious cancer. Devil facial tumour disease (DFTD) is spread between Tasmanian devils during biting. The disease is consistently fatal and devils succumb without developing a protective immune response. The aim of this study was to determine if Tasmanian devils were capable of forming cytotoxic antitumour responses and develop antibodies against DFTD cells and foreign tumour cells. The two Tasmanian devils immunised with irradiated DFTD cells did not form cytotoxic or humoral responses against DFTD cells, even after multiple immunisations. However, following immunisation with xenogenic K562 cells, devils did produce cytotoxic responses and antibodies against this foreign tumour cell line. The cytotoxicity appeared to occur through the activity of natural killer (NK) cells in an antibody dependent manner. Classical NK cell responses, such as innate killing of DFTD and foreign cancer cells, were not observed. Cells with an NK-like phenotype comprised approximately 4 percent of peripheral blood mononuclear cells. The results of this study suggest that Tasmanian devils have NK cells with functional cytotoxic pathways. Although devil NK cells do not directly recognise DFTD cancer cells, the development of antibody dependent cell-mediated cytotoxicity presents a potential pathway to induce cytotoxic responses against the disease. These findings have positive implications for future DFTD vaccine research. PMID:21957452

  20. [Additive effect of marihuana and retrovirus in the anergy of natural killer cells in mice].

    PubMed

    Ongrádi, J; Specter, S; Horváth, A; Friedman, H

    1999-01-10

    Among the immunosuppressive effects of marijuana, impairment of natural killer cell activity is significant. HIV also inhibits these cells. Friend leukemia virus complex and its helper component Rowson-Parr virus induce early immunosuppression in mice resembling human AIDS, and late leukemia, providing a small animal AIDS model. Leukemia susceptible BALB/c and resistant C57BL/6 mice were infected with these viruses. At different time points, their natural killer cells separated from spleens were treated with 0 to 10 micrograms/ml tetrahydrocannabinol, subsequently mixed with Yac-1 target cells for 4 and 18 h. The natural killer cell activity in both mouse strains infected by either virus complex or helper virus weakened on days 2 to 4 postinfection, normalized by day 8 and enhanced on days 11 to 14. Natural killer cell activity upon the effect of low concentration (1.0 to 2.5 micrograms/ml) of tetrahydrocannabinol slightly increased in BALB/c, was unaffected in C57BL/6, especially in 18 h assays. In the combined effects of marijuana and retrovirus, damages by marijuana dominated over those of retroviruses. Inhibition or reactive enhancement of natural killer cell activity on the effect of viruses are similar to those of infected but marijuana-free counterparts, but on the level of uninfected cells treated with marijuana. The effects of marijuana and retrovirus are additive resulting in anergy of natural killer cells.

  1. Evolution of non-cytotoxic uterine natural killer cells.

    PubMed

    Kalkunte, Satyan; Chichester, Clinton O; Gotsch, Francesca; Sentman, Charles L; Romero, Roberto; Sharma, Surendra

    2008-05-01

    The immune tolerance and de novo vascularization are two highly intriguing processes at the maternal-fetal interface that appear to be central to normal pregnancy outcome. Immune tolerance occurs despite the local presence of an active maternal immune system including macrophages, dendritic cells and specialized CD56(bright)CD16(-) uterine natural killer (uNK) cells (65-70%). Recent observations indicate that the phenotypic and functional repertoire of uNK cells is distinct from peripheral blood NK and endometrial NK cells, challenging the understanding of their temporal occurrence and function. Origin and specialized programming of uNK cells continue to be debated. uNK cells, replete with an armamentarium to kill the foreign, tolerate the conceptus and facilitate pregnancy. Why do these uNK cells remain non-cytotoxic? Are these NK cells 'multitasking' in nature harboring beneficial and detrimental roles in pregnancy? Are there distinct subpopulations of NK cells that may populate the decidua? We propose that the endometrium/decidua functions as an 'inducible tertiary lymphoid tissue' that supports the recruitment and expansion of CD56(bright)CD16(-) NK cells and induces transcriptional up-regulation of angiogenic machinery in response to exposure to local hormonal factors, cytokine milieu and perhaps hypoxia. The angiogenic features of uNK cells could further result in a 'multitasking' phenotype that still remains to be characterized. This article discusses the factors and pathways that bridge the angiogenic and non-cytotoxic response machineries at the maternal-fetal interface.

  2. Frequency and phenotype of natural killer cells and natural killer cell subsets in bovine lymphoid compartments and blood.

    PubMed

    Hamilton, Carly A; Mahan, Suman; Bell, Charlotte R; Villarreal-Ramos, Bernardo; Charleston, Bryan; Entrican, Gary; Hope, Jayne C

    2017-05-01

    Natural killer (NK) cells are widely distributed in lymphoid and non-lymphoid tissues, but little is known about the recirculation of NK cells between blood and tissues. This is relevant to understanding recirculation in the steady-state and also for determining the roles for NK cells in vaccine-induced immunity and responses to infection. Therefore, the percentage of NK cells and their phenotype across peripheral blood, afferent lymph and lymph nodes in steady-state conditions was investigated in cattle using the pseudo-afferent lymphatic cannulation model. CD2(+) CD25(lo) NK cells were the predominant subset of NK cells within the blood. In contrast, CD2(-) CD25(hi) NK cells were the main subset present within the skin-draining afferent lymphatic vessels and lymph nodes, indicating that CD2(-) NK cells are the principal NK cell subset trafficking to lymph nodes via the afferent lymphatic vessel. Furthermore, a low percentage of NK cells were present in efferent lymph, which were predominantly of the CD2(-) subset, indicating that NK cells can egress from lymph nodes and return to circulation in steady-state conditions. These compartmentalization data indicate that NK cells represent a population of recirculating lymphocytes in steady-state conditions and therefore may be important during immune responses to vaccination or infection. © 2017 The Authors. Immunology Published by John Wiley & Sons Ltd.

  3. Functional impairment of natural killer cells in active ulcerative colitis: reversion of the defective natural killer activity by interleukin 2.

    PubMed Central

    Manzano, L; Alvarez-Mon, M; Abreu, L; Antonio Vargas, J; de la Morena, E; Corugedo, F; Duràntez, A

    1992-01-01

    We have studied the functional characteristics and clinical importance of the natural killer (NK) cytotoxicity of peripheral blood mononuclear cells (PBMNC) from patients with ulcerative colitis. Normal NK activity was observed in PBMNC from patients with inactive disease, but a pronounced decrease was found in those with active disease. Clinical change from active to inactive disease was associated with enhancement of the depressed NK activity. The impairment of NK cytotoxicity found in patients with active disese could not be ascribed to a deficient number of NK cells as the amounts of HNK-1+, CD16+ (Leu 11), and CD11b (OKM1) cells in PBMNC were within normal ranges. This defective cytotoxic PBMNC activity was normalised by short term (18 hour) incubation with recombinant interleukin 2 (rIL-2). Moreover, long term (5 day) incubation of these effector cells with rIL-2 induced strong cytotoxic activity against NK resistant and NK sensitive target cells in patients with active and inactive disease. We also found that both precursors and effectors of cytotoxic activity promoted by short term and long term incubation with rIL-2 of PBMNC from the patients showed the phenotype of NK cells (CD16+, CD3-). Taken together, these results show that active ulcerative colitis is associated with a defective function of NK cells that is found to be normal in the inactive stage of the disease. The possible pathogenic and therapeutic implications of these findings are discussed. PMID:1541421

  4. Regulation of Natural Killer Cell Function by STAT3

    PubMed Central

    Cacalano, Nicholas A.

    2016-01-01

    Natural killer (NK) cells, key members of a distinct hematopoietic lineage, innate lymphoid cells, are not only critical effectors that mediate cytotoxicity toward tumor and virally infected cells but also regulate inflammation, antigen presentation, and the adaptive immune response. It has been shown that NK cells can regulate the development and activation of many other components of the immune response, such as dendritic cells, which in turn, modulate the function of NK cells in multiple synergistic feed back loops driven by cell–cell contact, and the secretion of cytokines and chemokines that control effector function and migration of cells to sites of immune activation. The signal transducer and activator of transcription (STAT)-3 is involved in driving almost all of the pathways that control NK cytolytic activity as well as the reciprocal regulatory interactions between NK cells and other components of the immune system. In the context of tumor immunology, NK cells are a first line of defense that eliminates pre-cancerous and transformed cells early in the process of carcinogenesis, through a mechanism of “immune surveillance.” Even after tumors become established, NK cells are critical components of anticancer immunity: dysfunctional NK cells are often found in the peripheral blood of cancer patients, and the lack of NK cells in the tumor microenvironment often correlates to poor prognosis. The pathways and soluble factors activated in tumor-associated NK cells, cancer cells, and regulatory myeloid cells, which determine the outcome of cancer immunity, are all critically regulated by STAT3. Using the tumor microenvironment as a paradigm, we present here an overview of the research that has revealed fundamental mechanisms through which STAT3 regulates all aspects of NK cell biology, including NK development, activation, target cell killing, and fine tuning of the innate and adaptive immune responses. PMID:27148255

  5. Natural killer cell function in trisomy-21 (Down's syndrome).

    PubMed Central

    Nurmi, T; Huttunen, K; Lassila, O; Henttonen, M; Säkkinen, A; Linna, S L; Tiilikainen, A

    1982-01-01

    Natural killer (NK) activity and antibody-dependent cell mediated cytotoxicity (ADCC) against a human myeloid target cell line (K 562) was measured in adult patients with trisomy-21 (Down's syndrome) and in chromosomally normal age and sex matched control subjects. The effect of human leucocyte interferon (IFN-alpha) on the NK activity was also estimated. Spontaneous NK activity was stronger in the adult patients with trisomy-21 than in the healthy controls, but the difference did not reach statistical significance. The augmentation of NK activity by IFN-alpha, measured using lymphocytes not depleted of monocytes as effector cells, was statistically significant in both the trisomic patients (P less than 0.004) and the healthy controls (P less than 0.0005). Using monocyte and macrophage depleted lymphocytes in the patients with trisomy-21 the NK activity proved stronger than in the healthy controls, but not significantly and IFN-alpha did not augment it as it did in the healthy controls (P = n.s., P less than 0.05), for augmentations respectively). These results support the view that monocytes and macrophages are connected with the NK cell system. ADCC correlated with NK activity in both groups. Since NK cells are important components of many immune processes, including tumour and virus and/or bacteria-infected cell elimination, and have regulatory functions in immune reactions, the deficient augmentation of trisomic NK cells shown in vitro with extrinsic human leucocyte interferon may, paradoxically be an explanation for the greater susceptibility of trisomic individuals to lymphatic leukaemia and virus and bacterial infections. In vivo, this could be explained by the more potent secondary suppression by the 'immune' interferon produced by the virus, bacteria and malignant cells. In other words, the potential of the 'fighting couple' of the immune system, NK cell/interferon, is perhaps disturbed genetically due to the chromosome 21. PMID:6177458

  6. Emotional stability, anxiety, and natural killer activity under examination stress.

    PubMed

    Borella, P; Bargellini, A; Rovesti, S; Pinelli, M; Vivoli, R; Solfrini, V; Vivoli, G

    1999-08-01

    This study was performed to evaluate the relation between a stable personality trait, a mood state and immune response to an examination stress. A self-reported measure of emotional stability (BFQ-ES scale) was obtained in a sample (n = 39) randomly selected from 277 cadets; this personality trait was also investigated by completing a neuroticism scale (Eysenck personality inventory) and a trait-anxiety scale (STAI). Natural killer (NK) cell activity was measured at baseline, long before the examination time and the examination day. The state-anxiety scale evaluated the response to the stressful stimulus. Taking subjects all together, the academic task did not result in significant modification over baseline in NK cell activity. Subjects were then divided into three groups based on emotional stability and state-anxiety scores: high emotional stability/low anxiety, medium, and low emotional stability/high anxiety. Examination stress induced significant increases in NK cell activity in the high emotional stability/low anxiety group, no effect in the medium group, and significant decreases in the low emotional stability/high anxiety group. The repeated-measure ANOVA revealed a significant interaction of group x period (baseline vs. examination) for both lytic units and percent cytolysis. The results did not change after introducing coffee and smoking habits as covariates. Our findings suggest that the state-anxiety acts in concert with a stable personality trait to modulate NK response in healthy subjects exposed to a psychological naturalistic stress. The relation between anxiety and poor immune control has been already described, whereas the ability of emotional stability to associate with an immunoenhancement has not yet reported. The peculiarity of our population, a very homogeneous and healthy group for life style and habits, can have highlighted the role of emotional stability, and may account for the difference with other studies.

  7. Effects of murine natural killer cells on Cryptococcus neoformans

    SciTech Connect

    Nabavi Nouri, N.

    1985-01-01

    Previous data generated by Murphy and McDaniel indicate that normal murine nylon wool nonadherent splenic cells, with the characteristics of natural killer (NK) cells, effectively inhibit the in vitro growth of Cryptococcus neoformans, a yeast-like pathogen. Nylon wood nonadherent cells from spleens of 7-8 week old mice were further fractionated on discontinuous Percoll gradients. The enrichment of NK cells in Percoll fractions 1 and 2 was confirmed by morphological examination, immunofluorescent staining, and by assessing the cytolytic activity of each Percoll cell fraction against YAC-1 targets in the 4 h /sup 51/Cr release assay. Cells isolated from each Percoll fraction were tested for growth inhibitory activity against C neoformans, using an in vitro 18 h growth inhibition assay. The results showed that NK cell enrichment was concomitant with the enrichment of anti-cryptococcal activity the Percoll fractions 1 and 2. An immunolabeling method combined with scanning electron microscopy was used to demonstrate that the effector cells attached to C. neoformans were asialo GM/sub 1/ positive and, therefore, had NK cell characteristics. NK cells have Fc receptors on their surfaces , and are capable of antibody-dependent cell-mediated cytotoxicity (ADCC) against IgG-coated target cells. The author examined the effects of the IgG fraction of rabbit anti-cryptococcal antibody on the NK cell-mediated growth inhibition of C. neoformans. The data indicated that the effector cells involved in antibody-dependent growth inhibition of cryptococci are either NK cells or copurify and coexist in the same population with NK cells.

  8. Heterogeneity of natural killer cells in the mouse

    SciTech Connect

    Lust, J.A.; Kumar, V.; Burton, R.C.; Bartlett, S.P.; Bennett, M.

    1981-08-01

    Mice were treated with the bone-seeking isotope, 89Sr, cyclophosphamide, and short-term lethal irradiation in vivo, and murine spleen cells are treated with anti-Nk-1.2 plus complement (C) in vitro. Fresh spleen cell suspensions from the above groups and from beige and neonatal mice were subsequently tested for natural killer (NK) cell activity against a panel of lymphoid and nonlymphoid tumor cell target. NK cell reactivities against YAC-1, MPC-11, and Cl.18 tumors were markedly and consistently reduced in (a) mice treated with 89Sr, (b) spleen cells treated with anti-Nk-1.2 plus C, and (c) C57BL/6 bg/bg mice. In contrast, NK activities against FLD-3 and WEHI-164.1 tumors were usually normal in mice treated with 89Sr, in beige mutant mice, and in spleen cells after treatment with anti-Nk-1.2 antibody and C. It appears, therefore, that two major groups of NK cells exist in fresh mouse spleen cells suspensions. NK-A cells are marrow dependent, Nk antigen positive, and deficient in beige mice; these lyse YAC-1, MPC-11, and Cl.18 tumors. NK-B cells, which are responsible for the lysis of WEHI-164.1 and FLD-3, are Nk antigen negative, marrow independent, and unaffected by the bg/bg mutation. Other features of NK-B cells, suggest that these NK cells, although they share the characteristics mentioned above, differ among themselves especially with respect to age of maturation and susceptibility to cyclophosphamide and total body irradiation. The NK-B group may therefore induce subsets that remain to be defined.

  9. Granule-Dependent Natural Killer Cell Cytotoxicity to Fungal Pathogens

    PubMed Central

    Ogbomo, Henry; Mody, Christopher H.

    2017-01-01

    Natural killer (NK) cells kill or inhibit the growth of a number of fungi including Cryptococcus, Candida, Aspergillus, Rhizopus, and Paracoccidioides. Although many fungi are not dangerous, invasive fungal pathogens, such as Cryptococcus neoformans, cause life-threatening disease in individuals with impaired cell-mediated immunity. While there are similarities to cell-mediated killing of tumor cells, there are also important differences. Similar to tumor killing, NK cells directly kill fungi in a receptor-mediated and cytotoxic granule-dependent manner. Unlike tumor cell killing where multiple NK cell-activating receptors cooperate and signal events that mediate cytotoxicity, only the NKp30 receptor has been described to mediate signaling events that trigger the NK cell to mobilize its cytolytic payload to the site of interaction with C. neoformans and Candida albicans, subsequently leading to granule exocytosis and fungal killing. More recently, the NKp46 receptor was reported to bind Candida glabrata adhesins Epa1, 6, and 7 and directly mediate fungal clearance. A number of unanswered questions remain. For example, is only one NK cell-activating receptor sufficient for signaling leading to fungal killing? Are the signaling pathways activated by fungi similar to those activated by tumor cells during NK cell killing? How do the cytolytic granules traffic to the site of interaction with fungi, and how does this process compare with tumor killing? Recent insights into receptor use, intracellular signaling and cytolytic granule trafficking during NK cell-mediated fungal killing will be compared to tumor killing, and the implications for therapeutic approaches will be discussed. PMID:28123389

  10. In vitro Natural Killer Cell Immunotherapy for Medulloblastoma

    PubMed Central

    Fernández, Lucia; Portugal, Raquel; Valentín, Jaime; Martín, Roberto; Maxwell, Hannah; González-Vicent, Marta; Díaz, Miguel Ángel; de Prada, Inmaculada; Pérez-Martínez, Antonio

    2013-01-01

    How the immune system attacks medulloblastoma (MB) tumors effectively is unclear, although natural killer (NK) cells play an important role in immune defense against tumor cells. Interactions between receptors on NK cells and ligands expressed by tumor cells are critical for tumor control by immunotherapy. In this study, we analyzed tumor samples from 54 MB patients for expression of major histocompatibility complex class I-related chains A (MICA) and UL16 binding protein (ULPB-2), which are ligands for the NK group 2 member D activatory receptor (NKG2D). The percentage of MICA and ULBP-2 positive cells was higher than 25% in 68% and 6% of MB patients, respectively. A moderate-high intensity of MICA cytoplasmic staining was observed in 46% MB patients and weak ULBP-2 staining was observed in 8% MB patients. No correlation between MICA/ULBP-2 expression and patient outcome was found. We observed that HTB-186, a MB cell line, was moderately resistant to NK cell cytotoxicity in vitro. Blocking MICA/ULBP-2 on HTB-186, and NKG2D receptor on NK cells increased resistance to NK cell lysis in vitro. However, HLA class I blocking on HTB-186 and overnight incubation with IL-15 stimulated NK cells efficiently killed tumor cells in vitro. We conclude that although NKG2D/MICA-ULBP-2 interactions have a role in NK cell cytotoxicity against MB, high expression of HLA class I can protect MB from NK cell cytotoxicity. Even so, our in vitro data indicate that if NK cells are appropriately stimulated, they may have the potential to target MB in vivo. PMID:23626949

  11. Role of Natural Killer Cells in HIV-Associated Malignancies

    PubMed Central

    Leal, Fabio E.; Premeaux, Thomas A.; Abdel-Mohsen, Mohamed; Ndhlovu, Lishomwa C.

    2017-01-01

    Now in its fourth decade, the burden of HIV disease still persists, despite significant milestone achievements in HIV prevention, diagnosis, treatment, care, and support. Even with long-term use of currently available antiretroviral therapies (ARTs), eradication of HIV remains elusive and now poses a unique set of challenges for the HIV-infected individual. The occurrence of HIV-associated non-AIDS-related comorbidities outside the scope of AIDS-defining illnesses, in particular non-AIDS-defining cancers, is much greater than the age-matched uninfected population. The underlying mechanism is now recognized in part to be related to the immune dysregulated and inflammatory status characteristic of HIV infection that persists despite ART. Natural killer (NK) cells are multifunctional effector immune cells that play a critical role in shaping the innate immune responses to viral infections and cancer. NK cells can modulate the adaptive immune response via their role in dendritic cell (DC) maturation, removal of immature tolerogenic DCs, and their ability to produce immunoregulatory cytokines. NK cells are therefore poised as attractive therapeutic targets that can be harnessed to control or clear both HIV and HIV-associated malignancies. To date, features of the tumor microenvironment and the evolution of NK-cell function among individuals with HIV-related malignancies remain unclear and may be distinct from malignancies observed in uninfected persons. This review intends to uncouple anti-HIV and antitumor NK-cell features that can be manipulated to halt the evolution of HIV disease and HIV-associated malignancies and serve as potential preventative and curative immunotherapeutic options. PMID:28377768

  12. Ozone exposed epithelial cells modify cocultured natural killer cells

    PubMed Central

    Müller, Loretta; Brighton, Luisa E.

    2013-01-01

    Ozone (O3) causes significant adverse health effects worldwide. Nasal epithelial cells (NECs) are among the first sites within the respiratory system to be exposed to inhaled air pollutants. They recruit, activate, and interact with immune cells via soluble mediators and direct cell-cell contacts. Based on our recent observation demonstrating the presence of natural killer (NK) cells in nasal lavages, the goal of this study was to establish a coculture model of NECs and NK cells and examine how exposure to O3 modifies this interaction. Flow cytometry analysis was used to assess immunophenotypes of NK cells cocultured with either air- or O3-exposed NECs. Our data show that coculturing NK cells with O3-exposed NECs decreased intracellular interferon-γ (IFN-γ), enhanced, albeit not statistically significant, IL-4, and increased CD16 expression on NK cells compared with air controls. Additionally, the cytotoxicity potential of NK cells was reduced after coculturing with O3-exposed NECs. To determine whether soluble mediators released by O3-exposed NECs caused this shift, apical and basolateral supernatants of air- and O3-exposed NECs were used to stimulate NK cells. While the conditioned media of O3-exposed NECs alone did not reduce intracellular IFN-γ, O3 enhanced the expression of NK cell ligands ULBP3 and MICA/B on NECs. Blocking ULBP3 and MICA/B reversed the effects of O3-exposed NECs on IFN-γ production in NK cells. Taken together, these data showed that interactions between NECs and NK cells in the context of O3 exposure changes NK cell activity via direct cell-cell interactions and is dependent on ULBP3/MICA/B expressed on NECs. PMID:23241529

  13. Analysis of uterine natural killer cells in mice.

    PubMed

    Croy, B Anne; Zhang, Jianhong; Tayade, Chandrakant; Colucci, Francesco; Yadi, Hakim; Yamada, Aureo T

    2010-01-01

    The term uterine natural killer (uNK) cell is applied in mice to an abundant but transient NK cell population that undergoes unique, terminal differentiation within embryo implantation sites during endometrial decidualization and pregnancy. In mice, decidualization is induced by attachment and implantation of hatched, blastocyst-stage embryos. Within each implantation site, uNK cells proliferate and rapidly differentiate into highly restricted regions called decidua basalis and the mesometrial lymphoid aggregate of pregnancy (MLAp). uNK cells begin to die within healthy decidua basalis by day 8 of the 19-20 day pregnancy of mice. By gestation day 12, uNK cell numbers have peaked and most uNK cells show in situ nuclear fragmentation indicative of disintegration. Morphological studies (standard histology, ultrastructure, immunohistochemistry, in situ hybridization, and RNA analyses from laser capture microdissected uNK cells) have provided most of the current understanding regarding this cell lineage. These approaches identified the special angiogenic properties of uNK cells and their regulatory relationships with normal physiological changes to the uterine (endometrial) arterial tree that accompany successful pregnancy. This chapter highlights key information needed for successful dissection of the dynamically changing decidua basalis that is enriched in uNK cells and special morphological procedures used for uNK cell study. Preparation of viable mouse uNK cell suspensions is difficult but can be achieved. This chapter includes techniques for isolation of uterine leukocyte suspensions and their enrichment for uNK cells that permit immediate downstream applications such as culture, isolation of high quality RNA, or flow cytometry.

  14. Are natural killer cells protecting the metabolically healthy obese patient?

    PubMed

    Lynch, Lydia A; O'Connell, Jean M; Kwasnik, Anna K; Cawood, Thomas J; O'Farrelly, Cliona; O'Shea, Donal B

    2009-03-01

    With the emerging obesity pandemic, identifying those who appear to be protected from adverse consequences such as type 2 diabetes and certain malignancies will become important. We propose that the circulating immune system plays a role in the development of these comorbidities. Clinical data and blood samples were collected from 52 patients with severe obesity attending a hospital weight-management clinic and 11 lean healthy controls. Patients were classified into metabolically "healthy obese" (n = 26; mean age 42.6 years, mean BMI 46.8 kg/m(2)) or "unhealthy obese" (n = 26; mean age 45 years, mean BMI 47.5 kg/m(2)) groups, based upon standard cutoff points for blood pressure, lipid profile, and fasting glucose. Circulating lymphoid populations and phenotypes were assessed by flow cytometry. Obese patients had significantly less circulating natural killer (NK) and cytotoxic T lymphocytes (CTL) compared to lean controls. There were significantly higher levels of NK cells and CTLs in the healthy obese group compared to the unhealthy obese group (NK: 11.7% vs. 6.5%, P < 0.0001, CD8 13.4% vs. 9.3%, P = 0.04), independent of age and BMI and these NK cells were also less activated in the healthy compared to the unhealthy group (CD69, 4.1% vs. 11.8%, P = 0.03). This is the first time that quantitative differences in the circulating immune system of obese patients with similar BMI but different metabolic profiles have been described. The significantly higher levels of CTLs and NK cells, which express fewer inhibitory molecules, could protect against malignancy, infection, and metabolic disease seen in obesity.

  15. Decidual Cell Regulation of Natural Killer Cell–Recruiting Chemokines

    PubMed Central

    Lockwood, Charles J.; Huang, S. Joseph; Chen, Chie-Pein; Huang, Yingqun; Xu, Jie; Faramarzi, Saeed; Kayisli, Ozlem; Kayisli, Umit; Koopman, Louise; Smedts, Dineke; Buchwalder, Lynn F.; Schatz, Frederick

    2014-01-01

    First trimester human decidua is composed of decidual cells, CD56brightCD16− decidual natural killer (dNK) cells, and macrophages. Decidual cells incubated with NK cell–derived IFN-γ and either macrophage-derived TNF-α or IL-1β synergistically enhanced mRNA and protein expression of IP-10 and I-TAC. Both chemokines recruit CXCR3-expressing NK cells. This synergy required IFN-γ receptor 1 and 2 mediation via JAK/STAT and NFκB signaling pathways. However, synergy was not observed on neutrophil, monocyte, and NK cell–recruiting chemokines. Immunostaining of first trimester decidua localized IP-10, I-TAC, IFN-γR1, and -R2 to vimentin-positive decidual cells versus cytokeratin-positive interstitial trophoblasts. Flow cytometry identified high CXCR3 levels on dNK cells and minority peripheral CD56brightCD16− pNK cells and intermediate CXCR3 levels on the majority of CD56dimCD16+ pNK cells. Incubation of pNK cells with either IP-10 or I-TAC elicited concentration-dependent enhanced CXCR3 levels and migration of both pNK cell subsets that peaked at 10 ng/mL, whereas each chemokine at a concentration of 50 ng/mL inhibited CXCR3 expression and pNK cell migration. Deciduae from women with preeclampsia, a leading cause of maternal and fetal morbidity and mortality, displayed significantly lower dNK cell numbers and higher IP-10 and I-TAC levels versus gestational age–matched controls. Significantly elevated IP-10 levels in first trimester sera from women eventually developing preeclampsia compared with controls, identifying IP-10 as a novel, robust early predictor of preeclampsia. PMID:23973270

  16. Immunosenescence: limitations of natural killer cell-based cancer immunotherapy.

    PubMed

    Tarazona, Raquel; Sanchez-Correa, Beatriz; Casas-Avilés, Ignacio; Campos, Carmen; Pera, Alejandra; Morgado, Sara; López-Sejas, Nelson; Hassouneh, Fakhri; Bergua, Juan M; Arcos, Maria Jose; Bañas, Helena; Casado, Javier G; Durán, Esther; Labella, Fernando; Solana, Rafael

    2017-02-01

    Cancer is primarily considered a disease of old age. Immunosenescence refers to the age-associated changes in the immune system, and its contribution to the increased risk of cancer in old individuals has been discussed for many years. Natural killer (NK) cells are cytotoxic innate immune cells specialized in defence against tumour and virus-infected cells. NK cell cytotoxicity is the result of a fine balance between activating and inhibitory receptors. Several activating receptors have been identified that recognize different ligands frequently found over-expressed on tumour cells or virus-infected cells. The most important NK cell inhibitory receptors interact with major histocompatibility complex class I molecules expressed on almost all nucleated cells preventing NK cell-mediated lysis of healthy cells. NK cell immunosenescence is characterized by a redistribution of NK cell subsets, a diminished expression of several activating receptors and lower per-cell cytotoxicity. Altered expression of activating receptors has also been described in young and elderly cancer patients probably due to chronic exposure to ligands on tumour cells. Thus, the effect of both age and cancer may act synergistically to diminish NK cell-mediated tumour immunosurveillance. Different strategies harnessing the power of NK cells to target tumour cells have been designed including adoptive therapy with autologous or allogeneic expanded NK cells. In addition, checkpoint blockade of inhibitory receptors and the use of agonist antibodies to stimulate activating receptors are emerging areas of research. In this context, the effect of immunosenescence should be considered to improve the efficiency of cancer immunotherapy.

  17. Cardif (MAVS) Regulates the Maturation of Natural Killer Cells

    PubMed Central

    Haynes, LaTeira D.; Verma, Shilpi; McDonald, Bryan; Wu, Runpei; Tacke, Robert; Ekstein, Jennifer; Feuvrier, Ariana; Benedict, Chris A.; Hedrick, Catherine C.

    2015-01-01

    Cardif, also known as IPS-1, VISA and, MAVS, is an intracellular adaptor protein that functions downstream of the RIG-I family of pattern recognition receptors. Cardif is required for the production of type I-IFNs and other inflammatory cytokines after RIG-I like receptors recognize intracellular antigenic RNA. Studies have recently shown that Cardif may have other roles in the immune system in addition to its role in viral immunity. In this study, we find that the absence of Cardif alters normal natural killer cell development and maturation. Cardif−/− mice have a 35% loss of mature CD27−CD11b+ NK cells in the periphery. Additionally, Cardif−/− NK cells have altered surface marker expression, lower cytoxicity, decreased intracellular STAT1 levels, increased apoptosis and decreased proliferation compared to wild-type NK cells. Mixed chimeric mice revealed that the defective maturation and increased apoptotic rate of peripheral Cardif−/− NK cells is cell-intrinsic. However, Cardif−/− mice showed enhanced control of mouse cytomegalovirus (MCMV, a DNA β-herpesvirus) by NK cells, commensurate with increased activation and IFNγ production by these immature NK cell subsets. These results indicate that the skewed differentiation and altered STAT expression of Cardif−/− NK cells can result in their hyper-responsiveness in some settings, and support recent findings that Cardif-dependent signaling can regulate aspects of immune cell development and/or function distinct from its well characterized role in mediating cell-intrinsic defense to RNA viruses. PMID:26232430

  18. Emerging role of Natural killer cells in oncolytic virotherapy.

    PubMed

    Bhat, Rauf; Rommelaere, Jean

    2015-01-01

    Natural killer (NK) cells constitute a subtype of lymphocytes that initiate innate immune responses against tumors and virus-infected cells. The ability of NK cells to kill target cells or to produce cytokines depends on the balance between signals from activating and inhibitory cell-surface receptors. Therapies with NK cells involve activation of endogenous NK cells and/or exogenous transfer by hematopoietic stem cell transplantation/adoptive cell therapy. To exploit the diverse functional abilities of NK cells for cancer immunotherapy, it is important to understand NK cell biology and the underlying regulatory mechanisms. The state of immune suppression prevalent in malignancies creates the need for innovative therapies. Oncolytic viruses are novel anticancer agents showing selective tropism for tumor cells and lacking pathogenicity in humans, but the use of oncolytic virotherapy (OVT) presents multiple challenges. An increasing body of evidence suggests that the host immune response may critically influence the outcome of OVT. Classically, the immune system is thought to limit the efficacy of therapy through virus clearance mediated by innate immune effectors or through adaptive antiviral immune responses eliminating infected cells. Effective strategies do need to be designed in OVT to circumvent the early antiviral activity of NK cells and to augment late NK-cell-mediated antitumor responses. The intrinsic immunostimulating capacity of oncolytic viruses and the possibility of engineering them to express heterologous immunostimulatory molecules (eg, cytokines) support the use of these agents to enhance antitumor immune responses besides inducing direct oncolytic effects. OVT has indeed shown promising therapeutic outcomes in various clinical trials. Here, we review the biology of NK cells, strategies involving NK cells for achieving cancer therapy, and, more particularly, the emerging role of NK cells in OVT.

  19. STAT4-associated natural killer cell tolerance following liver transplantation

    PubMed Central

    Jamil, K M; Hydes, T J; Cheent, K S; Cassidy, S A; Traherne, J A; Jayaraman, J; Trowsdale, J; Alexander, G J; Little, A-M; McFarlane, H; Heneghan, M A; Purbhoo, M A; Khakoo, S I

    2017-01-01

    Objective Natural killer (NK) cells are important mediators of liver inflammation in chronic liver disease. The aim of this study was to investigate why liver transplants (LTs) are not rejected by NK cells in the absence of human leukocyte antigen (HLA) matching, and to identify a tolerogenic NK cell phenotype. Design Phenotypic and functional analyses on NK cells from 54 LT recipients were performed, and comparisons made with healthy controls. Further investigation was performed using gene expression analysis and donor:recipient HLA typing. Results NK cells from non-HCV LT recipients were hypofunctional, with reduced expression of NKp46 (p<0.05) and NKp30 (p<0.001), reduced cytotoxicity (p<0.001) and interferon (IFN)-γ secretion (p<0.025). There was no segregation of this effect with HLA-C, and these functional changes were not observed in individuals with HCV. Microarray and RT-qPCR analysis demonstrated downregulation of STAT4 in NK cells from LT recipients (p<0.0001). Changes in the expression levels of the transcription factors Helios (p=0.06) and Hobit (p=0.07), which control NKp46 and IFNγ expression, respectively, were also detected. Hypofunctionality of NK cells was associated with impaired STAT4 phosphorylation and downregulation of the STAT4 target microRNA-155. Conversely in HCV-LT NK cell tolerance was reversed, consistent with the more aggressive outcome of LT for HCV. Conclusions LT is associated with transcriptional and functional changes in NK cells, resulting in reduced activation. NK cell tolerance occurs upstream of major histocompatibility complex (MHC) class I mediated education, and is associated with deficient STAT4 phosphorylation. STAT4 therefore represents a potential therapeutic target to induce NK cell tolerance in liver disease. PMID:26887815

  20. Emerging role of Natural killer cells in oncolytic virotherapy

    PubMed Central

    Bhat, Rauf; Rommelaere, Jean

    2015-01-01

    Natural killer (NK) cells constitute a subtype of lymphocytes that initiate innate immune responses against tumors and virus-infected cells. The ability of NK cells to kill target cells or to produce cytokines depends on the balance between signals from activating and inhibitory cell-surface receptors. Therapies with NK cells involve activation of endogenous NK cells and/or exogenous transfer by hematopoietic stem cell transplantation/adoptive cell therapy. To exploit the diverse functional abilities of NK cells for cancer immunotherapy, it is important to understand NK cell biology and the underlying regulatory mechanisms. The state of immune suppression prevalent in malignancies creates the need for innovative therapies. Oncolytic viruses are novel anticancer agents showing selective tropism for tumor cells and lacking pathogenicity in humans, but the use of oncolytic virotherapy (OVT) presents multiple challenges. An increasing body of evidence suggests that the host immune response may critically influence the outcome of OVT. Classically, the immune system is thought to limit the efficacy of therapy through virus clearance mediated by innate immune effectors or through adaptive antiviral immune responses eliminating infected cells. Effective strategies do need to be designed in OVT to circumvent the early antiviral activity of NK cells and to augment late NK-cell-mediated antitumor responses. The intrinsic immunostimulating capacity of oncolytic viruses and the possibility of engineering them to express heterologous immunostimulatory molecules (eg, cytokines) support the use of these agents to enhance antitumor immune responses besides inducing direct oncolytic effects. OVT has indeed shown promising therapeutic outcomes in various clinical trials. Here, we review the biology of NK cells, strategies involving NK cells for achieving cancer therapy, and, more particularly, the emerging role of NK cells in OVT. PMID:27471713

  1. Acquisition of enhanced natural killer cell activity under anesthesia.

    PubMed

    Hsueh, C M; Lorden, J F; Hiramoto, R N; Ghanta, V K

    1992-01-01

    An increase in natural killer (NK) cell activity can be conditioned with a one trial learning paradigm to demonstrate the interaction between the central nervous system (CNS) and the immune system. In order to demonstrate learning possibilities during 'non-conscious' state, mice were anesthetized with a ketamin/rompun mixture and underwent one trial learning with odor cue as the conditioned stimulus (CS) preceding the unconditioned stimulus (US). The results indicated that mice that were exposed to camphor odor cue under the influence of anesthesia can associate the signal with the poly I:C unconditioned stimulus and were able to recall the conditioned response upon reexposure to the CS. Secondly, the conditioned association made in a conscious state can be recalled by exposure to the same olfactory odor cue in a 'non-conscious' state. The increase in the conditioned change in NK cell activity of both situations was significantly higher than the control group. The results demonstrate that learning can take place and the learned response can be recalled under the reduced awareness caused by anesthesia. The findings we report are unusual and novel in that they demonstrate that the CNS can learn new associations under conditions where the host is apparently unaware of the signals being linked. Anesthesia combined with the long interstimulus interval indicates that certain neuronal pathways in the CNS are receptive to second signals (elicited by the US) even when the second signal is separated by one day. This means the conditioned learning of a physiological response can take place unconsciously at a separate level and under situations where the host is totally unaware of the events which the brain is processing and linking as incoming information.

  2. Psychosocial resources, aging, and natural killer cell terminal maturity

    PubMed Central

    Segerstrom, Suzanne C.; Al-Attar, Ahmad; Lutz, Charles T.

    2012-01-01

    Psychosocial factors may influence aspects of immunological aging. The present study tested the hypothesis that psychosocial resources correlate with the expression of the cell surface maker CD57 on natural killer (NK) immune cells. CD57 is a marker of terminal maturation and senescence in this cell subset. The study further tested the relative contribution of specific resources in the social, psychological, financial, and status-skill domains, given the potential differential value of different resources for younger and older adults, and the contribution of relative vs. absolute resources. Younger (N=38) and older (N=34) women completed measures of relative and absolute resources and had blood drawn. Examined both between groups and within the older women, older age and fewer total relative resources were associated with more CD57 expression on NK cells. One SD in resources was the equivalent of 5 years of aging among the older women. Among the specific resource types, a preponderance of financial resources, both relative and absolute, was associated with less CD57 expression on NK cells, and these relationships did not significantly vary between younger and older women. There was no evidence that depressive symptoms mediated the effects of resources on CD57 expression on NK cells. These findings provide support for the hypothesis that the sense that one has substantial resources, particular with regard to finances and possessions, may retard age-associated aspects of the microenvironment in which NK cells develop and mature, independent of effects on distress, and this process may begin in younger adulthood. PMID:22708535

  3. Potassium channels mediate killing by human natural killer cells

    SciTech Connect

    Schlichter, L.; Sidell N.; Hagiwara, S.

    1986-01-01

    Human natural killer (NK) cells in peripheral blood spontaneously recognize and kill a wide variety of target cells. It has been suggested that ion channels are involved in the killing process because there is a Ca-dependent stage and because killing by presensitized cytotoxic T lymphocytes, which in many respects resembles NK killing, is associated with changes in K and Na transport in the target cell. Using the whole-cell variation of the patch-clamp technique, the authors found a voltage-dependent potassium (K/sup +/) current in NK cells. The K/sup +/ current was reduced in a dose-dependent manner by the K-channel blockers 4-aminopyridine and quinidine and by the traditional Ca-channel blockers verapamil and Cd/sup 2 +/. They tested the effects of ion-channel blockers on killing of two commonly used target cell lines: K562, which is derived from a human myeloid leukemia, and U937, which is derived from a human histiocytic leukemia. Killing of K562 target cells, determined in a standard /sup 51/Cr-release assay, was inhibited in a dose-dependent manner by verapamil, quinidine, Cd/sup 2 +/, and 4-aminopyridine at concentrations comparable to those that blocked the K/sup +/ current in NK cells. In K562 target cells only a voltage-dependent Na= current was found and it was blocked by concentrations of tetrodotoxin that had no effect on killing. Killing of U937 target cells was also inhibited by the two ion-channel blockers tested, quinidine and verapamil. In this cell line only a small K/sup +/ current was found that was similar to the one in NK cells. The findings show that there are K channels in NK cells and that these channels play a necessary role in the killing process.

  4. Stress, Coping, and Infectious Illness: Persistently Low Natural Killer Cell Activity as a Host Risk Factor.

    DTIC Science & Technology

    1988-03-14

    Persistently Low Natural Killer Cell Activity as a Host Risk Factor " 12 PERSONAL AUTHOR(S) Sandra M. Levy, Ph.D., Ronald B. Herberman, M.D., Theresa...killer (NK) cell activity. In this prevbus work, a subgroup of individuals characterized by persistently low NK activity, and self-reported depression and... depression and chronic anxiety. In a very preliminary fashion, we have also found a trend of association between this low NK activity pattern, and some

  5. Statins inhibit proliferation and cytotoxicity of a human leukemic natural killer cell line

    PubMed Central

    2013-01-01

    Background Natural killer cells comprise the body’s first line of defense against virus-infected cells. As is true of all lymphocytes, natural killer cell malignancies can develop, however natural killer cell leukemias can be very difficult to treat due to their intrinsic resistance to chemotherapeutic agents. With the recent understanding that statin drugs may have anti-cancer properties, our investigations have focused on the ability of statins to inhibit the growth and cytotoxicity of the YT-INDY natural killer cell leukemia cell line. Results Our findings indicate that several statin compounds can inhibit YT-INDY proliferation disrupt cell cycle progression and abrogate natural killer cell cytotoxicity. Since natural killer cell leukemia cytotoxicity may play a role in the pulmonary damage seen in these patients, this is an important finding. Cytotoxicity, proliferation and cell cycle progression could be restored by the addition of mevalonate, signifying that the statin effects are brought about through HMG CoA reductase inhibition. The mevalonate pathway intermediate geranylgeranyl pyrophosphate, but not other intermediates in the mevalonate pathway, partially reversed statin-induced inhibition of YT-INDY proliferation and cytotoxicity. These results suggest that blockage of products made in the latter part of the mevalonate pathway may account for the observed inhibitory effects on YT-INDY proliferation and cytotoxicity. However, geranylgeranyl pyrophosphate could not reverse the statin-induced inhibition of the cell cycle. Conclusions These results suggest that the statin drugs should be investigated as a potential therapeutic strategy for human natural killer cell leukemias possibly in combination with chemotherapeutic agents. PMID:24359683

  6. Chromatin organization as an indicator of glucocorticoid induced natural killer cell dysfunction.

    PubMed

    Misale, Michael S; Witek Janusek, Linda; Tell, Dina; Mathews, Herbert L

    2017-09-12

    It is well-established that psychological distress reduces natural killer cell immune function and that this reduction can be due to the stress-induced release of glucocorticoids. Glucocorticoids are known to alter epigenetic marks associated with immune effector loci, and are also known to influence chromatin organization. The purpose of this investigation was to assess the effect of glucocorticoids on natural killer cell chromatin organization and to determine the relationship of chromatin organization to natural killer cell effector function, e.g. interferon gamma production. Interferon gamma production is the prototypic cytokine produced by natural killer cells and is known to modulate both innate and adaptive immunity. Glucocorticoid treatment of human peripheral blood mononuclear cells resulted in a significant reduction in interferon gamma production. Glucocorticoid treatment also resulted in a demonstrable natural killer cell nuclear phenotype. This phenotype was localization of the histone, post-translational epigenetic mark, H3K27me3, to the nuclear periphery. Peripheral nuclear localization of H3K27me3 was directly related to cellular levels of interferon gamma. This nuclear phenotype was determined by direct visual inspection and by use of an automated, high through-put technology, the Amnis ImageStream. This technology combines the per-cell information content provided by standard microscopy with the statistical significance afforded by large sample sizes common to standard flow cytometry. Most importantly, this technology provides for a direct assessment of the localization of signal intensity within individual cells. The results demonstrate glucocorticoids to dysregulate natural killer cell function at least in part through altered H3K27me3 nuclear organization and demonstrate H3K27me3 chromatin organization to be a predictive indicator of glucocorticoid induced immune dysregulation of natural killer cells. Copyright © 2017 Elsevier Inc. All rights

  7. Potassium Channels Mediate Killing by Human Natural Killer Cells

    NASA Astrophysics Data System (ADS)

    Schlichter, Lyanne; Sidell, Neil; Hagiwara, Susumu

    1986-01-01

    Human natural killer (NK) cells in peripheral blood spontaneously recognize and kill a wide variety of target cells. It has been suggested that ion channels are involved in the killing process because there is a Ca-dependent stage and because killing by presensitized cytotoxic T lymphocytes, which in many respects resembles NK killing, is associated with changes in K and Na transport in the target cell. However, no direct evidence exists for ion channels in NK cells or in their target cells. Using the whole-cell variation of the patch-clamp technique, we found a voltage-dependent potassium (K+) current in NK cells. The K+ current was reduced in a dose-dependent manner by the K-channel blockers 4-aminopyridine and quinidine and by the traditional Ca-channel blockers verapamil and Cd2+. We tested the effects of ion-channel blockers on killing of two commonly used target cell lines: K562, which is derived from a human myeloid leukemia, and U937, which is derived from a human histiocytic leukemia. Killing of K562 target cells, determined in a standard 51Cr-release assay, was inhibited in a dose-dependent manner by verapamil, quinidine, Cd2+, and 4-aminopyridine at concentrations comparable to those that blocked the K+ current in NK cells. In K562 target cells only a voltage-dependent Na+ current was found and it was blocked by concentrations of tetrodotoxin that had no effect on killing. Killing of U937 target cells was also inhibited by the two ion-channel blockers tested, quinidine and verapamil. In this cell line only a small K+ current was found that was similar to the one in NK cells. We could not find any evidence of a Ca2+ current in target cells or in NK cells; therefore, our results cannot explain the Ca dependence of killing. Our findings show that there are K channels in NK cells and that these channels play a necessary role in the killing process. In contrast, the endogenous channel type in the target cell is probably not a factor in determining target cell

  8. Monkeypox virus infection of rhesus macaques induces massive expansion of natural killer cells but suppresses natural killer cell functions.

    PubMed

    Song, Haifeng; Josleyn, Nicole; Janosko, Krisztina; Skinner, Jeff; Reeves, R Keith; Cohen, Melanie; Jett, Catherine; Johnson, Reed; Blaney, Joseph E; Bollinger, Laura; Jennings, Gerald; Jahrling, Peter B

    2013-01-01

    Natural killer (NK) cells play critical roles in innate immunity and in bridging innate and adaptive immune responses against viral infection. However, the response of NK cells to monkeypox virus (MPXV) infection is not well characterized. In this intravenous challenge study of MPXV infection in rhesus macaques (Macaca mulatta), we analyzed blood and lymph node NK cell changes in absolute cell numbers, cell proliferation, chemokine receptor expression, and cellular functions. Our results showed that the absolute number of total NK cells in the blood increased in response to MPXV infection at a magnitude of 23-fold, manifested by increases in CD56+, CD16+, CD16-CD56- double negative, and CD16+CD56+ double positive NK cell subsets. Similarly, the frequency and NK cell numbers in the lymph nodes also largely increased with the total NK cell number increasing 46.1-fold. NK cells both in the blood and lymph nodes massively proliferated in response to MPXV infection as measured by Ki67 expression. Chemokine receptor analysis revealed reduced expression of CXCR3, CCR7, and CCR6 on NK cells at early time points (days 2 and 4 after virus inoculation), followed by an increased expression of CXCR3 and CCR5 at later time points (days 7-8) of infection. In addition, MPXV infection impaired NK cell degranulation and ablated secretion of interferon-γ and tumor necrosis factor-α. Our data suggest a dynamic model by which NK cells respond to MPXV infection of rhesus macaques. Upon virus infection, NK cells proliferated robustly, resulting in massive increases in NK cell numbers. However, the migrating capacity of NK cells to tissues at early time points might be reduced, and the functions of cytotoxicity and cytokine secretion were largely compromised. Collectively, the data may explain, at least partially, the pathogenesis of MPXV infection in rhesus macaques.

  9. Monkeypox Virus Infection of Rhesus Macaques Induces Massive Expansion of Natural Killer Cells but Suppresses Natural Killer Cell Functions

    PubMed Central

    Song, Haifeng; Josleyn, Nicole; Janosko, Krisztina; Skinner, Jeff; Reeves, R. Keith; Cohen, Melanie; Jett, Catherine; Johnson, Reed; Blaney, Joseph E.; Bollinger, Laura; Jennings, Gerald; Jahrling, Peter B.

    2013-01-01

    Natural killer (NK) cells play critical roles in innate immunity and in bridging innate and adaptive immune responses against viral infection. However, the response of NK cells to monkeypox virus (MPXV) infection is not well characterized. In this intravenous challenge study of MPXV infection in rhesus macaques (Macaca mulatta), we analyzed blood and lymph node NK cell changes in absolute cell numbers, cell proliferation, chemokine receptor expression, and cellular functions. Our results showed that the absolute number of total NK cells in the blood increased in response to MPXV infection at a magnitude of 23-fold, manifested by increases in CD56+, CD16+, CD16-CD56- double negative, and CD16+CD56+ double positive NK cell subsets. Similarly, the frequency and NK cell numbers in the lymph nodes also largely increased with the total NK cell number increasing 46.1-fold. NK cells both in the blood and lymph nodes massively proliferated in response to MPXV infection as measured by Ki67 expression. Chemokine receptor analysis revealed reduced expression of CXCR3, CCR7, and CCR6 on NK cells at early time points (days 2 and 4 after virus inoculation), followed by an increased expression of CXCR3 and CCR5 at later time points (days 7-8) of infection. In addition, MPXV infection impaired NK cell degranulation and ablated secretion of interferon-γ and tumor necrosis factor-α. Our data suggest a dynamic model by which NK cells respond to MPXV infection of rhesus macaques. Upon virus infection, NK cells proliferated robustly, resulting in massive increases in NK cell numbers. However, the migrating capacity of NK cells to tissues at early time points might be reduced, and the functions of cytotoxicity and cytokine secretion were largely compromised. Collectively, the data may explain, at least partially, the pathogenesis of MPXV infection in rhesus macaques. PMID:24147080

  10. Killing defect of natural killer cells with the absence of natural killer cytotoxic factors in a child with Hodgkin's disease

    SciTech Connect

    Komiyama, A.; Kawai, H.; Yamada, S.; Kato, M.; Yanagisawa, M.; Miyagawa, Y.; Akabane, T.

    1987-06-01

    A killing defect of natural killer (NK) cells in the absence of NK cytotoxic factors (NKCF) was first demonstrated in a child with Hodgkin's disease. The patient lacked detectable NK cell activity in every phase of the disease as measured by a four-hour /sup 51/Cr-release assay using K562 cells as a target. The percent lysis at a 40:1 effector:target ratio by the patient's lymphocytes was persistently below 0.3% as compared with the normal lymphocyte value of 46.2% +/- 5.8% (mean +/- SD). NK cell activity was not detectable at effector:target ratios of 10:1 to 80:1 and by prolongation of the incubation time, and the NK cell defect was not restored or improved by lymphocyte stimulation with polyinosinic-polycytidilic acid, interferon (IFN)-alpha, or interleukin 2 (IL 2). The numbers of Leu-7+ cells and Leu-11+ cells were normal as counted by flow cytometry. A single cell-in-agarose assay demonstrated normal numbers of target binding cells (TBCs), and they showed the morphology of large granular lymphocytes. However, there were no TBCs with dead targets. These results indicated that the patient's lymphocytes contained normal numbers of NK cells that were capable of recognizing and binding to a target but were incapable of killing the bound target cell. The patient's lymphocytes were then studied for their release of NKCF upon interaction with K562 cells. The patient's cells did not release NKCF, and the NK cell defect was not restored or improved by stimulation of the cells with IFN or IL 2. It is suggested that the deficient release of NKCF may have been related to the killing defect of the NK cells in this patient.

  11. Innate immune responses involving natural killer and natural killer T cells promote liver regeneration after partial hepatectomy in mice.

    PubMed

    Hosoya, Satoko; Ikejima, Kenichi; Takeda, Kazuyoshi; Arai, Kumiko; Ishikawa, Sachiko; Yamagata, Hisafumi; Aoyama, Tomonori; Kon, Kazuyoshi; Yamashina, Shunhei; Watanabe, Sumio

    2013-02-01

    To clarify the roles of innate immune cells in liver regeneration, here, we investigated the alteration in regenerative responses after partial hepatectomy (PH) under selective depletion of natural killer (NK) and/or NKT cells. Male, wild-type (WT; C57Bl/6), and CD1d-knockout (KO) mice were injected with anti-NK1.1 or anti-asialo ganglio-N-tetraosylceramide (GM1) antibody and then underwent the 70% PH. Regenerative responses after PH were evaluated, and hepatic expression levels of cytokines and growth factors were measured by real-time RT-PCR and ELISA. Phosphorylation of STAT3 was detected by Western blotting. Depletion of both NK and NKT cells with an anti-NK1.1 antibody in WT mice caused drastic decreases in bromodeoxyuridine uptake, expression of proliferating cell nuclear antigen, and cyclin D1, 48 h after PH. In mice given NK1.1 antibody, increases in hepatic TNF-α, IL-6/phospho-STAT3, and hepatocyte growth factor (HGF) levels following PH were also blunted significantly, whereas IFN-γ mRNA levels were not different. CD1d-KO mice per se showed normal liver regeneration; however, pretreatment with an antiasialo GM1 antibody to CD1d-KO mice, resulting in depletion of both NK and NKT cells, also blunted regenerative responses. Collectively, these observations clearly indicated that depletion of both NK and NKT cells by two different ways results in impaired liver regeneration. NK and NKT cells most likely upregulate TNF-α, IL-6/STAT3, and HGF in a coordinate fashion, thus promoting normal regenerative responses in the liver.

  12. Invariant natural killer T cells in children with eosinophilic esophagitis.

    PubMed

    Jyonouchi, S; Smith, C L; Saretta, F; Abraham, V; Ruymann, K R; Modayur-Chandramouleeswaran, P; Wang, M-L; Spergel, J M; Cianferoni, A

    2014-01-01

    Eosinophilic esophagitis (EoE) is an atopic disease characterized by eosinophilic inflammation in which dietary antigens (in particular, milk) play a major role. EoE is most likely a mixed IgE and non-IgE food-mediated reaction in which overexpression of Th2 cytokines, particularly IL-13, play a major role; however, the cells responsible for IL-13 overexpression remain elusive. Th2-cytokines are secreted following the ligation of invariant natural killer T cell receptors to sphingolipids (SLs). Sphingolipids (SLs) are presented via the CD1d molecule on the INKTs surface. Cow's milk-derived SL has been shown to activate iNKTs from children with IgE-mediated food allergies to milk (FA-MA) to produce Th2 cytokines. The role of iNKTs and milk-SL in EoE pathogenesis is currently unknown. The aim of this study was to investigate the role of iNKTs and milk-SL in EoE. Peripheral blood mononuclear cells (PBMCs) from 10 children with active EoE (EoE-A), 10 children with controlled EoE (EoE-C) and 16 healthy controls (non-EoE) were measured ex vivo and then incubated with α-galactosylceramide (αGal) and milk-SL. INKTs from peripheral blood (PB) and oesophageal biopsies were studied. EoE-A children had significantly fewer peripheral blood iNKTs with a greater Th2-response to αGal and milk-SM compared with iNKTs of EoE-C and non-EoE children. Additionally, EoE-A children had increased iNKT levels in oesophageal biopsies compared with EoE-C children. Milk-SLs are able to activate peripheral blood iNKTs in EoE-A children to produce Th2 cytokines. Additionally, iNKT levels are higher at the site of active oesophageal eosinophilic inflammation. This study suggests that sphingolipids (SLs) contained in milk may drive the development of EoE by promoting an iNKT-cell-mediated Th2-type cytokine response that facilitates eosinophil-mediated allergic inflammation. © 2013 John Wiley & Sons Ltd.

  13. Recognition of Microbial Glycolipids by Natural Killer T Cells

    PubMed Central

    Zajonc, Dirk M.; Girardi, Enrico

    2015-01-01

    T cells can recognize microbial antigens when presented by dedicated antigen-presenting molecules. While peptides are presented by classical members of the major histocompatibility complex (MHC) family (MHC I and II), lipids, glycolipids, and lipopeptides can be presented by the non-classical MHC member, CD1. The best studied subset of lipid-reactive T cells are type I natural killer T (iNKT) cells that recognize a variety of different antigens when presented by the non-classical MHCI homolog CD1d. iNKT cells have been shown to be important for the protection against various microbial pathogens, including B. burgdorferi, the causative agents of Lyme disease, and S. pneumoniae, which causes pneumococcal meningitis and community-acquired pneumonia. Both pathogens carry microbial glycolipids that can trigger the T cell antigen receptor (TCR), leading to iNKT cell activation. iNKT cells have an evolutionary conserved TCR alpha chain, yet retain the ability to recognize structurally diverse glycolipids. They do so using a conserved recognition mode, in which the TCR enforces a conserved binding orientation on CD1d. TCR binding is accompanied by structural changes within the TCR binding site of CD1d, as well as the glycolipid antigen itself. In addition to direct recognition of microbial antigens, iNKT cells can also be activated by a combination of cytokines (IL-12/IL-18) and TCR stimulation. Many microbes carry TLR antigens, and microbial infections can lead to TLR activation. The subsequent cytokine response in turn lower the threshold of TCR-mediated iNKT cell activation, especially when weak microbial or even self-antigens are presented during the cause of the infection. In summary, iNKT cells can be directly activated through TCR triggering of strong antigens, while cytokines produced by the innate immune response may be necessary for TCR triggering and iNKT cell activation in the presence of weak antigens. Here, we will review the molecular basis of iNKT cell

  14. Effect of millimeter waves on natural killer cell activation.

    PubMed

    Makar, V R; Logani, M K; Bhanushali, A; Kataoka, M; Ziskin, M C

    2005-01-01

    Millimeter wave therapy (MMWT) is being widely used for the treatment of many diseases in Russia and other East European countries. MMWT has been reported to reduce the toxic effects of chemotherapy on the immune system. The present study was undertaken to investigate whether millimeter waves (MMWs) can modulate the effect of cyclophosphamide (CPA), an anticancer drug, on natural killer (NK) cell activity. NK cells play an important role in the antitumor response. MMWs were produced with a Russian-made YAV-1 generator. The device produced modulated 42.2 +/- 0.2 GHz radiation through a 10 x 20 mm rectangular output horn. Mice, restrained in plastic tubes, were irradiated on the nasal area. Peak SAR at the skin surface and peak incident power density were measured as 622 +/- 100 W/kg and 31 +/- 5 mW/cm2, respectively. The maximum temperature elevation, measured at the end of 30 min, was 1 degrees C. The animals, restrained in plastic tubes, were irradiated on the nasal area. CPA injection (100 mg/kg) was given intraperitoneally on the second day of 3-days exposure to MMWs. All the irradiation procedures were performed in a blinded manner. NK cell activation and cytotoxicity were measured after 2, 5, and 7 days following CPA injection. Flow cytometry of NK cells showed that CPA treatment caused a marked enhancement in NK cell activation. The level of CD69 expression, which represents a functional triggering molecule on activated NK cells, was increased in the CPA group at all the time points tested as compared to untreated mice. However, the most enhancement in CD69 expression was observed on day 7. A significant increase in TNF-alpha level was also observed on day 7 following CPA administration. On the other hand, CPA caused a suppression of the cytolytic activity of NK cells. MMW irradiation of the CPA treated groups resulted in further enhancement of CD69 expression on NK cells, as well as in production of TNF-alpha. Furthermore, MMW irradiation restored CPA

  15. Endogenous cannabinoid receptor ligand induces the migration of human natural killer cells.

    PubMed

    Kishimoto, Seishi; Muramatsu, Mayumi; Gokoh, Maiko; Oka, Saori; Waku, Keizo; Sugiura, Takayuki

    2005-02-01

    2-Arachidonoylglycerol is an endogenous ligand for the cannabinoid receptors (CB1 and CB2). Evidence is gradually accumulating which shows that 2-arachidonoylglycerol plays important physiological roles in several mammalian tissues and cells, yet the details remain ambiguous. In this study, we first examined the effects of 2-arachidonoylglycerol on the motility of human natural killer cells. We found that 2-arachidonoylglycerol induces the migration of KHYG-1 cells (a natural killer leukemia cell line) and human peripheral blood natural killer cells. The migration of natural killer cells induced by 2-arachidonoylglycerol was abolished by treating the cells with SR144528, a CB2 receptor antagonist, suggesting that the CB2 receptor is involved in the 2-arachidonoylglycerol-induced migration. In contrast to 2-arachidonoylglycerol, anandamide, another endogenous cannabinoid receptor ligand, did not induce the migration. Delta9-tetrahydrocannabinol, a major psychoactive constituent of marijuana, also failed to induce the migration; instead, the addition of delta9-tetrahydrocannabinol together with 2-arachidonoylglycerol abolished the migration induced by 2-arachidonoylglycerol. It is conceivable that the endogenous ligand for the cannabinoid receptor, that is, 2-arachidonoylglycerol, affects natural killer cell functions such as migration, thereby contributing to the host-defense mechanism against infectious viruses and tumor cells.

  16. Rare aggressive natural killer cell leukemia presented with bone marrow fibrosis - a diagnostic challenge.

    PubMed

    Soliman, Dina S; Sabbagh, Ahmad Al; Omri, Halima El; Ibrahim, Firyal A; Amer, Aliaa M; Otazu, Ivone B

    2014-01-01

    Aggressive natural killer cell leukemia is an extraordinary rare aggressive malignant neoplasm of natural killer cells. Although its first recognition as a specific entity was approximately 20 years ago, this leukemia has not yet been satisfactorily characterized as fewer than 200 cases have been reported in the literature and up to our knowledge, this is the first case report in Qatar. Reaching a diagnosis of aggressive natural killer leukemia was a challenging experience, because in addition to being a rare entity, the relative scarcity of circulating neoplastic cells, failure to obtain an adequate aspirate sample sufficient to perform flow cytometric analysis, together with the absence of applicable method to prove NK clonality (as it lack specific clonal marker); our case had atypical confusing presentation of striking increase in bone marrow fibrosis that was misleading and complicated the case further. The bone marrow fibrosis encountered may be related to the neoplastic natural killer cells' chemokine profile and it may raise the awareness for considering aggressive natural killer leukemia within the differential diagnosis of leukemia with heightened marrow fibrosis.

  17. Recognition of adult and pediatric acute lymphoblastic leukemia blasts by natural killer cells.

    PubMed

    Torelli, Giovanni F; Peragine, Nadia; Raponi, Sara; Pagliara, Daria; De Propris, Maria S; Vitale, Antonella; Bertaina, Alice; Barberi, Walter; Moretta, Lorenzo; Basso, Giuseppe; Santoni, Angela; Guarini, Anna; Locatelli, Franco; Foà, Robin

    2014-07-01

    In this study, we aimed to investigate the pathways of recognition of acute lymphoblastic leukemia blasts by natural killer cells and to verify whether differences in natural killer cell activating receptor ligand expression among groups defined by age of patients, or presence of cytogenetic/molecular aberrations correlate with the susceptibility to recognition and killing. We analyzed 103 newly diagnosed acute lymphoblastic leukemia patients: 46 adults and 57 children. Pediatric blasts showed a significantly higher expression of Nec-2 (P=0.03), ULBP-1 (P=0.01) and ULBP-3 (P=0.04) compared to adult cells. The differential expression of these ligands between adults and children was confined to B-lineage acute lymphoblastic leukemia with no known molecular alterations. Within molecularly defined subgroups of patients, a high surface expression of NKG2D and DNAM1 ligands was found on BCR-ABL(+) blasts, regardless of patient age. Accordingly, BCR-ABL(+) blasts proved to be significantly more susceptible to natural killer-dependent lysis than B-lineage blasts without molecular aberrations (P=0.03). Cytotoxic tests performed in the presence of neutralizing antibodies indicated a pathway of acute lymphoblastic leukemia cell recognition in the setting of the Nec-2/DNAM-1 interaction. These data provide a biological explanation of the different roles played by alloreactive natural killer cells in pediatric versus adult acute lymphoblastic leukemia and suggest that new natural killer-based strategies targeting specific subgroups of patients, particularly those BCR-ABL(+), are worth pursuing further.

  18. Why natural killer cells are not enough: a further understanding of killer immunoglobulin-like receptor and human leukocyte antigen.

    PubMed

    Alecsandru, Diana; García-Velasco, Juan A

    2017-06-01

    The immune system's role in recurrent reproductive failure is a controversial issue in assisted reproduction. Most studies into immune system implication in reproduction have focused on finding markers of peripheral blood and less on the uterine environment. Peripheral blood natural killer cells have become an "immune study core" for women with recurrent miscarriage or recurrent implantation failure, based on the mistaken notion that they cause reproductive failure by killing or "rejecting" the embryo. Maternal-fetal tolerance begins at the uterine level, so successful adaptation to the fetus occurs after a complicated process. Insufficient uterine lining invasion by an invading extravillous trophoblast is the primary defect in pregnancy disorders such as recurrent miscarriage. This process is regulated by the interaction between maternal killer immunoglobulin-like receptors (KIRs), expressed by uterine natural killer cells (uNK), and their ligand human leukocyte antigen (HLA) C, expressed by the extravillous trophoblast. Pregnancies are an increased risk of disorders in mothers with KIR AA when the fetus has paternal HLA-C2. A recent report has indicated that the expression of more than one paternal HLA-C by the extravillous trophoblast in assisted reproduction may affect placentation in mothers with KIR AA. This review provides insight into the immune system's role in assisted reproductive treatments. These insights can have an impact on the selection of single-embryo transfer and/or oocyte/sperm donor according to HLA-C in patients with recurrent implantation failure and recurrent miscarriage depending on their KIR haplotype. Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  19. Super natural killer cells that target metastases in the tumor draining lymph nodes.

    PubMed

    Chandrasekaran, Siddarth; Chan, Maxine F; Li, Jiahe; King, Michael R

    2016-01-01

    Tumor draining lymph nodes are the first site of metastasis in most types of cancer. The extent of metastasis in the lymph nodes is often used in staging cancer progression. We previously showed that nanoscale TRAIL liposomes conjugated to human natural killer cells enhance their endogenous therapeutic potential in killing cancer cells cultured in engineered lymph node microenvironments. In this work, it is shown that liposomes decorated with apoptosis-inducing ligand TRAIL and an antibody against a mouse natural killer cell marker are carried to the tumor draining inguinal lymph nodes and prevent the lymphatic spread of a subcutaneous tumor in mice. It is shown that targeting natural killer cells with TRAIL liposomes enhances their retention time within the tumor draining lymph nodes to induce apoptosis in cancer cells. It is concluded that this approach can be used to kill cancer cells within the tumor draining lymph nodes to prevent the lymphatic spread of cancer.

  20. Natural Sphingomonas glycolipids vary greatly in their ability to activate natural killer T cells.

    PubMed

    Kinjo, Yuki; Pei, Bo; Bufali, Simone; Raju, Ravinder; Richardson, Stewart K; Imamura, Masakazu; Fujio, Masakazu; Wu, Douglass; Khurana, Archana; Kawahara, Kazuyoshi; Wong, Chi-Huey; Howell, Amy R; Seeberger, Peter H; Kronenberg, Mitchell

    2008-07-21

    Mouse natural killer T (NKT) cells expressing an invariant T cell antigen receptor (TCR) recognize glycosphingolipids (GSLs) from Sphingomonas bacteria. The synthetic antigens previously tested, however, were designed to closely resemble the potent synthetic agonist alpha-galactosyl ceramide (alphaGalCer), which contains a monosaccharide and a C18:0 sphingosine lipid. Some Sphingomonas bacteria, however, also have oligosaccharide-containing GSLs, and they normally synthesize several GSLs with different sphingosine chains including one with a cyclopropyl ring-containing C21:0 (C21cycl) sphingosine. Here we studied the stimulation of NKT cells with synthetic GSL antigens containing natural tetrasaccharide sugars, or the C21cycl sphingosine. Our results indicate that there is a great degree of variability in the antigenic potency of different natural Sphingomonas glycolipids, with the C21cycl sphingosine having intermediate potency and the oligosaccharide-containing antigens exhibiting limited or no stimulatory capacity.

  1. Hydrocortisone prevents immunosuppression by interleukin-10+ natural killer cells after trauma-hemorrhage.

    PubMed

    Roquilly, Antoine; Broquet, Alexis; Jacqueline, Cédric; Masson, Damien; Segain, Jean Pierre; Braudeau, Cecile; Vourc'h, Mickael; Caillon, Jocelyne; Altare, Frédéric; Josien, Regis; Retière, Christelle; Villadangos, Jose; Asehnoune, Karim

    2014-12-01

    Trauma induces a state of immunosuppression, which is responsible for the development of nosocomial infections. Hydrocortisone reduces the rate of pneumonia in patients with trauma. Because alterations of dendritic cells and natural killer cells play a central role in trauma-induced immunosuppression, we investigated whether hydrocortisone modulates the dendritic cell/natural killer cell cross talk in the context of posttraumatic pneumonia. Experimental study. Research laboratory from an university hospital. Bagg Albino/cJ mice (weight, 20-24 g). First, in an a priori substudy of a multicenter, randomized, double-blind, placebo-controlled trial of hydrocortisone (200 mg/d for 7 d) in patients with severe trauma, we have measured the blood levels of five cytokines (tumor necrosis factor-α, interleukin-6, interleukin-10, interleukin-12, interleukin-17) at day 1 and day 8. In a second step, the effects of hydrocortisone on dendritic cell/natural killer cell cross talk were studied in a mouse model of posttraumatic pneumonia. Hydrocortisone (0.6 mg/mice i.p.) was administered immediately after hemorrhage. Twenty-four hours later, the mice were challenged with Staphylococcus aureus (7 × 10 colony-forming units). Using sera collected during a multicenter study in patients with trauma, we found that hydrocortisone decreased the blood level of interleukin-10, a cytokine centrally involved in the regulation of dendritic cell/natural killer cell cluster. In a mouse model of trauma-hemorrhage-induced immunosuppression, splenic natural killer cells induced an interleukin-10-dependent elimination of splenic dendritic cell. Hydrocortisone treatment reduced this suppressive function of natural killer cells and increased survival of mice with posthemorrhage pneumonia. The reduction of the interleukin-10 level in natural killer cells by hydrocortisone was partially dependent on the up-regulation of glucocorticoid-induced tumor necrosis factor receptor-ligand (TNFsf18) on

  2. Extranodal natural killer/T-cell lymphoma, nasal type: 'midline lethal granuloma.' A case report.

    PubMed

    Tlholoe, Martha M; Kotu, Monica; Khammissa, Razia A G; Bida, Meschack; Lemmer, Johan; Feller, Liviu

    2013-01-17

    Extranodal natural killer/T cell lymphoma, nasal type, is a non-Hodgkin lymphoma, most commonly affecting the nasal cavity, paranasal sinuses and nasopharynx. Clinically it is characterised by destruction of facial tissues, commencing in the midline. In most cases it arises from malignant transformation of natural killer cells (NK); sometimes from malignant transformation of cytotoxic T cells.Extranodal NK/T cell lymphoma, nasal type, is rare, but even more rare in black persons. The purpose of this article is to report a severe case of extranodal NK/T cell lymphoma, nasal type, in an elderly black male.

  3. Increased killer immunoglobulin-like receptor expression and functional defects in natural killer cells in lung cancer

    PubMed Central

    Al Omar, Suliman Y; Marshall, Ernie; Middleton, Derek; Christmas, Stephen E

    2011-01-01

    Frequencies of natural killer (NK) cells from patients with non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC) did not differ from healthy controls. A higher proportion of NK cells from NSCLC patients expressed the killer immunoglobulin-like receptor (KIR) CD158b than in controls (P = 0·0004), in the presence or absence of its ligand, HLA-C1. A similar result was obtained for CD158e in the presence of its ligand HLA-Bw4 in NSCLC patients (P = 0·003); this was entirely attributable to the Bw4I group of alleles in the presence of which a fivefold higher percentage of CD158e+ NK cells was found in NSCLC patients than controls. Proportions of CD158b+ NK cells declined with advancing disease in NSCLC patients. Expression of NKp46, CD25 and perforin A, and production of interferon-γ following stimulation with interleukin-12 and interleukin-18, were all significantly lower in NK cells from NSCLC patients than in controls. Both NK cell cytotoxicity and granzyme B expression were also reduced in lung cancer patients. Increased inhibitory KIR expression would decrease NK cell cytotoxic function against tumour cells retaining class I HLA expression. Furthermore, the reduced ability to produce interferon-γ would restrict the ability of NK cells to stimulate T-cell responses in patients with lung cancer. PMID:21342183

  4. Production of interferons by dendritic cells, plasmacytoid cells, natural killer cells, and interferon-producing killer dendritic cells.

    PubMed

    Vremec, David; O'Keeffe, Meredith; Hochrein, Hubertus; Fuchsberger, Martina; Caminschi, Irina; Lahoud, Mireille; Shortman, Ken

    2007-02-01

    The capacity of mouse spleen conventional dendritic cells (cDCs) and plasmacytoid dendritic cells (pDCs) to produce interferon-gamma (IFN-gamma) or IFN-alpha was assessed, and compared with that of natural killer (NK) cells and the recently identified interferon-producing killer dendritic cells (IKDCs), both of which are frequent contaminants in DC preparations. Fully developed cDCs or pDCs, if free of NK cells or IKDCs, showed little capacity for IFN-gamma production. However, an early developmental form of the CD4-8+ cDC subtype, and the Ly6C- Ly49Q- pDC subtype, both were able to produce moderate amounts of IFN-gamma, although less than IKDCs. In response to toll-like receptor 9 stimuli, both the Ly6C+ Ly49Q+ and the Ly6C- Ly49Q- pDC subtypes were effective producers of IFN-alpha. However, IKDCs, which efficiently produced IFN-gamma and showed immediate cytotoxicity on NK target cells, did not produce IFN-alpha under these conditions.

  5. Experimental tests of host-virus coevolution in natural killer yeast strains.

    PubMed

    Pieczynska, M D; Korona, R; De Visser, J A G M

    2017-04-01

    Fungi may carry cytoplasmic viruses that encode anticompetitor toxins. These so-called killer viruses may provide competitive benefits to their host, but also incur metabolic costs associated with viral replication, toxin production and immunity. Mechanisms responsible for the stable maintenance of these endosymbionts are insufficiently understood. Here, we test whether co-adaptation of host and killer virus underlies their stable maintenance in seven natural and one laboratory strain of the genus Saccharomyces. We employ cross-transfection of killer viruses, all encoding the K1-type toxin, to test predictions from host-virus co-adaptation. These tests support local adaptation of hosts and/or their killer viruses. First, new host-virus combinations have strongly reduced killing ability against a standard sensitive strain when compared with re-constructed native combinations. Second, viruses are more likely to be lost from new than from original hosts upon repeated bottlenecking or the application of stressful conditions. Third, host fitness is increased after the re-introduction of native viruses, but decreased after the introduction of new viruses. Finally, rather than a trade-off, original combinations show a positive correlation between killing ability and fitness. Together, these results suggest that natural yeast killer strains and their viruses have co-adapted, allowing the transition from a parasitic to a mutualistic symbiosis.

  6. Ocular presentation of natural killer/T-cell lymphoma in a Caucasian man.

    PubMed

    Hughes, Emily; Fogarty, Helen; Fortune, Anne; Keegan, David

    2016-04-26

    Natural killer/T-cell (NK/T-cell) lymphoma-nasal subtype, is a rare form of non-Hodgkin's lymphoma, most common in South East Asia, and can have an ophthalmological presentation. This report describes a 51-year-old Caucasian man with uveitis, recurrent retinal detachment and paraneoplastic features subsequently diagnosed as NK/T-cell lymphoma.

  7. Methylprednisolone pulse therapy induced fall in natural killer cell activity in rheumatoid arthritis.

    PubMed

    Pedersen, B K; Beyer, J M; Rasmussen, A; Klarlund, K; Pedersen, B N; Helin, P

    1984-10-01

    Natural killer (NK) cell activity was studied in 8 patients with classic or definite rheumatoid arthritis (RA) by investigating the killing of K 562 cells by peripheral blood lymphocytes before, during, and after intravenous methylprednisolone pulse therapy (MPPT). MPPT produced a considerable fall in NK activity and after 3 months NK activity was less than half that before MPPT.

  8. Natural killer T cells: innate lymphocytes positioned as a bridge between acute and chronic inflammation?

    PubMed Central

    Fox, Lisa; Hegde, Subramanya

    2010-01-01

    Natural killer T cells are an innate population of T lymphocytes that recognize antigens derived from host lipids and glycolipids. In this review, we focus on how these unique T cells are positioned to influence both acute and chronic inflammatory processes through their early recruitment to sites of inflammation, interactions with myeloid antigen presenting cells, and recognition of lipids associated with inflammation. PMID:20850561

  9. Paucity of natural killer and cytotoxic T cells in human neuromyelitis optica lesions

    PubMed Central

    Saadoun, Samira; Bridges, Leslie R.; Verkman, A. S.; Papadopoulos, Marios C.

    2013-01-01

    Neuromyelitis optica is a severe inflammatory demyelinating disease of the central nervous system. Most patients with neuromyelitis optica have circulating immunoglobulin G (IgG) antibodies against the astrocytic water channel protein aquaporin-4 (AQP4), which are pathogenic. Anti-AQP4 IgG-mediated complement-dependent astrocyte toxicity is a key mechanism of central nervous system damage in neuromyelitis optica, but the role of natural killer and cytotoxic T cells is unknown. Our objective was to determine whether natural killer and cytotoxic T cells play a role in human neuromyelitis optica lesions. We immunostained four actively demyelinating lesions, obtained from patients with anti-AQP4 IgG positive neuromyelitis optica, for Granzyme B and Perforin. The inflammatory cells were perivascular neutrophils, eosinophils and macrophages, with only occasional Granzyme B+ or Perforin + cells. Greater than 95% of inflamed vessels in each lesion had no surrounding Granzyme B+ or Perforin + cells. Granzyme B+ or Perforin+ cells were abundant in human spleen (positive control). Although natural killer cells produce central nervous system damage in mice injected with anti-AQP4 IgG, our findings here indicate that natural killer-mediated and T cell-mediated cytotoxicity are probably not involved in central nervous system damage in human neuromyelitis optica. PMID:23108041

  10. Paucity of natural killer and cytotoxic T cells in human neuromyelitis optica lesions.

    PubMed

    Saadoun, Samira; Bridges, Leslie R; Verkman, A S; Papadopoulos, Marios C

    2012-12-19

    Neuromyelitis optica is a severe inflammatory demyelinating disease of the central nervous system. Most patients with neuromyelitis optica have circulating immunoglobulin G (IgG) antibodies against the astrocytic water channel protein aquaporin-4 (AQP4), which are pathogenic. Anti-AQP4 IgG-mediated complement-dependent astrocyte toxicity is a key mechanism of central nervous system damage in neuromyelitis optica, but the role of natural killer and cytotoxic T cells is unknown. Our objective was to determine whether natural killer and cytotoxic T cells play a role in human neuromyelitis optica lesions. We immunostained four actively demyelinating lesions, obtained from patients with anti-AQP4 IgG positive neuromyelitis optica, for Granzyme B and Perforin. The inflammatory cells were perivascular neutrophils, eosinophils and macrophages, with only occasional Granzyme B+ or Perforin+ cells. Greater than 95% of inflamed vessels in each lesion had no surrounding Granzyme B+ or Perforin+ cells. Granzyme B+ or Perforin+ cells were abundant in human spleen (positive control). Although natural killer cells produce central nervous system damage in mice injected with anti-AQP4 IgG, our findings here indicate that natural killer-mediated and T cell-mediated cytotoxicity are probably not involved in central nervous system damage in human neuromyelitis optica.

  11. The correlation of lymphocyte subsets, natural killer cell, and Parkinson's disease: a meta-analysis.

    PubMed

    Jiang, Sen; Gao, Hua; Luo, Qin; Wang, Pengfei; Yang, Xinling

    2017-08-01

    The correlation between immunity and Parkinson's disease was presented in many papers, which also discussed lymphocyte and natural killer cell. But these studies have yielded inconsistent results. To systematically review the relationship between the lymphocyte subsets/natural killer cell and the risk of Parkinson's disease, we electronically searched the SpringerLink, Web of Science, Ebsco-medline with full text, Pubmed, Elsevier-ScienceDirect, Ovid-lww-oup, Wanfang Data for case-control trials on comparing the number of peripheral blood lymphocyte subsets and natural killer cell in Parkinson's patients and healthy controls. According to the Cochrane methods, the reviewers selected literature, extracted data, and assessed the quality. Then, a meta-analysis was performed using RevMan 5.2. Finally, 21 case-control trials including 943 cases of Parkinson's disease were fit into our data analysis. Meta-analysis showed that the decreased numbers of CD3+, CD4+ lymphocyte subsets and the increased number of natural killer cell were found in Parkinson's disease patients. In the intermediate and late stage of PD, CD8+ lymphocyte subsets had a significant decrement. However, the number of B lymphocyte subsets had no significant association with Parkinson's disease. The lymphocyte subsets and NK cell may be associated with the risk of Parkinson's disease.

  12. High folic acid intake reduces natural killer cell cytotoxicity in aged mice

    USDA-ARS?s Scientific Manuscript database

    Presence of unmetabolized folic acid in plasma, which is indicative of folic acid intake beyond the metabolic capacity of the body, is associated with reduced natural killer (NK) cell cytotoxicity in post-menopausal women >/= 50 years. NK cells are cytotoxic lymphocytes that are part of the innate i...

  13. Natural killer cell dysfunction during acute infection with foot-and-mouth diseaase virus

    USDA-ARS?s Scientific Manuscript database

    Natural killer cells (NK) provide one of the initial barriers of cellular host defense against pathogens, in particular intracellular pathogens. The role of these cells in foot-and-mouth disease virus (FMDV) infection is unknown. Previously, we characterized the phenotype and function of NK cells fr...

  14. Analysis of GzmbCre as a Model System for Gene Deletion in the Natural Killer Cell Lineage.

    PubMed

    Xu, Yiying; Evaristo, Cesar; Alegre, Maria-Luisa; Gurbuxani, Sandeep; Kee, Barbara L

    2015-01-01

    The analysis of gene function in mature and activated natural killer cells has been hampered by the lack of model systems for Cre-mediated recombination in these cells. Here we have investigated the utility of GzmbCre for recombination of loxp sequences in these cells predicated on the observation that Gzmb mRNA is highly expressed in mature and activated natural killer cells. Using two different reporter strains we determined that gene function could be investigated in mature natural killer cells after GzmbCre mediated recombination in vitro in conditions that lead to natural killer cell activation such as in the cytokine combination of interleukin 2 and interleukin 12. We demonstrated the utility of this model by creating GzmbCre;Rosa26IKKbca mice in which Cre-mediated recombination resulted in expression of constitutively active IKKβ, which results in activation of the NFκB transcription factor. In vivo and in vitro activation of IKKβ in natural killer cells revealed that constitutive activation of this pathway leads to natural killer cell hyper-activation and altered morphology. As a caveat to the use of GzmbCre we found that this transgene can lead to recombination in all hematopoietic cells the extent of which varies with the particular loxp flanked allele under investigation. We conclude that GzmbCre can be used under some conditions to investigate gene function in mature and activated natural killer cells.

  15. Tim-3 expression by peripheral natural killer cells and natural killer T cells increases in patients with lung cancer--reduction after surgical resection.

    PubMed

    Xu, Li-Yun; Chen, Dong-Dong; He, Jian-Ying; Lu, Chang-Chang; Liu, Xiao-Guang; Le, Han-Bo; Wang, Chao-Ye; Zhang, Yong-Kui

    2014-01-01

    The purpose of this study was to investigate Tim-3 expression on peripheral CD3-CD56+ natural killer (NK) cells and CD3+CD56+ natural killer T (NKT) cells in lung cancer patients. We analyzed Tim-3+CD3-CD56+ cells, Tim-3+CD3-CD56dim cells, Tim-3+CD3-CD56bright cells, and Tim- 3+CD3+CD56+ cells in fresh peripheral blood from 79 lung cancer cases preoperatively and 53 healthy controls by flow cytometry. Postoperative blood samples were also analyzed from 21 members of the lung cancer patient cohort. It was showed that expression of Tim-3 was significantly increased on CD3-CD56+ cells, CD3- CD56dim cells and CD3+CD56+ cells in lung cancer patients as compared to healthy controls (p=0.03, p=0.03 and p=0.04, respectively). When analyzing Tim-3 expression with cancer progression, results revealed more elevated Tim-3 expression in CD3-CD56+ cells, CD3-CD56dim cells and CD3+CD56+ cells in cases with advanced stages (III/IV) than those with stage I and II (p=0.02, p=0.04 and p=0.01, respectively). In addition, Tim-3 expression was significantly reduced on after surgical resection of the primary tumor (p<0.01). Tim-3 expression in natural killer cells from fresh peripheral blood may provide a useful indicator of disease progression of lung cancer. Furthermore, it was indicated that Tim-3 might be as a therapeutic target.

  16. Functional invariant natural killer T-cell and CD1d axis in chronic lymphocytic leukemia: implications for immunotherapy.

    PubMed

    Weinkove, Robert; Brooks, Collin R; Carter, John M; Hermans, Ian F; Ronchese, Franca

    2013-03-01

    Invariant natural killer T cells recognize glycolipid antigens such as α-galactosylceramide presented by CD1d. In preclinical models of B-cell malignancies, α-galactosylceramide is an adjuvant to tumor vaccination, enhancing tumor-specific T-cell responses and prolonging survival. However, numerical and functional invariant natural killer T-cell defects exist in patients with some cancers. Our aim was to assess this axis in patients with chronic lymphocytic leukemia. The numbers of circulating invariant natural killer T cells and the expression of CD1d on antigen-presenting cells were evaluated in patients with chronic lymphocytic leukemia and age-matched controls. Cytokine profile and in vitro proliferative capacity were determined. Patient- and control-derived invariant natural killer T-cell lines were generated and characterized, and allogeneic and autologous responses to α-galactosylce-ramide-treated leukemia cells were assessed. Absolute numbers and phenotype of invariant natural killer T cells were normal in patients with untreated chronic lymphocytic leukemia, and cytokine profile and proliferative capacity were intact. Chemotherapy-treated patients had reduced numbers of invariant natural killer T cells and myeloid dendritic cells, but α-galactosylceramide-induced proliferation was preserved. Invariant natural killer T-cell lines from patients lysed CD1d-expressing targets. Irradiated α-galactosylceramide-treated leukemic cells elicited allogeneic and autologous invariant natural killer T-cell proliferation, and α-galactosylceramide treatment led to increased proliferation of conventional T cells in response to tumor. In conclusion, the invariant natural killer T-cell and CD1d axis is fundamentally intact in patients with early-stage chronic lymphocytic leukemia and, despite reduced circulating numbers, function is retained in fludarabine-treated patients. Immunotherapies exploiting the adjuvant effect of α-galactosylceramide may be feasible.

  17. HPV vaccine stimulates cytotoxic activity of killer dendritic cells and natural killer cells against HPV-positive tumour cells.

    PubMed

    Van den Bergh, Johan M J; Guerti, Khadija; Willemen, Yannick; Lion, Eva; Cools, Nathalie; Goossens, Herman; Vorsters, Alex; Van Tendeloo, Viggo F I; Anguille, Sébastien; Van Damme, Pierre; Smits, Evelien L J M

    2014-07-01

    Cervarix™ is approved as a preventive vaccine against infection with the human papillomavirus (HPV) strains 16 and 18, which are causally related to the development of cervical cancer. We are the first to investigate in vitro the effects of this HPV vaccine on interleukin (IL)-15 dendritic cells (DC) as proxy of a naturally occurring subset of blood DC, and natural killer (NK) cells, two innate immune cell types that play an important role in antitumour immunity. Our results show that exposure of IL-15 DC to the HPV vaccine results in increased expression of phenotypic maturation markers, pro-inflammatory cytokine production and cytotoxic activity against HPV-positive tumour cells. These effects are mediated by the vaccine adjuvant, partly through Toll-like receptor 4 activation. Next, we demonstrate that vaccine-exposed IL-15 DC in turn induce phenotypic activation of NK cells, resulting in a synergistic cytotoxic action against HPV-infected tumour cells. Our study thus identifies a novel mode of action of the HPV vaccine in boosting innate immunity, including killing of HPV-infected cells by DC and NK cells.

  18. HPV vaccine stimulates cytotoxic activity of killer dendritic cells and natural killer cells against HPV-positive tumour cells

    PubMed Central

    Van den Bergh, Johan M J; Guerti, Khadija; Willemen, Yannick; Lion, Eva; Cools, Nathalie; Goossens, Herman; Vorsters, Alex; Van Tendeloo, Viggo F I; Anguille, Sébastien; Van Damme, Pierre; Smits, Evelien L J M

    2014-01-01

    Cervarix™ is approved as a preventive vaccine against infection with the human papillomavirus (HPV) strains 16 and 18, which are causally related to the development of cervical cancer. We are the first to investigate in vitro the effects of this HPV vaccine on interleukin (IL)-15 dendritic cells (DC) as proxy of a naturally occurring subset of blood DC, and natural killer (NK) cells, two innate immune cell types that play an important role in antitumour immunity. Our results show that exposure of IL-15 DC to the HPV vaccine results in increased expression of phenotypic maturation markers, pro-inflammatory cytokine production and cytotoxic activity against HPV-positive tumour cells. These effects are mediated by the vaccine adjuvant, partly through Toll-like receptor 4 activation. Next, we demonstrate that vaccine-exposed IL-15 DC in turn induce phenotypic activation of NK cells, resulting in a synergistic cytotoxic action against HPV-infected tumour cells. Our study thus identifies a novel mode of action of the HPV vaccine in boosting innate immunity, including killing of HPV-infected cells by DC and NK cells. PMID:24979331

  19. The influence of prophylactic immunosuppressive regimens on natural killer and lymphokine-activated killer cells in renal transplant recipients.

    PubMed

    Alamartine, E; Sabido, O; Berthoux, F C

    1990-12-01

    We investigated natural-killer cells in 81 renal transplant recipients (RTR) in order to define what kind of in vivo prophylactic immunosuppression could be responsible of the impairment of these NK cells. Cell-surface phenotyping was performed by direct immunofluorescence with Leu7 (CD57), Leu11 (CD16), and Leu19 (CD56) antibodies, in one- and two-color stainings. Functional properties were analyzed with freshly isolated nonadherent mononuclear cells (NK activity) and after in vitro activation with r-IL-2 (LAK activity), in cytotoxicity assays using K562 and Daudi tumor lines as specific targets. A flow cytometry technique using carboxy-Fluorodiacetate was applied to monitor the cytotoxicity of NK cells. Our data emphasize the already known deficiency of NK cells: both NK subsets (CD16+ and/or CD56+) and NK activity were decreased in RTR. Moreover, we demonstrated that the in vitro IL-2-induced LAK cytotoxicity was also diminished in RTR. NK cells and functions were normal in RTR treated with cyclosporine only, decreased in RTR treated with both cyclosporine and azathioprine, and at the lowest level in RTR treated with azathioprine without cyclosporine. A multivariate statistical analysis found a negative linear regression between the doses of azathioprine and the number of functions of NK cells, confirming that azathioprine was responsible for the deficiency of NK cells in our RTR.

  20. Effects of OK-432 on murine bone marrow and the production of natural killer cells

    SciTech Connect

    Pollack, S.B.; Rosse, C.

    1985-01-01

    The streptococcal preparation, OK-432, which augments anti-tumor responses in humans and mice, has been shown to be a potent immunomodulator. Among its effects is a pronounced augmentation of natural killer (NK) activity. The hypothesis that OK-432 alters the rates of production and maturation of NK cells in the bone marrow was tested. Studies to determine the kinetic parameters of NK cell production in normal C57BL/6J mice using tritiated thymidine, /sup 3/H-TdR, as a DNA marker are described. We are now extending those studies to determine the effect of OK-432 on the bone marrow and on the production of NK cells in the marrow. Initial observations are reported which indicate that OK-432 has profound effects on the cellularity and mitotic activity of the bone marrow, and in particular, on cells with the characteristics of natural killer cells within the marrow. 17 refs., 3 figs., 4 tabs.

  1. Severe cutaneous human papilloma virus infection associated with Natural Killer cell deficiency following stem cell transplantation for severe combined immunodeficiency

    PubMed Central

    Kamili, Qurat-ul-Ain; Seeborg, Filiz O; Saxena, Kapil; Nicholas, Sarah K; Banerjee, Pinaki P; Angelo, Laura S; Mace, Emily M; Forbes, Lisa R; Martinez, Caridad; Wright, Teresa S; Orange, Jordan S.; Hanson, Imelda Celine

    2016-01-01

    Capsule Summary The authors identify Natural Killer cell deficiency in post-transplant severe combined immunodeficiency patients who developed severe human papilloma virus infections as a long term complication. PMID:25159470

  2. Action of T-activin on activity of human natural killer cells in vitro

    SciTech Connect

    Cheknev, S.B.; Saidov, M.Z.; Koval'chuk, L.V.; Pavlyuk, A.S.; Arion, V.Ya.

    1986-09-01

    This paper describes a study of the action of T-activin on activity of human natural killer cells (NKC) in vitro. The K-562 chronic human myeloid leukemia cells, cultured in vitro, used as targets were labeled with /sup 3/H-uridine. The experimental results indicate that T-activin can depress NKC activity but under certain conditions, it can also stimulate NKC. T-activin possesses immunoregulatory properties relative to NKC activity in vitro.

  3. Benzodiazepines antagonize central corticotropin releasing hormone-induced suppression of natural killer cell activity.

    PubMed

    Irwin, M; Hauger, R L; Britton, K

    1993-12-17

    Benzodiazepines have anxiolytic properties and attenuate behavioral stress responses induced by corticotropin releasing hormone (CRH). To evaluate the effect of benzodiazepines on CRH-induced immune suppression, potent centrally acting benzodiazepines were administered prior to central infusion of CRH (i.c.v.; 1.0 microgram). CRH induced a significant (P < 0.01) reduction of splenic natural killer cell activity which was completely antagonized by pretreatment with either diazepam or alprazolam.

  4. Natural killer cells: can they be useful as adoptive immunotherapy for cancer?

    PubMed

    Arai, Sally; Klingemann, Hans-G

    2005-02-01

    As part of the innate immune system, natural killer (NK) cells form the first line of defence against pathogens or transformed/cancerous host cells. Recent experimental and clinical data show the possibility of exploiting NK activity as a cell-based immunotherapy to treat cancer. This review discusses the recent knowledge on NK cell biology that has impacted on its development as a treatment for cancer.

  5. Noninvasive Imaging of Natural Killer Cell-Mediated Apoptosis in a Mouse Tumor Model.

    PubMed

    Singh, Thoudam Debraj; Lee, Jaetae; Jeon, Yong Hyun

    2016-01-01

    Natural killer (NK) cells are cytotoxic lymphocytes that induce apoptosis in cancer cells infected with viruses and bacteria through a caspase-3-dependent pathway. Effective NK cell-based immunotherapy requires highly sensitive imaging tools for in vivo monitoring of the dynamic events involved in apoptosis. Here, we describe a noninvasive bioluminescence imaging approach to determine the antitumor effects of NK cell-based therapy by serial imaging of caspase-3-dependent apoptosis in a mouse model of human glioma.

  6. Carbamate pesticide-induced apoptosis and necrosis in human natural killer cells.

    PubMed

    Li, Q; Kobayashi, M; Kawada, T

    2014-01-01

    We previously found that ziram, a carbamate fungicide, significantly induced apoptosis and necrosis in human NK-92MI, a natural killer cell line. To investigate whether other carbamate pesticides also induce apoptosis and necrosis in human natural killer cell, we conducted further experiments with NK-92CI, a human natural killer cell line using a more sensitive assay. NK-92CI cells were treated with ziram, thiram, maneb or carbaryl at 0.031-40 microM for 2-24 h in the present study. Apoptosis and necrosis were determined by FITC-Annexin-V/PI staining. To explore the mechanism of apoptosis, intracellular levels of active caspases 3 and mitochondrial cytochrome-c release were determined by flow cytometry. We found that ziram and thiram also induced apoptosis and necrosis in a time- and dose-dependent manner; however, maneb and carbaryl induced apoptosis and necrosis only at higher doses in NK-92CI cells. The strength of the apoptosis-inducing effect differed among the pesticides, and the order was as follows: thiram > ziram greater than maneb greater than carbaryl. NK-92CI was more sensitive to ziram than NK-92MI. Moreover, ziram and thiram significantly increased the intracellular level of active caspase 3 in NK-92CI and caspase inhibitor significantly inhibited the apoptosis. Ziram and thiram significantly caused mitochondrial cytochrome-c release in NK-92CI. These findings indicate that carbamate pesticides can induce apoptosis in natural killer cells, and the apoptosis is mediated by both the caspase-cascade and mitochondrial cytochrome-c pathways.

  7. Mechanisms of Invariant Natural Killer T Cell-Mediated Immunoregulation in Cancer

    DTIC Science & Technology

    2011-05-01

    immunoregulatory phenotype. Specifically, three non-mutually exclusive hypothesis will be tested –1) that a lipid antigen derived from 4T1 tumor cells can be...made significant progress in demonstrating that lipid antigen/s derived from 4T1 tumors can differentially modulate the maturational markers in...4 INTRODUCTION Invariant natural killer T (iNKT) cells comprise a unique group of immune cells that specifically recognize lipid antigens

  8. Carbohydrate affects natural killer cell redistribution but not activity after running.

    PubMed

    Nieman, D C; Henson, D A; Garner, E B; Butterworth, D E; Warren, B J; Utter, A; Davis, J M; Fagoaga, O R; Nehlsen-Cannarella, S L

    1997-10-01

    This randomized, double-blind, placebo-controlled study was designed to determine the influence of carbohydrate supplementation on the natural killer cell response to 2.5 h of high-intensity running (76.7 +/- 0.4% VO2max). Thirty experienced marathon runners (VO2max 53.4 +/- 1.0 mL x kg[-1] x min[-1], age 41.5 +/- 1.4 yr) were randomized into carbohydrate supplement (N = 17) and placebo (N = 13) groups. Subjects rested for 10-15 min before a blood sample at 0715, and then ingested 0.75 L of carbohydrate beverage (Gatorade) or placebo. At 0730, subjects began running at 75-80% VO2max for 2.5 h and drank 0.25 L of carbohydrate or placebo fluid every 15 min. Immediately after the 2.5 h run (1000), another blood sample was taken, followed by 1.5 h, 3 h, and 6-h recovery samples. Carbohydrate supplementation versus placebo had a significant effect on the pattern of change in glucose, cortisol, and the blood concentration of natural killer cells ([F (4,25) = 3.79, P = 0.015], but not natural killer cell activity following 2.5 h of intensive running.

  9. Toll-like receptor-4 agonist in post-haemorrhage pneumonia: role of dendritic and natural killer cells.

    PubMed

    Roquilly, Antoine; Broquet, Alexis; Jacqueline, Cedric; Gautreau, Laetitia; Segain, Jean Pierre; de Coppet, Pierre; Caillon, Jocelyne; Altare, Frédéric; Josien, Regis; Asehnoune, Karim

    2013-11-01

    Haemorrhage-induced immunosuppression has been linked to nosocomial infections. We assessed the impact of monophosphoryl lipid A, a Toll/interleukin-1 receptor-domain-containing adaptor protein inducing interferon-biased Toll-like receptor-4 agonist currently used as a vaccine adjuvant in humans, on post-haemorrhage susceptibility to infection. We used a mouse model of post-haemorrhage pneumonia induced by methicillin-susceptible Staphylococcus aureus. Monophosphoryl lipid A was administered intravenously after haemorrhage and before pneumonia onset. Haemorrhage altered survival rate, increased lung damage (neutrophil accumulation, oedema and cytokine release) and altered the functions of dendritic and natural killer cells. Here, we show that monophosphoryl lipid A decreased systemic dissemination of S. aureus and dampened inflammatory lung lesions. Monophosphoryl lipid A partially restored the capacity for antigen presentation and the transcriptional activity in dendritic cells. Monophosphoryl lipid A did not restore the interferon-γ mRNA but prevented interleukin-10 mRNA overexpression in natural killer cells compared with untreated mice. Ex vivo monophosphoryl lipid A-stimulated dendritic cells or natural killer cells harvested from haemorrhaged animals were adoptively transferred into mice undergoing post-haemorrhage pneumonia. Stimulated dendritic cells (but not stimulated natural killer cells) improved the survival rate compared with mice left untreated. In vivo depletion of natural killer cells decreased survival rate of monophosphoryl lipid A-treated mice. Dendritic and natural killer cells are critically involved in the beneficial effects of monophosphoryl lipid A within post-haemorrhage pneumonia.

  10. Impaired liver regeneration is associated with reduced cyclin B1 in natural killer T cell-deficient mice.

    PubMed

    Ben Ya'acov, Ami; Meir, Hadar; Zolotaryova, Lydia; Ilan, Yaron; Shteyer, Eyal

    2017-03-23

    It has been shown that the proportion of natural killer T cells is markedly elevated during liver regeneration and their activation under different conditions can modulate this process. As natural killer T cells and liver injury are central in liver regeneration, elucidating their role is important. The aim of the current study is to explore the role of natural killer T cells in impaired liver regeneration. Concanvalin A was injected 4 days before partial hepatectomy to natural killer T cells- deficient mice or to anti CD1d1-treated mice. Ki-67 and proliferating cell nuclear antigen were used to measure hepatocytes proliferation. Expression of hepatic cyclin B1 and proliferating cell nuclear antigen were evaluated by Western Blot and liver injury was assessed by ALT and histology. Natural killer T cells- deficient or mice injected with anti CD1d antibodies exhibited reduced liver regeneration. These mice were considerably resistant to ConA-induced liver injury. In the absence of NKT cells hepatic proliferating cell nuclear antigen and cyclin B1 decreased in mice injected with Concanvalin A before partial hepatectomy. This was accompanied with reduced serum interleukin-6 levels. Natural killer T cells play an important role in liver regeneration, which is associated with cyclin B1 and interleukin-6.

  11. Differential loss of natural killer cell activity in patients with acute myocardial infarction and stable angina pectoris.

    PubMed

    Yan, Wenwen; Zhou, Lin; Wen, Siwan; Duan, Qianglin; Huang, Feifei; Tang, Yu; Liu, Xiaohong; Chai, Yongyan; Wang, Lemin

    2015-01-01

    To evaluate the activity of natural killer cells through their inhibitory and activating receptors and quantity in peripheral blood mononuclear cells extracted from patients with acute myocardial infarction, stable angina pectoris and the controls. 100 patients with myocardial infarction, 100 with stable angina, and 20 healthy volunteers were recruited into the study. 20 randomly chosen people per group were examined for the whole human genome microarray analysis to detect the gene expressions of all 40 inhibitory and activating natural killer cell receptors. Flow cytometry analysis was applied to all 200 patients to measure the quantity of natural killer cells. In myocardial infarction group, the mRNA expressions of six inhibitory receptors KIR2DL2, KIR3DL3, CD94, NKG2A, KLRB1, KLRG1, and eight activating receptors KIR2DS3, KIR2DS5, NKp30, NTB-A, CRACC, CD2, CD7 and CD96 were significantly down-regulated (P<0.05) compared with both angina patients and the controls. There was no statistical difference in receptor expressions between angina patients and control group. The quantity of natural killer cells was significantly decreased in both infarction and angina patients compared with normal range (P<0.001). The significant mRNAs down-regulation of several receptors in myocardial infarction group and reduction in the quantity of natural killer cells in both myocardial infarction and angina patients showed a quantitative loss and dysfunction of natural killer cells in myocardial infarction patients.

  12. Diversification of both KIR and NKG2 natural killer cell receptor genes in macaques - implications for highly complex MHC-dependent regulation of natural killer cells.

    PubMed

    Walter, Lutz; Petersen, Beatrix

    2017-02-01

    The killer immunoglobulin-like receptors (KIR) as well as their MHC class I ligands display enormous genetic diversity and polymorphism in macaque species. Signals resulting from interaction between KIR or CD94/NKG2 receptors and their cognate MHC class I proteins essentially regulate the activity of natural killer (NK) cells. Macaque and human KIR share many features, such as clonal expression patterns, gene copy number variations, specificity for particular MHC class I allotypes, or epistasis between KIR and MHC class I genes that influence susceptibility and resistance to immunodeficiency virus infection. In this review article we also annotated publicly available rhesus macaque BAC clone sequences and provide the first description of the CD94-NKG2 genomic region. Besides the presence of genes that are orthologous to human NKG2A and NKG2F, this region contains three NKG2C paralogues. Hence, the genome of rhesus macaques contains moderately expanded and diversified NKG2 genes in addition to highly diversified KIR genes. The presence of two diversified NK cell receptor families in one species has not been described before and is expected to require a complex MHC-dependent regulation of NK cells.

  13. Natural killer cells: the journey from puzzles in biology to treatment of cancer.

    PubMed

    Bodduluru, Lakshmi Narendra; Kasala, Eshvendar Reddy; Madhana, Rajaram Mohan Rao; Sriram, Chandra Shaker

    2015-02-28

    Natural Killer (NK) cells are innate immune effectors that are primarily involved in immunosurveillance to spontaneously eliminate malignantly transformed and virally infected cells without prior sensitization. NK cells trigger targeted attack through release of cytotoxic granules, and secrete various cytokines and chemokines to promote subsequent adaptive immune responses. NK cells selectively attack target cells with diminished major histocompatibility complex (MHC) class I expression. This "Missing-self" recognition by NK cells at first puzzled researchers in the early 1990s, and the mystery was solved with the discovery of germ line encoded killer immunoglobulin receptors that recognize MHC-I molecules. This review summarizes the biology of NK cells detailing the phenotypes, receptors and functions; interactions of NK cells with dendritic cells (DCs), macrophages and T cells. Further we discuss the various strategies to modulate NK cell activity and the practice of NK cells in cancer immunotherapy employing NK cell lines, autologous, allogeneic and genetically engineered cell populations.

  14. Possible damage to immune-privileged sites in natural killer cell therapy in cancer patients: side effects of natural killer cell therapy.

    PubMed

    Bolourian, Alireza; Mojtahedi, Zahra

    2017-03-01

    Natural killer (NK) cells target the cells losing MHC-I in cancer, a phenotype that is similar to certain cells in immune-privileged sites whose milieus are separated from peripheral blood. NK cells are reported to be quantitatively and qualitatively different in immune-privileged sites from those cytotoxic ones in the blood. We hypothesize that cytotoxic and expanded NK cells induced in cancer patients may be turned into pathogenic factors if they enter immune-privileged microenvironments in susceptible individuals, such as, patients with brain cancer or a blood-brain barrier dysfunction. Therefore, in susceptible individuals, different levels of caution should be taken based on the seriousness of the side effect as discussed in this perspective.

  15. High frequency of activated natural killer and natural killer T-cells in patients with new onset of type 2 diabetes mellitus.

    PubMed

    Guo, Hui; Xu, Bingchuan; Gao, Lichao; Sun, Xiguang; Qu, Xiaozhang; Li, Xiaowei; Liu, Shumei; Feng, Junyan; Wang, Juan; Tang, Ying; Yan, Guoqiang; Gao, Xiuzhu; Jiang, Yanfang

    2012-05-01

    Chronic low-grade inflammation is crucial for the development of insulin resistance and type 2 diabetes mellitus (T2DM), and immunocompetent cells, such as T-cells, B-cells, mast cells and macrophages, regulate the pathogenesis of T2DM. However, little is known about the role of natural killer (NK) and natural killer T (NKT) cells in the pathogenic process of T2DM. A total of 16 patients with new onset T2DM and nine healthy subjects were recruited, and the frequency of peripheral blood activated and inhibitory NK and NKT cells in individual subjects was determined by flow cytometry. The frequency of spontaneous and inducible interferon gamma (IFN-γ) and CD107a(+) NK cells was further examined, and the potential association of the frequency of NK cells with clinical measures was analyzed. While there was no significant difference in the frequency of peripheral blood NK and NKT cells between patients and controls, the frequency of NKG2D(+) NK and NKT cells in patients was significantly higher than those in the controls (P = 0.011). In contrast, the frequency of NKG2A(+) and KIR2DL3(+) inhibitory NK and NKT cells in patients was significantly lower than those in the controls (P = 0.002, P < 0.0001, respectively). Furthermore, the frequencies of NKG2D(+) NK cells were correlated significantly with the values of body mass index in patients. Moreover, the frequencies of spontaneous and inducible CD107a(+), but not IFN-γ-secreting, NK cells in patients were significantly higher than those in the controls (P < 0.004, P < 0.0001). Our data indicated that a higher frequency of activated NK cells may participate in the obesity-related chronic inflammation involved in the pathogenesis of T2DM.

  16. Studies on the mechanism of natural killer cytotoxicity. III. Activation of NK cells by interferon augments the lytic activity of released natural killer cytotoxic factors (NKCF).

    PubMed

    Wright, S C; Bonavida, B

    1983-06-01

    The mechanism by which interferon (IFN) pretreatment of effector cells augments natural killer (NK) cell-mediated cytotoxicity (CMC) was examined by determining whether IFN has any effect on the production of natural killer cytotoxic factors (NKCF). NKCF are released into the supernatant of co-cultures of murine spleen cells and YAC-1 stimulator cells, and their lytic activity is measured against YAC-1 target cells. It was demonstrated that pretreatment of effector cells with murine fibroblast IFN or polyinosinic-polycytidylic acid (pIC) resulted in the release of NKCF with augmented lytic activity. Evidence indicated that the IFN-induced augmentation of NKCF activity required protein synthesis during the IFN pretreatment period, because concurrent pretreatment with both IFN and cycloheximide abrogated the IFN effect. Protein synthesis, however, is not required for the production of base levels of NKCF because emetine pretreatment of normal spleen cells did not result in a decrease in NKCF production. Furthermore, substantial levels of NKCF activity could be detected in freeze-thaw lysates of freshly isolated spleen cells. Cell populations enriched for NK effector cells, such as nylon wool-nonadherent nude mouse spleen cells, produced lysates with high levels of NKCF activity, whereas lysates of CBA thymocytes were devoid of NKCF activity. Pretreatment of spleen cells with either IFN or pIC resulted in an augmentation of the NKCF activity present in their cell lysates. Taken altogether, these findings suggest that freshly isolated NK cells contain preformed pools of NKCF. Pretreatment of these cells with IFN causes de novo synthesis of additional NKCF and/or activation of preexisting NKCF. According to our model for the mechanism of NK CMC, target cell lysis is ultimately the result of transfer of NKCF from the effector cell to the target cell. The evidence presented here suggests that the IFN-induced augmentation of NK activity could be accounted for by an

  17. Interactive effects of Na and K in killing by natural killer cells

    SciTech Connect

    Schlichter, L.C.; MacCoubrey, I.C. )

    1989-09-01

    Contact-mediated lysis by human natural killer cells is inhibited by a number of drugs that block the predominant K channel. In this study the authors have further examined the role of the K channel and the interactions between passive K and Na transport in killing. Low external Na-inhibited killing and inhibition were not due to reduced inward current through the Na channels in the target cell. A role for the Na/H antiport is suggested since amiloride inhibited killing in a dose-dependent manner that was competitive with external Na. Depolarizing the killer cell with elevated external K did not inhibit killing. On the contrary, high K{sub 0} reduced the inhibition caused by low Na{sub 0} and by the K-channel blockers quinidine, verapamil, and retinoic acid. Hyperpolarizing the killer cell with low K{sub 0} or valinomycin inhibited killing. Hence, the primary role of the K channels during killing is not to maintain the negative membrane potential. On the contrary, depolarization may promote killing under conditions where killing is submaximal.

  18. Regulation of natural killer activity of lymphocytes from normal subjects and patients with chronic lymphatic leukemia by interaction between T and non-T cells

    SciTech Connect

    Khonina, N.A.; Shubinskii, G.Z.; Lozovoi, V.P.

    1987-08-01

    The authors study the effect of culture of human cells on functional activity of natural killer cells and investigate the possible mechanisms of regulation of natural killer activity by acting on cytodifferentiation of lymphocytes in normal subjects and in patients with the B-cell variant of chromic lymphatic leukemia. To estimate natural killer cell function, a membranotoxic test was carried out, using cells of the transplantable line K-562, labeled with /sup 3/H-uridine as the targets.

  19. Phenotypic modulation of porcine CD14+ monocytes, natural killer/natural killer T cells and CD8αβ+ T cell subsets by an antibody-derived killer peptide (KP).

    PubMed

    Ferrari, Luca; Borghetti, Paolo; Ferrarini, Giulia; De Angelis, Elena; Canelli, Elena; Ogno, Giulia; Catella, Alessia; Ciociola, Tecla; Magliani, Walter; Martelli, Paolo

    2016-12-01

    An engineered killer peptide (KP) based on a recombinant anti-idiotypic antibody representing the functional image of a yeast killer toxin (KT) was demonstrated to mediate antimicrobial effects against fungi and viruses. KP binds to murine dendritic cells and macrophages and up-regulate co-receptor expression, thus sustaining CD4+ lymphocyte activation. No immunological data are available in domestic animals thus KP-induced immunomodulation was evaluated in porcine monocyte and lymphocyte subsets. PBMC from healthy adult pigs were stimulated with KP or a scramble peptide (SP), or kept unstimulated for 24, 48 and 72h, and subsequently analyzed by flow cytometry. In monocytes, KP induced a strong dose-dependent shift from a major fraction of CD172α+CD14+(low) cells to a predominant fraction of CD172α+CD14+(high) cells, known to sustain leukocyte activation/differentiation and inflammatory responses. The CD16+ cell percentages, specifically the CD3+CD16+ natural killer T (NKT) cell fraction and CD16 expression showed an intense and stable dose-dependent increase while the CD3-CD16+ NK cell fraction decreased. CD4+ and CD8+ T cells increased and CD8α and CD8β expression were up-regulated. CD8β+ cytotoxic T cells and CD16+ cells comparably increased. A marked stimulation of activated CD16+CD25+ and CD8β+CD25+ cells was observed at 24h. The increase of CD8α+ cells and CD8α expression were due to increased CD4+CD8α+ (memory T helper) cells, also showing a CD8α+(high) phenotype. Concomitantly, the CD4+CD8α- T helper lymphocyte fraction significantly decreased. Overall, KP induced a wide modulation of innate immune and T cells that can exert regulatory and cytotoxic functions, which are fundamental for an efficient Th1 response.

  20. Invariant Natural Killer T Cell Deficiency and Functional Impairment in Sleep Apnea: Links to Cancer Comorbidity.

    PubMed

    Gaoatswe, Gadintshware; Kent, Brian D; Corrigan, Michelle A; Nolan, Geraldine; Hogan, Andrew E; McNicholas, Walter T; O'Shea, Donal

    2015-10-01

    Emerging evidence links obstructive sleep apnea (OSA) with increased cancer incidence and mortality. Invariant natural killer T (iNKT) cells play an important role in cancer immunity. We hypothesized that patients with OSA have low number of circulating invariant natural killer T (iNKT) cells, which may also be functionally impaired. This study aims to evaluate the frequency of circulating iNKT cells in OSA. We evaluated the frequency of circulating iNKT cells by flow cytometry in 33 snorers being assessed for possible OSA. Using iNKT cell lines, we also evaluated the effect of exposure to hypoxia over 24 hours on apoptosis, cytotoxicity, and cytokine production. Teaching hospital based sleep unit and research laboratory. Thirty-three snorers were evaluated: 9 with no OSA (apnea-hypopnea frequency [AHI] < 5/h), 12 with mild-moderate OSA (AHI 5-30) and 12 with severe OSA (AHI > 30). Patients with severe OSA had considerably fewer iNKT cells (0.18%) compared to patients with mild-moderate (0.24%) or no OSA (0.35%), P = 0.0026. The frequency of iNKT cells correlated negatively with apnea-hypopnea index (r = -0.58, P = 0.001), oxygen desaturation index (r = -0.58, P = 0.0003), and SpO2% < 90% (r = -0.5407, P = 0.005). The frequency of iNKT cells increased following 12 months of nCPAP therapy (P = 0.015). Hypoxia resulted in increased apoptosis (P = 0.016) and impaired cytotoxicity (P = 0.035). Patients with obstructive sleep apnea (OSA) have significantly reduced levels of circulating invariant natural killer T (iNKT) cells and hypoxia leads to impaired iNKT cell function. These observations may partly explain the increased cancer risk reported in patients with OSA. © 2015 Associated Professional Sleep Societies, LLC.

  1. NCR1 Expression Identifies Canine Natural Killer Cell Subsets with Phenotypic Similarity to Human Natural Killer Cells.

    PubMed

    Foltz, Jennifer A; Somanchi, Srinivas S; Yang, Yanwen; Aquino-Lopez, Arianexys; Bishop, Erin E; Lee, Dean A

    2016-01-01

    Canines spontaneously develop many cancers similar to humans - including osteosarcoma, leukemia, and lymphoma - offering the opportunity to study immune therapies in a genetically heterogeneous and immunocompetent environment. However, a lack of antibodies recognizing canine NK cell markers has resulted in suboptimal characterization and unknown purity of NK cell products, hindering the development of canine models of NK cell adoptive immunotherapy. To this end, we generated a novel antibody to canine NCR1 (NKp46), the putative species-wide marker of NK cells, enabling purification of NK cells for further characterization. We demonstrate that CD3(-)/NKp46(+) cells in healthy and osteosarcoma-bearing canines have phenotypic similarity to human CD3(-)/NKp46(+) NK cells, expressing mRNA for CD16 and the natural cytotoxicity receptors NKp30, NKp44, and NKp80. Functionally, we demonstrate with the calcein release assay that canine CD3(-)/NKp46(+) cells kill canine tumor cell lines without prior sensitization and secrete IFN-γ, TNF-α, IL-8, IL-10, and granulocyte-macrophage colony-stimulating factor as measured by Luminex. Similar to human NK cells, CD3(-)/NKp46(+) cells expand rapidly on feeder cells expressing 4-1BBL and membrane-bound IL-21 (median = 20,283-fold in 21 days). Furthermore, we identify a minor Null population (CD3(-)/CD21(-)/CD14(-)/NKp46(-)) with reduced cytotoxicity against osteosarcoma cells, but similar cytokine secretion as CD3(-)/NKp46(+) cells. Null cells in canines and humans have reduced expression of NKG2D, NKp44, and CD16 compared to NKp46(+) NK cells and can be induced to express NKp46 with further expansion on feeder cells. In conclusion, we have identified and characterized canine NK cells, including an NKp46(-) subset of canine and human NK cells, using a novel anti-canine NKp46 antibody, and report robust ex vivo expansion of canine NK cells sufficient for adoptive immunotherapy.

  2. The role of natural killer cells in tumor control--effectors and regulators of adaptive immunity.

    PubMed

    Wallace, Morgan E; Smyth, Mark J

    2005-06-01

    Natural killer (NK) cells are the primary effector cells of the innate immune system and have a well-established role in tumor rejection in a variety of spontaneous and induced cancer models. NK cell function is regulated by a complex balance of inhibitory and activating signals that allow them to selectively target and kill cells that display an abnormal pattern of cell surface molecules, while leaving normal healthy cells unharmed. In this review we discuss NK cell function, the role of NK cells in cancer therapies, the emerging concept of bi-directional cross-talk between NK cells and dendritic cells, and the implications of these interactions for tumor immunotherapy.

  3. Umbilical Cord Blood Natural Killer Cells, Their Characteristics, and Potential Clinical Applications

    PubMed Central

    Sarvaria, Anushruti; Jawdat, Dunia; Madrigal, J. Alejandro; Saudemont, Aurore

    2017-01-01

    Natural killer (NK) cells are lymphocytes of the innate immune system able to kill different targets such as cancer cells and virally infected cells without prior activation making then attractive candidates for cancer immunotherapy. Umbilical cord blood (UCB) has become a source of hematopoietic stem cells for transplantation but as we gain a better understanding of the characteristics of each immune cell that UCB contains, we will also be able to develop new cell therapies for cancer. In this review, we present what is currently known of the phenotype and functions of UCB NK cells and how these cells could be used in the future for cancer immunotherapy. PMID:28386260

  4. Clinical applications of adoptive natural killer cell immunotherapy for cancer: current status and future prospects.

    PubMed

    Guo, Hongfeng; Qian, Xifeng

    2010-01-01

    Natural killer (NK) cells are cytotoxic and cytokine-producing lymphocytes involved in the immune defense against viral infections and tumors. NK cells activated with cytokines, such as interleukin-2, have been used since the 1980s as adoptive immunotherapy against cancer. NK cell alloreactivity has been demonstrated to enhance control of acute myeloid leukemia relapse and greatly reduce the risk of graft-versus-host disease in HLA haplotype-mismatched hematopoietic transplantation, and has been explored as a tool for adoptive immunotherapy for cancer patients. Future manipulation to improve NK cell adoptive immunotherapy by means of increasing target recognition and reducing inhibitory signaling is being explored.

  5. The Expanding Role of Natural Killer Cells in Type 1 Diabetes and Immunotherapy.

    PubMed

    Fraker, Chris; Bayer, Allison L

    2016-11-01

    Treatments for autoimmune diseases including type 1 diabetes (T1D) are aimed at resetting the immune system, especially its adaptive arm. The innate immune system is often ignored in the design of novel immune-based therapies. There is increasing evidence for multiple natural killer (NK) subpopulations, but their role is poorly understood in autoimmunity and likely is contributing to the controversial role reported for NKs. In this review, we will summarize NK subsets and their roles in tolerance, autoimmune diabetes, and immunotherapy.

  6. Maternal uterine natural killer cells nurture fetal growth: in medio stat virtus.

    PubMed

    Colucci, Francesco; Kieckbusch, Jens

    2015-02-01

    Much research in reproductive immunology is preoccupied with maternal tolerance of the semi-allogeneic fetus. This inevitably leads to the assumption that the maternal immune system should be suppressed, similarly to the immunosuppression needed to avoid rejection of an allograft. However, the parallels with transplantation immunology are misleading, and we discuss how interactions between variable immune system genes expressed on maternal natural killer (NK) cells and on the fetal trophoblast modulate fetal growth. Exaggerated suppression or activation of maternal NK cells associates with both extremes of birth weight. Copyright © 2015. Published by Elsevier Ltd.

  7. [Natural killer cells and the innate immune system in infectious pathology].

    PubMed

    Sepúlveda, C; Puente, J

    2000-12-01

    Natural killer (NK) cells form a unique third group of lymphocytes that differs from T and B cells in surface phenotype, target cell recognition and function. NK cells have two relevant functions, related to the innate immune response against pathogens microorganisms. One is cytotoxicity, mediated by the recognition and lysis of target cells such as virus and bacteria infected-cells. The second NK cell function is to produce cytokines, mainly IFN-gamma, that can modulate innate and specific immune responses. Cytotoxicity and cytokine secretion contribute to host resistance against microorganisms and both functions are significantly altered in infectious diseases.

  8. Natural Killer T-Cell Lymphoma of the Orbit: An Evidence-Based Approach.

    PubMed

    Jiménez-Pérez, Juan C; Yoon, Michael K

    2017-01-01

    Natural killer T-cell lymphoma (NKTCL) is a rare and aggressive condition with a high mortality rate. It is most commonly seen in the nasal sinuses, generally affecting the orbit by direct extension. Primary orbital NKTCL is even more rare, with only a few published cases with occasional secondary nasal involvement. This malignancy can present as a "masquerade syndrome," delaying proper diagnosis and treatment. Biopsy is required for diagnosis, which shows specific histopathological characteristics. Radiation and chemotherapy are the mainstay of treatment. Newer chemotherapies show improved prognosis.

  9. Increase in natural killer cell activity during diethylcarbamazine treatment of patients with filariasis.

    PubMed

    Pedersen, B K; Bygbjerg, I C; Svenson, M

    1987-09-01

    Two patients, one with Bancroftian filariasis and the other with onchocerciasis, and two healthy controls were treated with diethylcarbamazine (DEC). The natural killer (NK) cell activity of the two patients increased during DEC treatment to 2.5 and 2.8 times, respectively, while that of the controls remained unchanged. We conclude that the augmentation of baseline NK cell activity, as well as interferon- and interleukin-2-enhanced NK cell activity seen in the patients, is not a direct effect of DEC, but is related to the reaction to DEC in lymphatic filariasis and onchocerciasis.

  10. NCR1 Expression Identifies Canine Natural Killer Cell Subsets with Phenotypic Similarity to Human Natural Killer Cells

    PubMed Central

    Foltz, Jennifer A.; Somanchi, Srinivas S.; Yang, Yanwen; Aquino-Lopez, Arianexys; Bishop, Erin E.; Lee, Dean A.

    2016-01-01

    Canines spontaneously develop many cancers similar to humans – including osteosarcoma, leukemia, and lymphoma – offering the opportunity to study immune therapies in a genetically heterogeneous and immunocompetent environment. However, a lack of antibodies recognizing canine NK cell markers has resulted in suboptimal characterization and unknown purity of NK cell products, hindering the development of canine models of NK cell adoptive immunotherapy. To this end, we generated a novel antibody to canine NCR1 (NKp46), the putative species-wide marker of NK cells, enabling purification of NK cells for further characterization. We demonstrate that CD3−/NKp46+ cells in healthy and osteosarcoma-bearing canines have phenotypic similarity to human CD3−/NKp46+ NK cells, expressing mRNA for CD16 and the natural cytotoxicity receptors NKp30, NKp44, and NKp80. Functionally, we demonstrate with the calcein release assay that canine CD3−/NKp46+ cells kill canine tumor cell lines without prior sensitization and secrete IFN-γ, TNF-α, IL-8, IL-10, and granulocyte-macrophage colony-stimulating factor as measured by Luminex. Similar to human NK cells, CD3−/NKp46+ cells expand rapidly on feeder cells expressing 4-1BBL and membrane-bound IL-21 (median = 20,283-fold in 21 days). Furthermore, we identify a minor Null population (CD3−/CD21−/CD14−/NKp46−) with reduced cytotoxicity against osteosarcoma cells, but similar cytokine secretion as CD3−/NKp46+ cells. Null cells in canines and humans have reduced expression of NKG2D, NKp44, and CD16 compared to NKp46+ NK cells and can be induced to express NKp46 with further expansion on feeder cells. In conclusion, we have identified and characterized canine NK cells, including an NKp46− subset of canine and human NK cells, using a novel anti-canine NKp46 antibody, and report robust ex vivo expansion of canine NK cells sufficient for adoptive immunotherapy. PMID:27933061

  11. Deciphering the killer-cell immunoglobulin-like receptor system at super-resolution for natural killer and T-cell biology.

    PubMed

    Béziat, Vivien; Hilton, Hugo G; Norman, Paul J; Traherne, James A

    2017-03-01

    Killer-cell immunoglobulin-like receptors (KIRs) are components of two fundamental biological systems essential for human health and survival. First, they contribute to host immune responses, both innate and adaptive, through their expression by natural killer cells and T cells. Second, KIR play a key role in regulating placentation, and hence reproductive success. Analogous to the diversity of their human leucocyte antigen class I ligands, KIR are extremely polymorphic. In this review, we describe recent developments, fuelled by methodological advances, that are helping to decipher the KIR system in terms of haplotypes, polymorphisms, expression patterns and their ligand interactions. These developments are delivering deeper insight into the relevance of KIR in immune system function, evolution and disease.

  12. Association of polymorphisms in natural killer cell-related genes with preterm birth.

    PubMed

    Harmon, Quaker E; Engel, Stephanie M; Olshan, Andrew F; Moran, Thomas; Stuebe, Alison M; Luo, Jingchun; Wu, Michael C; Avery, Christy L

    2013-10-15

    Inflammation is implicated in preterm birth, but genetic studies of inflammatory genes have yielded inconsistent results. Maternal DNA from 1,646 participants in the Pregnancy, Infection, and Nutrition Cohort, enrolled in Orange and Wake counties, North Carolina (1995-2005), were genotyped for 432 tag single-nucleotide polymorphisms (SNPs) in 30 candidate genes. Gene-level and SNP associations were modeled within strata of genetic ancestry. Six genes were associated with preterm birth among European Americans: interleukin 12A (IL12A); colony-stimulating factor 2 (CSF2); interferon γ receptor 2 (IFNGR2); killer cell immunoglobulin-like receptor, three domain, long cytoplasmic tail, 2 (KIR3DL2); interleukin 4 (IL4); and interleukin 13 (IL13). Of these, relatively strong single-SNP associations were seen in IFNGR2 and KIR3DL2. Among the 4 genes related to natural killer cell function, 2 (IL12A and CSF2) were consistently associated with reduced risk of prematurity for both European and African Americans. SNPs tagging a locus control region for IL4 and IL13 were associated with an increased risk of spontaneous preterm birth for European Americans (rs3091307; risk ratio = 1.9; 95% confidence interval: 1.4, 2.5). Although gene-level associations were detected only in European Americans, single-SNP associations among European and African Americans were often similar in direction, though estimated with less precision among African Americans. In conclusion, we identified novel associations between variants in the natural killer cell immune pathway and prematurity in this biracial US population.

  13. IMPAIRED NATURAL KILLER CELL LYSIS IN BREAST CANCER PATIENTS WITH HIGH LEVELS OF PSYCHOLOGICAL STRESS IS ASSOCIATED WITH ALTERED EXPRESSION OF KILLER IMMUNOGLOBULIN-LIKE RECEPTORS

    PubMed Central

    Varker, Kimberly A.; Terrell, Catherine E.; Welt, Marilyn; Suleiman, Samer; Thornton, Lisa; Andersen, Barbara L.; Carson, William E.

    2007-01-01

    Background We previously reported that cancer-related psychological stress is associated with reduced natural killer (NK) cell lysis. We hypothesized that reduced NK cell cytotoxicity in patients with increased levels of stress would correlate with alterations in the expression of inhibitory NK cell receptors (killer immunoglobulin-like receptors, or KIRs). The specific aim of this study was to examine KIR expression in patients with high or low levels of psychologic stress and correlate alterations in KIR expression with NK cell function. Materials and Methods 227 patients underwent baseline evaluation of cancer-related psychological stress and were randomized to psychosocial intervention versus observation. From this population, two groups were defined based on pre-treatment measurements of NK lytic activity, stress levels, and the availability of cryopreserved peripheral blood mononuclear cells (PBMC). Group I (n = 9) had low stress by the Impact of Events Scale (IES), and high NK cell lysis at the 50:1 effector: target ratio (NK50 = 52–89%). Group II (n = 8) had high stress and low NK50 (27–52%). Lymphokine activated killer (LAK) activity, antibody dependent cellular cytotoxicity (ADCC), and expression of cytokine receptors, adhesion molecules, and killer immunoglobulin-like receptors (KIRs) were assessed in PBMC. Results Incubation of PBMC with NK-stimulatory cytokines (IL-2, IL-12, or IL-15) led to significant increases in cytotoxic activity regardless of IES/NK50 scores. There were no significant group differences in NK cell surface expression of the IL-2 receptor components CD25 and CD122, antibody-dependent lysis of HER2/neu-positive SKBr3 cells treated with an anti-HER2/neu monoclonal antibody, expression of adhesion molecules (CD2, CD11a, CD18) and markers of activation (CD69), or expression of the KIRs CD158a, NKG2a, NKB1, and CD161. However, levels of CD158b were significantly higher in Group I after incubation in media alone or with IL-2, and CD94

  14. Natural killer cell activity of peripheral blood mononuclear cells from patients with various forms of systemic scleroderma.

    PubMed

    Majewski, S; Blaszczyk, M; Wasik, M; Jablonska, S

    1987-01-01

    Peripheral blood mononuclear cells from 63 patients with systemic scleroderma, including incipient or prodromal acrosclerosis, and from 20 healthy individuals were tested for natural killer (NK) cell activity and antibody-dependent cell cytotoxicity in a 4 h 51Cr release assay using K562 and L1210 cell lines respectively. In patients with systemic scleroderma natural killer cell activity was significantly decreased compared with the controls. NK cell activity was markedly lowered in patients with diffuse scleroderma and in transitional form acrosclerosis-diffuse scleroderma, and was normal in cases of acrosclerosis and/or CREST syndrome and in cases of prodromal or incipient scleroderma. Antibody-dependent cell cytotoxicity of mononuclear cells from the systemic scleroderma patients was within the normal range. The lowered natural killer cell activity correlated with the severity of systemic scleroderma, in terms of the extent of skin and organ involvement.

  15. Novel strategies of adoptive immunotherapy: How natural killer cells may change the treatment of elderly patients with acute myeloblastic leukemia.

    PubMed

    Lemoli, Roberto M; Parisi, Sarah; Curti, Antonio

    2017-01-01

    Although many attempts have been made to identify novel molecular-targeted therapies for patients with acute myeloid leukemia, their translation into the clinic have had limited impact. In particular, the question of effective and curative treatments for elderly patients, who are not eligible for stem cell transplantation, remains an unmet medical need. To answer this question, a wide range of immunologic therapeutic strategies, mostly T cell based, have been proposed and investigated. At present, however, the clinical results have been largely unsatisfactory. Natural killer cells have recently been used as a means of adoptive immunotherapy with promising clinical results. On the basis of recent clinical reports and moving from the basic immunobiology of natural killer cells, here we discuss some open issues in the clinical translation of natural killer-based adoptive immunotherapy for the management of elderly patients with acute myeloid leukemia.

  16. Relation of Depression, Natural Killer Cell Function, and Infections after Coronary Artery Bypass in Women

    PubMed Central

    Doering, Lynn V.; Martínez-Maza, Otoniel; Vredevoe, Donna L.; Cowan, Marie J.

    2008-01-01

    Background After hospital discharge for coronary artery bypass grafting (CABG), infection is a common cause of morbidity. Although depression has been associated with immune dysfunction, its role in post-CABG infection is unknown. Aims The purpose of this study was to: 1) compare natural killer cell cytotoxicity (NKCC) and post-hospitalization infections in depressed and non-depressed women after CABG; and 2) test whether NKCC mediated the relationship between post-discharge depression and infections. Methods Sixty-seven women recovering from CABG were assessed for depression prior to hospital discharge and followed for six months. Major depression was identified by a structured clinical interview. Infections were identified by patient report using the Modified Health Review and by medical chart audit. Results Compared to non-depressed women after CABG, women with major depression had reduced NKCC, more all-cause infections, and more self-reported illnesses. Although NKCC did not mediate the relationship between depression and wound (i.e. incisional) infections after CABG, it did mediate the relationship between depression and non-wound infections, including pneumonias and upper respiratory infections. Conclusions For the first six months after CABG, women with major depression are at increased risk for infections. Natural killer cell cytotoxicity may be related to this phenomenon, particularly to non-wound infections. PMID:17716947

  17. Natural Killer Group 2, Member D/NKG2D Ligands in Hematopoietic Cell Transplantation

    PubMed Central

    Carapito, Raphael; Aouadi, Ismail; Ilias, Wassila; Bahram, Seiamak

    2017-01-01

    Natural killer group 2, member D (NKG2D) is an invariant activatory receptor present on subsets of natural killer and T lymphocytes. It stimulates the cytolytic effector response upon engagement of its various stress-induced ligands NKG2D ligands (NKG2DL). Malignant transformation and conditioning treatment prior to hematopoietic cell transplantation (HCT) are stress factors leading to the activation of the NKG2D/NKG2DL signaling in clinical settings. In the context of HCT, NKG2D-bearing cells can kill both tumor and healthy cells expressing NKG2DL. The NKG2D/NKG2DL engagement has therefore a key role in the regulation of one of the most salient issues in allogeneic HCT, i.e., maintaining a balance between graft-vs.-leukemia effect and graft-vs.-host disease. The present review summarizes the current state of our knowledge pertaining to the role of the NKG2D and NKG2DL in HCT. PMID:28396673

  18. Antibody-dependent cellular cytotoxicity toward neuroblastoma enhanced by activated invariant natural killer T cells.

    PubMed

    Mise, Naoko; Takami, Mariko; Suzuki, Akane; Kamata, Toshiko; Harada, Kazuaki; Hishiki, Tomoro; Saito, Takeshi; Terui, Keita; Mitsunaga, Tetsuya; Nakata, Mitsuyuki; Ikeuchi, Takayuki; Nakayama, Toshinori; Yoshida, Hideo; Motohashi, Shinichiro

    2016-03-01

    Anti-ganglioside GD2 antibodies mainly work through antibody-dependent cellular cytotoxicity (ADCC) and have demonstrated clinical benefit for children with neuroblastoma. However, high-risk neuroblastoma still has a high recurrence rate. For further improvement in patient outcomes, ways to maximize the cytotoxic effects of anti-GD2 therapies with minimal toxicity are required. Activated invariant natural killer T (iNKT) cells enhance both innate and type I acquired anti-tumor immunity by producing several kinds of cytokines. In this report, we investigated the feasibility of combination therapy using iNKT cells and an anti-GD2 antibody. Although some of the expanded iNKT cells expressed natural killer (NK) cell markers, including FcγR, iNKT cells were not directly associated with ADCC. When co-cultured with activated iNKT cells, granzyme A, granzyme B and interferon gamma (IFNγ) production from NK cells were upregulated, and the cytotoxicity of NK cells treated with anti-GD2 antibodies was increased. Not only cytokines produced by activated iNKT cells, but also NK-NKT cell contact or NK cell-dendritic cell contact contributed to the increase in NK cell cytotoxicity and further IFNγ production by iNKT cells and NK cells. In conclusion, iNKT cell-based immunotherapy could be an appropriate candidate for anti-GD2 antibody therapy for neuroblastoma.

  19. Abnormalities of quantities and functions of natural killer cells in severe aplastic anemia.

    PubMed

    Liu, Chunyan; Li, Zhishang; Sheng, Weiwei; Fu, Rong; Li, Lijuan; Zhang, Tian; Wu, Yuhong; Xing, Limin; Song, Jia; Wang, Huaquan; Shao, Zonghong

    2014-01-01

    Severe aplastic anemia (SAA) is a rare disease characterized by severe pancytopenia and bone marrow failure. Natural killer (NK) cells are large granular lymphocytes derived from hematopoietic stem cells (HSCs) or common lymphoid progenitors (CLP). They play a key role in n the innate immunity and adaptive immune. In this study, the quantitative and functional changes of natural killer (NK) cell subsets in peripheral blood of severe aplastic anemia (SAA) patients before and after immunosuppressive therapy (IST) were investigated. Results showed that the percentage of NK cells and its subsets in peripheral blood lymphocytes was decreased in SAA patients. After IST, the percentage of NK cells and their subsets increased dramatically. The median expressions of CD158a, NKG2D and NKp46 on NK cells were higher in SAA patients compared to that in normal controls, and the expressions of perforin in newly diagnosed and recovery SAA patients were higher than that in controls. Therefore, we concluded that the decrease of total NK cells, and CD56(bright), CD56(dim) NK cell subsets and the higher expressions of NKp46 and perforin on NK cells may cause the over-function of T lymphocytes and thus lead to hematopoiesis failure in SAA.

  20. A STED-FLIM microscope applied to imaging the natural killer cell immune synapse

    NASA Astrophysics Data System (ADS)

    Lenz, M. O.; Brown, A. C. N.; Auksorius, E.; Davis, D. M.; Dunsby, C.; Neil, M. A. A.; French, P. M. W.

    2011-03-01

    We present a stimulated emission depletion (STED) fluorescence lifetime imaging (FLIM) microscope, excited by a microstructured optical fibre supercontinuum source that is pumped by a femtosecond Ti:Sapphire-laser, which is also used for depletion. Implemented using a piezo-scanning stage on a laser scanning confocal fluorescence microscope system with FLIM realised using time correlated single photon counting (TCSPC), this provides convenient switching between confocal and STED-FLIM with spatial resolution down to below 60 nm. We will present our design considerations to make a robust instrument for biological applications including a comparison between fixed phase plate and spatial light modulator (SLM) approaches to shape the STED beam and the correlation of STED and confocal FLIM microscopy. Following our previous application of FLIM-FRET to study intercellular signalling at the immunological synapse (IS), we are employing STED microscopy to characterize the spatial distribution of cellular molecules with subdiffraction resolution at the IS. In particular, we are imaging cytoskeletal structure at the Natural Killer cell activated immune synapse. We will also present our progress towards multilabel STED microscopy to determine how relative spatial molecular organization, previously undetectable by conventional microscopy techniques, is important for NK cell cytotoxic function. Keywords: STED, Stimulated Emission Depletion Microscopy, Natural Killer (NK) cell, Fluorescence lifetime imaging, FLIM, Super resolution microscopy.

  1. Interactions between natural killer cells, cortisol and prolactin in malaria during pregnancy.

    PubMed

    Mavoungou, Elie

    2006-03-01

    Natural killer cells derived from pluripotent hematopoietic stem cells are important cells of the immune system that have two main functions: a cytolytic activity and a cytokine-producing capacity. These functions are tightly regulated by numerous activating and inhibitory receptors, including newly discovered receptors that selectively trigger the cytolytic activity in a major histocompatibility complex independent manner. Based on their defining function of spontaneous cytotoxicity without prior immunization, natural killer (NK) cells have been thought to play a critical role in immune surveillance and cancer therapy. New insights into NK cell biology have suggested their major roles in the control of infections, particularly in Plasmodium falciparum infection and in fetal implantation. P. falciparum is the main protozoan parasite responsible for malaria causing 200-300 million clinical cases and killing over 3 million people each year. This review provides an update on NK cell function, ontogeny and biology in order to better understand the role of NK cells in pregnancy in regions where malaria is endemic. Understanding mechanisms of NK cell functions may lead to novel therapeutic strategies for the treatment of human disease, in general, and particularly in the fight against malaria.

  2. Reciprocal Crosstalk between Dendritic Cells and Natural Killer T Cells: Mechanisms and Therapeutic Potential

    PubMed Central

    Keller, Christian W.; Freigang, Stefan; Lünemann, Jan D.

    2017-01-01

    Natural killer T cells carrying a highly conserved, semi-invariant T cell receptor (TCR) [invariant natural killer T (iNKT) cells] are a subset of unconventional T lymphocytes that recognize glycolipids presented by CD1d molecules. Although CD1d is expressed on a variety of hematopoietic and non-hematopoietic cells, dendritic cells (DCs) are key presenters of glycolipid antigen in vivo. When stimulated through their TCR, iNKT cells rapidly secrete copious amounts of cytokines and induce maturation of DCs, thereby facilitating coordinated stimulation of innate and adaptive immune responses. The bidirectional crosstalk between DCs and iNKT cells determines the functional outcome of iNKT cell-targeted responses and iNKT cell agonists are used and currently being evaluated as adjuvants to enhance the efficacy of antitumor immunotherapy. This review illustrates mechanistic underpinnings of reciprocal DCs and iNKT cell interactions and discusses how those can be harnessed for cancer therapy. PMID:28596767

  3. Natural Killer-like B Cells Prime Innate Lymphocytes against Microbial Infection.

    PubMed

    Wang, Shuo; Xia, Pengyan; Chen, Yi; Huang, Guanling; Xiong, Zhen; Liu, Jing; Li, Chong; Ye, Buqing; Du, Ying; Fan, Zusen

    2016-07-19

    Natural killer (NK) cells and non-cytotoxic interferon-γ (IFN-γ)-producing group I innate lymphoid cells (ILC1s) produce large amounts of IFN-γ and cause activation of innate and adaptive immunity. However, how NKs and ILC1s are primed during infection remains elusive. Here we have shown that a lymphocyte subpopulation natural killer-like B (NKB) cells existed in spleen and mesenteric lymph nodes (MLNs). NKBs had unique features that differed from T and B cells, and produced interleukin-18 (IL-18) and IL-12 at an early phase of infection. NKB cells played a critical role in eradication of microbial infection via secretion of IL-18 and IL-12. Moreover, IL-18 deficiency abrogated the antibacterial effect of NKBs. Upon bacterial challenge, NKB precursors (NKBPs) rapidly differentiated to NKBs that activated NKs and ILC1s against microbial infection. Our findings suggest that NKBs might be exploited to develop effective therapies for treatment of infectious diseases. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Identification of a potent microbial lipid antigen for diverse Natural Killer T cells1

    PubMed Central

    Wolf, Benjamin J.; Tatituri, Raju V. V.; Almeida, Catarina F.; Le Nours, Jérôme; Bhowruth, Veemal; Johnson, Darryl; Uldrich, Adam P.; Hsu, Fong-Fu; Brigl, Manfred; Besra, Gurdyal S.; Rossjohn, Jamie; Godfrey, Dale I.; Brenner, Michael B.

    2016-01-01

    Invariant Natural Killer T (iNKT) cells are a well-characterized CD1d-restricted T cell subset. The availability of potent antigens and tetramers for iNKT cells has allowed this population to be extensively studied and has revealed their central roles in infection, autoimmunity, and tumor immunity. In contrast, diverse Natural Killer T (dNKT) cells are poorly understood because the lipid antigens they recognize are largely unknown. We sought to identify dNKT cell lipid antigen(s) by interrogating a panel of dNKT mouse cell hybridomas with lipid extracts from the pathogen Listeria monocytogenes. We identified Listeria phosphatidylglycerol (PG) as a microbial antigen that was significantly more potent than a previously characterized dNKT cell antigen, mammalian PG. Further, while mammalian PG loaded CD1d tetramers did not stain dNKT cells, the Listeria-derived PG loaded tetramers did. The structure of Listeria PG was distinct from mammalian PG since it contained shorter, fully-saturated anteiso fatty acid lipid tails. CD1d binding lipid displacement studies revealed that the microbial PG antigen binds significantly better to CD1d than counterparts with the same headgroup. These data reveal a highly-potent microbial lipid antigen for a subset of dNKT cells and provide an explanation for its increased antigen potency compared to the mammalian counterpart. PMID:26254340

  5. Bone marrow mesenchymal stem cells suppressing activation of allogeneic cytokine-induced killer/natural killer cells either by direct or indirect interaction.

    PubMed

    Li, Yang; Qu, Yu H; Wu, Yan F; Liu, Ling; Lin, Xiang H; Huang, Ke; Wei, Jing

    2015-04-01

    Bone marrow mesenchymal stem cells (MSC) were recently found to be associated with some special immunological characteristics, the immunoregulatory effect of MSC was dose-dependent. Low amount of MSC was associated with mild immunosuppression or even immune activation, while the high amount of that was associated with significant immunosuppressive effect. In this study, by using a transwell system, we explored the effect of MSC on the cell cycle, apoptosis rate and the expression of CD69, an activation marker, on the allogeneic cord blood derived cytokine-induced killer(CIK)/natural killer(NK) cells. The results showed that either by transwell or mixed cell-cell co-culture, the MSC can effect CIK/NK cells on the cell cycle, such as arrested in the G0/G1 phase, diminished the ratio of cells in S, G2/M phase, and increased the apoptosis of them. MSC can also depress the expression of CD69 on these killer cells, as well as increased the ratio of CD4(+) CD25(+) CD127(low) T regulatory (Treg) cells in the CIK/NK cell culture system. We draw conclusions that either by transwell or mixed co-culture, the MSC can suppress activation of allogeneic CB-CIK/NK cells in a dose-dependent manner.

  6. Lidocaine Stimulates the Function of Natural Killer Cells in Different Experimental Settings.

    PubMed

    Cata, Juan P; Ramirez, Maria F; Velasquez, Jose F; Di, A I; Popat, Keyuri U; Gottumukkala, Vijaya; Black, Dahlia M; Lewis, Valerae O; Vauthey, Jean N

    2017-09-01

    One of the functions of natural killer (NK) cells is to eliminate cancer cells. The cytolytic activity of NK cells is tightly regulated by inhibitory and activation receptors located in the surface membrane. Lidocaine stimulates the function of NK cells at clinically relevant concentrations. It remains unknown whether this effect of lidocaine has an impact on the expression of surface receptors of NK cells, can uniformly stimulate across different cancer cell lines, and enhances the function of cells obtained during oncological surgery. NK cells from healthy donors and 43 patients who had undergone surgery for cancer were isolated. The function of NK cells was measured by lactate dehydrogenase release assay. NK cells were incubated with clinically relevant concentrations of lidocaine. By flow cytometry, we determined the impact of lidocaine on the expression of galactosylgalactosylxylosylprotein3-beta-glucuronosytranferase 1, marker of cell maturation (CD57), killer cell lectin like receptor A, inhibitory (NKG2A) receptors and killer cell lectin like receptor D, activation (NKG2D) receptors of NK cells. Differences in expression at p<0.05 were considered statistically significant. Lidocaine increased the expression of NKG2D receptors and stimulated the function of NK cells against ovarian, pancreatic and ovarian cancer cell lines. Lidocaine also increased the cytolytic activity of NK cells from patients who underwent oncological surgery, except for those who had orthopedic procedures. Lidocaine showed an important stimulatory activity on NK cells. Our findings suggest that lidocaine might be used perioperatively to minimize the impact of surgery on NK cells. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  7. Natural Killer Cell Receptor Genes in the Family Equidae: Not only Ly49

    PubMed Central

    Futas, Jan; Horin, Petr

    2013-01-01

    Natural killer (NK) cells have important functions in immunity. NK recognition in mammals can be mediated through killer cell immunoglobulin-like receptors (KIR) and/or killer cell lectin-like Ly49 receptors. Genes encoding highly variable NK cell receptors (NKR) represent rapidly evolving genomic regions. No single conservative model of NKR genes was observed in mammals. Single-copy low polymorphic NKR genes present in one mammalian species may expand into highly polymorphic multigene families in other species. In contrast to other non-rodent mammals, multiple Ly49-like genes appear to exist in the horse, while no functional KIR genes were observed in this species. In this study, Ly49 and KIR were sought and their evolution was characterized in the entire family Equidae. Genomic sequences retrieved showed the presence of at least five highly conserved polymorphic Ly49 genes in horses, asses and zebras. These findings confirmed that the expansion of Ly49 occurred in the entire family. Several KIR-like sequences were also identified in the genome of Equids. Besides a previously identified non-functional KIR-Immunoglobulin-like transcript fusion gene (KIR-ILTA) and two putative pseudogenes, a KIR3DL-like sequence was analyzed. In contrast to previous observations made in the horse, the KIR3DL sequence, genomic organization and mRNA expression suggest that all Equids might produce a functional KIR receptor protein molecule with a single non-mutated immune tyrosine-based inhibition motif (ITIM) domain. No evidence for positive selection in the KIR3DL gene was found. Phylogenetic analysis including rhinoceros and tapir genomic DNA and deduced amino acid KIR-related sequences showed differences between families and even between species within the order Perissodactyla. The results suggest that the order Perissodactyla and its family Equidae with expanded Ly49 genes and with a potentially functional KIR gene may represent an interesting model for evolutionary biology of

  8. Natural killer cell receptor genes in the family Equidae: not only Ly49.

    PubMed

    Futas, Jan; Horin, Petr

    2013-01-01

    Natural killer (NK) cells have important functions in immunity. NK recognition in mammals can be mediated through killer cell immunoglobulin-like receptors (KIR) and/or killer cell lectin-like Ly49 receptors. Genes encoding highly variable NK cell receptors (NKR) represent rapidly evolving genomic regions. No single conservative model of NKR genes was observed in mammals. Single-copy low polymorphic NKR genes present in one mammalian species may expand into highly polymorphic multigene families in other species. In contrast to other non-rodent mammals, multiple Ly49-like genes appear to exist in the horse, while no functional KIR genes were observed in this species. In this study, Ly49 and KIR were sought and their evolution was characterized in the entire family Equidae. Genomic sequences retrieved showed the presence of at least five highly conserved polymorphic Ly49 genes in horses, asses and zebras. These findings confirmed that the expansion of Ly49 occurred in the entire family. Several KIR-like sequences were also identified in the genome of Equids. Besides a previously identified non-functional KIR-Immunoglobulin-like transcript fusion gene (KIR-ILTA) and two putative pseudogenes, a KIR3DL-like sequence was analyzed. In contrast to previous observations made in the horse, the KIR3DL sequence, genomic organization and mRNA expression suggest that all Equids might produce a functional KIR receptor protein molecule with a single non-mutated immune tyrosine-based inhibition motif (ITIM) domain. No evidence for positive selection in the KIR3DL gene was found. Phylogenetic analysis including rhinoceros and tapir genomic DNA and deduced amino acid KIR-related sequences showed differences between families and even between species within the order Perissodactyla. The results suggest that the order Perissodactyla and its family Equidae with expanded Ly49 genes and with a potentially functional KIR gene may represent an interesting model for evolutionary biology of

  9. Leukemia-induced phenotypic and functional defects in natural killer cells predict failure to achieve remission in acute myeloid leukemia.

    PubMed

    Stringaris, Kate; Sekine, Takuya; Khoder, Ahmad; Alsuliman, Abdullah; Razzaghi, Bonnie; Sargeant, Ruhena; Pavlu, Jiri; Brisley, Gill; de Lavallade, Hugues; Sarvaria, Anushruthi; Marin, David; Mielke, Stephan; Apperley, Jane F; Shpall, Elizabeth J; Barrett, A John; Rezvani, Katayoun

    2014-05-01

    The majority of patients with acute myeloid leukemia will relapse, and older patients often fail to achieve remission with induction chemotherapy. We explored the possibility that leukemic suppression of innate immunity might contribute to treatment failure. Natural killer cell phenotype and function was measured in 32 consecutive acute myeloid leukemia patients at presentation, including 12 achieving complete remission. Compared to 15 healthy age-matched controls, natural killer cells from acute myeloid leukemia patients were abnormal at presentation, with downregulation of the activating receptor NKp46 (P=0.007) and upregulation of the inhibitory receptor NKG2A (P=0.04). Natural killer cells from acute myeloid leukemia patients had impaired effector function against autologous blasts and K562 targets, with significantly reduced CD107a degranulation, TNF-α and IFN-γ production. Failure to achieve remission was associated with NKG2A overexpression and reduced TNF-α production. These phenotypic and functional abnormalities were partially restored in the 12 patients achieving remission. In vitro co-incubation of acute myeloid leukemia blasts with natural killer cells from healthy donors induced significant impairment in natural killer cell TNF-α and IFN-γ production (P=0.02 and P=0.01, respectively) against K562 targets and a trend to reduced CD107a degranulation (P=0.07). Under transwell conditions, the inhibitory effect of AML blasts on NK cytotoxicity and effector function was still present, and this inhibitory effect was primarily mediated by IL-10. These results suggest that acute myeloid leukemia blasts induce long-lasting changes in natural killer cells, impairing their effector function and reducing the competence of the innate immune system, favoring leukemia survival.

  10. A Case of Hypersensitivity to Mosquito Bite Associated with Epstein-Barr Viral Infection and Natural Killer Cell Lymphocytosis

    PubMed Central

    Roh, Eui Jung; Chang, Young Pyo; Myoung, Na Hye; Jee, Young Koo; Seo, Min; Kang, Jin Han

    2010-01-01

    Hypersensitivity to mosquito bites (HMB) is a disorder characterized by a necrotic skin reaction and generalized symptoms subsequent to mosquito bites. It has been suggested that HMB is associated with chronic Epstein-Barr virus (EBV) infection and natural killer cell leukemia/lymphoma. We describe here a Korean child who had HMB associated with chronic EBV infection and natural killer cell lymphocytosis. A 5-yr-old boy was suffered from necrotic skin lesions on the right ear lobe. Type A EB virus was detected from hlood cells and bone marrow biospy recognized hemophagocyrosis. PMID:20119592

  11. A case of hypersensitivity to mosquito bite associated with Epstein-barr viral infection and natural killer cell lymphocytosis.

    PubMed

    Roh, Eui Jung; Chung, Eun Hee; Chang, Young Pyo; Myoung, Na Hye; Jee, Young Koo; Seo, Min; Kang, Jin Han

    2010-02-01

    Hypersensitivity to mosquito bites (HMB) is a disorder characterized by a necrotic skin reaction and generalized symptoms subsequent to mosquito bites. It has been suggested that HMB is associated with chronic Epstein-Barr virus (EBV) infection and natural killer cell leukemia/lymphoma. We describe here a Korean child who had HMB associated with chronic EBV infection and natural killer cell lymphocytosis. A 5-yr-old boy was suffered from necrotic skin lesions on the right ear lobe. Type A EB virus was detected from hlood cells and bone marrow biospy recognized hemophagocyrosis.

  12. Human Adipose-Derived Stem Cells Impair Natural Killer Cell Function and Exhibit Low Susceptibility to Natural Killer-Mediated Lysis

    PubMed Central

    DelaRosa, Olga; Sánchez-Correa, Beatriz; Morgado, Sara; Ramírez, Cristina; del Río, Borja; Menta, Ramón; Lombardo, Eleuterio

    2012-01-01

    Human adipose-derived stem cells (hASCs) have been successfully used in treating numerous diseases. However, several aspects need to be considered, particularly in the context of allogeneic cell therapy. To better understand hASCs-host interactions, we studied the phenotype of hASCs and their modulatory effect on natural killer (NK) cells by using bone marrow-mesenchymal stem cells (hBM-MSCs) as a reference. The hASCs displayed a lower susceptibility to NK cell-mediated lysis and a lower expression of ligands for DNAM-1 when compared with hBM-MSCs. Moreover, here we demonstrated that hASCs and hBM-MSCs can modulate NK cells through the action of soluble factors such as indoleamine 2,3-dioxygenase. Altogether, these results suggest that for an adoptive cell therapy based on the transfer of allogeneic hASCs, the NK-hASCs crosstalk will not result in an immediate recognition of the transferred cells. Thus, hASCs may remain in the tissue long enough to balance the immune response before being cleared. PMID:21867426

  13. Occurrence of Nodular Lymphocyte-Predominant Hodgkin Lymphoma in Hermansky-Pudlak Type 2 Syndrome Is Associated to Natural Killer and Natural Killer T Cell Defects

    PubMed Central

    Moratto, Daniele; Porta, Fulvio; Notarangelo, Lucia D.; Patrizi, Ornella; Sozzani, Silvano; de Saint Basile, Genevieve; Latour, Sylvain; Pace, David; Lonardi, Silvia; Facchetti, Fabio; Badolato, Raffaele; Parolini, Silvia

    2013-01-01

    Hermansky Pudlak type 2 syndrome (HPS2) is a rare autosomal recessive primary immune deficiency caused by mutations on β3A gene (AP3B1 gene). The defect results in the impairment of the adaptor protein 3 (AP-3) complex, responsible for protein sorting to secretory lysosomes leading to oculo-cutaneous albinism, bleeding disorders and immunodeficiency. We have studied peripheral blood and lymph node biopsies from two siblings affected by HPS2. Lymph node histology showed a nodular lymphocyte predominance type Hodgkin lymphoma (NLPHL) in both HPS2 siblings. By immunohistochemistry, CD8 T-cells from HPS2 NLPHL contained an increased amount of perforin (Prf) + suggesting a defect in the release of this granules-associated protein. By analyzing peripheral blood immune cells we found a significant reduction of circulating NKT cells and of CD56brightCD16− Natural Killer (NK) cells subset. Functionally, NK cells were defective in their cytotoxic activity against tumor cell lines including Hodgkin Lymphoma as well as in IFN-γ production. This defect was associated with increased baseline level of CD107a and CD63 at the surface level of unstimulated and IL-2-activated NK cells. In summary, these results suggest that a combined and profound defect of innate and adaptive effector cells might explain the susceptibility to infections and lymphoma in these HPS2 patients. PMID:24302998

  14. Effects of X-ray irradiation on natural killer (NK) cell system. II. Increased sensitivity to natural killer cytotoxic factor (NKCF)

    SciTech Connect

    Uchida, A.; Mizutani, Y.; Nagamuta, M.; Ikenaga, M. )

    1989-01-01

    Irradiation with low-doses of X-rays of tumor cells elevated their susceptibility to lysis by natural killer (NK) cells in an accompanying paper. Cytotoxicity assays conducted at the single cell level revealed that X-ray irradiation of K562 cells did not affect the number of effector-target conjugates but increased the frequency of dead conjugated target cells. During interaction with K562 cells large granular lymphocytes released a soluble cytotoxic factor (NKCF) that killed the target cells. X-ray irradiation did not affect the NKCF stimulatory ability of K562 cells, while it elevated their sensitivity to the lytic effect of NKCF. In contrast to X-rays, exposure to ultraviolet (UV) radiation of K562 cells did not elevate their NK sensitivity but rather reduced it. Treatment with mitomycin C produced no effect on NK sensitivity. These results indicate that X-ray irradiation elevates the target sensitivity to NKCF, which may be involved in the increased NK sensitivity, and that the X-ray effect may be different from that of UV radiation or DNA synthesis inhibition.

  15. Recognition of tumors by the innate immune system and natural killer cells.

    PubMed

    Marcus, Assaf; Gowen, Benjamin G; Thompson, Thornton W; Iannello, Alexandre; Ardolino, Michele; Deng, Weiwen; Wang, Lin; Shifrin, Nataliya; Raulet, David H

    2014-01-01

    In recent years, roles of the immune system in immune surveillance of cancer have been explored using a variety of approaches. The roles of the adaptive immune system have been a major emphasis, but increasing evidence supports a role for innate immune effector cells such as natural killer (NK) cells in tumor surveillance. Here, we discuss some of the evidence for roles in tumor surveillance of innate immune cells. In particular, we focus on NK cells and other immune cells that express germline-encoded receptors, often labeled NK receptors. The impact of these receptors and the cells that express them on tumor suppression is summarized. We discuss in detail some of the pathways and events in tumor cells that induce or upregulate cell-surface expression of the ligands for these receptors, and the logic of how those pathways serve to identify malignant, or potentially malignant cells. How tumors often evade tumor suppression mediated by innate killer cells is another major subject of the review. We end with a discussion on some of the implications of the various findings with respect to possible therapeutic approaches. © 2014 Elsevier Inc. All rights reserved.

  16. TGF-β-inducible microRNA-183 silences tumor-associated natural killer cells.

    PubMed

    Donatelli, Sarah S; Zhou, Jun-Min; Gilvary, Danielle L; Eksioglu, Erika A; Chen, Xianghong; Cress, W Douglas; Haura, Eric B; Schabath, Matthew B; Coppola, Domenico; Wei, Sheng; Djeu, Julie Y

    2014-03-18

    Transforming growth factor β1 (TGF-β), enriched in the tumor microenvironment and broadly immunosuppressive, inhibits natural killer (NK) cell function by yet-unknown mechanisms. Here we show that TGF-β-treated human NK cells exhibit reduced tumor cytolysis and abrogated perforin polarization to the immune synapse. This result was accompanied by loss of surface expression of activating killer Ig-like receptor 2DS4 and NKp44, despite intact cytoplasmic stores of these receptors. Instead, TGF-β depleted DNAX activating protein 12 kDa (DAP12), which is critical for surface NK receptor stabilization and downstream signal transduction. Mechanistic analysis revealed that TGF-β induced microRNA (miR)-183 to repress DAP12 transcription/translation. This pathway was confirmed with luciferase reporter constructs bearing the DAP12 3' untranslated region as well as in human NK cells by use of sense and antisense miR-183. Moreover, we documented reduced DAP12 expression in tumor-associated NK cells in lung cancer patients, illustrating this pathway to be consistently perturbed in the human tumor microenvironment.

  17. Opportunities and limitations of natural killer cells as adoptive therapy for malignant disease.

    PubMed

    Davies, James O J; Stringaris, Kate; Barrett, A John; Rezvani, Katayoun

    2014-11-01

    Although natural killer (NK) cells can be readily generated for adoptive therapy with current techniques, their optimal application to treat malignant diseases requires an appreciation of the dynamic balance between signals that either synergize with or antagonize each other. Individuals display wide differences in NK function that determine their therapeutic efficacy. The ability of NK cells to kill target cells or produce cytokines depends on the balance between signals from activating and inhibitory cell-surface receptors. The selection of NK cells with a predominant activating profile is critical for delivering successful anti-tumor activity. This can be achieved through selection of killer immunoglobulin-like receptor-mismatched NK donors and by use of blocking molecules against inhibitory pathways. Optimum NK cytotoxicity may require licensing or priming with tumor cells. Recent discoveries in the molecular and cellular biology of NK cells inform in the design of new strategies, including adjuvant therapies, to maximize the cytotoxic potential of NK cells for adoptive transfer to treat human malignancies.

  18. Clinical utility of natural killer cells in cancer therapy and transplantation

    PubMed Central

    Knorr, David; Bachanova, Veronika; Verneris, Michael R.; Miller, Jeffrey S.

    2014-01-01

    Natural killer (NK) cells recognize deranged cells that display stress receptors or loss of major histocompatibility complex (MHC) class I. During development, NK cells become “licensed” only after they encounter cognate human leucocyte antigen (HLA) class I, leading to the acquisition of effector function. NK cells can be exploited for cancer therapy in several ways. These include targeting within monoclonal antibodies alone or combined with ex vivo and in vivo NK cell activation to facilitate adoptive immunotherapy using donor-derived NK cell products to induce graft-vs-tumor effects. In the adoptive transfer setting, persistence and in vivo expansion requires lymphodepleting chemotherapy to prevent rejection and provide homeostatic cytokines (such as IL-15) that activate NK cells. IL-15 has the advantage of avoiding regulatory T-cell expansion. Clinical applications are currently being tested. To enhance in vivo expansion, IL-2 has been used at low doses. However, low dose administration also leads to the stimulation of regulatory T cells. Monoclonal antibodies and bispecific killer engagers (BiKEs) may enhance specificity by targeting CD16 on NK cells to tumor antigens. Inhibition of CD16 shedding may also promote enhanced cytotoxicity. Future strategies include exploiting favorable donor immunogenetics or ex vivo expansion of NK cells from blood, progenitors, or pluripotent cells. Comparative clinical trials are needed to test these approaches. PMID:24618042

  19. Recognition of tumors by the innate immune system and natural killer cells

    PubMed Central

    Marcus, Assaf; Gowen, Benjamin G.; Thompson, Thornton W.; Iannello, Alexandre; Ardolino, Michele; Deng, Weiwen; Wang, Lin; Shifrin, Nataliya; Raulet, David H.

    2014-01-01

    In recent years, roles of the immune system in immune surveillance of cancer have been explored using a variety of approaches. The roles of the adaptive immune system have been a major emphasis, but increasing evidence supports a role for innate immune effector cells such as natural killer (NK) cells in tumor surveillance. Here, we discuss some of the evidence for roles in tumor surveillance of innate immune cells, particularly NK cells and other immune cells that express germline-encoded receptors that are often labeled NK receptors. The impact of these receptors and the cells that express them on tumor suppression are summarized. We discuss in detail some of the pathways and events in tumor cells that induce or upregulate cell surface expression of the ligands for these receptors, and the logic of how those pathways serve to identify malignant, or potentially malignant cells. How tumors often evade tumor suppression mediated by innate killer cells is another major subject of the review. We end with a discussion of some of the implications of the various findings with respect to possibly therapeutic approaches. PMID:24507156

  20. Innate immune natural killer cells and their role in HIV and SIV infection

    PubMed Central

    Bostik, Pavel; Takahashi, Yoshiaki; Mayne, Ann E; Ansari, Aftab A

    2010-01-01

    The findings that early events during HIV-1 and SIV infection of Asian rhesus macaques dictate the levels of viremia and rate of disease progression prior to the establishment of mature and effective adaptive immune responses strongly suggest an important role for innate immune mechanisms. In addition, the fact that the major target of HIV and SIV during this period of acute infection is the gastrointestinal tissue suggests that whatever role the innate immune system plays must either directly and/or indirectly focus on the GI tract. The object of this article is to provide a general overview of the innate immune system with a focus on natural killer (NK) cells and their role in the pathogenesis of lentivirus infection. The studies summarized include our current understanding of the phenotypic heterogeneity, the putative functions ascribed to the subsets, the maturation/differentiation of NK cells, the mechanisms by which their function is mediated and regulated, the studies of these NK-cell subsets, with a focus on killer cell immunoglobulin-like receptors (KIRs) in nonhuman primates and humans, and finally, how HIV and SIV infection affects these NK cells in vivo. Clearly much has yet to be learnt on how the innate immune system influences the interaction between lentiviruses and the host within the GI tract, knowledge of which is reasoned to be critical for the formulation of effective vaccines against HIV-1. PMID:20730028

  1. HLA and killer cell immunoglobulin-like receptors influence the natural course of CMV infection.

    PubMed

    Di Bona, Danilo; Scafidi, Valeria; Plaia, Antonella; Colomba, Claudia; Nuzzo, Domenico; Occhino, Cecilia; Tuttolomondo, Antonino; Giammanco, Giovanni; De Grazia, Simona; Montalto, Giuseppe; Duro, Giovanni; Cippitelli, Marco; Caruso, Calogero

    2014-10-01

    Natural killer (NK) cells provide a major defense against cytomegalovirus (CMV) infection through the interaction of their surface receptors, including the activating and inhibitory killer immunoglobulin-like receptors (KIRs), and human leukocyte antigens (HLA) class I molecules. This study assessed whether the KIR and HLA repertoire may influence the risk of developing symptomatic or asymptomatic disease after primary CMV infection in the immunocompetent host. Sixty immunocompetent patients with primary symptomatic CMV infection were genotyped for KIR and their HLA ligands, along with 60 subjects with a previous asymptomatic infection as controls. The frequency of the homozygous A haplotype (only KIR2DS4 as activating KIR) was higher in symptomatic patients than controls (30% vs 12%, respectively; odds ratio [OR] = 3.24; P = .01). By logistic regression, the risk of developing symptomatic disease was associated with the homozygous A haplotype and the HLABw4(T) allele. Combining the 2 independent variables, we found that 37 out of 60 (62%) symptomatic patients but only 18 out of 60 (30%) of controls possessed the homozygous A haplotype or the HLABw4(T) allele with a highly significant OR (OR = 3.75, P < .0005). Immunocompetent subjects carrying the homozygous A haplotype or the HLABw4(T) allele are at higher risk of developing symptomatic disease after primary CMV infection. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  2. Receptor systems controlling natural killer cell function are genetically stratified in Europe.

    PubMed

    Guinan, K J; Cunningham, R T; Meenagh, A; Dring, M M; Middleton, D; Gardiner, C M

    2010-01-01

    Natural killer (NK) cells are components of the innate immune system that function in identifying and destroying aberrant or pathogen-infected cells. These functions are largely controlled by killer cell immunoglobulin-like receptors (KIRs). KIRs inhibit and activate NK cell functions through interactions with their ligands, epitopes encoded by human leukocyte antigen (HLA) class I genes (HLA-C1, C2 and Bw4). Genes that encode KIR and their HLA ligands vary in frequency across human populations. Here, we characterize two Irish populations for KIR and HLA and determine the spatial distribution of functionally important KIR:HLA systems in Europe, a region known for its considerable underlying genetic stratification. We find that Southern Europe is a region characterized by higher frequencies of activatory KIR and strong inhibitory HLA ligand systems (2DL1:HLA-C2 and 3DL1:Bw4). A lower frequency of activatory KIR and the predominance of a comparatively weaker inhibitory ligand system (2DL3:HLA-C1) are observed northwards. Despite contrasting KIR:HLA systems in Northern and Southern Europe, there is a clear balance between inhibitory and activatory repertoires, and their ligands in both regions. These findings show 'functional stratification' of the epistatic KIR:HLA receptor system in Europe, the presence of which will likely affect NK cell-mediated immunity across different populations.

  3. Classification of human natural killer cells based on migration behavior and cytotoxic response.

    PubMed

    Vanherberghen, Bruno; Olofsson, Per E; Forslund, Elin; Sternberg-Simon, Michal; Khorshidi, Mohammad Ali; Pacouret, Simon; Guldevall, Karolin; Enqvist, Monika; Malmberg, Karl-Johan; Mehr, Ramit; Önfelt, Björn

    2013-02-21

    Despite intense scrutiny of the molecular interactions between natural killer (NK) and target cells, few studies have been devoted to dissection of the basic functional heterogeneity in individual NK cell behavior. Using a microchip-based, time-lapse imaging approach allowing the entire contact history of each NK cell to be recorded, in the present study, we were able to quantify how the cytotoxic response varied between individual NK cells. Strikingly, approximately half of the NK cells did not kill any target cells at all, whereas a minority of NK cells was responsible for a majority of the target cell deaths. These dynamic cytotoxicity data allowed categorization of NK cells into 5 distinct classes. A small but particularly active subclass of NK cells killed several target cells in a consecutive fashion. These "serial killers" delivered their lytic hits faster and induced faster target cell death than other NK cells. Fast, necrotic target cell death was correlated with the amount of perforin released by the NK cells. Our data are consistent with a model in which a small fraction of NK cells drives tumor elimination and inflammation.

  4. HLA-C levels impact natural killer cell subset distribution and function.

    PubMed

    Sips, Magdalena; Liu, Qingquan; Draghi, Monia; Ghebremichael, Musie; Berger, Christoph T; Suscovich, Todd J; Sun, Yongtao; Walker, Bruce D; Carrington, Mary; Altfeld, Marcus; Brouckaert, Peter; De Jager, Philip L; Alter, Galit

    2016-12-01

    Differences in HLA-C expression are inversely correlated with HIV viral load set-point and slower progression to AIDS, linked to enhanced cytotoxic T cell immunity. Yet, beyond T cells, HLA-C serves as a dominant ligand for natural killer (NK) cell killer immunoglobulin-like receptors (KIR). Thus, we speculated that HLA-C expression levels may also impact NK activity, thereby modulating HIV antiviral control. Phenotypic and functional profiling was performed on freshly isolated PBMCs. HLA-C expression was linked to changes in NK subset distribution and licensing, particularly in HLA-C1/C1, KIR2DL3+2DL2-individuals. Moreover, high levels of HLA-C, were associated with reduced frequencies of anergic CD56(neg) NKs and lower frequencies of KIR2DL1/2/3+ NK cells, pointing to an HLA-C induced influence on the NK cell development in the absence of disease. In HIV infection, several spontaneous controllers, that expressed higher levels of HLA-C demonstrated robust NK-IFN-γ secretion in response to target cells, highlighting a second disease induced licensing phenotype. Thus this population study points to a potential role for HLA-C levels both in NK cell education and development.

  5. Chromosomal localization of the human natural killer cell class I receptor family genes to 19q13.4 by fluorescence in situ hybridization

    SciTech Connect

    Suto, Yumiko; Maenaka, Katsumi; yabe, Toshio

    1996-07-01

    This report describes the localization of the human natural killer cell I receptor family genes to human chromosome 19q13.4 using fluorescence in situ hybridization. These genes mediate the inhibition of the cytotoxicity of subsets of natural killer cells. 8 refs., 1 fig.

  6. Measurement of uterine natural killer cell percentage in the periimplantation endometrium from fertile women and women with recurrent reproductive failure: establishment of a reference range.

    PubMed

    Chen, Xiaoyan; Mariee, Najat; Jiang, Lingming; Liu, Yingyu; Wang, Chi Chiu; Li, Tin Chiu; Laird, Susan

    2017-09-19

    Uterine natural killer cells are the major leukocytes present in the periimplantation endometrium. Previous studies have found controversial differences in uterine natural killer cell percentage in women with recurrent reproductive failure compared with fertile controls. We sought to compare the uterine natural killer cell percentage in women with recurrent reproductive failure and fertile controls. This was a retrospective study carried out in university hospitals. A total of 215 women from 3 university centers participated in the study, including 97 women with recurrent miscarriage, 34 women with recurrent implantation failure, and 84 fertile controls. Endometrial biopsy samples were obtained precisely 7 days after luteinization hormone surge in a natural cycle. Endometrial sections were immunostained for CD56 and cell counting was performed by a standardized protocol. Results were expressed as percentage of positive uterine natural killer cell/total stromal cells. The median uterine natural killer cell percentage in Chinese ovulatory fertile controls in natural cycles was 2.5% (range 0.9-5.3%). Using 5th and 95th percentile to define the lower and upper limits of uterine natural killer cell percentage, the reference range was 1.2-4.5%. Overall, the groups with recurrent reproductive failure had significantly higher uterine natural killer cell percentage than the controls (recurrent miscarriage: median 3.2%, range 0.6-8.8%; recurrent implantation failure: median 3.1%, range 0.8-8.3%). However, there was a subset of both groups (recurrent miscarriage: 16/97; recurrent implantation failure: 6/34) that had lower uterine natural killer cell percentage compared to fertile controls. A reference range for uterine natural killer cell percentage in fertile women was established. Women with recurrent reproductive failure had uterine natural killer cell percentages both above and below the reference range. Copyright © 2017. Published by Elsevier Inc.

  7. Natural cytotoxicity in immunodeficiency diseases: preservation of natural killer activity and the in vivo appearance of radioresistant killing

    SciTech Connect

    Pierce, G.F.; Polmar, S.H.; Schacter, B.Z.; Brovall, C.; Hornick, D.L.; Sorensen, R.U.

    1986-01-01

    We studied spontaneous natural killer (NK) cell activity and radiation-resistant NK mediated cytotoxicity in four patients with clinically documented severe combined immune deficiency disease (SCID), and in one subject each with intestinal lymphangiectasia and cartilage-hair hypoplasia. We observed the preservation of spontaneous NK activity in all patients despite the presence of profound B- and T-lymphocytopenia and clinical immunodeficiency. NK activity was associated with relatively normal circulating numbers of OKM1+ lymphocytes, a population known to contain NK effectors. Spontaneous NK activity resistant to 3000 rad was increased in all patients, indicating the presence of activated natural killer cells in vivo. The concept of a chronically activated immune system in these patients was further supported by the presence of increased Ia positive T cells in all subjects tested, suggesting that radioresistant NK activity may be a useful parameter to measure when assessing in vivo immune activation. Our data, as well as that of others, supports the hypothesis that at least one population of NK cells is a distinct lineage arising at the differentiation level of myeloid and lymphoid stem cells in the bone marrow.

  8. Hypersensitivity to Mosquito Bites Associated with Natural Killer Cell–derived Large Granular Lymphocyte Lymphocytosis: A Case Report in Korea

    PubMed Central

    Chung, Joo Seop; Shin, Ho Jin; Lee, Eun Yup; Cho, Goon Jae

    2003-01-01

    Hypersensitivity to mosquito bites (HMB) is characterized by intense skin reactions at bite sites. The pathogenesis of HMB might be related to clonal lymphoproliferation of Epstein-Barr virus DNA-positive natural killer (NK) cells. We report the first case of HMB possibly associated with NK cell-derived large granular lymphocyte (NK-LGL) lymphocytosis in Korea. PMID:12760269

  9. Glucocorticoid cell reception in mice of different strains with natural killer cell activity depressed during immobilization stress

    SciTech Connect

    Lyashko, V.N.; Sukhikh, G.T.

    1987-08-01

    The authors study differences in stress-induced depression of natural killer cell activity in mice of different inbred lines, depending on parameters of glucocorticoid binding with glucorticoid receptors of spleen cells and on the hormonal status of the animals. In determining the parameters of glucocorticoid binding on intact splenocytes, aliquots of a suspension of washed splenocytes were incubated with tritium-labeled dexamethasone.

  10. Interleukin (IL)-2 and IL-15 have different effects on human natural killer lymphocytes.

    PubMed

    Pillet, Anne-Hélène; Thèze, Jacques; Rose, Thierry

    2011-11-01

    Although interleukin (IL)-2 and IL-15 share the common signal transducing receptor chains IL-2Rβ and γ(c) and give rise to the same signaling patterns in human natural killer (NK) cells in vitro, they differ in their effects on the development, activation, and proliferation of these cells in vivo. We have previously demonstrated that the activation of NK cells induces a cellular program characterized by the sequential transcription-regulated expression of IL-15 and IL-2 high-affinity receptors. We demonstrate here that these receptors induce different responses. IL-15 sustains the expression of its high-affinity receptor, leading to long-lasting STAT5 phosphorylation and BCL2 expression. By contrast, IL-2 induces the rapid disappearance of IL-2Rα and γ(c) chains when the gene transcription is downregulated, shutting down IL-2-responses as demonstrated by the absence of STAT5 phosphorylation and BCL2 expression.

  11. Dexamethasone induces apoptosis in mouse natural killer cells and cytotoxic T lymphocytes.

    PubMed Central

    Migliorati, G; Nicoletti, I; D'Adamio, F; Spreca, A; Pagliacci, C; Riccardi, C

    1994-01-01

    Glucocorticoid hormones (GCH) induce apoptotic cell death in immature thymocytes through an active mechanism, characterized by extensive DNA fragmentation into oligonucleosomal subunits. This requires macromolecular synthesis and is inhibited by protein kinase C (PKC) inhibitors, interleukin-4 (IL-4) and heat shock (hs). We performed experiments to analyse the possible effect of GCH on more differentiated lymphocytes, i.e. mouse natural killer (NK) cells and CD8+ alloreactive cytotoxic T lymphocytes (CTL). The results show that dexamethasone (DEX) induces DNA fragmentation and cell death in NK cells and CTL in vitro. In both NK cells and CTL, DEX-induced apoptosis is inhibited by IL-2 and IL-4 but, unlike that induced in thymocytes, is augmented by mRNA and protein synthesis inhibitors, PKC inhibitors and HS. Images Figure 2 Figure 3 PMID:8132215

  12. Type 1 Innate Lymphoid Cell Biology: Lessons Learnt from Natural Killer Cells

    PubMed Central

    Jiao, Yuhao; Huntington, Nicholas D.; Belz, Gabrielle T.; Seillet, Cyril

    2016-01-01

    Group 1 innate lymphoid cells (ILCs) comprise the natural killer (NK) cells and ILC1s that reside within peripheral tissues. Several different ILC1 subsets have recently been characterized; however, no unique markers have been identified that uniquely define these subsets. Whether ILC1s and NK cells are in fact distinct lineages, or alternately exhibit transitional molecular programs that allow them to adapt to different tissue niches remains an open question. NK cells are the prototypic member of the Group 1 ILCs and have been historically assigned the functions of what now appears to be a multi-subset family that are distributed throughout the body. This raises the question of whether each of these populations mediate distinct functions during infection and tumor immunosurveillance. Here, we review the diversity of the Group 1 ILC subsets in their transcriptional regulation, localization, mobility, and receptor expression, and highlight the challenges in unraveling the individual functions of these different populations of cells. PMID:27785129

  13. Inflammasomes Coordinate Pyroptosis and Natural Killer Cell Cytotoxicity to Clear Infection by a Ubiquitous Environmental Bacterium.

    PubMed

    Maltez, Vivien I; Tubbs, Alan L; Cook, Kevin D; Aachoui, Youssef; Falcone, E Liana; Holland, Steven M; Whitmire, Jason K; Miao, Edward A

    2015-11-17

    Defective neutrophils in patients with chronic granulomatous disease (CGD) cause susceptibility to extracellular and intracellular infections. Microbes must first be ejected from intracellular niches to expose them to neutrophil attack, so we hypothesized that inflammasomes detect certain CGD pathogens upstream of neutrophil killing. Here, we identified one such ubiquitous environmental bacterium, Chromobacterium violaceum, whose extreme virulence was fully counteracted by the NLRC4 inflammasome. Caspase-1 protected via two parallel pathways that eliminated intracellular replication niches. Pyroptosis was the primary bacterial clearance mechanism in the spleen, but both pyroptosis and interleukin-18 (IL-18)-driven natural killer (NK) cell responses were required for liver defense. NK cells cleared hepatocyte replication niches via perforin-dependent cytotoxicity, whereas interferon-γ was not required. These insights suggested a therapeutic approach: exogenous IL-18 restored perforin-dependent cytotoxicity during infection by the inflammasome-evasive bacterium Listeria monocytogenes. Therefore, inflammasomes can trigger complementary programmed cell death mechanisms, directing sterilizing immunity against intracellular bacterial pathogens.

  14. Therapeutic manipulation of natural killer (NK) T cells in autoimmunity: are we close to reality?

    PubMed Central

    Simoni, Y; Diana, J; Ghazarian, L; Beaudoin, L; Lehuen, A

    2013-01-01

    T cells reactive to lipids and restricted by major histocompatibility complex (MHC) class I-like molecules represent more than 15% of all lymphocytes in human blood. This heterogeneous population of innate cells includes the invariant natural killer T cells (iNK T), type II NK T cells, CD1a,b,c-restricted T cells and mucosal-associated invariant T (MAIT) cells. These populations are implicated in cancer, infection and autoimmunity. In this review, we focus on the role of these cells in autoimmunity. We summarize data obtained in humans and preclinical models of autoimmune diseases such as primary biliary cirrhosis, type 1 diabetes, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, psoriasis and atherosclerosis. We also discuss the promise of NK T cell manipulations: restoration of function, specific activation, depletion and the relevance of these treatments to human autoimmune diseases. PMID:23199318

  15. A new self: MHC-class-I-independent natural-killer-cell self-tolerance.

    PubMed

    Kumar, Vinay; McNerney, Megan E

    2005-05-01

    A fundamental tenet of the immune system is the requirement for lymphocytes to respond to transformed or infected cells while remaining tolerant of normal cells. Natural killer (NK) cells discriminate between self and non-self by monitoring the expression of MHC class I molecules. According to the 'missing-self' hypothesis, cells that express self-MHC class I molecules are protected from NK cells, but those that lack this self-marker are eliminated by NK cells. Recent work has revealed that there is another system of NK-cell inhibition, which is independent of MHC class I molecules. Newly discovered NK-cell inhibitory receptors that have non-MHC-molecule ligands broaden the definition of self as seen by NK cells.

  16. Acupuncture May Stimulate Anticancer Immunity via Activation of Natural Killer Cells

    PubMed Central

    Johnston, Michael Francis; Ortiz Sánchez, Elizabeth; Vujanovic, Nikola L.; Li, Wenhui

    2011-01-01

    This article presents the hypothesis that acupuncture enhances anticancer immune functions by stimulating natural killer (NK) cells. It provides background information on acupuncture, summarizes the current scientific understanding of the mechanisms through which NK cells act to eliminate cancer cells, and reviews evidence that acupuncture is associated with increases in NK cell quantity and function in both animals and humans. The key contribution of this article involves the use of cellular immunology and molecular biological theory to interpret and synthesize evidence from disparate animal and human studies in formulating the ‘acupuncture immuno-enhancement hypothesis': clinicians may use acupuncture to promote the induction and secretion of NK-cell activating cytokines that engage specific NK cell receptors that endogenously enhance anticancer immune function. PMID:21785626

  17. Designed DNA Surfaces for in Vitro Modulation of Natural Killer Cells.

    PubMed

    Garrecht, Ruben; Meyer, Rebecca; Duppach, Janine; Reipschläger, Simone; Watzl, Carsten; Niemeyer, Christof M

    2016-03-15

    Natural killer (NK) cells are at the junction of the innate and the adaptive immune response and play a very important role in host defense against viral infections and cancer. They have numerous cell surface receptors that activate or inhibit various intracellular signaling cascades that are then integrated to determine the functional activity of these cells. Here we present a surface-based approach that aims to tackle the largely unknown molecular mechanisms of signal integration. We use DNA microarrays containing capture oligonucleotides for the DNA-directed immobilization (DDI) of oligonucleotide-tagged αCD16 antibodies as ligands for NK cells. We demonstrate that the resulting surfaces can be gradually tuned in terms of ligand density to trigger the activation of living NK cells, as evidenced by degranulation, the release of cytokines, and intracellular Ca(2+) flux, measured at the level of single cells.

  18. Neural stem cells sustain natural killer cells that dictate recovery from brain inflammation

    PubMed Central

    Liu, Qiang; Sanai, Nader; Jin, Wei-Na; La Cava, Antonio; Van Kaer, Luc; Shi, Fu-Dong

    2017-01-01

    Recovery from organ-specific autoimmune diseases largely relies on the mobilization of endogenous repair mechanisms and local factors that control them. Natural killer (NK) cells are swiftly mobilized to organs targeted by autoimmunity and typically undergo numerical contraction when inflammation wanes. We report the unexpected finding that NK cells are retained in the brain subventricular zone (SVZ) during the chronic phase of multiple sclerosis in humans and its animal model in mice. These NK cells were found preferentially in close proximity to SVZ neural stem cells (NSCs) that produce interleukin-15 and sustain functionally competent NK cells. Moreover, NK cells limited the reparative capacity of NSCs following brain inflammation. These findings reveal that reciprocal interactions between NSCs and NK cells regulate neurorepair. PMID:26752157

  19. Inhibition of natural killer cell activity by eicosapentaenoic acid in vivo and in vitro

    SciTech Connect

    Yamashita, N.; Sugiyama, E.; Hamazaki, T.; Yano, S.

    1988-01-15

    To examine the effects of in vivo eicosapentaenoic acid (EPA) on natural killer (NK) cell activity, C3H/He mice each received a single intraperitoneal bolus of an emulsion of trieicosapentaenoyl-glycerol (EPA-TG). Spleen cells were tested for NK activity using /sup 51/Chromium-release assays against YAC-1 target cells. Forty eight hours after injection, NK activity was inhibited in a dose-dependent manner. EPA-TG emulsion also inhibited the NK activity of NK-enriched effector cells. Decreased cytotoxicity was first noted 24 hr after injection; it resumed the baseline by 7 days. The addition of EPA-TG emulsion to a cytotoxicity assay system resulted in moderate depression of NK activity. These results demonstrate that EPA has significant immunomodulatory effects on NK activity.

  20. Resistance to RadLV-induced leukemia: non-participation of splenic natural killer cells

    SciTech Connect

    St.-Pierre, Y.; Hugo, P.; Lemieux, S.; Lussier, G.; Potworowski, E.F.

    1988-08-01

    The phenotypic expression of genetically determined resistance to radiation leukemia virus (RadLV)-induced leukemia in mice has been shown to reside in the bone marrow. Because the bone marrow contains precursors of natural killer (NK) cells, known to play a role in retrovirally induced infections, and because these cells have been suggested as participating in resistance to radiation-induced leukemia, it was pertinent to establish whether their levels differed in strains of mice susceptible and resistant to leukemia. We therefore tested splenic NK cell levels in C57BL/Ka (susceptible) and B10.A(5R) (resistant) mice before viral inoculation, immediately after viral inoculation, and throughout the preleukemic period and showed that they were not different. This indicates that splenic NK cell levels have no bearing on the resistance to RadLV-induced leukemia and that other immune or non-immune mechanisms must be sought.

  1. Effects of in vitro asbestos exposure on natural killer and antibody-dependent cellular cytotoxicity

    SciTech Connect

    Barbers, R.G.; Oishi, J.

    1987-06-01

    Human peripheral blood lymphocytes (PBL) were exposed in vitro to asbestos fibers. Antibody-dependent cellular cytotoxicity (ADCC) activity and natural killer (NK) activity were examined by a chromium-51 release assay. There was a statistically significant enhancement of ADCC and NK activity by chrysotile and crocidolite fibers when cultured together with PBL for a period of 42 hr in medium containing a concentration of at least 2.5% fetal calf serum. Isolation of large granular lymphocytes to measure NK activity, however, showed the opposite effect when exposed to asbestos fibers. Their results indicated that asbestos fibers can directly affect lymphoid cytotoxic responses in vitro and may provide clues to immunopathogenic mechanisms for the occurrence of neoplasms in vivo.

  2. G-protein-coupled receptors in control of natural killer cell migration.

    PubMed

    Walzer, Thierry; Vivier, Eric

    2011-10-01

    Natural killer (NK) cells are highly motile cells that patrol lymphoid and non-lymphoid organs, and are poised to react to infectious or other inflammatory situations. Several NK cell subsets equipped with different sets of chemotactic G-protein-coupled receptors, and which display distinct distribution across lymphoid and non-lymphoid organs, have been described. These receptors detect various guidance cues including sphingosine-1-phosphate and chemokines that orchestrate NK cell trafficking. Here, we highlight recent advances regarding the receptors involved in NK cell migration, with a focus on bone marrow egress, entry into activated lymph nodes, extravasation into inflamed tissues, and motility within lymph nodes or tumors. Understanding NK cell migration could provide a rational basis for the design of novel therapies in various clinical conditions.

  3. Natural Killers Are Made Not Born: How to Exploit NK Cells in Lung Malignancies

    PubMed Central

    Carrega, Paolo; Ferlazzo, Guido

    2017-01-01

    In recent years, progress has been made in the characterization of natural killer (NK) cells in lung malignancies, and we have now gained a better understanding of the frequency, localization, phenotype, and functional status of NK cells infiltrating these tumors. NK cell subset recruited in lung cancer is mainly capable of producing relevant cytokines rather than exerting direct cancer cell killing. Thus, the relevance of NK cells in tumor microenvironment might also go beyond the killing of tumor cells, being NK cells endowed with regulatory functions toward an ample array of immune effectors. Nevertheless, boosting their cytotoxic functions and redirecting the migration of cytotoxic NK cell subset to the tumor site might open new therapeutic avenues for lung cancer. Also, we believe that a deeper investigation into the impact of both conventional (e.g., chemotherapy) or new therapies (e.g., anti-immune checkpoints mAbs) on NK cell homeostasis in lung cancer patients is now required. PMID:28348567

  4. [Music therapy induced alternations in natural killer cell count and function].

    PubMed

    Hasegawa, Y; Kubota, N; Inagaki, T; Shinagawa, N

    2001-03-01

    The effects of music therapy on natural killer (NK) cell count and activity (NKCA) were studied in 19 persons. Alzheimer's disease, cerebrovessel disease and Parkinson's disease subjects were assigned to a music therapy. Blood samples were drawn at rest and after completion of music therapy. Music therapy did not change the number of circulating lymphocytes. The percentage of NK cells increased during music therapy, along with an increase in the NK cell activity. The proportion of T cells, CD4 and CD8 did not change significantly during music therapy. One hour after the music therapy session, plasma adrenaline increased but cortisol and noradrenalin did not change. The results indicate that music therapy can significantly increase NK cell count and activity. The change in NK cell and function were independent of neuro-degenerative diseases.

  5. Critical roles of co-activation receptor DNAX accessory molecule-1 in natural killer cell immunity

    PubMed Central

    Xiong, Peng; Sang, Hai-Wei; Zhu, Min

    2015-01-01

    Natural killer (NK) cells, which can exert early and powerful anti-tumour and anti-viral responses, are important components of the innate immune system. DNAX accessory molecule-1 (DNAM-1) is an activating receptor molecule expressed on the surface of NK cells. Recent findings suggest that DNAM-1 is a critical regulator of NK cell biology. DNAM-1 is involved in NK cell education and differentiation, and also plays a pivotal role in the development of cancer, viral infections and immune-related diseases. However, tumours and viruses have developed multiple mechanisms to evade the immune system. They are able to impair DNAM-1 activity by targeting the DNAM-1 receptor–ligand system. We have reviewed the roles of DNAM-1, and its biological functions, with respect to NK cell biology and DNAM-1 chimeric antigen receptor-based immunotherapy. PMID:26235210

  6. A long noncoding RNA positively regulates CD56 in human natural killer cells

    PubMed Central

    Fu, Binqing; Wu, Yang; Sun, Rui; Tian, Zhigang; Wei, Haiming

    2016-01-01

    Natural killer (NK) cells are innate immune lymphocytes that play critical roles in host defense against viral infection and surveillance against malignant transformation. Long noncoding RNAs (lncRNAs) are important immune system regulators. Here, we analyzed human primary lymphocyte lncRNA expression profiles to identify NK-lncRNA signatures. We detected numerous novel NK-specific lncRNAs with potential roles in regulating human NK cell differentiation and function. Expression of lnc-CD56, an NK-specific lncRNA, was positively correlated with that of CD56, a classical human NK cell surface marker. We showed that lnc-CD56 may function as a positive regulator of CD56 in primary human NK cells and differentiated NK cells from human CD34+ hematopoietic progenitor cells. Our data provide an annotated human NK cell lncRNA expression catalog and demonstrate a key role for lncRNAs in NK cell biology. PMID:27713137

  7. Large-Scale Culture and Genetic Modification of Human Natural Killer Cells for Cellular Therapy.

    PubMed

    Lapteva, Natalia; Parihar, Robin; Rollins, Lisa A; Gee, Adrian P; Rooney, Cliona M

    2016-01-01

    Recent advances in methods for the ex vivo expansion of human natural killer (NK) cells have facilitated the use of these powerful immune cells in clinical protocols. Further, the ability to genetically modify primary human NK cells following rapid expansion allows targeting and enhancement of their immune function. We have successfully adapted an expansion method for primary NK cells from peripheral blood mononuclear cells or from apheresis products in gas permeable rapid expansion devices (G-Rexes). Here, we describe an optimized protocol for rapid and robust NK cell expansion as well as a method for highly efficient retroviral transduction of these ex vivo expanded cells. These methodologies are good manufacturing practice (GMP) compliant and could be used for clinical-grade product manufacturing.

  8. Gene deregulation and chronic activation in natural killer cells deficient in the transcription factor ETS1.

    PubMed

    Ramirez, Kevin; Chandler, Katherine J; Spaulding, Christina; Zandi, Sasan; Sigvardsson, Mikael; Graves, Barbara J; Kee, Barbara L

    2012-06-29

    Multiple transcription factors guide the development of mature functional natural killer (NK) cells, yet little is known about their function. We used global gene expression and genome-wide binding analyses combined with developmental and functional studies to unveil three roles for the ETS1 transcription factor in NK cells. ETS1 functions at the earliest stages of NK cell development to promote expression of critical transcriptional regulators including T-BET and ID2, NK cell receptors (NKRs) including NKp46, Ly49H, and Ly49D, and signaling molecules essential for NKR function. As a consequence, Ets1(-/-) NK cells fail to degranulate after stimulation through activating NKRs. Nonetheless, these cells are hyperresponsive to cytokines and have characteristics of chronic stimulation including increased expression of inhibitory NKRs and multiple activation-associated genes. Therefore, ETS1 regulates a broad gene expression program in NK cells that promotes target cell recognition while limiting cytokine-driven activation.

  9. Activated adherent large granular lymphocytes/natural killer (LGL/NK) cells change their migratory behaviour.

    PubMed Central

    Pirelli, A; Allavena, P; Mantovani, A

    1988-01-01

    Unstimulated large granular lymphocytes/natural killer (LGL/NK) cells, unlike small T lymphocytes, exhibit prompt locomotion into nitrocellulose filters in response to chemo-attactrants, but, unlike monocytes, are unable to migrate as adherent cells across polycarbonate filters. Upon activation with 4-B-phorbol 12,13 dibutyrate (PDBU), LGL/NK cells become adherent and change their migratory behaviour, having the ability to migrate as adherent cells across polycarbonate filters. PDBU-treated high-density T lymphocytes did not show, under the same conditions, locomotory activity. The change in migratory behaviour following activation may represent an important determinant of the ability of activated LGL/NK cells to adhere to vascular linings and localize in tissues. PMID:3220508

  10. Glycolipid presentation to natural killer T cells differs in an organ-dependent fashion

    NASA Astrophysics Data System (ADS)

    Schmieg, John; Yang, Guangli; Franck, Richard W.; van Rooijen, Nico; Tsuji, Moriya

    2005-01-01

    It has been shown that dendritic cells (DCs) are able to present glycolipids to natural killer (NK) T cells in vivo. However, the essential role of DCs, as well as the role of other cells in glycolipid presentation, is unknown. Here, we show that DCs are the crucial antigen-presenting cells (APCs) for splenic NK T cells, whereas Kupffer cells are the key APCs for hepatic NK T cells. Both cell types stimulate cytokine production by NK T cells within 2 h of glycolipid administration, but only DCs are involved in the systemic, downstream responses to glycolipid administration. More specifically, CD8+ DCs produce IL-12 in response to glycolipid presentation, which stimulates secondary IFN- production by NK cells in different organs. Different APCs participate in glycolipid presentation to NK T cells in vivo but differ in their involvement in the overall glycolipid response. dendritic cell | Kupffer cell

  11. Inhibition of human natural killer cell activity by Pseudomonas aeruginosa alkaline protease and elastase.

    PubMed Central

    Pedersen, B K; Kharazmi, A

    1987-01-01

    The present study was designed to examine the effect of Pseudomonas aeruginosa alkaline protease (AP) and elastase (Ela) on human natural killer (NK) cell activity in vitro. AP and Ela were found to inhibit NK cell function. Addition of alpha interferon and interleukin-2 did not abolish this inhibition of NK cell activity. Adhesion of effector to target cells was studied in a single-cell agarose assay of monocyte-depleted NK-cell-enriched cell populations. AP and Ela were shown to inhibit effector/target cell conjugate formation. Furthermore, AP and Ela inhibited the binding of the monoclonal antibody Leu-11, which reacts with the Fc receptor of NK cells. The inhibition of NK cell binding to the target cell by P. aeruginosa proteases is most likely due to proteolytic cleavage of the surface receptors involved in the binding of the effector cell to the target cell. PMID:3030937

  12. Natural killer cell immunosenescence in acute myeloid leukaemia patients: new targets for immunotherapeutic strategies?

    PubMed

    Sanchez-Correa, Beatriz; Campos, Carmen; Pera, Alejandra; Bergua, Juan M; Arcos, Maria Jose; Bañas, Helena; Casado, Javier G; Morgado, Sara; Duran, Esther; Solana, Rafael; Tarazona, Raquel

    2016-04-01

    Several age-associated changes in natural killer (NK) cell phenotype have been reported that contribute to the defective NK cell response observed in elderly patients. A remodelling of the NK cell compartment occurs in the elderly with a reduction in the output of immature CD56(bright) cells and an accumulation of highly differentiated CD56(dim) NK cells. Acute myeloid leukaemia (AML) is generally a disease of older adults. NK cells in AML patients show diminished expression of several activating receptors that contribute to impaired NK cell function and, in consequence, to AML blast escape from NK cell immunosurveillance. In AML patients, phenotypic changes in NK cells have been correlated with disease progression and survival. NK cell-based immunotherapy has emerged as a possibility for the treatment of AML patients. The understanding of age-associated alterations in NK cells is therefore necessary to define adequate therapeutic strategies in older AML patients.

  13. Innate-like functions of natural killer T cell subsets result from highly divergent gene programs.

    PubMed

    Engel, Isaac; Seumois, Grégory; Chavez, Lukas; Samaniego-Castruita, Daniela; White, Brandie; Chawla, Ashu; Mock, Dennis; Vijayanand, Pandurangan; Kronenberg, Mitchell

    2016-06-01

    Natural killer T cells (NKT cells) have stimulatory or inhibitory effects on the immune response that can be attributed in part to the existence of functional subsets of NKT cells. These subsets have been characterized only on the basis of the differential expression of a few transcription factors and cell-surface molecules. Here we have analyzed purified populations of thymic NKT cell subsets at both the transcriptomic level and epigenomic level and by single-cell RNA sequencing. Our data indicated that despite their similar antigen specificity, the functional NKT cell subsets were highly divergent populations with many gene-expression and epigenetic differences. Therefore, the thymus 'imprints' distinct gene programs on subsets of innate-like NKT cells that probably impart differences in proliferative capacity, homing, and effector functions.

  14. Innate-like functions of natural killer T cell subsets result from highly divergent gene programs

    PubMed Central

    Engel, Isaac; Seumois, Grégory; Chavez, Lukas; Samaniego-Castruita, Daniela; White, Brandie; Chawla, Ashu; Mock, Dennis; Vijayanand, Pandurangan; Kronenberg, Mitchell

    2016-01-01

    Natural killer T cells (NKT cells) have stimulatory or inhibitory effects on the immune response that can be attributed in part to the existence of functional subsets of NKT cells. These subsets have been characterized only on the basis of the differential expression of a few transcription factors and cell-surface molecules. Here we have analyzed purified populations of thymic NKT cell subsets at both the transcriptomic level and epigenomic level and by single-cell RNA sequencing. Our data indicated that despite their similar antigen specificity, the functional NKT cell subsets were highly divergent populations with many gene-expression and epigenetic differences. Therefore, the thymus ‘imprints’ distinct gene programs on subsets of innate-like NKT cells that probably impart differences in proliferative capacity, homing, and effector functions. PMID:27089380

  15. Uterine Natural Killer Cells: Functional Distinctions and Influence on Pregnancy in Humans and Mice

    PubMed Central

    Gaynor, Louise M.; Colucci, Francesco

    2017-01-01

    Our understanding of development and function of natural killer (NK) cells has progressed significantly in recent years. However, exactly how uterine NK (uNK) cells develop and function is still unclear. To help investigators that are beginning to study tissue NK cells, we summarize in this review our current knowledge of the development and function of uNK cells, and what is yet to be elucidated. We compare and contrast the biology of human and mouse uNK cells in the broader context of the biology of innate lymphoid cells and with reference to peripheral NK cells. We also review how uNK cells may regulate trophoblast invasion and uterine spiral arterial remodeling in human and murine pregnancy. PMID:28484462

  16. Inhibition of hematopoietic recovery from radiation-induced myelosuppression by natural killer cells

    SciTech Connect

    Pantel, K.; Boertman, J.; Nakeff, A. )

    1990-05-01

    We have examined the role of natural killer (NK) cells in situ in the recovery of marrow hematopoiesis in B6D2F1 mice receiving various doses of total-body irradiation (TBI) as a well-characterized model for treatment-induced myelosuppression. Applying an in situ cytotoxic approach for ablating NK 1.1 cells, we have demonstrated that NK 1.1 cells differentially inhibit the recovery of hematopoietic stem cells (CFU-S) and their progenitor cells committed to granulocyte-macrophage differentiation from a sublethal dose of TBI (9 Gy) while not affecting the recovery of progenitor cells committed to either erythroid or megakaryocyte differentiation from TBI. However, recoveries of CFU-S and progenitor cells were unaffected by the ablation of NK cells prior to a moderate dose of TBI (2 Gy). These findings provide in situ evidence that NK cells are potential inhibitors of hematopoietic recovery from treatment-induced myelosuppression.

  17. The Molecular Mechanism of Natural Killer Cells Function and Its Importance in Cancer Immunotherapy

    PubMed Central

    Paul, Sourav; Lal, Girdhari

    2017-01-01

    Natural killer (NK) cells are innate immune cells that show strong cytolytic function against physiologically stressed cells such as tumor cells and virus-infected cells. NK cells show a broad array of tissue distribution and phenotypic variability. NK cells express several activating and inhibitory receptors that recognize the altered expression of proteins on target cells and control the cytolytic function. NK cells have been used in several clinical trials to control tumor growth. However, the results are encouraging only in hematological malignancies but not very promising in solid tumors. Increasing evidence suggests that tumor microenvironment regulate the phenotype and function of NK cells. In this review, we discussed the NK cell phenotypes and its effector function and impact of the tumor microenvironment on effector and cytolytic function of NK cells. We also summarized various NK cell-based immunotherapeutic strategies used in the past and the possibilities to improve the function of NK cell for the better clinical outcome. PMID:28955340

  18. A shed NKG2D ligand that promotes natural killer cell activation and tumor rejection

    PubMed Central

    Deng, Weiwen; Gowen, Benjamin G.; Zhang, Li; Wang, Lin; Lau, Stephanie; Iannello, Alexandre; Xu, Jianfeng; Rovis, Tihana L.; Xiong, Na; Raulet, David H.

    2016-01-01

    Immune cells, including natural killer (NK) cells, recognize transformed cells and eliminate them in a process termed immunosurveillance. It is thought that tumor cells evade immunosurveillance by shedding membrane ligands that bind to the NKG2D activating receptor on NK cells and/or T cells, and desensitize these cells. In contrast, we show that in mice, shedding of MULT1, a high affinity NKG2D ligand, causes NK cell activation and tumor rejection. Recombinant soluble MULT1 stimulated tumor rejection in mice. Soluble MULT1 functions, at least in part, by competitively reversing a global desensitization of NK cells imposed by engagement of membrane NKG2D ligands on tumor-associated cells, such as myeloid cells. The results overturn conventional wisdom that soluble ligands are inhibitory, and suggest a new approach for cancer immunotherapy. PMID:25745066

  19. Generation of natural killer cells from hematopoietic stem cells in vitro for immunotherapy

    PubMed Central

    Luevano, Martha; Madrigal, Alejandro; Saudemont, Aurore

    2012-01-01

    Natural killer (NK) cells are part of the innate immune system and are an alluring option for immunotherapy due to their ability to kill infected cells or cancer cells without prior sensitization. Throughout the past 20 years, different groups have been able to reproduce NK cell development in vitro, and NK cell ontogeny studies have provided the basis for the establishment of protocols to produce NK cells in vitro for immunotherapy. Here, we briefly discuss NK cell development and NK cell immunotherapy approaches. We review the factors needed for NK cell differentiation in vitro, which stem cell sources have been used, published protocols, challenges and future directions for Good Manufacturing Practice protocols. PMID:22705914

  20. Natural Killer Cells—An Epigenetic Perspective of Development and Regulation

    PubMed Central

    Schenk, Alexander; Bloch, Wilhelm; Zimmer, Philipp

    2016-01-01

    Based on their ability to recognize and eliminate various endo- and exogenous pathogens as well as pathological alterations, Natural Killer (NK) cells represent an important part of the cellular innate immune system. Although the knowledge about their function is growing, little is known about their development and regulation on the molecular level. Research of the past decade suggests that modifications of the chromatin, which do not affect the base sequence of the DNA, also known as epigenetic alterations, are strongly involved in these processes. Here, the impact of epigenetic modifications on the development as well as the expression of important activating and inhibiting NK-cell receptors and their effector function is reviewed. Furthermore, external stimuli such as physical activity and their influence on the epigenetic level are discussed. PMID:26938533

  1. Liaison between natural killer cells and dendritic cells in human gestation

    PubMed Central

    Leno-Durán, Ester; Muñoz-Fernández, Raquel; García Olivares, Enrique; Tirado-González, Irene

    2014-01-01

    A successful pregnancy relies on immunological adaptations that allow the fetus to grow and develop in the uterus, despite being recognized by maternal immune cells. Among several immunocompetent cell types present within the human maternal/fetal interface, DC-SIGN+ dendritic cells (DCs) and CD56+ natural killer (NK) cells are of major importance for early pregnancy maintenance, not only generating maternal immunological tolerance but also regulating stromal cell differentiation. Previous reports show the presence of NK–DC cell conjugates in first trimester human decidua, suggesting that these cells may play a role in the modulation of the local immune response within the uterus. While effective immunity is necessary to protect the mother from harmful pathogens, some form of tolerance must be activated to avoid an immune response against fetal antigens. This review article discusses current evidence concerning the functions of DC and NK cells in pregnancy and their liaison in human decidua. PMID:24954224

  2. Interleukin-17D mediates tumor rejection through recruitment of natural killer cells

    PubMed Central

    O'Sullivan, Timothy; Saddawi-Konefka, Robert; Gross, Emilie; Tran, Miller; Mayfield, Stephen P.; Ikeda, Hiroaki; Bui, Jack D.

    2014-01-01

    The process of cancer immunoediting generates a repertoire of cancer cells that can persist in immune competent hosts. In its most complex form, this process begins with the elimination of highly immunogenic unedited tumor cells followed by the escape of less immunogenic, edited cells. Although edited tumors can release immunosuppressive factors, it is unknown whether unedited tumors produce cytokines that enhance antitumor function. Utilizing gene microarray analysis, we found the cytokine interleukin 17D (IL-17D) was highly expressed in certain unedited tumors but not edited mouse tumor cell lines. Moreover, forced expression of IL-17D in edited tumor cells induced rejection by stimulating CCL2 production from tumor endothelial cells leading to the recruitment of natural killer (NK) cells. NK cells promoted M1 macrophage development leading to adaptive immune responses. IL-17D expression was also decreased in certain high-grade and metastatic human tumors, suggesting that it can be targeted for tumor immune therapy. PMID:24794441

  3. Interleukin-22-producing natural killer cells and lymphoid tissue inducer-like cells in mucosal immunity.

    PubMed

    Colonna, Marco

    2009-07-17

    Blood, lymphoid tissues, and placenta contain diverse subpopulations of natural killer (NK) cells that possess distinct immune functions. Recent studies have shown that human and mouse gut-associated lymphoid tissues harbor a unique NK cell subset that specializes in production of interleukin (IL)-22. This cytokine plays a role in host defense of mucosal barriers, although dysregulated secretion may cause autoimmune disease. In parallel, human fetal lymphoid tissue inducer (LTi) cells and mouse adult LTi-like cells in secondary lymphoid tissues were found to release IL-22, as well as IL-17, a proinflammatory cytokine that mediates host defense against extracellular pathogens. Here, we compare these recently identified immune cells, reviewing what is known about their anatomical location, differentiation requirements, function, and potential involvement in host defense and autoimmunity. Finally, we discuss the challenges faced in furthering our understanding of the developmental relationships and role of NK and LTi-like cells in mucosal immune responses.

  4. Natural killer cells eradicate galectin-1-deficient glioma in the absence of adaptive immunity.

    PubMed

    Baker, Gregory J; Chockley, Peter; Yadav, Viveka Nand; Doherty, Robert; Ritt, Michael; Sivaramakrishnan, Sivaraj; Castro, Maria G; Lowenstein, Pedro R

    2014-09-15

    Natural killer (NK) cells safeguard against early tumor formation by destroying transformed target cells in a process referred to as NK immune surveillance. However, the immune escape mechanisms used by malignant brain tumors to subvert this innate type of immune surveillance remain unclear. Here we show that malignant glioma cells suppress NK immune surveillance by overexpressing the β-galactoside-binding lectin galectin-1. Conversely, galectin-1-deficient glioma cells could be eradicated by host NK cells before the initiation of an antitumor T-cell response. In vitro experiments demonstrated that galectin-1-deficient GL26-Cit glioma cells are ∼3-fold more sensitive to NK-mediated tumor lysis than galectin-1-expressing cells. Our findings suggest that galectin-1 suppression in human glioma could improve patient survival by restoring NK immune surveillance that can eradicate glioma cells. Cancer Res; 74(18); 5079-90. ©2014 AACR. ©2014 American Association for Cancer Research.

  5. Natural killer cell responses during viral infections: flexibility and conditioning of innate immunity by experience.

    PubMed

    Vidal, Silvia M; Khakoo, Salim I; Biron, Christine A

    2011-12-01

    Natural killer (NK) cells mediate innate defense against viral infections, but the mechanisms in place to access their functions as needed during diverse challenges while limiting collateral damage are poorly understood. Recent molecular characterization of effects mediated through infection-induced inhibitory/activating NK receptor-ligand pairs and cytokines are providing new insights into pathways regulating their responses and revealing unexpected consequences for NK cell subset effects, maintenance, proliferation and function through times overlapping with adaptive and long-lived immunity. The observations define flexible pathways for experience-induced 'conditioning' and challenge narrowly defined roles for NK cells and innate immunity as first responders with prescribed functions. They suggest that individual experiences as well as genes influence the innate immune resources available to fight off an infection.

  6. Critical roles of co-activation receptor DNAX accessory molecule-1 in natural killer cell immunity.

    PubMed

    Xiong, Peng; Sang, Hai-Wei; Zhu, Min

    2015-11-01

    Natural killer (NK) cells, which can exert early and powerful anti-tumour and anti-viral responses, are important components of the innate immune system. DNAX accessory molecule-1 (DNAM-1) is an activating receptor molecule expressed on the surface of NK cells. Recent findings suggest that DNAM-1 is a critical regulator of NK cell biology. DNAM-1 is involved in NK cell education and differentiation, and also plays a pivotal role in the development of cancer, viral infections and immune-related diseases. However, tumours and viruses have developed multiple mechanisms to evade the immune system. They are able to impair DNAM-1 activity by targeting the DNAM-1 receptor-ligand system. We have reviewed the roles of DNAM-1, and its biological functions, with respect to NK cell biology and DNAM-1 chimeric antigen receptor-based immunotherapy. © 2015 John Wiley & Sons Ltd.

  7. Hidden talents of natural killers: NK cells in innate and adaptive immunity.

    PubMed

    Cooper, Megan A; Colonna, Marco; Yokoyama, Wayne M

    2009-10-01

    Natural killer (NK) cells are innate immune lymphocytes capable of killing target cells and producing immunoregulatory cytokines. Herein, we discuss recent studies that indicate that NK cells span the conventional boundaries between innate and adaptive immunity. For example, it was recently discovered that NK cells have the capacity for memory-like responses, a property that was previously thought to be limited to adaptive immunity. NK cells have also been identified in multiple tissues, and a subset of cells that specialize in the production of the T(H)17 cytokine IL-22, NK-22s, was recently described in mucosal-associated lymphoid tissue. Finally, we review work that shows that NK cells develop at sites that were traditionally thought to be occupied only by adaptive immune cells, including the thymus and lymph nodes.

  8. Natural killer/T-cell lymphoma-associated hemophagocytic syndrome: A case report

    PubMed Central

    HAN, LIJUAN; ZHANG, MINGZHI; LI, LING; ZHANG, LEI; WU, JINGJING; LI, XIN; WANG, XINHUA; YOUNG, KEN. H.; FU, XIAORUI; MA, WANG; SUN, ZHENCHANG; ZHANG, XUDONG; CHANG, YU; QIAO, ZHI

    2014-01-01

    Natural killer (NK)/T-cell lymphoma-associated hemophagocytic syndrome (HPS) is a rare and fatal disease with no optimal treatment. The present study reports the clinical features, diagnosis and treatment process of three patients with relapsed NK/T-cell lymphoma-associated HPS. All of the patients were classified as Ann Arbor stage IV and presented with a poor performance status. Two patients were successfully treated with a pegaspargase-containing combination regimen and one patient succumbed due to serious complications. These cases indicate that for patients with a history of lymphoma, the diagnosis of HPS should be considered when patients present with progressive high fever, pancytopenia and liver dysfunction. Early identification and effective treatments, including pegaspargase-based regimens are essential for an enhanced prognosis. PMID:25013513

  9. Angiogenic non-Hodgkin T/natural killer (NK)-cell lymphoma: report of three cases.

    PubMed

    Martins-Filho, Rubens A; Demarco, Ricardo C; Valera, Fabiana C; Shaletich, Catarina; Félix, Paulo R; Badiale, Giovana B; Anselmo-Lima, Wilma T

    2008-10-01

    Angiogenic T/natural killer (NK)-cell lymphoma is a non-Hodgkin lymphoma characterized by necrosis and vascular destruction that is strongly associated with Epstein-Barr virus and AIDS. Early diagnosis is essential to improve the chances of patient survival, but severe local inflammatory infiltrate impairs histologic diagnosis by obscuring neoplastic cells. The most common markers are CD2, CD56, cytoplasmic CD3, and CD43 EBV. We describe 3 cases of angiogenic T/NK-cell lymphoma that show the diverse presentation of the same disease. Patient 1 was HIV positive and had nasal obstruction, facial edema, and ulceration of the nasal mucosa. Patient 2 had fever, a sore throat, and weight loss. Patient 3 had facial edema, fever, proptosis, and rapid development of neurologic alterations. Several biopsies were needed for histologic confirmation in these patients, despite positivity for the CD3 and CD56 markers.

  10. Invariant natural killer T cells as sensors and managers of inflammation.

    PubMed

    Van Kaer, Luc; Parekh, Vrajesh V; Wu, Lan

    2013-02-01

    Invariant natural killer T (iNKT) cells are a subset of innate-like lymphocytes that recognize glycolipid antigens bound by the major histocompatibility complex (MHC)-class-I-related protein CD1d. iNKT cells are activated early during a variety of infections and inflammatory diseases and contribute to the subsequent development of adaptive immune responses. Consequently, iNKT cells play a critical role in the development and resolution of inflammatory diseases and represent attractive targets for the development of immunotherapies. Recent studies have provided important insight into the mechanisms by which iNKT cells become activated in response to diverse inflammatory stimuli. These new findings should be instrumental to promote the immunomodulatory properties of iNKT cells for treatment of inflammatory diseases.

  11. Stage-dependent gene expression profiles during natural killer cell development.

    PubMed

    Kang, Hyung-Sik; Kim, Eun-Mi; Lee, Sanggyu; Yoon, Suk-Ran; Kawamura, Toshihiko; Lee, Young-Cheol; Kim, Sangsoo; Myung, Pyung-Keun; Wang, San Ming; Choi, Inpyo

    2005-11-01

    Natural killer (NK) cells develop from hematopoietic stem cells (HSCs) in the bone marrow. To understand the molecular regulation of NK cell development, serial analysis of gene expression (SAGE) was applied to HSCs, NK precursor (pNK) cells, and mature NK cells (mNK) cultured without or with OP9 stromal cells. From 170,464 total individual tags from four SAGE libraries, 35,385 unique genes were identified. A set of genes was expressed in a stage-specific manner: 15 genes in HSCs, 30 genes in pNK cells, and 27 genes in mNK cells. Among them, lipoprotein lipase induced NK cell maturation and cytotoxic activity. Identification of genome-wide profiles of gene expression in different stages of NK cell development affords us a fundamental basis for defining the molecular network during NK cell development.

  12. Increase in natural killer cell activity following living-related liver transplantation.

    PubMed

    Hirata, M; Kita, Y; Saito, S; Nishimura, M; Ito, M; Mizuta, K; Tanaka, H; Harihara, Y; Kawarasaki, H; Hashizume, K; Makuuchi, M

    1998-01-01

    We monitored the serial changes of natural killer cell (NK) activity in eight recipients of living-related liver transplantation. The HLA types of all eight patients were haplotypically identical with those of their donors. Tacrolimus and methylprednisolone were used for immunosuppression. The NK activity before transplantation was 24.1 +/- 20.2% which is surprisingly low when compared with the value for normal individuals (67.7 +/- 13.2%, P < 0.01) or a liver dysfunction group (49.4 +/- 21.9%, P < 0.05). Serial changes in NK activity revealed a minimum of 6.1 +/- 3.6% 1 week after transplantation, gradually increasing to 49.2 +/- 12.5% at 2 months after transplantation. These results suggest that the diseased liver might play an important role in the suppression of NK activity.

  13. Type 1 Innate Lymphoid Cell Biology: Lessons Learnt from Natural Killer Cells.

    PubMed

    Jiao, Yuhao; Huntington, Nicholas D; Belz, Gabrielle T; Seillet, Cyril

    2016-01-01

    Group 1 innate lymphoid cells (ILCs) comprise the natural killer (NK) cells and ILC1s that reside within peripheral tissues. Several different ILC1 subsets have recently been characterized; however, no unique markers have been identified that uniquely define these subsets. Whether ILC1s and NK cells are in fact distinct lineages, or alternately exhibit transitional molecular programs that allow them to adapt to different tissue niches remains an open question. NK cells are the prototypic member of the Group 1 ILCs and have been historically assigned the functions of what now appears to be a multi-subset family that are distributed throughout the body. This raises the question of whether each of these populations mediate distinct functions during infection and tumor immunosurveillance. Here, we review the diversity of the Group 1 ILC subsets in their transcriptional regulation, localization, mobility, and receptor expression, and highlight the challenges in unraveling the individual functions of these different populations of cells.

  14. [HMGB1 as metabolic weapon in the arsenal of natural killer cells].

    PubMed

    Gdynia, G

    2016-11-01

    The German Nobel Prize winner Otto Warburg discovered the importance of glycolysis in cancer cells in the 1920s. Nearly one century later the inhibition of tumor glycolysis in cancer cells could literally be the Achilles Heel in cancer therapy. Surprisingly, we could show that Natural Killer (NK) cells pursue this strategy. They employ specific metabolic weapons to eliminate cancer cells by targeting tumor glycolysis. In colon cancer cells a specifically modified form of high mobility group box 1 (HMGB1) protein released by NK cells induced a previously unknown form of cell death. This new link between the killing of cancer cells and the innate immune system opened up new perspectives for immunotherapy in oncology.

  15. Glutathione diminishes tributyltin- and dibutyltin-induced loss of lytic function in human natural killer cells.

    PubMed

    Powell, Jeralyn J; Davis, McLisa V; Whalen, Margaret M

    2009-01-01

    This study investigated whether reduced glutathione (GSH) was able to alter the negative effects of tributyltin (TBT) or dibutyltin (DBT) on the lytic function of human natural killer (NK) cells. NK cells are an initial immune defense against the development of tumors or viral infections. TBT and DBT are widespread environmental contaminants, due to their various industrial applications. Both TBT and DBT have been shown to decrease the ability of NK cells to lyse tumor cells (lytic function). The results indicated that the presence of GSH during the exposure of NK cells to TBT or DBT diminished the negative effect of the butyltin on the lytic function of NK cells. This suggests that the interaction of TBT and DBT with functionally relevant sulfhydryl groups in NK cells may be part of the mechanism by which they decrease NK lytic function.

  16. Inflammatory infiltrates and natural killer cell presence in human brain tumors.

    PubMed

    Stevens, A; Klöter, I; Roggendorf, W

    1988-02-15

    Immunohistochemical analysis of subpopulations of inflammatory cells in 81 primary and secondary human brain tumors was done. Natural killer (NK) cells, representing non-major histocompatibility complex-restricted, spontaneous cytotoxicity and monocytic cells are virtually absent in infiltrates of gliomas and account only for a minor percentage of inflammatory cells in brain metastases of carcinoma and in craniopharyngeomas. Infiltrates in gliomas consist almost exclusively of T-cells of the suppressor/cytotoxic type whereas infiltrates in carcinoma metastases and craniopharyngeomas contain considerable numbers of T-helper/inducer cells and B-cells. From this the authors conclude (1) that NK cells do not play a major role in tumor rejection, and (2) that the kind of inflammatory reaction does not depend upon the tumor site but more likely on the tumor type. No correlation between tumor differentiation and infiltrate composition is evident.

  17. Toxicity of chronic high alcohol intake on mouse natural killer cell activity.

    PubMed

    Abdallah, R M; Starkey, J R; Meadows, G G

    1988-02-01

    The toxicity of chronic alcohol intake on natural killer (NK) cell activity of spleen cells from well-nourished, female C57BL/6 mice was studied in a 4-hour cytolytic chromium-release assay against YAC-1 lymphoma cells. Mice were fed a nutritionally complete crystalline amino acid diet and received 20% w/v alcohol solution for 12 weeks. Ad libitum and pair-fed control mice were given diet and either an isocaloric glucose solution or water. Decreased NK cell activity was observed in alcohol-consuming mice relative to all other control groups. NK cell activity was moderately decreased by feeding mice a high glucose diet, but more severely lowered in pair-fed groups compared to ad libitum control groups.

  18. Immunomodulatory effects of Viscum album extracts on natural killer cells: review of clinical trials.

    PubMed

    Braedel-Ruoff, Sibylla

    2010-04-01

    Extracts produced from Viscum album L. (mistletoe) are widely used in complementary medicine for the treatment of cancer. In many preclinical and clinical studies, Viscum album extracts were shown to exert immunomodulatory functions. Natural killer (NK) cells play an important role in cell-mediated immune responses against tumor cells. This article reviews clinical trials that address the influence of the mistletoe extract Iscador on NK cells and discusses the results with regard to the NK cell functions assayed, to putative underlying mechanisms, and to the role of different mistletoe components. Although many trials demonstrated a positive effect of Iscador treatment on NK cell function, further dedicated studies with optimized treatment schedules and comparable mistletoe doses are necessary to confirm these results regarding involvement of NK cells on the immunomodulatory functions of Iscador therapy and to investigate the clinical relevance of these findings. Copyright 2010 S. Karger AG, Basel.

  19. Exploiting natural killer group 2D receptors for CAR T-cell therapy.

    PubMed

    Demoulin, Benjamin; Cook, W James; Murad, Joana; Graber, David J; Sentman, Marie-Louise; Lonez, Caroline; Gilham, David E; Sentman, Charles L; Agaugue, Sophie

    2017-08-01

    Chimeric antigen receptors (CARs) are genetically engineered proteins that combine an extracellular antigen-specific recognition domain with one or several intracellular T-cell signaling domains. When expressed in T cells, these CARs specifically trigger T-cell activation upon antigen recognition. While the clinical proof of principle of CAR T-cell therapy has been established in hematological cancers, CAR T cells are only at the early stages of being explored to tackle solid cancers. This special report discusses the concept of exploiting natural killer cell receptors as an approach that could broaden the specificity of CAR T cells and potentially enhance the efficacy of this therapy against solid tumors. New data demonstrating feasibility of this approach in humans and supporting the ongoing clinical trial are also presented.

  20. Mouse Adenovirus Type 1 Infection of Natural Killer Cell-Deficient Mice

    PubMed Central

    Welton, Amanda R.; Gralinski, Lisa E.; Spindler, Katherine R.

    2008-01-01

    Natural killer (NK) cells contribute to the initial nonspecific response to viral infection, and viruses exhibit a range of sensitivities to NK cells in vivo. We investigated the role of NK cells in infection of mice by mouse adenovirus type 1 (MAV-1) using antibody-mediated depletion and knockout mice. MAV-1 causes encephalomyelitis and replicates to highest levels in brains. NK cell-depleted mice infected with MAV-1 showed brain viral loads 8-20 days p.i. that were similar to wild-type control non-depleted mice. Mice genetically deficient for NK cells behaved similarly to wild-type control mice with respect to brain viral loads and survival. We conclude that NK cells are not required to control virus replication in the brains of MAV-1-infected mice. PMID:18155121

  1. Human natural killer cells prevent infectious mononucleosis features by targeting lytic Epstein-Barr virus infection.

    PubMed

    Chijioke, Obinna; Müller, Anne; Feederle, Regina; Barros, Mario Henrique M; Krieg, Carsten; Emmel, Vanessa; Marcenaro, Emanuela; Leung, Carol S; Antsiferova, Olga; Landtwing, Vanessa; Bossart, Walter; Moretta, Alessandro; Hassan, Rocio; Boyman, Onur; Niedobitek, Gerald; Delecluse, Henri-Jacques; Capaul, Riccarda; Münz, Christian

    2013-12-26

    Primary infection with the human oncogenic Epstein-Barr virus (EBV) can result in infectious mononucleosis (IM), a self-limiting disease caused by massive lymphocyte expansion that predisposes for the development of distinct EBV-associated lymphomas. Why some individuals experience this symptomatic primary EBV infection, whereas the majority acquires the virus asymptomatically, remains unclear. Using a mouse model with reconstituted human immune system components, we show that depletion of human natural killer (NK) cells enhances IM symptoms and promotes EBV-associated tumorigenesis mainly because of a loss of immune control over lytic EBV infection. These data suggest that failure of innate immune control by human NK cells augments symptomatic lytic EBV infection, which drives lymphocyte expansion and predisposes for EBV-associated malignancies.

  2. Liaison between natural killer cells and dendritic cells in human gestation.

    PubMed

    Leno-Durán, Ester; Muñoz-Fernández, Raquel; Olivares, Enrique García; Tirado-González, Irene

    2014-09-01

    A successful pregnancy relies on immunological adaptations that allow the fetus to grow and develop in the uterus, despite being recognized by maternal immune cells. Among several immunocompetent cell types present within the human maternal/fetal interface, DC-SIGN(+) dendritic cells (DCs) and CD56(+) natural killer (NK) cells are of major importance for early pregnancy maintenance, not only generating maternal immunological tolerance but also regulating stromal cell differentiation. Previous reports show the presence of NK-DC cell conjugates in first trimester human decidua, suggesting that these cells may play a role in the modulation of the local immune response within the uterus. While effective immunity is necessary to protect the mother from harmful pathogens, some form of tolerance must be activated to avoid an immune response against fetal antigens. This review article discusses current evidence concerning the functions of DC and NK cells in pregnancy and their liaison in human decidua.

  3. Natural Killer Cell Adoptive Transfer Therapy: Exploiting the First Line of Defense Against Cancer.

    PubMed

    Davis, Zachary B; Felices, Martin; Verneris, Michael R; Miller, Jeffrey S

    2015-01-01

    Natural killer (NK) cells constitute an important component of the initial immunological response against transformed cells. However, chronic exposure to the tumor microenvironment can fundamentally alter the ability of NK cells to sufficiently control tumor progression. Thus, the adoptive transfer of healthy, functional NK cells as an interventional therapy has been an area of great interest for improving patient outcomes. Recent developments in the field have provided a better understanding of what makes the NK compartment effective against malignant cells. Moreover, there are now multiple potential sources of NK cell products for infusion as well as techniques to manipulate these cells to enhance their antitumor functions. This review explores the advantages and disadvantages of various sources of NK cells as well as prospective therapeutic enhancements to adoptively transferred NK cells.

  4. Control of immune ligands by members of a cytomegalovirus gene expansion suppresses natural killer cell activation

    PubMed Central

    Fielding, Ceri A; Weekes, Michael P; Nobre, Luis V; Ruckova, Eva; Wilkie, Gavin S; Paulo, Joao A; Chang, Chiwen; Suárez, Nicolás M; Davies, James A; Antrobus, Robin; Stanton, Richard J; Aicheler, Rebecca J; Nichols, Hester; Vojtesek, Borek; Trowsdale, John; Davison, Andrew J; Gygi, Steven P

    2017-01-01

    The human cytomegalovirus (HCMV) US12 family consists of ten sequentially arranged genes (US12-21) with poorly characterized function. We now identify novel natural killer (NK) cell evasion functions for four members: US12, US14, US18 and US20. Using a systematic multiplexed proteomics approach to quantify ~1300 cell surface and ~7200 whole cell proteins, we demonstrate that the US12 family selectively targets plasma membrane proteins and plays key roles in regulating NK ligands, adhesion molecules and cytokine receptors. US18 and US20 work in concert to suppress cell surface expression of the critical NKp30 ligand B7-H6 thus inhibiting NK cell activation. The US12 family is therefore identified as a major new hub of immune regulation. DOI: http://dx.doi.org/10.7554/eLife.22206.001 PMID:28186488

  5. Psychoneuroimmunology and natural killer cells: the chromium release whole blood assay.

    PubMed

    Fletcher, Mary Ann; Barnes, Zachary; Broderick, Gordon; Klimas, Nancy G

    2012-01-01

    Natural killer (NK) cells are an essential component of innate immunity. These lymphocytes are also sensitive barometers of the effects of endogenous and exogenous stressors on the immune system. This chapter will describe a chromium ((51)Cr) release bioassay designed to measure the target cell killing capacity of NK cells (NKCC). Key features of the cytotoxicity assay are that it is done with whole blood and that numbers of effector cells are determined for each sample by flow cytometry and lymphocyte count. Effector cells are defined as CD3-CD56+ lymphocytes. Target cells are the K562 eyrthroleukemia cell line. Killing capacity is defined as number of target cells killed per effector cell, at an effector cell/target cell ratio of 1:1 during a 4 h in vitro assay.

  6. Transcription factor Foxo1 is a negative regulator of natural killer cell maturation and function.

    PubMed

    Deng, Youcai; Kerdiles, Yann; Chu, Jianhong; Yuan, Shunzong; Wang, Youwei; Chen, Xilin; Mao, Hsiaoyin; Zhang, Lingling; Zhang, Jianying; Hughes, Tiffany; Deng, Yafei; Zhang, Qi; Wang, Fangjie; Zou, Xianghong; Liu, Chang-Gong; Freud, Aharon G; Li, Xiaohui; Caligiuri, Michael A; Vivier, Eric; Yu, Jianhua

    2015-03-17

    Little is known about the role of negative regulators in controlling natural killer (NK) cell development and effector functions. Foxo1 is a multifunctional transcription factor of the forkhead family. Using a mouse model of conditional deletion in NK cells, we found that Foxo1 negatively controlled NK cell differentiation and function. Immature NK cells expressed abundant Foxo1 and little Tbx21 relative to mature NK cells, but these two transcription factors reversed their expression as NK cells proceeded through development. Foxo1 promoted NK cell homing to lymph nodes by upregulating CD62L expression and inhibited late-stage maturation and effector functions by repressing Tbx21 expression. Loss of Foxo1 rescued the defect in late-stage NK cell maturation in heterozygous Tbx21(+/-) mice. Collectively, our data reveal a regulatory pathway by which the negative regulator Foxo1 and the positive regulator Tbx21 play opposing roles in controlling NK cell development and effector functions.

  7. Natural Killer Cell Recognition of Melanoma: New Clues for a More Effective Immunotherapy

    PubMed Central

    Tarazona, Raquel; Duran, Esther; Solana, Rafael

    2016-01-01

    Natural killer (NK) cells participate in the early immune response against melanoma and also contribute to the development of an adequate adaptive immune response by their crosstalk with dendritic cells and cytokine secretion. Melanoma resistance to conventional therapies together with its high immunogenicity justifies the development of novel therapies aimed to stimulate effective immune responses against melanoma. However, melanoma cells frequently escape to CD8 T cell recognition by the down-regulation of major histocompatibility complex (MHC) class I molecules. In this scenario, NK cells emerge as potential candidates for melanoma immunotherapy due to their capacity to recognize and destroy melanoma cells expressing low levels of MHC class I molecules. In addition, the possibility to combine immune checkpoint blockade with other NK cell potentiating strategies (e.g., cytokine induction of activating receptors) has opened new perspectives in the potential use of adoptive NK cell-based immunotherapy in melanoma. PMID:26779186

  8. Enough! Stop the arguments and get on with the science of natural killer cell testing.

    PubMed

    Sacks, Gavin

    2015-07-01

    Natural killer cell testing is currently practised widely, and there are studies indicating potential benefit in terms of targeting women with repeated reproductive failure for immune therapy. This may be a better approach than empirical immune therapy without any investigation. More and better studies are needed before such an approach can be fully endorsed. There is still uncertainty over the precise pathophysiological basis for all immune investigation and therapy, but this should not be a barrier for clinical observation and empirical care. On the contrary, clinicians and researchers should work more closely together to provide the best care for our patients. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  9. Characterization of human invariant natural killer T subsets in health and disease using a novel invariant natural killer T cell-clonotypic monoclonal antibody, 6B11

    PubMed Central

    Montoya, Carlos J; Pollard, David; Martinson, Jeffrey; Kumari, Kumud; Wasserfall, Clive; Mulder, Candice B; Rugeles, Maria T; Atkinson, Mark A; Landay, Alan L; Wilson, S Brian

    2007-01-01

    Identification of human CD1d-restricted T-cell receptor (TCR)-invariant natural killer T (iNKT) cells has been dependent on utilizing combinations of monoclonal antibodies or CD1d tetramers, which do not allow for the most specific analysis of this T-cell subpopulation. A novel monoclonal antibody (clone 6B11), specific for the invariant CDR3 loop of human canonical Vα24Jα18 TCR α chain, was developed and used to specifically characterize iNKT cells. In healthy individuals studied for up to 1 year, a wide but stable frequency of circulating iNKT cells (range: 0·01–0·92%) was observed, with no differences in frequency by gender. Four stable iNKT cell subsets were characterized in peripheral blood based on the expression of CD4 and CD8, with CD8+ iNKT cells being a phenotypic and functionally different subset from CD4+ and double negative iNKT cells; in particular, LAG-3 was preferentially expressed on CD8+ iNKT cells. In addition, a strong negative linear correlation between the frequency of total iNKT cells and percentage of the CD4+ subset was observed. In terms of their potential association with disease, patients at risk for type 1 diabetes had significantly expanded frequencies of double negative iNKT cells when compared to matched controls and first-degree relatives. Moreover, peripheral blood CD4+ iNKT cells were the highest producers of interleukin-4, while the production of interferon-γ and tumour necrosis factor-α was similar amongst all iNKT cell subsets. These differences in iNKT cell subsets suggest that in humans the relative ratio of iNKT cell subsets may influence susceptibility vs. resistance to immune-mediated diseases. PMID:17662044

  10. Terminal Differentiation of CD56(dim)CD16(+) Natural Killer Cells Is Associated with Increase in Natural Killer Cell Frequencies After Antiretroviral Treatment in HIV-1 Infection.

    PubMed

    Ahmad, Fareed; Tufa, Dejene Milkessa; Mishra, Neha; Jacobs, Roland; Schmidt, Reinhold E

    2015-12-01

    HIV-1 infection results in immunological abnormalities of natural killer (NK) cells such as disturbed distribution of NK cell subsets and downmodulation of activating and upregulation of inhibitory receptors thereby diminishing NK cell killing capacity and cytokine secretion. Antiretroviral treatment (ART) is known to restore phenotype and functions of NK cells. However, the effects of ART on NK cell terminal differentiation, activation, and disturbed distribution have not been studied yet longitudinally. Here, we analyzed the effects of ART on these parameters of peripheral blood NK cells in a longitudinal as well as in a cross-sectional study. We observed that expanded CD56(-)CD16(+) NK cell frequency is inversely correlated with the frequency of CD56(dim)CD16(+) NK cells in treatment-naive HIV-1 patients. Loss of CD56(dim)CD16(+) and expansion of CD56(-)CD16(+) NK cells again restore to the levels of healthy controls after ART. Enhanced immune activation of different NK cell subsets is partially restored after ART. Terminal differentiation of CD56(dim)CD16(+) NK cells is enhanced after ART as measured by CD57 expression. Frequencies of CD57(+)CD56(dim)CD16(+) NK cells are directly correlated with the frequencies of total NK cells suggesting that an increase in the frequencies of CD57(+)CD56(dim)CD16(+) NK cells is reflected by increased frequencies of total NK cells after ART. Taken together these data demonstrate that ART has an effect on the immune restoration of NK cells and is enhanced in the terminal differentiation of CD56(dim)CD16(+) NK cells, which is associated with increased frequencies of total NK cells after ART.

  11. Fine specificity of natural killer T cells against GD3 ganglioside and identification of GM3 as an inhibitory natural killer T-cell ligand.

    PubMed

    Park, Jun-Eui; Wu, Dianna Y; Prendes, Maria; Lu, Sharon X; Ragupathi, Govind; Schrantz, Nicolas; Chapman, Paul B

    2008-01-01

    GD3, a ganglioside expressed on melanoma, is the only tumour-associated glycolipid described to date that can induce a CD1d-restricted natural killer T (NKT)-cell response. We analysed the fine specificity of GD3-reactive NKT cells and discovered that immunization with GD3 induced two populations of GD3-reactive NKT cells. One population was CD4+ CD8- and was specific for GD3; the other population was CD4- CD8- and cross-reacted with GM3 in a CD1d-restricted manner, but did not cross-react with GM2, GD2, or lactosylceramide. This indicated that the T-cell receptors reacting with GD3 recognize glucose-galactose linked to at least one N-acetyl-neuraminic acid but will not accommodate a terminal N-acetylgalactosamine. Immunization with GM2, GM3, GD2, or lactosylceramide did not induce an NKT-cell response. Coimmunization of GM3-loaded antigen-presenting cells (APCs) with GD3-loaded APCs suppressed the NKT-cell response to GD3 in a CD1d-restricted manner. This suppressive effect was specific for GM3 and was a local effect lasting 2-4 days. In vitro, GM3-loaded APCs also suppressed the interleukin-4 response, but not the interferon-gamma response, of NKT cells to alpha-galactosylceramide. However, there was no effect on the T helper type 2 responses of conventional T cells. We found that this suppression was not mediated by soluble factors. We hypothesize that GM3 induces changes to the APC that lead to suppression of T helper type 2-like NKT-cell responses.

  12. Tributyltin and dibutyltin alter secretion of tumor necrosis factor alpha from human natural killer cells and a mixture of T cells and natural killer cells.

    PubMed

    Hurt, Kelsi; Hurd-Brown, Tasia; Whalen, Margaret

    2013-06-01

    Butyltins (BTs) have been in widespread use. Tributyltin (TBT) has been used as a biocide in a variety of applications and is found in human blood samples. Dibutyltin (DBT) has been used as a stabilizer in polyvinyl chloride plastics and as a de-worming agent in poultry. DBT, like TBT, is found in human blood. Human natural killer (NK) cells are the earliest defense against tumors and viral infections and secrete the cytokine tumor necrosis factor-alpha (TNF-α). TNF-α is an important regulator of adaptive and innate immune responses. TNF-α promotes inflammation and an association between malignant transformation and inflammation has been established. Previously, we have shown that TBT and DBT were able to interfere with the ability of NK cells to lyse tumor target cells. Here we show that BTs alter cytokine secretion by NK cells as well as a mixture of T and NK lymphocytes (T/NK cells). We examined 24-, 48-h and 6-day exposures to TBT (200-2.5 nM) and DBT (5-0.05 μM) on TNF-α secretion by highly enriched human NK cells and T/NK cells. The results indicate that TBT (200-2.5 nM) decreased TNF-α secretion from NK cells. In the T/NK cells, 200 nM TBT decreased secretion whereas 100-5 nM TBT increased secretion of TNF-α. NK cells or T/NK cells exposed to higher concentrations of DBT showed decreased TNF-α secretion whereas lower concentrations showed increased secretion. The effects of BTs on TNF-α secretion are seen at concentrations present in human blood.

  13. Production of interferon-gamma by natural killer cells and aging in chronic human schistosomiasis.

    PubMed Central

    Speziali, E; Bethony, J; Martins-Filho, O; Fraga, L A O; Lemos, D S; Souza, L J; Correa-Oliveira, R; Faria, A M C

    2004-01-01

    BACKGROUND: Aging is associated with several alterations in the phenotype, repertoire and activation status of lymphocytes as well as in the cytokine profile produced by these cells. As a lifelong condition, chronic parasitic diseases such as human schistosomiasis overlaps with the aging process and no systematic study has yet addressed the changes in immune response during infection with Schistosoma mansoni in older individuals. AIM: Herein we study the influence of immunological alterations brought about by senescence in the course of schistosomiasis. MATERIALS AND METHODS: Individuals 10-95 years of age, from both sexes, from an endemic area for S. mansoni infection were matched by intensity of infection as measured by egg counts. We analyzed, as a parameter, cytokine expression by lymphocytes and natural killer cells after in vitro stimulation with soluble egg antigen and soluble worm antigen using flow cytometry. RESULTS: We demonstrated that the frequency of CD16+ interferon-gamma (IFN-gamma)+ natural killer cells in negative individuals over the age of 70 years is significantly higher than in positive individuals after in vitro stimulation with S. mansoni antigen extracts. The frequency of these cells is increased in all individuals over the age of 50 years and only declines in positive individuals after 70 years of age. Analysis of either CD4? or CD8? cells after antigen stimulation show no significant increase in frequency of IFN-gamma in negative or in positive individuals of this age group, suggesting that the effect on CD16+ cells is not T-cell dependent. CONCLUSION: Since production of IFN-gamma has been related to resistance to schistosome infection, our data suggest that age-associated changes in CD16+ cells may play a role in controlling infection intensity in the elderly in S. mansoni endemic areas of Brazil. PMID:15770048

  14. Bone marrow mesenchymal stem cells reduce the antitumor activity of cytokine-induced killer/natural killer cells in K562 NOD/SCID mice.

    PubMed

    Li, Yang; Qu, Yu-Hua; Wu, Yan-Feng; Wang, Xiao-Ping; Wei, Jing; Huang, Wen-Ge; Zhou, Dun-Hua; Fang, Jianpei; Huang, Ke; Huang, Shao-Liang

    2011-08-01

    Adoptive cellular immunotherapy is an important treatment to eliminate residual tumor cells after hematopoietic stem-cell transplantation. Bone marrow mesenchymal stem cells (MSC) have previously been shown to exert immunoregulation functions, including inhibition of proliferation and killing activities of T cells and natural killer (NK) cells in vitro and reduction of the graft-versus-host disease. MSC can survive in vivo for a long period of time, the influence of MSC on the antitumor activity of subsequently infused immune killer cells is not clear. The aim of this study was to investigate the influences of MSC infused via different paths and at different times on the antitumor activities of cytokine-induced killer (CIK)/NK cells derived from umbilical cord blood in K562 NOD/SCID mice. The potential interaction mechanisms of MSC and CIK/NK cells infused through different paths using different intervals in vivo were subsequently explored. The results show that the antitumor activities of CIK/NK cells was inhibited by MSC when injected via the same path (tail vein), and the suppressive effect of MSC on CIK/NK cells were less pronounced when they were injected separately through different paths. There were no effects of MSC on the antitumor activities of CIK/NK cells if the MSC and CIK/NK cells were injected with a 48-h interval. Moreover, the suppressive effect continuous, even if MSC were infused 48 h earlier than CIK/NK cells. It suggests that pre-injected MSC can reduce the antitumor activities of CIK/NK cells in vivo. The probable mechanisms are that MSC and CIK/NK cells might have a greater opportunity to meet and interact if they are injected simultaneously via the same path. The suppression of MSC on CIK/NK cells in vivo mainly takes place in the reticuloendothelial system, including the lung and the liver.

  15. Identification of Anti-tumor Cells Carrying Natural Killer (NK) Cell Antigens in Patients With Hematological Cancers.

    PubMed

    Krzywinska, Ewelina; Allende-Vega, Nerea; Cornillon, Amelie; Vo, Dang-Nghiem; Cayrefourcq, Laure; Panabieres, Catherine; Vilches, Carlos; Déchanet-Merville, Julie; Hicheri, Yosr; Rossi, Jean-François; Cartron, Guillaume; Villalba, Martin

    2015-10-01

    Natural killer (NK) cells, a cytotoxic lymphocyte lineage, are able to kill tumor cells in vitro and in mouse models. However, whether these cells display an anti-tumor activity in cancer patients has not been demonstrated. Here we have addressed this issue in patients with several hematological cancers. We found a population of highly activated CD56(dim)CD16(+) NK cells that have recently degranulated, evidence of killing activity, and it is absent in healthy donors. A high percentage of these cells expressed natural killer cell p46-related protein (NKp46), natural-killer group 2, member D (NKG2D) and killer inhibitory receptors (KIRs) and a low percentage expressed NKG2A and CD94. They are also characterized by a high metabolic activity and active proliferation. Notably, we found that activated NK cells from hematological cancer patients have non-NK tumor cell antigens on their surface, evidence of trogocytosis during tumor cell killing. Finally, we found that these activated NK cells are distinguished by their CD45RA(+)RO(+) phenotype, as opposed to non-activated cells in patients or in healthy donors displaying a CD45RA(+)RO(-) phenotype similar to naïve T cells. In summary, we show that CD45RA(+)RO(+) cells, which resemble a unique NK population, have recognized tumor cells and degranulate in patients with hematological neoplasias.

  16. Identification of Anti-tumor Cells Carrying Natural Killer (NK) Cell Antigens in Patients With Hematological Cancers

    PubMed Central

    Krzywinska, Ewelina; Allende-Vega, Nerea; Cornillon, Amelie; Vo, Dang-Nghiem; Cayrefourcq, Laure; Panabieres, Catherine; Vilches, Carlos; Déchanet-Merville, Julie; Hicheri, Yosr; Rossi, Jean-François; Cartron, Guillaume; Villalba, Martin

    2015-01-01

    Natural killer (NK) cells, a cytotoxic lymphocyte lineage, are able to kill tumor cells in vitro and in mouse models. However, whether these cells display an anti-tumor activity in cancer patients has not been demonstrated. Here we have addressed this issue in patients with several hematological cancers. We found a population of highly activated CD56dimCD16+ NK cells that have recently degranulated, evidence of killing activity, and it is absent in healthy donors. A high percentage of these cells expressed natural killer cell p46-related protein (NKp46), natural-killer group 2, member D (NKG2D) and killer inhibitory receptors (KIRs) and a low percentage expressed NKG2A and CD94. They are also characterized by a high metabolic activity and active proliferation. Notably, we found that activated NK cells from hematological cancer patients have non-NK tumor cell antigens on their surface, evidence of trogocytosis during tumor cell killing. Finally, we found that these activated NK cells are distinguished by their CD45RA+RO+ phenotype, as opposed to non-activated cells in patients or in healthy donors displaying a CD45RA+RO− phenotype similar to naïve T cells. In summary, we show that CD45RA+RO+ cells, which resemble a unique NK population, have recognized tumor cells and degranulate in patients with hematological neoplasias. PMID:26629531

  17. The genetic predisposition of natural killer cell to BK virus-associated nephropathy in renal transplant patients.

    PubMed

    Trydzenskaya, Hanna; Juerchott, Karsten; Lachmann, Nils; Kotsch, Katja; Kunert, Kristina; Weist, Benjamin; Schönemann, Constanze; Schindler, Ralf; Nickel, Peter; Melzig, Matthias F; Hugo, Christian; Thomusch, Oliver; Neumann, Avidan U; Reinke, Petra; Babel, Nina

    2013-08-01

    BK virus (BKV) infection represents a serious complication in renal transplant patients resulting in BKV-associated nephropathy and subsequent allograft loss. Natural killer cells are crucial in the antiviral immune response; however, an understanding of the role of natural killer cells in protection against BKV is limited. To elucidate whether killer-cell immunoglobulin-like receptors and their interaction between donor-/recipient-related ligands have a role in BKV infection, we performed genotyping analysis in 48 kidney transplant recipients with a history of severe BKV infection/BKV-associated nephropathy and 110 recipients with stable renal function and no BKV reactivation. Of interest, we found that telomeric gene content motif was significantly associated with severe course of BKV infection/BKV-associated nephropathy and detected significantly higher percentage of patients with BKV-associated nephropathy carrying low numbers of activating receptors compared with the control group. Detailed analysis of each single receptor revealed significantly lower frequencies of the activating receptor KIR3DS1 in patients with BKV infection/nephropathy as compared with the controls. Thus, our study supports protective effects of activating receptors in BKV infection and suggest natural killer-cell-related genetic predisposition to the development of BKV-associated nephropathy.

  18. The Natural Cytotoxicity Receptor 1 Contribution to Early Clearance of Streptococcus pneumoniae and to Natural Killer-Macrophage Cross Talk

    PubMed Central

    Yossef, Rami; Hadad, Uzi; Elkabets, Moshe; Vallon-Eberhard, Alexandra; Hulihel, Luai; Jung, Steffen; Ghadially, Hormas; Braiman, Alex; Apte, Ron N.; Mandelboim, Ofer; Dagan, Ron; Mizrachi-Nebenzahl, Yaffa; Porgador, Angel

    2011-01-01

    Natural killer (NK) cells serve as a crucial first line of defense against tumors, viral and bacterial infections. We studied the involvement of a principal activating natural killer cell receptor, natural cytotoxicity receptor 1 (NCR1), in the innate immune response to S. pneumoniae infection. Our results demonstrate that the presence of the NCR1 receptor is imperative for the early clearance of S. pneumoniae. We tied the ends in vivo by showing that deficiency in NCR1 resulted in reduced lung NK cell activation and lung IFNγ production at the early stages of S. pneumoniae infection. NCR1 did not mediate direct recognition of S. pneumoniae. Therefore, we studied the involvement of lung macrophages and dendritic cells (DC) as the mediators of NK-expressed NCR1 involvement in response to S. pneumoniae. In vitro, wild type BM-derived macrophages and DC expressed ligands to NCR1 and co-incubation of S. pneumoniae-infected macrophages/DC with NCR1-deficient NK cells resulted in significantly lesser IFNγ levels compared to NCR1-expressing NK cells. In vivo, ablation of lung macrophages and DC was detrimental to the early clearance of S. pneumoniae. NCR1-expressing mice had more potent alveolar macrophages as compared to NCR1-deficient mice. This result correlated with the higher fraction of NCR1-ligandhigh lung macrophages, in NCR1-expressing mice, that had better phagocytic activity compared to NCR1-liganddull macrophages. Overall, our results point to the essential contribution of NK-expressed NCR1 in early response to S. pneumoniae infection and to NCR1-mediated interaction of NK and S. pneumoniae infected-macrophages and -DC. PMID:21887255

  19. The natural cytotoxicity receptor 1 contribution to early clearance of Streptococcus pneumoniae and to natural killer-macrophage cross talk.

    PubMed

    Elhaik-Goldman, Shirin; Kafka, Daniel; Yossef, Rami; Hadad, Uzi; Elkabets, Moshe; Vallon-Eberhard, Alexandra; Hulihel, Luai; Jung, Steffen; Ghadially, Hormas; Braiman, Alex; Apte, Ron N; Mandelboim, Ofer; Dagan, Ron; Mizrachi-Nebenzahl, Yaffa; Porgador, Angel

    2011-01-01

    Natural killer (NK) cells serve as a crucial first line of defense against tumors, viral and bacterial infections. We studied the involvement of a principal activating natural killer cell receptor, natural cytotoxicity receptor 1 (NCR1), in the innate immune response to S. pneumoniae infection. Our results demonstrate that the presence of the NCR1 receptor is imperative for the early clearance of S. pneumoniae. We tied the ends in vivo by showing that deficiency in NCR1 resulted in reduced lung NK cell activation and lung IFNγ production at the early stages of S. pneumoniae infection. NCR1 did not mediate direct recognition of S. pneumoniae. Therefore, we studied the involvement of lung macrophages and dendritic cells (DC) as the mediators of NK-expressed NCR1 involvement in response to S. pneumoniae. In vitro, wild type BM-derived macrophages and DC expressed ligands to NCR1 and co-incubation of S. pneumoniae-infected macrophages/DC with NCR1-deficient NK cells resulted in significantly lesser IFNγ levels compared to NCR1-expressing NK cells. In vivo, ablation of lung macrophages and DC was detrimental to the early clearance of S. pneumoniae. NCR1-expressing mice had more potent alveolar macrophages as compared to NCR1-deficient mice. This result correlated with the higher fraction of NCR1-ligand(high) lung macrophages, in NCR1-expressing mice, that had better phagocytic activity compared to NCR1-ligand(dull) macrophages. Overall, our results point to the essential contribution of NK-expressed NCR1 in early response to S. pneumoniae infection and to NCR1-mediated interaction of NK and S. pneumoniae infected-macrophages and -DC.

  20. Natural killer cell activity in a population of leukemia-prone wild mice (Mus musculus).

    PubMed

    Scott, J L; Pal, B K; Rasheed, S; Gardner, M B

    1981-08-15

    Natural cell-mediated cytotoxicity against YAC-I targets was measured in splenocytes from leukemia-prone wild mice trapped near Lake Casitas (LC) in southern California. Cytotoxicity was mediated by cells that were non-adherent to nylon wool, non-phagocytic and resistant to thy-1.2 antiserum plus complement. Natural MuLV viremia in LC mice did not impair splenic cytotoxicity against TAC-I target cells, Cells infected with amphotropic and ecotropic MuLV of wild mouse origin were not appreciably lysed by LC splenic effectors. Although variable levels of cytotoxicity were detected against TAC-1 by normal spleen cells, consistently low levels of cytotoxicity against allogenic LC lymphoma, sarcoma and carcinoma targets were found using the same splenocytes. These results indicate that LC mice possess splenocytes with the characteristics of natural killer (NK) cells as defined in inbred mice. The resistance of LC-derived targets to lysis by LC NK cells suggests that NK cells may not be involved in natural tumor immunosurveillance or that the development of spontaneous tumors may involve escape from NK-mediated effector mechanisms.

  1. Differential regulation of interleukin-12- and interleukin-15-induced natural killer cell activation by interleukin-4.

    PubMed

    Salvucci, O; Mami-Chouaib, F; Moreau, J L; Thèze, J; Chehimi, J; Chouaib, S

    1996-11-01

    The regulation of human natural killer (NK) cell activation is under the control of a network of regulatory signals provided by cytokines. In the present study, we investigated the functional interaction between interleukin (IL)-4 and two monocyte/macrophage-derived cytokines, IL-12 and IL-15, during the process of NK stimulation. Using freshly isolated human NK cells, we have demonstrated that IL-4 negatively regulates lymphokine-activated killer (LAK) activity induced by IL-15 against the NK-resistant Daudi target cells. In contrast, IL-4 had no effect on IL-12-stimulated LAK generation. The differential effect of IL-4 on NK cell activation by IL-12 and IL-15 correlates with its ability to increase or to down-regulate the level of tumor necrosis factor-alpha and interferon-gamma release by NK cells, respectively. In contrast, endogenous transforming growth factor-beta 1 does not appear to be involved in the IL-4 regulatory pathway. Furthermore, while IL-4 was found to decrease the basal expression of the IL-2 receptor beta subunit utilized by IL-15, it had no effect on the expression of the beta 1 chain of the IL-12 receptor compared to untreated cells. Northern blot analysis indicated that the IL-4 regulatory effect on NK lytic function was associated with its capacity to down-regulate granzyme B and perforin gene transcription in response to IL-15 and its failure to affect the expression of both gene's in response to IL-12. Together, these data suggest the existence of a distinct cross-talk between IL-4 and IL-15 or IL-12 signaling pathways during the regulation of human non-major histocompatibility complex-restricted cytotoxicity.

  2. Blast-derived microvesicles in sera from patients with acute myeloid leukemia suppress natural killer cell function via membrane-associated transforming growth factor-beta1.

    PubMed

    Szczepanski, Miroslaw J; Szajnik, Marta; Welsh, Ann; Whiteside, Theresa L; Boyiadzis, Michael

    2011-09-01

    Natural killer cell cytotoxicity is decreased in patients with acute myeloid leukemia in comparison to that in normal controls. Tumor-derived microvesicles present in patients' sera exert detrimental effects on immune cells and may influence tumor progression. We investigated the microvesicle protein level, molecular profile and suppression of natural killer cell activity in patients with newly diagnosed acute myeloid leukemia. The patients' sera contained higher levels of microvesicles compared to the levels in controls (P<0.001). Isolated microvesicles had a distinct molecular profile: in addition to conventional microvesicle markers, they contained membrane-associated transforming growth factor-β1, MICA/MICB and myeloid blasts markers, CD34, CD33 and CD117. These microvesicles decreased natural killer cell cytotoxicity (P<0.002) and down-regulated expression of NKG2D in normal natural killer cells (P<0.001). Sera from patients with acute myeloid leukemia contained elevated levels of transforming growth factor-β, and urea-mediated dissociation of microvesicles further increased the levels of this protein. Neutralizing anti-transforming growth factor-β1 antibodies inhibited microvesicle-mediated suppression of natural killer cell activity and NKG2D down-regulation. Interleukin-15 protected natural killer cells from adverse effects of tumor-derived microvesicles. We provide evidence for the existence in acute myeloid leukemia of a novel mechanism of natural killer cell suppression mediated by tumor-derived microvesicles and for the ability of interleukin-15 to counteract this suppression.

  3. In vitro analysis of the proliferative capacity and cytotoxic effects of ex vivo induced natural killer cells, cytokine-induced killer cells, and gamma-delta T cells.

    PubMed

    Niu, Chao; Jin, Haofan; Li, Min; Xu, Jianting; Xu, Dongsheng; Hu, Jifan; He, Hua; Li, Wei; Cui, Jiuwei

    2015-10-12

    Recent studies have focused on the significant cytotoxicity of natural killer (NK) cells, cytokine-induced killer (CIK) cells, and gamma-delta (γδ) T cells in tumor cells. Nevertheless, the therapeutic features of these cell types have not been compared in the literature. The aim of this study was to evaluate the feasibility of activation and expansion of NK, CIK, and γδ T cells from cancer patients in vitro, and to clarify the differences in their antitumor capacities. NK, CIK, and γδ T cells were induced from the peripheral blood mononuclear cells of 20 cancer patients by using specific cytokines. Expression of CD69, NKG2D, CD16, granzyme B, perforin, IFN-γ, and IL-2 was measured by flow cytometry. Cytokine production and cytotoxicity were analyzed by enzyme-linked immunosorbent assay and Calcein-AM methods. NK cell proliferation was superior to that of CIK cells, but lower than that of γδ T cells. NK cells had a much stronger ability to secrete perforin, granzyme B, IFN-γ, and IL-2 than did CIK and γδ T cells, and imparted significantly higher overall cytotoxicity. Expanded NK cells from cancer patients are the most effective immune cells in the context of cytokine secretion and anti-tumor cytotoxicity in comparison to CIK and γδ T cells, making them an optimal candidate for adoptive cellular immunotherapy.

  4. Killer Cell Immunoglobulin-like Receptor Genotype and Haplotype Investigation of Natural Killer Cells from an Australian Population of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients.

    PubMed

    Huth, T K; Brenu, E W; Staines, D R; Marshall-Gradisnik, S M

    2016-01-01

    Killer cell immunoglobulin-like receptor (KIR) genes encode for activating and inhibitory surface receptors, which are correlated with the regulation of Natural Killer (NK) cell cytotoxic activity. Reduced NK cell cytotoxic activity has been consistently reported in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) patients, and KIR haplotypes and allelic polymorphism remain to be investigated. The aim of this article was to conduct a pilot study to examine KIR genotypes, haplotypes, and allelic polymorphism in CFS/ME patients and nonfatigued controls (NFCs). Comparison of KIR and allelic polymorphism frequencies revealed no significant differences between 20 CFS/ME patients and 20 NFCs. A lower frequency of the telomeric A/B motif (P < 0.05) was observed in CFS/ME patients compared with NFCs. This pilot study is the first to report the differences in the frequency of KIR on the telomeric A/B motif in CFS/ME patients. Further studies with a larger CFS/ME cohort are required to validate these results.

  5. Lack of the programmed death-1 receptor renders host susceptible to enteric microbial infection through impairing the production of the mucosal natural killer cell effector molecules.

    PubMed

    Solaymani-Mohammadi, Shahram; Lakhdari, Omar; Minev, Ivelina; Shenouda, Steve; Frey, Blake F; Billeskov, Rolf; Singer, Steven M; Berzofsky, Jay A; Eckmann, Lars; Kagnoff, Martin F

    2016-03-01

    The programmed death-1 receptor is expressed on a wide range of immune effector cells, including T cells, natural killer T cells, dendritic cells, macrophages, and natural killer cells. In malignancies and chronic viral infections, increased expression of programmed death-1 by T cells is generally associated with a poor prognosis. However, its role in early host microbial defense at the intestinal mucosa is not well understood. We report that programmed death-1 expression is increased on conventional natural killer cells but not on CD4(+), CD8(+) or natural killer T cells, or CD11b(+) or CD11c(+) macrophages or dendritic cells after infection with the mouse pathogen Citrobacter rodentium. Mice genetically deficient in programmed death-1 or treated with anti-programmed death-1 antibody were more susceptible to acute enteric and systemic infection with Citrobacter rodentium. Wild-type but not programmed death-1-deficient mice infected with Citrobacter rodentium showed significantly increased expression of the conventional mucosal NK cell effector molecules granzyme B and perforin. In contrast, natural killer cells from programmed death-1-deficient mice had impaired expression of those mediators. Consistent with programmed death-1 being important for intracellular expression of natural killer cell effector molecules, mice depleted of natural killer cells and perforin-deficient mice manifested increased susceptibility to acute enteric infection with Citrobacter rodentium. Our findings suggest that increased programmed death-1 signaling pathway expression by conventional natural killer cells promotes host protection at the intestinal mucosa during acute infection with a bacterial gut pathogen by enhancing the expression and production of important effectors of natural killer cell function.

  6. Assessment of human natural killer and lymphokine-activated killer cell cytotoxicity against Toxoplasma gondii trophozoites and brain cysts

    SciTech Connect

    Dannemann, B.R.; Morris, V.A.; Araujo, F.G.; Remington, J.S. )

    1989-10-15

    Because previous work has suggested that NK cells may be important in host resistance against the intracellular parasite Toxoplasma gondii we examined whether human NK cells and lymphokine-activated killer (LAK) cells have activity against trophozoites and cysts of this organism in vitro. A method to radiolabel Toxoplasma trophozoites with 51Cr was developed and direct cytotoxic activity was determined by using modifications of the standard 51Cr release assay. Viability of 51Cr-labeled trophozoites assessed by both methylene blue staining and trypan blue exclusion was greater than 90%. Significantly more 51Cr was released by anti-Toxoplasma antibody and C than by antibody in the absence of C. Incubation of trophozoites with freshly isolated human NK cells or NK cells activated with either rIL-2 or rIFN-alpha did not result in significant release of 51Cr (specific lysis was 0 to 2.3%). In contrast, the average specific lysis of radiolabeled trophozoites by LAK cells was significant. In a series of separate experiments, preincubation of radiolabeled trophozoites with heat-inactivated normal or Toxoplasma antibody-positive human serum increased the cytotoxicity of LAK cells from a mean specific lysis of 15% +/- 4.5 to 39% +/- 8.5, respectively, as assessed by 51Cr release. Because previous work has shown that radioisotope release from parasites may be nonspecific, separate experiments were performed to determine the cytotoxicity of LAK cells against antibody-coated trophozoites by using ethidium bromide-acridine orange staining to assess effector cell damage. LAK cells had a mean specific lysis of 51% against antibody-coated trophozoites by ethidium bromide-acridine orange staining. Preincubation with heat-inactivated Toxoplasma-antibody positive human serum did not increase activity of rIL-2-activated NK cells against 51CR-labeled trophozoites.

  7. Multifunctional human CD56 low CD16 low natural killer cells are the prominent subset in bone marrow of both healthy pediatric donors and leukemic patients.

    PubMed

    Stabile, Helena; Nisti, Paolo; Morrone, Stefania; Pagliara, Daria; Bertaina, Alice; Locatelli, Franco; Santoni, Angela; Gismondi, Angela

    2015-04-01

    We phenotypically and functionally characterized a distinct CD56(low) natural killer cell subset based on CD16 expression levels in bone marrow and peripheral blood of healthy children and pediatric patients with acute lymphoblastic leukemia. Our findings demonstrate for the first time that CD56(low)CD16(low) natural killer cells are more abundant in bone marrow than in peripheral blood and that their frequency is further increased in children with acute lymphoblastic leukemia. Bone marrow and peripheral blood CD56(low)CD16(low) natural killer cells compared with CD56(low)CD16(high) natural killer cells express lower levels of killer inhibitory receptors, higher levels of CD27, CD127, CD122, CD25, but undetectable levels of CD57, suggesting that they have a higher proliferative and differentiation potential. Moreover, CD56(low)CD16(low) natural killer cells display higher levels of CXCR4 and undetectable levels of CX3CR1 and can be consistently and rapidly mobilized in peripheral blood in response to CXCR4 antagonist. Unlike CD56(low)CD16(high), both bone marrow and peripheral blood CD56(low)CD16(low) natural killer cells release IFNγ following cytokine stimulation, and represent the major cytotoxic natural killer cell population against K562 or acute lymphoblastic leukemia target cells. All these data suggest that CD56(low)CD16(low) natural killer cells are multifunctional cells, and that the presence of hematologic malignancies affects their frequency and functional ability at both tumor site and in the periphery.

  8. Multifunctional human CD56low CD16low natural killer cells are the prominent subset in bone marrow of both healthy pediatric donors and leukemic patients

    PubMed Central

    Stabile, Helena; Nisti, Paolo; Morrone, Stefania; Pagliara, Daria; Bertaina, Alice; Locatelli, Franco; Santoni, Angela; Gismondi, Angela

    2015-01-01

    We phenotypically and functionally characterized a distinct CD56low natural killer cell subset based on CD16 expression levels in bone marrow and peripheral blood of healthy children and pediatric patients with acute lymphoblastic leukemia. Our findings demonstrate for the first time that CD56lowCD16low natural killer cells are more abundant in bone marrow than in peripheral blood and that their frequency is further increased in children with acute lymphoblastic leukemia. Bone marrow and peripheral blood CD56lowCD16low natural killer cells compared with CD56lowCD16high natural killer cells express lower levels of killer inhibitory receptors, higher levels of CD27, CD127, CD122, CD25, but undetectable levels of CD57, suggesting that they have a higher proliferative and differentiation potential. Moreover, CD56lowCD16low natural killer cells display higher levels of CXCR4 and undetectable levels of CX3CR1 and can be consistently and rapidly mobilized in peripheral blood in response to CXCR4 antagonist. Unlike CD56lowCD16high, both bone marrow and peripheral blood CD56lowCD16low natural killer cells release IFNγ following cytokine stimulation, and represent the major cytotoxic natural killer cell population against K562 or acute lymphoblastic leukemia target cells. All these data suggest that CD56lowCD16low natural killer cells are multifunctional cells, and that the presence of hematologic malignancies affects their frequency and functional ability at both tumor site and in the periphery. PMID:25596273

  9. Human herpesvirus-6 enhances natural killer cell cytotoxicity via IL-15.

    PubMed Central

    Flamand, L; Stefanescu, I; Menezes, J

    1996-01-01

    The marked tropism of human herpesvirus-6 (HHV-6) for natural killer (NK) cells and T lymphocytes has led us to investigate the effect of HHV-6 on cellular cytotoxicity. We describe here how HHV-6 infection of peripheral blood mononuclear cells (PBMC) leads to upregulation of their NK cell cytotoxicity. The induction of NK cell activity by HHV-6 was abrogated by monoclonal antibodies (mAbs) to IL-15 but not by mAbs to other cytokines (IFN-alpha, IFN-gamma, TNF-alpha, TNF-beta, IL-2, IL-12) suggesting that IL-15 secreted in response to viral infection was responsible for the observed effect. Furthermore, NK activation by HHV-6 was blocked with mAb to CD122, as well as by human anti-HHV-6 neutralizing antibodies. Using RT-PCR, we were able to detect IL-15 mRNA upregulation in purified monocyte and NK cell preparations. IL-15 protein synthesis was increased in response to HHV-6. Finally, addition of IL-15 to PBMC cultures was found to severely curtail HHV-6 expression. Taken together, our data suggest that enhanced NK activity in response to viral infection represent a natural anti-viral defense mechanism aimed at rapidly eliminating virus-infected cells. PMID:8617868

  10. Natural Killer Cells in Graft-versus-Host-Disease after Allogeneic Hematopoietic Cell Transplantation

    PubMed Central

    Simonetta, Federico; Alvarez, Maite; Negrin, Robert S.

    2017-01-01

    Allogeneic hematopoietic cell transplantation (HCT) is a well-established therapeutic modality effective for a variety of hematological malignancies but, unfortunately, is associated with significant morbidity and mortality related to cancer relapse as well as to transplant-related complications including graft-versus-host-disease (GvHD). Natural killer (NK) cells are the first donor-derived lymphocyte subset to recover after HCT, and their crucial role in protection against cancer relapse and infections is well established. Conversely, the role played by NK cells in GvHD is still controversial. Early studies suggested a participation of NK cells in GvHD induction or exacerbation. Subsequently, experimental evidence obtained in mice as well observational studies performed in humans led to a model in which NK cells play a regulatory role in GvHD by repressing alloreactive T cell responses. This widely accepted model has been recently challenged by clinical evidence indicating that NK cells can in some cases promote GvHD. In this review, we summarize available knowledge about the role of NK cells in GVHD pathogenesis. We review studies uncovering cellular mechanisms through which NK cells interact with other immune cell subsets during GvHD leading to a model in which NK cells naturally suppress GvHD through their cytotoxic ability to inhibit T cell activation unless exogenous hyperactivation lead them to produce proinflammatory cytokines that can conversely sustain T cell-mediated GvHD induction. PMID:28487696

  11. CD38 triggers cytotoxic responses in activated human natural killer cells.

    PubMed

    Sconocchia, G; Titus, J A; Mazzoni, A; Visintin, A; Pericle, F; Hicks, S W; Malavasi, F; Segal, D M

    1999-12-01

    Receptors used by natural killer (NK) cells to mediate natural cytotoxicity are poorly defined, although it is now clear that a number of adhesion molecules can serve this function. CD38 transduces signals on T- and B-cell lines, and we asked whether it could trigger lytic and secretory responses in human NK cells. By using an anti-CD38 monoclonal antibody in reverse antibody-dependent cellular cytotoxicity experiments, it is shown that CD38 engagement triggers cytotoxic responses by activated NK cells, but not by cytotoxic T lymphocytes or fresh NK cells. Cross-linking with anti-CD38 F(ab')(2) caused activated NK cells to release granzymes and cytokines, but did not trigger an increase in intracellular Ca(2+). Fresh NK cells acquired CD38-dependent lytic function during activation with interleukin-2 (IL-2), and inhibitor studies suggested that IL-2 stimulated the de novo expression of proteins that act between CD38 and the lytic machinery in NK cells. The induction of proteins that link commonly expressed adhesion molecules to effector mechanisms could provide a paradigm for pathogen recognition by the innate immune system.

  12. Therapeutic CD94/NKG2A blockade improves natural killer cell dysfunction in chronic lymphocytic leukemia

    PubMed Central

    McWilliams, Emily M.; Mele, Jennifer M.; Cheney, Carolyn; Timmerman, Elizabeth A.; Fiazuddin, Faraz; Strattan, Ethan J.; Mo, Xiaokui; Byrd, John C.; Muthusamy, Natarajan; Awan, Farrukh T.

    2016-01-01

    ABSTRACT Natural killer (NK)-cell count is predictive of chronic lymphoid leukemia (CLL) disease progression and their dysfunction is well documented, but the etiology of this is currently lacking. CLL cells have been shown to over-express HLA-E, the natural ligand for NKG2A expressed on NK-cells that generates a distinct negative signal relative to direct NK-cell cytotoxicity in other disease models. Utilizing a novel anti-NKG2A monoclonal blocking antibody (mAb), monalizumab, we explored the in vitro preclinical activity of targeting the NKG2A receptor, and the NKG2A/HLA-E interaction as a mechanism of tumor evasion in CLL patients. Our work confirmed overexpression of HLA-E on CLL B-cells and demonstrated NKG2A expression on CD56+/16+ NK-cells from CLL patients. We also demonstrate that blocking NKG2A on CLL NK-cells was sufficient to restore direct cytotoxicity ability of NK-cells against HLA-E-expressing targets without impacting NK-cell mediated antibody-dependent cellular cytotoxicity. Additionally, we proved the specificity of monalizumab in blocking NKG2A through Fc-blocking mechanisms. This paper provides justification for the potential clinical utility of monalizumab in the treatment of patients with CLL. PMID:27853650

  13. Therapeutic CD94/NKG2A blockade improves natural killer cell dysfunction in chronic lymphocytic leukemia.

    PubMed

    McWilliams, Emily M; Mele, Jennifer M; Cheney, Carolyn; Timmerman, Elizabeth A; Fiazuddin, Faraz; Strattan, Ethan J; Mo, Xiaokui; Byrd, John C; Muthusamy, Natarajan; Awan, Farrukh T

    2016-01-01

    Natural killer (NK)-cell count is predictive of chronic lymphoid leukemia (CLL) disease progression and their dysfunction is well documented, but the etiology of this is currently lacking. CLL cells have been shown to over-express HLA-E, the natural ligand for NKG2A expressed on NK-cells that generates a distinct negative signal relative to direct NK-cell cytotoxicity in other disease models. Utilizing a novel anti-NKG2A monoclonal blocking antibody (mAb), monalizumab, we explored the in vitro preclinical activity of targeting the NKG2A receptor, and the NKG2A/HLA-E interaction as a mechanism of tumor evasion in CLL patients. Our work confirmed overexpression of HLA-E on CLL B-cells and demonstrated NKG2A expression on CD56+/16+ NK-cells from CLL patients. We also demonstrate that blocking NKG2A on CLL NK-cells was sufficient to restore direct cytotoxicity ability of NK-cells against HLA-E-expressing targets without impacting NK-cell mediated antibody-dependent cellular cytotoxicity. Additionally, we proved the specificity of monalizumab in blocking NKG2A through Fc-blocking mechanisms. This paper provides justification for the potential clinical utility of monalizumab in the treatment of patients with CLL.

  14. CD1d and natural killer T cells in immunity to Mycobacterium tuberculosis.

    PubMed

    Arora, Pooja; Foster, Erin L; Porcelli, Steven A

    2013-01-01

    The critical role of peptide antigen-specific T cells in controlling mycobacterial infections is well documented in natural resistance and vaccine-induced immunity against Mycobacterium tuberculosis. However, many other populations of leukocytes contribute to innate and adaptive immunity against mycobacteria. Among these, non-conventional T cells recognizing lipid antigens presented by the CD1 antigen presentation system have attracted particular interest. In this chapter, we review the basic immunobiology and potential antimycobacterial properties of a subset of CD1-restricted T cells that have come to be known as Natural Killer T cells. This group of lipid reactive T cells is notable for its high level of conservation between humans and mice, thus enabling a wide range of highly informative studies in mouse models. As reviewed below, NKT cells appear to have subtle but potentially significant activities in the host response to mycobacteria. Importantly, they also provide a framework for investigations into other types of lipid antigen-specific T cells that may be more abundant in larger mammals such as humans.

  15. In vitro effects of natural killer cells against Paracoccidioides brasiliensis yeast phase.

    PubMed Central

    Jimenez, B E; Murphy, J W

    1984-01-01

    Recently, data have been reported suggesting natural killer (NK) cells may function in natural resistance against a fungus, Cryptococcus neoformans. The primary objective of this study was to examine the reactivity of murine splenic cells against another fungus, Paracoccidioides brasiliensis. Levels of NK activity in effector cell pools were varied by: (i) removing nylon wool-adherent cells, (ii) fractionating splenic cells on Percoll discontinuous gradients, (iii) using old and young effector cell donor mice, (iv) using donors from different strains, and (v) pretreating donors with NK-augmenting and -depressing agents. The various effector cell pools were simultaneously used in the 4-h 51Cr release assay with YAC-1 targets to determine the NK reactivity and in the in vitro growth inhibition assay against P. brasiliensis yeast phase targets. In each case, the level of NK reactivity correlated with the ability of the effector cells to inhibit the in vitro growth of P. brasiliensis. NK activity and P. brasiliensis growth-inhibiting ability could be augmented by fractionation of splenic cells through nylon wool or Percoll gradients. The effector cells responsible for the NK activity and P. brasiliensis growth inhibition were characterized as being nylon wool nonadherent, being found in the low-density fractions from Percoll discontinuous gradients, and having no detectable Thy-1 antigen or immunoglobulin but having asialo GM1 on their surface. These data support the contention that NK or NK-like cells are responsible for limiting the in vitro growth of P. brasiliensis. PMID:6500701

  16. What Lies Beneath: Antibody Dependent Natural Killer Cell Activation by Antibodies to Internal Influenza Virus Proteins.

    PubMed

    Vanderven, Hillary A; Ana-Sosa-Batiz, Fernanda; Jegaskanda, Sinthujan; Rockman, Steven; Laurie, Karen; Barr, Ian; Chen, Weisan; Wines, Bruce; Hogarth, P Mark; Lambe, Teresa; Gilbert, Sarah C; Parsons, Matthew S; Kent, Stephen J

    2016-06-01

    The conserved internal influenza proteins nucleoprotein (NP) and matrix 1 (M1) are well characterised for T cell immunity, but whether they also elicit functional antibodies capable of activating natural killer (NK) cells has not been explored. We studied NP and M1-specific ADCC activity using biochemical, NK cell activation and killing assays with plasma from healthy and influenza-infected subjects. Healthy adults had antibodies to M1 and NP capable of binding dimeric FcγRIIIa and activating NK cells. Natural symptomatic and experimental influenza infections resulted in a rise in antibody dependent NK cell activation post-infection to the hemagglutinin of the infecting strain, but changes in NK cell activation to M1 and NP were variable. Although antibody dependent killing of target cells infected with vaccinia viruses expressing internal influenza proteins was not detected, opsonising antibodies to NP and M1 likely contribute to an antiviral microenvironment by stimulating innate immune cells to secrete cytokines early in infection. We conclude that effector cell activating antibodies to conserved internal influenza proteins are common in healthy and influenza-infected adults. Given the significance of such antibodies in animal models of heterologous influenza infection, the definition of their importance and mechanism of action in human immunity to influenza is essential.

  17. MicroRNA-155 is a potential molecular marker of natural killer/T-cell lymphoma

    PubMed Central

    Huang, Ruixia; Li, Lifeng; Wang, Xinhua; Li, Ling; Fu, Xiaorui; Sun, Zhenchang; Li, Zhaoming; Chen, Qingjiang; Zhang, Mingzhi

    2016-01-01

    Natural killer/T-cell lymphoma (NKTCL) is characterized by its highly aggressive nature and rapid progression. MicroRNAs (miRNAs) play key roles in the development of NKTCL. We utilized next-generation Solexa high-throughput sequencing to compare miRNA expression in the SNK-6 and YTS NKTCL cell lines with expression in normal NK cells. We found that 195 miRNAs were upregulated in the SNK-6 cells and 286 miRNAs were upregulated in the YTS cells. Based on those results, we selected six miRNAs, including miRNA-155, and confirmed their expression using real-time polymerase chain reaction. Expression of miRNA-155 was higher in SNK-6 and YKS cells than in normal NK cells. We next determined the levels of miRNA-155 in the serum of healthy individuals and NKTCL patients, and correlated its expression with clinical parameters and inflammatory factors detected using enzyme-linked immunoabsorbent assays. Levels of miRNA-155 were higher in NKTCL patients’ serum than in serum from healthy individuals. miRNA-155 expression was higher in patients with stable or progressive disease (SD+PD) than in those with partial or complete remission (PR+CR). While further studies are needed to clarify the underlying molecular mechanisms, it appears miRNA-155 may be a molecular marker of NKTCL. PMID:27462776

  18. Tentative and transient natural killer cell polarization balances the requirements for discriminatory recognition and cytolytic efficacy.

    PubMed

    Sinai, Parisa; Roybal, Kole T; Wülfing, Christoph

    2010-11-01

    Natural killer (NK) cells are immune cells that lyse virally infected and tumor cells. Initially, their cytolytic capability is induced by cytokines. Subsequently, in their decision whether to kill a potential target cell, NK cells have to distinguish between small differences in the expression of ligands that report on the viral infection or transformation of the target. NK killing requires tight coupling to the target cell and extensive NK cell polarization. Here we discuss, often in contrast to the second cytolytic immune cell type, cytotoxic T cells, how NK cell polarization is shaped by three constraints of their activation. First, NK cell have to respond to cytokines: Different priming cytokines yield dramatically divergent NK cell polarization. Second, NK cells have to distinguish small differences in ligand expression: NK cell polarization is tentative, likely to allow discriminatory recognition close to the NK cell activation threshold. A critical contributor to the tentative nature of NK cell polarization may be poorly developed spatiotemporal organization of NK cell signaling. Third, NK cells have to kill effectively: NK cell polarization is transient, allowing for efficient killing by sequential interactions of a single NK cell with numerous target cells.

  19. Large-scale isolation and cytotoxicity of extracellular vesicles derived from activated human natural killer cells

    PubMed Central

    Jong, Ambrose Y.; Wu, Chun-Hua; Li, Jingbo; Sun, Jianping; Fabbri, Muller; Wayne, Alan S.; Seeger, Robert C.

    2017-01-01

    ABSTRACT Extracellular vesicles (EVs) have been the focus of great interest, as they appear to be involved in numerous important cellular processes. They deliver bioactive macromolecules such as proteins, lipids, and nucleic acids, allowing intercellular communication in multicellular organisms. EVs are secreted by all cell types, including immune cells such as natural killer cells (NK), and they may play important roles in the immune system. Currently, a large-scale procedure to obtain functional NK EVs is lacking, limiting their use clinically. In this report, we present a simple, robust, and cost-effective method to isolate a large quantity of NK EVs. After propagating and activating NK cells ex vivo and then incubating them in exosome-free medium for 48 h, EVs were isolated using a polymer precipitation method. The isolated vesicles contain the tetraspanin CD63, an EV marker, and associated proteins (fibronectin), but are devoid of cytochrome C, a cytoplasmic marker. Nanoparticle tracking analysis showed a size distribution between 100 and 200 nm while transmission electron microscopy imaging displayed vesicles with an oval shape and comparable sizes, fulfilling the definition of EV. Importantly, isolated EV fractions were cytotoxic against cancer cells. Furthermore, our results demonstrate for the first time that isolated activated NK (aNK) cell EVs contain the cytotoxic proteins perforin, granulysin, and granzymes A and B, incorporated from the aNK cells. Activation of caspase -3, -7 and -9 was detected in cancer cells incubated with aNK EVs, and caspase inhibitors blocked aNK EV-induced cytotoxicity, suggesting that aNK EVs activate caspase pathways in target cells. The ability to isolate functional aNK EVs on a large scale may lead to new clinical applications. Abbreviations: NK: natural killer cells; activated NK (aNK) cells; EVs: extracellular vesicles; ALL: acute lymphoblastic leukaemia; aAPC: artificial antigen-presenting cell; TEM: transmission

  20. The role of natural killer cells in autoimmune liver disease: a comprehensive review.

    PubMed

    Hudspeth, Kelly; Pontarini, Elena; Tentorio, Paolo; Cimino, Matteo; Donadon, Matteo; Torzilli, Guido; Lugli, Enrico; Della Bella, Silvia; Gershwin, M Eric; Mavilio, Domenico

    2013-10-01

    Natural Killer (NK) cells are important players of the innate arm of the immune system and provide an early defense against pathogens and tumor-transformed cells. Peripheral blood NK (PB-NK) cells were first identified because of their ability to spontaneously kill tumor-cell targets in vitro without the need for specific antigen priming, which is the reason that they were named 'natural killer' cells. The characterization of NK cells in human tissues and body organs represented another important step forward to better understand their physiology and physiopathology. In this regard, many reports revealed over the past decade a differential anatomic distribution of NK cell subsets in several sites such as the intestine, lung, cervix, placenta and liver as well as in secondary lymphoid organs such as spleen, lymph nodes and tonsils. Among all these tissues, the liver is certainly unique as its parenchyma contains an unusually high number of infiltrating immune cells with 30-50% of total lymphocytes being NK cells. Given the constant liver intake of non-self antigens from the gastrointestinal tract via the portal vein, hepatic NK (H-NK) cells must retain a certain degree of tolerance in the context of their immune-surveillance against dangers to the host. Indeed, the breakdown of the tolerogenic state of the liver-associated immune system has been shown to induce autoimmunity. However, the role of NK cells during the course of autoimmune liver diseases is still being debated mainly because a complete characterization of H-NK cells normally resident in healthy human liver has not yet been fully disclosed. Furthermore, the differences in phenotype and functions between human and mouse H-NK cells often preclude translation of results obtained from murine models into experimental approaches to be performed in humans. Here, we provide an extensive characterization of the phenotype of H-NK cells physiologically resident in the human liver by both mentioning data available

  1. Roles of 3′ and 4′ Hydroxyls in α-Galactosylceramide Stimulation of Invariant Natural Killer T Cells

    PubMed Central

    Zhang, Wenpeng; Zhang, Yalong; Chen, Wenlan; Nadas, Janos; Severin, Ryan; Woodward, Robert; Wang, Bin; Wang, Xin; Kronenberg, Mitchell

    2012-01-01

    The marine-derived α-galactosylceramide is an exogenous ligand for natural killer T cells and leads to the secretion of both T help 1 (Th1) and Th2 cytokines. The relationship between the sugar moiety structure and invariant natural killer T (iNKT) cell stimulation ability has not been fully understood. With the series α-galactosylceramide analogues varied on C3′ and C4′ position, subjected to a murine system, we discovered that the 3′ hydroxyl is very crucial in maintaining the molecule’s immunogenicity. Any modification on this position will lead to the losing of activity. We also found that the C4′ position is not so sensitive and can tolerate some small modifications on it. Moreover, the C4′ substituted analogues induced biased Th2 cytokines release was observed. PMID:19780098

  2. Interleukin-7 receptor alpha is essential for the development of gamma delta + T cells, but not natural killer cells

    PubMed Central

    1996-01-01

    Mice that lack a functional gamma c subunit of the receptors for interleukin (IL)-2, IL-4, IL-7, IL-9, and IL-15 display profound defects in lymphoid development. The IL-7/IL-7R system represents a critical interaction for conventional T and B cell development. In this report, the role of IL-7R alpha in the development of lymphoid lineages other than conventional T and B cells was examined. We demonstrate that gamma delta + T cells were absent in IL-7R alpha-deficient mice, whereas the development and function of natural killer cells were normal. Thus, IL-7R alpha function is required for the development of gamma delta + T cells but not natural killer cells. PMID:8691145

  3. Killer activity of yeasts isolated from natural environments against some medically important Candida species.

    PubMed

    Vadkertiová, Renata; Sláviková, Elena

    2007-01-01

    Twenty-five yeast cultures, mainly of human origin, belonging to four pathogenic yeast species--Candida albicans, Candida krusei, Candida parapsilosis, and Candida tropicalis were tested for their sensitivity to ten basidiomycetous and eleven ascomycetous yeast species isolated from the water and soil environments and from tree leaves. The best killer activity among basidiomycetous species was exhibited by Rhodotorula glutinis, and R. mucilaginosa. The other carotenoid producing species Cystofilobasidium capitatum, Sporobolomyces salmonicolor, and S. roseus were active only against about 40% of the tested strains and exhibited weak activity. The broadest killer activity among ascomycetous yeasts was shown by the strains Pichia anomala and Metschnikowia pulcherrima. The species Debaryomyces castellii, Debaryomyces hansenii, Hanseniaspora guilliermondii, Pichia membranifaciens, and Williopsis californica did not show any killer activity. The best killer activity exhibited the strains isolated from leafy material. The lowest activity pattern was found among strains originating from soil environment.

  4. Suppression of a Natural Killer Cell Response by Simian Immunodeficiency Virus Peptides.

    PubMed

    Schafer, Jamie L; Ries, Moritz; Guha, Natasha; Connole, Michelle; Colantonio, Arnaud D; Wiertz, Emmanuel J; Wilson, Nancy A; Kaur, Amitinder; Evans, David T

    2015-09-01

    Natural killer (NK) cell responses in primates are regulated in part through interactions between two highly polymorphic molecules, the killer-cell immunoglobulin-like receptors (KIRs) on NK cells and their major histocompatibility complex (MHC) class I ligands on target cells. We previously reported that the binding of a common MHC class I molecule in the rhesus macaque, Mamu-A1*002, to the inhibitory receptor Mamu-KIR3DL05 is stabilized by certain simian immunodeficiency virus (SIV) peptides, but not by others. Here we investigated the functional implications of these interactions by testing SIV peptides bound by Mamu-A1*002 for the ability to modulate Mamu-KIR3DL05+ NK cell responses. Twenty-eight of 75 SIV peptides bound by Mamu-A1*002 suppressed the cytolytic activity of primary Mamu-KIR3DL05+ NK cells, including three immunodominant CD8+ T cell epitopes previously shown to stabilize Mamu-A1*002 tetramer binding to Mamu-KIR3DL05. Substitutions at C-terminal positions changed inhibitory peptides into disinhibitory peptides, and vice versa, without altering binding to Mamu-A1*002. The functional effects of these peptide variants on NK cell responses also corresponded to their effects on Mamu-A1*002 tetramer binding to Mamu-KIR3DL05. In assays with mixtures of inhibitory and disinhibitory peptides, low concentrations of inhibitory peptides dominated to suppress NK cell responses. Consistent with the inhibition of Mamu-KIR3DL05+ NK cells by viral epitopes presented by Mamu-A1*002, SIV replication was significantly higher in Mamu-A1*002+ CD4+ lymphocytes co-cultured with Mamu-KIR3DL05+ NK cells than with Mamu-KIR3DL05- NK cells. These results demonstrate that viral peptides can differentially affect NK cell responses by modulating MHC class I interactions with inhibitory KIRs, and provide a mechanism by which immunodeficiency viruses may evade NK cell responses.

  5. Natural Killer Cell Receptors and Cytotoxic Activity in Phosphomannomutase 2 Deficiency (PMM2-CDG).

    PubMed

    García-López, Roberto; de la Morena-Barrio, María Eugenia; Alsina, Laia; Pérez-Dueñas, Belén; Jaeken, Jaak; Serrano, Mercedes; Casado, Mercedes; Hernández-Caselles, Trinidad

    2016-01-01

    PMM2-CDG is the most common N-glycosylation defect and shows an increased risk of recurrent and/or severe, sometimes fatal, infections in early life. We hypothesized that natural killer (NK) cells, as important mediators of the immune response against microbial pathogens and regulators of adaptive immunity, might be affected in this genetic disorder. To evaluate possible defects on PMM2-CDG NK peripheral blood cell number, killing activity and expression of membrane receptors. We studied fresh and activated NK cells from twelve PMM2-CDG cells. The number and expression of lymphoid surface receptors were studied by flow cytometry. The NK responsiveness (frequency of degranulated NK cells) and killing activity against K562 target cells was determined in the NK cytotoxicity assay. We found an increase of blood NK cells in three patients with a severe phenotype. Two of them, who had suffered from moderate/severe viral infections during their first year of life, also had reduced T lymphocyte numbers. Patient activated NK cells showed increased expression of CD54 adhesion molecule and NKG2D and NKp46 activating receptors. NKp46 and 2B4 expression was inversely correlated with the expression of NKG2D in activated PMM2-CDG cells. Maximal NK activity against K562 target cells was similar in control and PMM2-CDG cells. Interestingly, the NK cell responsiveness was higher in patient cells. NKG2D and specially CD54 increased surface expression significantly correlated with the increased NK cell cytolytic activity according to the modulation of the killer activity by expression of triggering receptors and adhesion molecules. Our results indicate that hypoglycosylation in PMM2-CDG altered NK cell reactivity against target cells and the expression of CD54 and NKG2D, NKp46 and 2B4 activating receptors during NK cell activation. This suggests a defective control of NK cell killing activity and the overall anti-viral immune response in PMM2-CDG patients. The present work improves

  6. Natural Killer Cell Receptors and Cytotoxic Activity in Phosphomannomutase 2 Deficiency (PMM2-CDG)

    PubMed Central

    García-López, Roberto; de la Morena-Barrio, María Eugenia; Alsina, Laia; Pérez-Dueñas, Belén; Jaeken, Jaak; Serrano, Mercedes; Casado, Mercedes; Hernández-Caselles, Trinidad

    2016-01-01

    Background PMM2-CDG is the most common N-glycosylation defect and shows an increased risk of recurrent and/or severe, sometimes fatal, infections in early life. We hypothesized that natural killer (NK) cells, as important mediators of the immune response against microbial pathogens and regulators of adaptive immunity, might be affected in this genetic disorder. Objective To evaluate possible defects on PMM2-CDG NK peripheral blood cell number, killing activity and expression of membrane receptors. Methods We studied fresh and activated NK cells from twelve PMM2-CDG cells. The number and expression of lymphoid surface receptors were studied by flow cytometry. The NK responsiveness (frequency of degranulated NK cells) and killing activity against K562 target cells was determined in the NK cytotoxicity assay. Results We found an increase of blood NK cells in three patients with a severe phenotype. Two of them, who had suffered from moderate/severe viral infections during their first year of life, also had reduced T lymphocyte numbers. Patient activated NK cells showed increased expression of CD54 adhesion molecule and NKG2D and NKp46 activating receptors. NKp46 and 2B4 expression was inversely correlated with the expression of NKG2D in activated PMM2-CDG cells. Maximal NK activity against K562 target cells was similar in control and PMM2-CDG cells. Interestingly, the NK cell responsiveness was higher in patient cells. NKG2D and specially CD54 increased surface expression significantly correlated with the increased NK cell cytolytic activity according to the modulation of the killer activity by expression of triggering receptors and adhesion molecules. Conclusions Our results indicate that hypoglycosylation in PMM2-CDG altered NK cell reactivity against target cells and the expression of CD54 and NKG2D, NKp46 and 2B4 activating receptors during NK cell activation. This suggests a defective control of NK cell killing activity and the overall anti-viral immune response

  7. Study of CD4(+), CD8(+), and natural killer cells (CD16(+), CD56(+)) in children with immune thrombocytopenic purpura.

    PubMed

    El-Rashedi, Farida Hussein; El-Hawy, Mahmoud Ahmed; Helwa, Mohamed Ahmed; Abd-Allah, Sameh Said

    2017-03-01

    To assess the percentage of CD4(+), CD8(+), and natural killer cells (CD16(+), CD56(+)) in children with immune thrombocytopenic purpura (ITP) at presentation and study their impact on disease chronicity. This case-control study was conducted at the Pediatric Hematology and Oncology Unit, Menoufia University Hospital (tertiary care center in Egypt). The study was held on 30 children presenting with ITP; they were followed-up and classified into two groups: 15 children with acute ITP; and 15 children with chronic ITP. Patients were compared to a group of 15 healthy children of matched age and sex. Measurements of CD4(+), CD8(+), and natural killer cells (CD16(+), CD56(+)) by flow cytometry were assessed and compared in these groups. CD4(+) and CD4(+)/CD8(+) were significantly lower in acute and chronic patients than the control group (p<0.05 and p<0.001, respectively), with no significant difference between acute and chronic patients (p>0.05). However, CD8(+) was significantly higher in acute and chronic patients than the control group (p<0.05), with no significant difference between acute and chronic patients (p>0.05). Natural killer cell percent was significantly lower in acute patients than the control group (p<0.001), with no significant difference between chronic and control groups (p>0.05). ITP is associated with immunity dysfunction denoted by the increase in cytotoxic T lymphocytes and the decrease in natural killer cells. Copyright © 2017 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.

  8. Interleukin-21 activates cytotoxic T lymphocytes and natural killer cells to generate antitumor response in mouse renal cell carcinoma.

    PubMed

    Kumano, Masafumi; Hara, Isao; Furukawa, Junya; Oniki, Shuntaro; Nagai, Hiroshi; Miyake, Hideaki; Fujisawa, Masato

    2007-10-01

    We evaluated the antitumor effects of IL-21 gene transfer into mouse RenCa renal cell carcinoma cells, so that cells could spontaneously secrete IL-21. We also investigated the mechanisms underlying this antitumor effect. The IL-21 gene was introduced into RenCa cells by the liposome mediated method using Lipofectamine. The in vivo antitumor effect of IL-21 secreting RenCa cells was assessed by subcutaneous injection into syngeneic BALB/c mice. Mechanisms underlying the antitumor effects were investigated in syngeneic mice in which CD8 T, CD4 T or natural killer cells had been depleted using the corresponding antibody. The cytotoxic activity of splenocytes in mice injected with IL-21 secreting RenCa cells was determined using the CytoTox 96 nonradioactive cytotoxicity assay. Immunohistochemical examinations were performed to investigate infiltrating cells around tumor sites in vivo. Tumor vaccine study was also performed. IL-21 secreting RenCa cells were almost all rejected following subcutaneous injection into syngeneic mice. The antitumor effect of IL-21 secreting RenCa cells remained in mice in which CD4 T cells had been depleted but it was totally abrogated in mice depleted of CD8 T cells or natural killer cells. Cytotoxic activities of splenocytes were higher in IL-21 secreting RenCa cell rejected mice than in parental RenCa mice. Immunohistochemical study also supported the involvement of CD8 T cells and natural killer cells in the antitumor effect of IL-21 secreting RenCa cells. Moreover, mitomycin C treated IL-21 secreting RenCa cells inhibited the growth of parental RenCa at distant site. IL-21 secreting RenCa could be rejected in syngeneic mice by the activation of CD8 T cells and natural killer cells. Moreover, mitomycin C treated IL-21 secreting RenCa cells could work as a tumor vaccine for parental RenCa.

  9. Epstein-Barr virus-positive blastoid nasal T/natural killer-cell lymphoma in a caucasian.

    PubMed

    Ling, T C; Harris, M; Craven, N M

    2002-04-01

    T/natural killer (NK)-cell lymphoma is a subtype of non-Hodgkin's lymphoma, with frequent cutaneous involvement; it follows an aggressive course. Most cases are reported in Asia, and typically present with nasopharyngeal involvement. There is a distinct variant known as blastoid T/NK-cell lymphoma, which affects elderly, non-Asian patients, with absence of nasal involvement. We report a middle-aged caucasian man who had blastoid T/NK-cell lymphoma with nasal involvement.

  10. New prognostic model for extranodal natural killer/T cell lymphoma, nasal type.

    PubMed

    Cai, Qingqing; Luo, Xiaolin; Zhang, Guanrong; Huang, Huiqiang; Huang, Hui; Lin, Tongyu; Jiang, Wenqi; Xia, Zhongjun; Young, Ken H

    2014-09-01

    Extranodal natural killer/T cell lymphoma, nasal type (ENKTL) is an aggressive disease with a poor prognosis, requiring risk stratification in affected patients. We designed a new prognostic model specifically for ENKTL to identify high-risk patients who need more aggressive therapy. We retrospectively reviewed 158 patients who were newly diagnosed with ENKTL. The estimated 5-year overall survival rate was 39.4 %. Independent prognostic factors included total protein (TP) <60 g/L, fasting blood glucose (FBG) >100 mg/dL, and Korean Prognostic Index (KPI) score ≥2. We constructed a new prognostic model by combining these prognostic factors: group 1 (64 cases (41.0 %)), no adverse factors; group 2 (58 cases (37.2 %)), one adverse factor; and group 3 (34 cases (21.8 %)), two or three adverse factors. The 5-year overall survival (OS) rates of these groups were 66.7, 23.0, and 5.9 %, respectively (p < 0.001). Our new prognostic model had a better prognostic value than did the KPI model alone (p < 0.001). Our proposed prognostic model for ENKTL, including the newly identified prognostic indicators, TP and FBG, demonstrated a balanced distribution of patients into different risk groups with better prognostic discrimination compared with the KPI model alone.

  11. Selection and expansion of natural killer cells for NK cell-based immunotherapy.

    PubMed

    Becker, Petra S A; Suck, Garnet; Nowakowska, Paulina; Ullrich, Evelyn; Seifried, Erhard; Bader, Peter; Tonn, Torsten; Seidl, Christian

    2016-04-01

    Natural killer (NK) cells have been used in several clinical trials as adaptive immunotherapy. The low numbers of these cells in peripheral blood mononuclear cells (PBMC) have resulted in various approaches to preferentially expand primary NK cells from PBMC. While some clinical trials have used the addition of interleukin 2 (IL-2) to co-stimulate the expansion of purified NK cells from allogeneic donors, recent studies have shown promising results in achieving in vitro expansion of NK cells to large numbers for adoptive immunotherapy. NK cell expansion requires multiple cell signals for survival, proliferation and activation. Thus, expansion strategies have been focused either to substitute these factors using autologous feeder cells or to use genetically modified allogeneic feeder cells. Recent developments in the clinical use of genetically modified NK cell lines with chimeric antigen receptors, the development of expansion protocols for the clinical use of NK cell from human embryonic stem cells and induced pluripotent stem cells are challenging improvements for NK cell-based immunotherapy. Transfer of several of these protocols to clinical-grade production of NK cells necessitates adaptation of good manufacturing practice conditions, and the development of freezing conditions to establish NK cell stocks will require some effort and, however, should enhance the therapeutic options of NK cells in clinical medicine.

  12. Modeling Human Natural Killer Cell Development in the Era of Innate Lymphoid Cells.

    PubMed

    Scoville, Steven D; Freud, Aharon G; Caligiuri, Michael A

    2017-01-01

    Decades after the discovery of natural killer (NK) cells, their developmental pathways in mice and humans have not yet been completely deciphered. Accumulating evidence indicates that NK cells can develop in multiple tissues throughout the body. Moreover, detailed and comprehensive models of NK cell development were proposed soon after the turn of the century. However, with the recent identification and characterization of other subtypes of innate lymphoid cells (ILCs), which show some overlapping functional and phenotypic features with NK cell developmental intermediates, the distinct stages through which human NK cells develop from early hematopoietic progenitor cells remain unclear. Thus, there is a need to reassess and refine older models of NK cell development in the context of new data and in the era of ILCs. Our group has focused on elucidating the developmental pathway of human NK cells in secondary lymphoid tissues (SLTs), including tonsils and lymph nodes. Here, we provide an update of recent progress that has been made with regard to human NK cell development in SLTs, and we discuss these new findings in the context of contemporary models of ILC development.

  13. Hematopoietic and nature killer cell development from human pluripotent stem cells.

    PubMed

    Ni, Zhenya; Knorr, David A; Kaufman, Dan S

    2013-01-01

    Natural killer (NK) cells are key effectors of the innate immune system, protecting the host from a variety of infections, as well as malignant cells. Recent advances in the field of NK cell biology have led to a better understanding of how NK cells develop. This progress has directly translated to improved outcomes in patients receiving hematopoietic stem cell transplants to treat potentially lethal malignancies. However, key differences between mouse and human NK cell development and biology limits the use of rodents to attain a more in depth understanding of NK cell development. Therefore, a readily accessible and genetically tractable cell source to study human NK cell development is warranted. Our lab has pioneered the development of lymphocytes, specifically NK cells, from human embryonic stem cells (hESCs) and more recently induced pluripotent stem cells (iPSCs). This chapter describes a reliable method to generate NK cells from hESCs and iPSCs using murine stromal cell lines. Additionally, we include an updated approach using a spin-embryoid body (spin-EB) differentiation system that allows for human NK cell development completely defined in vitro conditions.

  14. Steroid-responsive demyelinating peripheral neuropathy associated with chronic lymphoproliferative disorders of natural killer cells.

    PubMed

    Sano, Hironori; Maeda, Toshihiko; Omoto, Masatoshi; Ogasawara, Jun-Ichi; Koga, Michiaki; Kawai, Motoharu; Kanda, Takashi

    2017-09-28

    We herein report the findings of a 67-year-old woman with steroid-responsive multiple mononeuropathy associated with chronic natural killer (NK) cell lymphocytosis. The patient developed progressive, asymmetric weakness and numbness in all four extremities in the course of a three-month period. Nerve conduction studies revealed asymmetric demyelination in both the motor and sensory nerves, and a biopsy specimen of the sural nerve showed a conspicuous difference in the demyelination between the neighboring fascicles and the infiltration of NK cells in the endoneurium. We considered the multiple mononeuropathy in this patient to have been caused by NK cell infiltration in the endoneurium, and the observed asymmetry might have been due to differences in the NK cell intrusion among the fascicles. Corticosteroid administration resulted in a rapid neurological, electrophysiological and hematological improvement. The rapid clinical amelioration that was observed after corticosteroid therapy suggested that the neuropathy in this case had been mainly caused by the mechanical compression of the endoneurial NK cells or the inflammatory cytokines that had been released by them.

  15. The proinflammatory cytokine interleukin-18 alters multiple signaling pathways to inhibit natural killer cell death

    USGS Publications Warehouse

    Hodge, D.L.; Subleski, J.J.; Reynolds, D.A.; Buschman, M.D.; Schill, W.B.; Burkett, M.W.; Malyguine, A.M.; Young, H.A.

    2006-01-01

    The proinflammatory cytokine, interleukin-18 (IL-18), is a natural killer (NK) cell activator that induces NK cell cytotoxicity and interferon-?? (IFN-??) expression. In this report, we define a novel role for IL-18 as an NK cell protective agent. Specifically, IL-18 prevents NK cell death initiated by different and distinct stress mechanisms. IL-18 reduces NK cell self-destruction during NK-targeted cell killing, and in the presence of staurosporin, a potent apoptotic inducer, IL-18 reduces caspase-3 activity. The critical regulatory step in this process is downstream of the mitochondrion and involves reduced cleavage and activation of caspase-9 and caspase-3. The ability of IL-18 to regulate cell survival is not limited to a caspase death pathway in that IL-18 augments tumor necrosis factor (TNF) signaling, resulting in increased and prolonged mRNA expression of c-apoptosis inhibitor 2 (cIAP2), a prosurvival factor and caspase-3 inhibitor, and TNF receptor-associated factor 1 (TRAF1), a prosurvival protein. The cumulative effects of IL-18 define a novel role for this cytokine as a molecular survival switch that functions to both decrease cell death through inhibition of the mitochondrial apoptotic pathway and enhance TNF induction of prosurvival factors. ?? Mary Ann Liebert, Inc.

  16. Primary naive and interleukin-2-activated natural killer cells do not support efficient ectromelia virus replication.

    PubMed

    Parker, April Keim; Yokoyama, Wayne M; Corbett, John A; Chen, Nanhai; Buller, R Mark L

    2008-03-01

    Natural killer (NK) cells are known for their ability to lyse tumour cell targets. Studies of infections by a number of viruses, including poxviruses and herpesviruses, have demonstrated that NK cells are vital for recovery from these infections. Little is known of the ability of viruses to infect and complete a productive replication cycle within NK cells. Even less is known concerning the effect of infection on NK cell biology. This study investigated the ability of ectromelia virus (ECTV) to infect NK cells in vitro and in vivo. Following ECTV infection, NK cell gamma interferon (IFN-gamma) production was diminished and infected cells ceased proliferating and lost viability. ECTV infection of NK cells led to early and late virus gene expression and visualization of immature and mature virus particles, but no detectable increase in viable progeny virus. It was not unexpected that early gene expression occurred in infected NK cells, as the complete early transcription system is packaged within the virions. The detection of the secreted early virus-encoded immunomodulatory proteins IFN-gamma-binding protein and ectromelia inhibitor of complement enzymes (EMICE) in NK cell culture supernatants suggests that even semi-permissive infection may permit immunomodulation of the local environment.

  17. Role of natural killer cells in innate protection against lethal ebola virus infection.

    PubMed

    Warfield, Kelly L; Perkins, Jeremy G; Swenson, Dana L; Deal, Emily M; Bosio, Catharine M; Aman, M Javad; Yokoyama, Wayne M; Young, Howard A; Bavari, Sina

    2004-07-19

    Ebola virus is a highly lethal human pathogen and is rapidly driving many wild primate populations toward extinction. Several lines of evidence suggest that innate, nonspecific host factors are potentially critical for survival after Ebola virus infection. Here, we show that nonreplicating Ebola virus-like particles (VLPs), containing the glycoprotein (GP) and matrix protein virus protein (VP)40, administered 1-3 d before Ebola virus infection rapidly induced protective immunity. VLP injection enhanced the numbers of natural killer (NK) cells in lymphoid tissues. In contrast to live Ebola virus, VLP treatment of NK cells enhanced cytokine secretion and cytolytic activity against NK-sensitive targets. Unlike wild-type mice, treatment of NK-deficient or -depleted mice with VLPs had no protective effect against Ebola virus infection and NK cells treated with VLPs protected against Ebola virus infection when adoptively transferred to naive mice. The mechanism of NK cell-mediated protection clearly depended on perforin, but not interferon-gamma secretion. Particles containing only VP40 were sufficient to induce NK cell responses and provide protection from infection in the absence of the viral GP. These findings revealed a decisive role for NK cells during lethal Ebola virus infection. This work should open new doors for better understanding of Ebola virus pathogenesis and direct the development of immunotherapeutics, which target the innate immune system, for treatment of Ebola virus infection.

  18. Interleukin-12 bypasses common gamma-chain signalling in emergency natural killer cell lymphopoiesis

    PubMed Central

    Ohs, Isabel; van den Broek, Maries; Nussbaum, Kathrin; Münz, Christian; Arnold, Sebastian J.; Quezada, Sergio A.; Tugues, Sonia; Becher, Burkhard

    2016-01-01

    Differentiation and homeostasis of natural killer (NK) cells relies on common gamma-chain (γc)-dependent cytokines, in particular IL-15. Consequently, NK cells do not develop in mice with targeted γc deletion. Herein we identify an alternative pathway of NK-cell development driven by the proinflammatory cytokine IL-12, which can occur independently of γc-signalling. In response to viral infection or upon exogenous administration, IL-12 is sufficient to elicit the emergence of a population of CD122+CD49b+ cells by targeting NK-cell precursors (NKPs) in the bone marrow (BM). We confirm the NK-cell identity of these cells by transcriptome-wide analyses and their ability to eliminate tumour cells. Rather than using the conventional pathway of NK-cell development, IL-12-driven CD122+CD49b+ cells remain confined to a NK1.1lowNKp46low stage, but differentiate into NK1.1+NKp46+ cells in the presence of γc-cytokines. Our data reveal an IL-12-driven hard-wired pathway of emergency NK-cell lymphopoiesis bypassing steady-state γc-signalling. PMID:27982126

  19. Natural Killer (NK) Cells in Antibacterial Innate Immunity: Angels or Devils?

    PubMed Central

    Souza-Fonseca-Guimaraes, Fernando; Adib-Conquy, Minou; Cavaillon, Jean-Marc

    2012-01-01

    Natural killer (NK) cells were first described as immune leukocytes that could kill tumor cells and soon after were reported to kill virus-infected cells. In the mid-1980s, 10 years after their discovery, NK cells were also demonstrated to contribute to the fight against bacterial infection, particularly because of crosstalk with other leukocytes. A wide variety of immune cells are now recognized to interact with NK cells through the production of cytokines such as interleukin (IL)-2, IL-12, IL-15 and IL-18, which boost NK cell activities. The recent demonstration that NK cells express pattern recognition receptors, namely Toll-like and nucleotide oligomerization domain (NOD)-like receptors, led to the understanding that these cells are not only under the control of accessory cells, but can be directly involved in the antibacterial response thanks to their capacity to recognize pathogen-associated molecular patterns. Interferon (IFN)-γ is the predominant cytokine produced by activated NK cells. IFN-γ is a key contributor to antibacterial immune defense. However, in synergy with other inflammatory cytokines, IFN-γ can also lead to deleterious effects similar to those observed during sepsis. Accordingly, as the main source of IFN-γ in the early phase of infection, NK cells display both beneficial and deleterious effects, depending on the circumstances. PMID:22105606

  20. Natural killer cell therapy and aerosol interleukin-2 for the treatment of osteosarcoma lung metastasis.

    PubMed

    Guma, Sergei R; Lee, Dean A; Yu, Ling; Gordon, Nancy; Hughes, Dennis; Stewart, John; Wang, Wei Lien; Kleinerman, Eugenie S

    2014-04-01

    Survival of patients with osteosarcoma lung metastases has not improved in 20 years. We evaluated the efficacy of combining natural killer (NK) cells with aerosol interleukin-2 (IL-2) to achieve organ-specific NK cell migration and expansion in the metastatic organ, and to decrease toxicity associated with systemic IL-2. Five human osteosarcoma cell lines and 103 patient samples (47 primary and 56 metastatic) were analyzed for NKG2D ligand (NKG2DL) expression. Therapeutic efficacy of aerosol IL-2 + NK cells was evaluated in vivo compared with aerosol IL-2 alone and NK cells without aerosol IL-2. Osteosarcoma cell lines and patient samples expressed various levels of NKG2DL. NK-mediated killing was NKG2DL-dependent and correlated with expression levels. Aerosol IL-2 increased NK cell numbers in the lung and within metastatic nodules but not in other organs. Therapeutic efficacy, as judged by tumor number, size, and quantification of apoptosis, was also increased compared with NK cells or aerosol IL-2 alone. There were no IL-2-associated systemic toxicities. Aerosol IL-2 augmented the efficacy of NK cell therapy against osteosarcoma lung metastasis, without inducing systemic toxicity. Our data suggest that lung-targeted IL-2 delivery circumvents toxicities induced by systemic administration. Combining aerosol IL-2 with NK cell infusions, may be a potential new therapeutic approach for patients with osteosarcoma lung metastasis. © 2013 Wiley Periodicals, Inc.

  1. Enterogenous bacterial glycolipids are required for the generation of natural killer T cells mediated liver injury

    PubMed Central

    Wei, Yingfeng; Zeng, Benhua; Chen, Jianing; Cui, Guangying; Lu, Chong; Wu, Wei; Yang, Jiezuan; Wei, Hong; Xue, Rufeng; Bai, Li; Chen, Zhi; Li, Lanjuan; Iwabuchi, Kazuya; Uede, Toshimitsu; Van Kaer, Luc; Diao, Hongyan

    2016-01-01

    Glycolipids are potent activator of natural killer T (NKT) cells. The relationship between NKT cells and intestinal bacterial glycolipids in liver disorders remained unclear. We found that, in sharp contrast to specific pathogen-free (SPF) mice, germ-free (GF) mice are resistant to Concanavalin A (ConA)-induced liver injury. ConA treatment failed to trigger the activation of hepatic NKT cells in GF mice. These defects correlated with the sharply reduced levels of CD1d-presented glycolipid antigens in ConA-treated GF mice compared with SPF counterparts. Nevertheless, CD1d expression was similar between these two kinds of mice. The absence of intestinal bacteria did not affect the incidence of αGalCer-induced liver injury in GF mice. Importantly, we found the intestinal bacteria contain glycolipids which can be presented by CD1d and recognized by NKT cells. Furthermore, supplement of killed intestinal bacteria was able to restore ConA-mediated NKT cell activation and liver injury in GF mice. Our results suggest that glycolipid antigens derived from intestinal commensal bacteria are important hepatic NKT cell agonist and these antigens are required for the activation of NKT cells during ConA-induced liver injury. These finding provide a mechanistic explanation for the capacity of intestinal microflora to control liver inflammation. PMID:27821872

  2. Extranodal nasal-type natural killer/T-cell lymphoma masquerading as recalcitrant sinusitis.

    PubMed

    Paik, Young S; Liess, Benjamin D; Scheidt, Troy D; Ingram, Ellis A; Zitsch, Robert P

    2010-02-01

    Extranodal nasal-type natural killer (NK)/T-cell lymphoma is a very uncommon disease process often mimicking refractory sinusitis. The diagnosis may be discovered after an extensive exclusion process. Careful immunohistochemical evaluation is crucial to differentiate NK/T-cell lymphoma from other malignancies. We describe a 46-year-old white man presenting with a 4-month history of refractory sinusitis and new onset visual field loss in his right eye, right facial tingling, and pain. Examination revealed right periorbital edema and scleritis, and necrotic appearing turbinates with purulence and fibrinous debris. CT/MRI delineated extensive paranasal sinus involvement. Immunohistopathology demonstrated extranodal nasal-type NK/T-cell lymphoma. Additional radiography revealed widespread involvement. Severe recalcitrant sinusitis with orbital involvement may be the initial presentation of NK/T-cell lymphoma. Ulcerative or necrotic lesions in the midline of the head and neck should raise concern for this disease. In addition to radiographic and laboratory testing, large biopsies should be taken for immunohistochemical analysis to achieve diagnosis and guide further management. Copyright 2009 Wiley Periodicals, Inc.

  3. Modeling Human Natural Killer Cell Development in the Era of Innate Lymphoid Cells

    PubMed Central

    Scoville, Steven D.; Freud, Aharon G.; Caligiuri, Michael A.

    2017-01-01

    Decades after the discovery of natural killer (NK) cells, their developmental pathways in mice and humans have not yet been completely deciphered. Accumulating evidence indicates that NK cells can develop in multiple tissues throughout the body. Moreover, detailed and comprehensive models of NK cell development were proposed soon after the turn of the century. However, with the recent identification and characterization of other subtypes of innate lymphoid cells (ILCs), which show some overlapping functional and phenotypic features with NK cell developmental intermediates, the distinct stages through which human NK cells develop from early hematopoietic progenitor cells remain unclear. Thus, there is a need to reassess and refine older models of NK cell development in the context of new data and in the era of ILCs. Our group has focused on elucidating the developmental pathway of human NK cells in secondary lymphoid tissues (SLTs), including tonsils and lymph nodes. Here, we provide an update of recent progress that has been made with regard to human NK cell development in SLTs, and we discuss these new findings in the context of contemporary models of ILC development. PMID:28396671

  4. Enrichment of mouse splenic natural killer cells using discontinuous polyvinylpyrrolidone silica (Percoll) gradients.

    PubMed Central

    Patel, M R; Linna, T J

    1984-01-01

    A simple and rapid method is reported here for enriching murine spleen cells with natural killer (NK) function as assessed by short-term cytolysis assay of 51Cr-labelled YAC-1 lymphoma target cells. The established method used for the enrichment of NK reactive cells, including large granular lymphocytes (LGL) from human and rat peripheral blood lymphocytes, does not substantially enrich for mouse splenic NK cell activity. A reproducible procedure for enriching mouse splenic NK cells has been developed using a four- or five-step discontinuous Percoll gradient in the density range of 1.062 g/ml (top) to 1.092 g/ml (bottom) and osmolarity (310-340 mOsm/kg) nearer to that of mouse blood and tissue. A four- to 25-fold (usually about nine-fold) increase in NK cell activity, consisting of 50-100% of the recovered lytic unit activity, is found in which are the cells forming band 3, approximately 10% of the recovered cell number. This cell population with enriched NK cell activity has a characteristic density less than or equal to 1.077 g/ml, but more than 1.070 g/ml when centrifuged under appropriate conditions. Similar enrichment was obtained with a four-step gradient at an uniform osmolarity of 320 mOsm/kg throughout. Although the lymphocytes in band 3 show relatively little heterogeneity in appearance, only a minor population of the cells contain granules. Images Figure 3 PMID:6094339

  5. Murine cytomegalovirus stimulates natural killer cell function but kills genetically resistant mice treated with radioactive strontium

    SciTech Connect

    Masuda, A.; Bennett, M.

    1981-12-01

    Treatment of C3H/St mice with 100 microCi of 89Sr weakened their genetic resistance to murine cytomegalovirus (MCMV) infection. The criteria utilized to detect increased susceptibility were: (i) survival of mice; (ii) numbers of MCMV-infected cells in the spleens and liver; and (iii) serum glutamic pyruvic transaminase levels. The natural killer (NK) cell activity of spleen cells from mice treated with 89Sr is very low. However, the NK activities of spleen cells of both normal and 89Sr-treated mice were greatly augmented 3 days after infection with MCMV. These NK cells lysed a variety of tumor cells and shared several features with conventional NK cells, but were not lysed by anti-Nk-1.2 serum (specific for NK cells) plus complement. Splenic adherent cells did not lyse tumor cells themselves but were necessary for the stimulation of NK cells by MCMV. The paradox of high NK cell function and poor survival in 89Sr-treated mice infected with MCMV was a surprise. We conclude that these augmented NK cells, of themselves, cannot account for the genetic resistance of C3H/St mice to infection with MCMV.

  6. Natural Killer Cell Evasion Is Essential for Infection by Rhesus Cytomegalovirus.

    PubMed

    Sturgill, Elizabeth R; Malouli, Daniel; Hansen, Scott G; Burwitz, Benjamin J; Seo, Seongkyung; Schneider, Christine L; Womack, Jennie L; Verweij, Marieke C; Ventura, Abigail B; Bhusari, Amruta; Jeffries, Krystal M; Legasse, Alfred W; Axthelm, Michael K; Hudson, Amy W; Sacha, Jonah B; Picker, Louis J; Früh, Klaus

    2016-08-01

    The natural killer cell receptor NKG2D activates NK cells by engaging one of several ligands (NKG2DLs) belonging to either the MIC or ULBP families. Human cytomegalovirus (HCMV) UL16 and UL142 counteract this activation by retaining NKG2DLs and US18 and US20 act via lysomal degradation but the importance of NK cell evasion for infection is unknown. Since NKG2DLs are highly conserved in rhesus macaques, we characterized how NKG2DL interception by rhesus cytomegalovirus (RhCMV) impacts infection in vivo. Interestingly, RhCMV lacks homologs of UL16 and UL142 but instead employs Rh159, the homolog of UL148, to prevent NKG2DL surface expression. Rh159 resides in the endoplasmic reticulum and retains several NKG2DLs whereas UL148 does not interfere with NKG2DL expression. Deletion of Rh159 releases human and rhesus MIC proteins, but not ULBPs, from retention while increasing NK cell stimulation by infected cells. Importantly, RhCMV lacking Rh159 cannot infect CMV-naïve animals unless CD8+ cells, including NK cells, are depleted. However, infection can be rescued by replacing Rh159 with HCMV UL16 suggesting that Rh159 and UL16 perform similar functions in vivo. We therefore conclude that cytomegaloviral interference with NK cell activation is essential to establish but not to maintain chronic infection.

  7. mTORC1-dependent metabolic reprogramming is a prerequisite for Natural Killer cell effector function

    PubMed Central

    Donnelly, Raymond P.; Loftus, Róisín M.; Keating, Sinéad E.; Liou, Kevin T.; Biron, Christine A.; Gardiner, Clair M.; Finlay, David K.

    2014-01-01

    The mammalian target of rapamcyin complex 1 (mTORC1) is a key regulator of cellular metabolism and also has fundamental roles in controlling immune responses. Emerging evidence suggests that these two functions of mTORC1 are integrally linked. However, little is known regarding mTORC1 function in controlling the metabolism and function of natural killer (NK) cells, lymphocytes that play key roles in anti-viral and anti-tumour immunity. This study investigated the hypothesis that mTORC1-controlled metabolism underpins normal NK cell pro-inflammatory function. We demonstrate that mTORC1 is robustly stimulated in NK cells activated in vivo and in vitro. This mTORC1 activity is required for the production of the key NK cell effector molecules IFNγ, important in delivering antimicrobial and immunoregulatory functions, and granzyme B, a critical component of NK cell cytotoxic granules. The data reveal that NK cells undergo dramatic metabolic reprogramming upon activation, up-regulating rates of glucose uptake and glycolysis, and that mTORC1 activity is essential for attaining this elevated glycolytic state. Directly limiting the rate of glycolysis is sufficient to inhibit IFNγ production and granzyme B expression. This study provides the highly novel insight that mTORC1-mediated metabolic reprogramming of NK cells is a prerequisite for the acquisition of normal effector functions. PMID:25261477

  8. Phosphatidylinositol turnover is associated with human natural killer cell activation by tumor target cells

    SciTech Connect

    Steele, T.A.; Brahmi, Z.

    1986-03-01

    Natural Killer (NK) cell activity has been shown to be a binding-dependent event leading to the destruction of various targets. This suggests a possible role for plasma membrane phospholipid turnover in coupling a receptor-mediated binding event with transduction of a intracellular signal to result in the activation of the effector cell. Currently, phosphatidylinositol (PI) turnover is implicated in several immune cell systems. Therefore, in this study, the authors examined phospholipid turnover in human NK cells upon exposure to a sensitive (K562) and a resistant (YAC-1) target cell (TC). NK cell membrane phospholipids were labelled with Phosphorus-32 (/sup 32/P) and, following stimulation, were extracted and run on silica gel thin-layer chromatography. Labelled phospholipids were visualized by autoradiography then scraped and counted in a liquid scintillation counter. A 2.5 fold increase in label incorporation into PI relative to controls was shown to occur when NK cells were stimulated by K562 for 2 hours. In contrast, no increased labelling of PI relative to controls was noted when NK cells were stimulated by YAC-1 for the same period of time. No change in incorporation of /sup 32/P into phosphatidylcholine or phosphatidylethanolamine occurred in either set of conditions. These results suggest that PI turnover may be an early activation event in NK cells following binding of K562.

  9. Cloning and sequence analysis of candidate human natural killer-enhancing factor genes

    SciTech Connect

    Shau, H.; Butterfield, L.H.; Chiu, R.; Kim, A.

    1994-12-31

    A cytosol factor from human red blood cells enhances natural killer (NK) activity. This factor, termed NK-enhancing factor (NKEF), is a protein of 44000 M{sub r} consisting of two subunits of equal size linked by disulfide bonds. NKEF is expressed in the NK-sensitive erythroleukemic cell line K562. Using an antibody specific for NKEF as a probe for immunoblot screening, we isolated several clones from a {lambda}gt11 cDNA library of K562. Additional subcloning and sequencing revealed that the candidate NKEF cDNAs fell into one of two categories of closely related but non-identical genes, referred to as NKEF A and B. They are 88% identical in amino acid sequence and 71% identical in nucleotide sequence. Southern blot analysis suggests that there are two to three NKEF family members in the genome. Analysis of predicted amino acid sequences indicates that both NKEF A and B are cytosol proteins with several phosphorylation sites each, but that they have no glycosylation sites. They are significantly homologous to several other proteins from a wide variety of organisms ranging from prokaryotes to mammals, especially with regard to several well-conserved motifs within the amino acid sequences. The biological functions of these proteins in other species are mostly unknown, but some of them were reported to be induced by oxidative stress. Therefore, as well as for immunoregulation of NK activity, NKEF may be important for cells in coping with oxidative insults. 32 refs., 3 figs.

  10. Effect of radiotherapy on the natural killer (NK)-cell activity of cancer patients

    SciTech Connect

    McGinnes, K.; Florence, J.; Penny, R.

    1987-05-01

    The aim of this study was to determine the effect of radiotherapy on peripheral blood natural killer (NK)-cell number and activity in 15 patients with cancer, prior to the commencement and at the completion of radiotherapy. The following observations were made. Prior to radiotherapy NK activity could not be correlated with the stage of malignancy. In all patients with advanced disease and with subnormal baseline NK activity, the outcome of radiotherapy was unfavorable. Following radiotherapy to sites including the mediastinum, patients had decreased NK activity compared with those receiving treatment to other sites. This decrease was not related to the dose of radiotherapy or stage of malignancy. The tumor response was favorable in most patients whose NK activity decreased as a result of radiotherapy. The decrease in NK activity may be associated with a decrease in the percentage of NK (N901) cells in the peripheral blood. The reduction in NK activity in those patients receiving mediastinal irradiation may be due to the large volume of blood which transits the field, so that the NK cells, or their more radiosensitive precursors, may be damaged and/or differentiation inhibited. Thus, these new observations show that radiotherapy does indeed affect the NK activity in cancer patients predominantly when the irradiation site includes the mediastinum.

  11. Natural Killer Cells for Immunotherapy - Advantages of the NK-92 Cell Line over Blood NK Cells.

    PubMed

    Klingemann, Hans; Boissel, Laurent; Toneguzzo, Frances

    2016-01-01

    Natural killer (NK) cells are potent cytotoxic effector cells for cancer therapy and potentially for severe viral infections. However, there are technical challenges to obtain sufficient numbers of functionally active NK cells from a patient's blood since they represent only 10% of the lymphocytes and are often dysfunctional. The alternative is to obtain cells from a healthy donor, which requires depletion of the allogeneic T cells to prevent graft-versus-host reactions. Cytotoxic cell lines have been established from patients with clonal NK-cell lymphoma. Those cells can be expanded in culture in the presence of IL-2. Except for the NK-92 cell line, though, none of the other six known NK cell lines has consistently and reproducibly shown high antitumor cytotoxicity. Only NK-92 cells can easily be genetically manipulated to recognize specific tumor antigens or to augment monoclonal antibody activity through antibody-dependent cellular cytotoxicity. NK-92 is also the only cell line product that has been infused into patients with advanced cancer with clinical benefit and minimal side effects.

  12. AHR prevents human IL-1R1hi ILC3 differentiation to natural killer cells

    PubMed Central

    Hughes, Tiffany; Briercheck, Edward L.; Freud, Aharon G.; Trotta, Rossana; McClory, Susan; Scoville, Steven D.; Keller, Karen; Deng, Youcai; Cole, Jordan; Harrison, Nicholas; Mao, Charlene; Zhang, Jianying; Benson, Don M.; Yu, Jianhua; Caligiuri, Michael A.

    2014-01-01

    SUMMARY Accumulating evidence indicates that human natural killer (NK) cells develop in secondary lymphoid tissue (SLT) through a so-called “stage 3” developmental intermediate minimally characterized by a CD34-CD117+CD94- immunophenotype that lacks mature NK cell function. This stage 3 population is heterogeneous, potentially composed of functionally distinct innate lymphoid cell (ILC) types that includes interleukin-1 receptor (IL-1R1) positive, IL-22-producing ILC3s. Whether human ILC3s are developmentally related to NK cells is a subject of ongoing investigation. Here we show that antagonism of the aryl hydrocarbon receptor (AHR) or silencing of AHR gene expression promotes differentiation of tonsillar IL-22-producing IL-1R1hi human ILC3s to CD56brightCD94+ IFN-gamma-producing cytolytic mature NK cells expressing eomesodermin (EOMES) and T-Box Protein 21 (TBX21 or TBET). Hence, AHR is a transcription factor that prevents human IL-1R1hi ILC3s from differentiating into NK cells. PMID:24953655

  13. Natural Killer Cells and Mast Cells from gp49B Null Mutant Mice Are Functional

    PubMed Central

    Rojo, Susana; Stebbins, Christopher C.; Peterson, Mary E.; Dombrowicz, David; Wagtmann, Nicolai; Long, Eric O.

    2000-01-01

    Immune responses are controlled by a combination of positive and negative cellular signals. Effector cells in the immune system express inhibitory receptors that serve to limit effector cell expansion and to protect the host from autoreactivity. gp49B is a receptor of unknown function that is expressed on activated mast cells and natural killer (NK) cells and whose cytoplasmic tail endows it with inhibitory potential. To gain insight into the function of gp49B in mice, we disrupted the gp49B gene by homologous recombination. gp49B0 mice were born at expected ratios, were healthy and fertile, and displayed normal long-term survival rates. gp49B0 mice showed no defect in NK or mast cell development. Furthermore, NK and mast cells from the gp49B0 mice showed activation properties in vitro similar to those of cells isolated from wild-type mice. Therefore, gp49B is not critical for the development, expansion, and maturation of mast cells and NK cells in vivo. The healthy status of gp49B0 mice makes them suitable for testing the role of gp49B in immune responses to infectious agents. PMID:10982834

  14. The up side of decidual natural killer cells: new developments in immunology of pregnancy

    PubMed Central

    Jabrane-Ferrat, Nabila; Siewiera, Johan

    2014-01-01

    Early phases of human pregnancy are associated with the accumulation of a unique subset of natural killer (NK) cells in the maternal decidua. Decidual NK (dNK) cells that are devoid of cytotoxicity play a pivotal role in successful pregnancy. By secreting large amounts of cytokines/chemokines and angiogenic factors, dNK cells participate in all steps of placentation including trophoblast invasion into the maternal endometrium and vascular remodelling. In this review, we summarize some of dNK cell features and discuss more recent exciting data that challenge the conventional view of these cells. Our new data demonstrate that dNK cells undergo fine tuning or even subvert their classical inhibitory machinery and turn into a real defence force in order to prevent the spread of viruses to fetal tissue. Today it is not clear how these phenotypic and functional adaptations impact cellular cross-talk at the fetal–maternal interface and tissue homeostasis. Ultimately, precise understanding of the molecular mechanisms that govern dNK cell plasticity during congenital human cytomegalovirus infection should lead to the design of more robust strategies to reverse immune escape during viral infection and cancer. PMID:24256296

  15. Clonal tracking of rhesus macaque hematopoiesis highlights a distinct lineage origin for natural killer cells.

    PubMed

    Wu, Chuanfeng; Li, Brian; Lu, Rong; Koelle, Samson J; Yang, Yanqin; Jares, Alexander; Krouse, Alan E; Metzger, Mark; Liang, Frank; Loré, Karin; Wu, Colin O; Donahue, Robert E; Chen, Irvin S Y; Weissman, Irving; Dunbar, Cynthia E

    2014-04-03

    Analysis of hematopoietic stem cell function in nonhuman primates provides insights that are relevant for human biology and therapeutic strategies. In this study, we applied quantitative genetic barcoding to track the clonal output of transplanted autologous rhesus macaque hematopoietic stem and progenitor cells over a time period of up to 9.5 months. We found that unilineage short-term progenitors reconstituted myeloid and lymphoid lineages at 1 month but were supplanted over time by multilineage clones, initially myeloid restricted, then myeloid-B clones, and then stable myeloid-B-T multilineage, long-term repopulating clones. Surprisingly, reconstitution of the natural killer (NK) cell lineage, and particularly the major CD16(+)/CD56(-) peripheral blood NK compartment, showed limited clonal overlap with T, B, or myeloid lineages, and therefore appears to be ontologically distinct. Thus, in addition to providing insights into clonal behavior over time, our analysis suggests an unexpected paradigm for the relationship between NK cells and other hematopoietic lineages in primates. Copyright © 2014 Elsevier Inc. All rights reserved.

  16. Characterization of natural killer cells cultured from human bone marrow cells

    SciTech Connect

    Yoda, Y.; Kawakami, Z.; Shibuya, A.; Abe, T.

    1988-09-01

    Human bone marrow (BM) cells, depleted of nylon wool-adherent cells, T cells, and natural killer (NK) cells, were cultured in medium containing recombinant interleukin 2 (rIL2). After 21 or 24 days in culture, numerous lymphoid cells with multiple azurophilic granules and a morphology similar to large granular lymphocytes (LGL) were found. Two-color analysis of surface phenotype showed many of these cells to be NKH1-positive and a limited number of cells had other NK markers such as CD16, CD2, or CD8. The CD3 antigen was not coexpressed with NKH1. The cultured BM cells were cytotoxic for K562, Daudi, and Raji cell lines. The NKH1+, CD2-, CD3-, CD16- cells were sorted and, in addition to having the LGL morphology, were found to be cytotoxic for K562 cells (NK (K562)). The generation of NK(K562) activity was significantly suppressed by 5-bromodeoxyuridine plus ultraviolet light treatment, indicating that DNA synthesis is required. These experiments suggest that the described culture conditions allow differentiation of progenitor cells, into immature, but functionally active, NK cells.

  17. Molecular checkpoints controlling natural killer cell activation and their modulation for cancer immunotherapy

    PubMed Central

    Kwon, Hyung-Joon; Kim, Nayoung; Kim, Hun Sik

    2017-01-01

    Natural killer (NK) cells have gained considerable attention as promising therapeutic tools for cancer therapy due to their innate selectivity against cancer cells over normal healthy cells. With an array of receptors evolved to sense cellular alterations, NK cells provide early protection against cancer cells by producing cytokines and chemokines and exerting direct cytolytic activity. These effector functions are governed by signals transmitted through multiple receptor–ligand interactions but are not achieved by engaging a single activating receptor on resting NK cells. Rather, they require the co-engagement of different activating receptors that use distinct signaling modules, due to a cell-intrinsic inhibition mechanism. The redundancy of synergizing receptors and the inhibition of NK cell function by a single class of inhibitory receptor suggest the presence of common checkpoints to control NK cell activation through different receptors. These molecular checkpoints would be therapeutically targeted to harness the power of NK cells against diverse cancer cells that express heterogeneous ligands for NK cell receptors. Recent advances in understanding the activation of NK cells have revealed promising candidates in this category. Targeting such molecular checkpoints will facilitate NK cell activation by lowering activation thresholds, thereby providing therapeutic strategies that optimize NK cell reactivity against cancer. PMID:28360428

  18. Activation of human natural killer cells by the soluble form of cellular prion protein.

    PubMed

    Seong, Yeon-Jae; Sung, Pil Soo; Jang, Young-Soon; Choi, Young Joon; Park, Bum-Chan; Park, Su-Hyung; Park, Young Woo; Shin, Eui-Cheol

    2015-08-21

    Cellular prion protein (PrP(C)) is widely expressed in various cell types, including cells of the immune system. However, the specific roles of PrP(C) in the immune system have not been clearly elucidated. In the present study, we investigated the effects of a soluble form of recombinant PrP(C) protein on human natural killer (NK) cells. Recombinant soluble PrP(C) protein was generated by fusion of human PrP(C) with the Fc portion of human IgG1 (PrP(C)-Fc). PrP(C)-Fc binds to the surface of human NK cells, particularly to CD56(dim) NK cells. PrP(C)-Fc induced the production of cytokines and chemokines and the degranulation of granzyme B from NK cells. In addition, PrP(C)-Fc facilitated the IL-15-induced proliferation of NK cells. PrP(C)-Fc induced phosphorylation of ERK-1/2 and JNK in NK cells, and inhibitors of the ERK or the JNK pathways abrogated PrP(C)-Fc-induced cytokine production in NK cells. In conclusion, the soluble form of recombinant PrP(C)-Fc protein activates human NK cells via the ERK and JNK signaling pathways.

  19. Sphingolipids from a symbiotic microbe regulate homeostasis of host intestinal natural killer T cells

    PubMed Central

    An, Dingding; Oh, Sungwhan F.; Olszak, Torsten; Neves, Joana F.; Avci, Fikri; Erturk-Hasdemir, Deniz; Lu, Xi; Zeissig, Sebastian; Blumberg, Richard S.; Kasper, Dennis L.

    2014-01-01

    Summary Co-evolution of beneficial microorganisms with the mammalian intestine fundamentally shapes mammalian physiology. Herein we report that the intestinal microbe Bacteroides fragilis modifies the homeostasis of host invariant natural killer T (iNKT) cells by supplementing the host’s endogenous lipid antigen milieu with unique inhibitory sphingolipids. The process occurs early in life and effectively impedes iNKT cell proliferation during neonatal development. Consequently, total colonic iNKT cell numbers are restricted into adulthood and hosts are protected against experimental iNKT cell–mediated, oxazolone-induced colitis. In studies with neonatal mice lacking access to bacterial sphingolipids, we found that treatment with B. fragilis glycosphingolipids—exemplified by an isolated peak (M.W.=717.6) called GSL-Bf717—reduces colonic iNKT cell numbers and confers protection against oxazolone-induced colitis in adulthood. Our results suggest that the distinctive inhibitory capacity of GSL-Bf717 and similar molecules may prove useful in the treatment of autoimmune and allergic disorders in which iNKT cell activation is destructive. PMID:24439373

  20. Different subsets of natural killer T cells may vary in their roles in health and disease

    PubMed Central

    Kumar, Vipin; Delovitch, Terry L

    2014-01-01

    Natural killer T cells (NKT) can regulate innate and adaptive immune responses. Type I and type II NKT cell subsets recognize different lipid antigens presented by CD1d, an MHC class-I-like molecule. Most type I NKT cells express a semi-invariant T-cell receptor (TCR), but a major subset of type II NKT cells reactive to a self antigen sulphatide use an oligoclonal TCR. Whereas TCR-α dominates CD1d-lipid recognition by type I NKT cells, TCR-α and TCR-β contribute equally to CD1d-lipid recognition by type II NKT cells. These variable modes of NKT cell recognition of lipid–CD1d complexes activate a host of cytokine-dependent responses that can either exacerbate or protect from disease. Recent studies of chronic inflammatory and autoimmune diseases have led to a hypothesis that: (i) although type I NKT cells can promote pathogenic and regulatory responses, they are more frequently pathogenic, and (ii) type II NKT cells are predominantly inhibitory and protective from such responses and diseases. This review focuses on a further test of this hypothesis by the use of recently developed techniques, intravital imaging and mass cytometry, to analyse the molecular and cellular dynamics of type I and type II NKT cell antigen-presenting cell motility, interaction, activation and immunoregulation that promote immune responses leading to health versus disease outcomes. PMID:24428389

  1. Natural killer cell subsets in cerebrospinal fluid of patients with multiple sclerosis

    PubMed Central

    Rodríguez-Martín, E; Picón, C; Costa-Frossard, L; Alenda, R; Sainz de la Maza, S; Roldán, E; Espiño, M; Villar, L M; Álvarez-Cermeño, J C

    2015-01-01

    Changes in blood natural killer (NK) cells, important players of the immune innate system, have been described in multiple sclerosis (MS). We studied percentages and total cell counts of different effector and regulatory NK cells in cerebrospinal fluid (CSF) of MS patients and other neurological diseases to gain clearer knowledge of the role of these cells in neuroinflammation. NK cell subsets were assessed by flow cytometry in CSF of 85 consecutive MS patients (33 with active disease and 52 with stable MS), 16 with other inflammatory diseases of the central nervous system (IND) and 17 with non-inflammatory neurological diseases (NIND). MS patients showed a decrease in percentages of different CSF NK subpopulations compared to the NIND group. However, absolute cell counts showed a significant increase of all NK subsets in MS and IND patients, revealing that the decrease in percentages does not reflect a real reduction of these immune cells. Remarkably, MS patients showed a significant increase of regulatory/effector (CD56bright/CD56dim) NK ratio compared to IND and NIND groups. In addition, MS activity associated with an expansion of NK T cells. These data show that NK cell subsets do not increase uniformly in all inflammatory neurological disease and suggest strongly that regulatory CD56bright and NK T cells may arise in CSF of MS patients as an attempt to counteract the CNS immune activation characteristic of the disease. PMID:25565222

  2. DNAM-1 control of natural killer cells functions through nectin and nectin-like proteins.

    PubMed

    de Andrade, Lucas Ferrari; Smyth, Mark J; Martinet, Ludovic

    2014-03-01

    Natural killer (NK) cells represent key innate immune cells that restrain viral infection and malignant transformation and help mount an adaptive immune response. To perform such complicated tasks, NK cells express a wide set of inhibitory and activating receptors that alert them against cellular stress without damaging healthy cells. A new family of receptors that recognize nectin and nectin-like molecules has recently emerged as a critical regulator of NK cell functions. The most famous member of this family, DNAX accessory molecule (DNAM-1, CD226), is an adhesion molecule that control NK cell cytotoxicity and interferon-γ production against a wide range of cancer and infected cells. Its ligands CD112 and CD155 have been described in different pathological conditions, and recent evidence indicates that their expression is regulated by cellular stress. Additional receptors have been shown to bind DNAM-1 ligands and modulate NK cell functions bringing another level of complexity. These include CD96 (TACTILE) and TIGIT (WUCAM, VSTM3). Here, we review the role of DNAM-1, TIGIT and CD96 in NK cell biology summarizing the recent advances made on the role of these receptors in various pathologies, such as cancer, viral infections and autoimmunity.

  3. Dynamics of Natural Killer Cell Receptor Revealed by Quantitative Analysis of Photoswitchable Protein

    NASA Astrophysics Data System (ADS)

    Pageon, Sophie V.; Aquino, Gerardo; Lagrue, Kathryn; Köhler, Karsten; Endres, Robert G.; Davis, Daniel M.

    2013-11-01

    Natural Killer (NK) cell activation is dynamically regulated by numerous activating and inhibitory surface receptors that accumulate at the immune synapse. Quantitative analysis of receptor dynamics has been limited by methodologies which rely on indirect measurements such as fluorescence recovery after photobleaching. Here, we report a novel approach to study how proteins traffic to and from the immune synapse using NK cell receptors tagged with the photoswitchable fluorescent protein tdEosFP, which can be irreversibly photoswitched from a green to red fluorescent state by ultraviolet light. Thus, following a localized switching event, the movement of the photoswitched molecules can be temporally and spatially resolved by monitoring fluorescence in two regions of interest. By comparing images with mathematical models, we evaluated the diffusion coefficient of the receptor KIR2DL1 (0.23 +- 0.06 micron^2/s) and assessed how synapse formation affects receptor dynamics. Our data conclude that the inhibitory NK cell receptor KIR2DL1 is continually trafficked into the synapse and remains surprisingly stable there. Unexpectedly however, in NK cells forming synapses with multiple target cells simultaneously, KIR2DL1 at one synapse can relocate to another synapse. Thus, our results reveal a previously undetected inter-synaptic exchange of protein.

  4. Natural killer cell-mediated lysis of autologous cells modified by gene therapy.

    PubMed

    Liberatore, C; Capanni, M; Albi, N; Volpi, I; Urbani, E; Ruggeri, L; Mencarelli, A; Grignani, F; Velardi, A

    1999-06-21

    This study investigated the role of natural killer (NK) cells as effectors of an immune response against autologous cells modified by gene therapy. T lymphocytes were transduced with LXSN, a retroviral vector adopted for human gene therapy that carries the selectable marker gene neo, and the autologous NK response was evaluated. We found that (i) infection with LXSN makes cells susceptible to autologous NK cell-mediated lysis; (ii) expression of the neo gene is responsible for conferring susceptibility to lysis; (iii) lysis of neo-expressing cells is clonally distributed and mediated only by NK clones that exhibit human histocompatibility leukocyte antigen (HLA)-Bw4 specificity and bear KIR3DL1, a Bw4-specific NK inhibitory receptor; and (iv) the targets are cells from HLA-Bw4(+) individuals. Finally, neo peptides anchoring to the Bw4 allele HLA-B27 interfered with KIR3DL1-mediated recognition of HLA-B27, i.e., they triggered NK lysis. Moreover, neo gene mutations preventing translation of two of the four potentially nonprotective peptides reduced KIR3DL1(+) NK clone-mediated autologous lysis. Thus, individuals expressing Bw4 alleles possess an NK repertoire with the potential to eliminate autologous cells modified by gene therapy. By demonstrating that NK cells can selectively detect the expression of heterologous genes, these observations provide a general model of the NK cell-mediated control of viral infections.

  5. Preventing postoperative metastatic disease by inhibiting surgery-induced dysfunction in natural killer cells.

    PubMed

    Tai, Lee-Hwa; de Souza, Christiano Tanese; Bélanger, Simon; Ly, Lundi; Alkayyal, Almohanad A; Zhang, Jiqing; Rintoul, Julia L; Ananth, Abhirami A; Lam, Tiffany; Breitbach, Caroline J; Falls, Theresa J; Kirn, David H; Bell, John C; Makrigiannis, Andrew P; Auer, Rebecca A

    2013-01-01

    Natural killer (NK) cell clearance of tumor cell emboli following surgery is thought to be vital in preventing postoperative metastases. Using a mouse model of surgical stress, we transferred surgically stressed NK cells into NK-deficient mice and observed enhanced lung metastases in tumor-bearing mice as compared with mice that received untreated NK cells. These results establish that NK cells play a crucial role in mediating tumor clearance following surgery. Surgery markedly reduced NK cell total numbers in the spleen and affected NK cell migration. Ex vivo and in vivo tumor cell killing by NK cells were significantly reduced in surgically stressed mice. Furthermore, secreted tissue signals and myeloid-derived suppressor cell populations were altered in surgically stressed mice. Significantly, perioperative administration of oncolytic parapoxvirus ovis (ORFV) and vaccinia virus can reverse NK cell suppression, which correlates with a reduction in the postoperative formation of metastases. In human studies, postoperative cancer surgery patients had reduced NK cell cytotoxicity, and we show for the first time that oncolytic vaccinia virus markedly increases NK cell activity in patients with cancer. These data provide direct in vivo evidence that surgical stress impairs global NK cell function. Perioperative therapies aimed at enhancing NK cell function will reduce metastatic recurrence and improve survival in surgical cancer patients.

  6. Natural killer cell biology illuminated by primary immunodeficiency syndromes in humans.

    PubMed

    Voss, Matthias; Bryceson, Yenan T

    2017-04-01

    Natural killer (NK) cells are innate immune cytotoxic effector cells well known for their role in antiviral immunity and tumor immunosurveillance. In parts, this knowledge stems from rare inherited immunodeficiency disorders in humans that abrogate NK cell function leading to immune impairments, most notably associated with a high susceptibility to viral infections. Phenotypically, these disorders range from deficiencies selectively affecting NK cells to complex general immune defects that affect NK cells but also other immune cell subsets. Moreover, deficiencies may be associated with reduced NK cell numbers or rather impair specific NK cell effector functions. In recent years, genetic defects underlying the various NK cell deficiencies have been uncovered and have triggered investigative efforts to decipher the molecular mechanisms underlying these disorders. Here we review the associations between inherited human diseases and NK cell development as well as function, with a particular focus on defects in NK cell exocytosis and cytotoxicity. Furthermore we outline how reports of diverse genetic defects have shaped our understanding of NK cell biology. Copyright © 2015. Published by Elsevier Inc.

  7. Extranodal natural killer/T-cell lymphoma presenting as orbital cellulitis

    PubMed Central

    Zuhaimy, Hanis; Aziz, Hayati Abdul; Vasudevan, Suresh; Hui Hui, Siah

    2017-01-01

    Objective: To report an aggressive case of extranodal natural killer/T-cell lymphoma (NKTCL) of the ethmoid sinus presenting as orbital cellulitis Method: Case report Results: A 56-year-old male presented with right eye redness, reduced vision, and periorbital swelling for 5 weeks duration associated with a two-month history of blocked nose. The visual acuity of the right eye was 6/18. The eye was proptosed with periorbital oedema and conjunctival chemosis. The pupil was mid-dilated but there was no relative afferent pupillary defect. The fundus was normal. The extraocular movements were restricted in all directions of gaze. Nasal endoscopy revealed pansinusitis that corresponded with CT scan orbit and paranasal sinuses findings. Despite treatment, he showed no clinical improvement. Ethmoidal sinus biopsies performed revealed extranodal NKTCL. Further imaging showed involvement of the right orbital contents and its adnexa with intracranial extension into the right cavernous sinus and meninges over right temporal fossa. The patient underwent chemotherapy. However he succumbed to his illness two months after the diagnosis. Conclusion: Extranodal NKTCL is a great mimicker. This case demonstrated how an acute initial presentation of extranodal NKTCL can present as orbital cellulitis with pansinusitis. PMID:28194321

  8. Invariant natural killer T cells in adipose tissue: novel regulators of immune-mediated metabolic disease.

    PubMed

    Rakhshandehroo, M; Kalkhoven, E; Boes, M

    2013-12-01

    Adipose tissue (AT) represents a microenvironment where intersection takes place between immune processes and metabolic pathways. A variety of immune cells have been characterized in AT over the past decades, with the most recent addition of invariant natural killer T (iNKT) cells. As members of the T cell family, iNKT cells represent a subset that exhibits both innate and adaptive characteristics and directs ensuing immune responses. In disease conditions, iNKT cells have established roles that include disorders in the autoimmune spectrum in malignancies and infectious diseases. Recent work supports a role for iNKT cells in the maintenance of AT homeostasis through both immune and metabolic pathways. The deficiency of iNKT cells can result in AT metabolic disruptions and insulin resistance. In this review, we summarize recent work on iNKT cells in immune regulation, with an emphasis on AT-resident iNKT cells, and identify the potential mechanisms by which adipocytes can mediate iNKT cell activity.

  9. Human T cell leukemia virus type 1 infection drives spontaneous proliferation of natural killer cells

    PubMed Central

    Hirschkorn, Dale F; DeVita, Deborah A; Lee, Tzong-Hae; Murphy, Eedward L

    2010-01-01

    Most human T cell leukemia virus type 1 (HTLV-1) infected subjects remain asymptomatic throughout their lives, with a few individuals developing HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) or adult T cell leukemia. Lymphocytes from about half of HTLV-1 infected subjects spontaneously proliferate in vitro, and how this phenomenon relates to symptomatic disease outcome and viral burden is poorly understood. Spontaneous proliferation was measured in lymphocyte subsets, and these findings were correlated with HTLV-1 proviral load and Tax expression in peripheral blood mononuclear cells (PBMCs). We found that in addition to previously described vigorous CD8+ T cell spontaneous proliferation, natural killer (NK) cells spontaneously proliferated to a similar high level, resulting in expansion of CD56-expressing NK cells. Spontaneous NK cell proliferation positively correlated with HTLV-1 proviral load but not with Tax expression or the presence of HAM/TSP. The strongest correlate with clinical outcome in this cohort was the ability of cells to express Tax, while HTLV-1 proviral load was more closely related to spontaneous NK cell proliferation. These results demonstrate that spontaneous proliferation, Tax expression, and proviral load are inter-related but not equivalent, and that spontaneous lymphocyte proliferation is not restricted to T cells, the targets of HTLV-1 infection. PMID:20640055

  10. Clinical applications of natural killer T cell-based immunotherapy for cancer.

    PubMed

    Motohashi, Shinichiro; Nakayama, Toshinori

    2008-04-01

    Human invariant V alpha 24 natural killer T (NKT) cells are a novel, distinct lymphocyte population, characterized by an invariant T-cell receptor V alpha 24 chain paired with V beta 11. V alpha 24 NKT cells are activated by a specific glicolipid ligand, alpha-GalCer, and rapidly produce a large amount of Th1 and Th2 cytokines, thereby modulating other immune cells such as antigen-specific CD4 and CD8 T cells, NK cells, and dendritic cells. Recent studies have shown that NKT cells play pivotal regulatory roles in many immune responses, including antitumor immunity. We herein review the quantitative alteration and functional deterioration of circulating V alpha 24 NKT cells in various cancer-bearing patients. We also summarize the recent progress in the clinical studies of NKT cell-based tumor immunotherapy. Novel immunological results including the increased peripheral blood V alpha 24 NKT cells and IFN-producing cells after the immunotherapy were revealed. The details of the safety profile and the antitumor responses were also disclosed. Although the objective clinical responses still remain unclear, some encouraging results have emerged. Therefore, NKT cell-based immunotherapy may potentially be an effective strategy for the treatment of cancer patients.

  11. Invariant natural killer T cells: front line fighters in the war against pathogenic microbes.

    PubMed

    Crosby, Catherine M; Kronenberg, Mitchell

    2016-08-01

    Invariant natural killer T (iNKT) cells constitute a unique subset of innate-like T cells that have been shown to have crucial roles in a variety of immune responses. iNKT cells are characterized by their expression of both NK cell markers and an invariant T cell receptor (TCR) α chain, which recognizes glycolipids presented by the MHC class I-like molecule CD1d. Despite having a limited antigen repertoire, the iNKT cell response can be very complex, and participate in both protective and harmful immune responses. The protective role of these cells against a variety of pathogens has been particularly well documented. Through the use of these pathogen models, our knowledge of the breadth of the iNKT cell response has been expanded. Specific iNKT cell antigens have been isolated from several different bacteria, from which iNKT cells are critical for protection in mouse models. These responses can be generated by direct, CD1d-mediated activation, or indirect, cytokine-mediated activation, or a combination of the two. This can lead to secretion of a variety of different Th1, Th2, or Th17 cytokines, which differentially impact the downstream immune response against these pathogens. This critical role is emphasized by the conservation of these cells between mice and humans, warranting further investigation into how iNKT cells participate in protective immune responses, with the ultimate goal of harnessing their potential for treatment.

  12. Innate-like recognition of microbes by invariant natural killer T cells.

    PubMed

    Kronenberg, Mitchell; Kinjo, Yuki

    2009-08-01

    Invariant natural killer T cells (iNKT cells) express a restricted T cell antigen receptor (TCR) repertoire and they respond rapidly to glycolipid antigens presented by CD1d. These glycolipid antigens have hexose sugars in alpha-linkage to two types of lipids that can bind to CD1d. Recent work has shown that the responses of iNKT cells to antigen-bearing microbes can have a profound impact on the development of inflammatory diseases. iNKT cells overcome the limitation of their limited TCR diversity by also responding in a foreign antigen-independent fashion to some infectious agents, similar to NK cells. Recent results demonstrate several mechanisms for the indirect activation of iNKT cells by viruses or TLR ligands, dependent on self-antigen recognition and/or different cytokines produced by antigen presenting cells. The means by which iNKT cells influence other cell types and overall host defense are likewise diverse, illustrating the flexibility and functional diversity of this T lymphocyte sublineage.

  13. Carbohydrate specificity of the recognition of diverse glycolipids by natural killer T cells.

    PubMed

    Zajonc, Dirk M; Kronenberg, Mitchell

    2009-07-01

    Most T lymphocytes recognize peptide antigens bound to or presented by molecules encoded in the major histocompatibility complex (MHC). The CD1 family of antigen-presenting molecules is related to the MHC-encoded molecules, but CD1 proteins present lipid antigens, mostly glycolipids. Here we review T-lymphocyte recognition of glycolipids, with particular emphasis on the subpopulation known as natural killer T (NKT) cells. NKT cells influence many immune responses, they have a T-cell antigen receptor (TCR) that is restricted in diversity, and they share properties with cells of the innate immune system. NKT cells recognize antigens presented by CD1d with hexose sugars in alpha-linkage to lipids, although other, related antigens are known. The hydrophobic alkyl chains are buried in the CD1d groove, with the carbohydrate exposed for TCR recognition, together with the surface of the CD1d molecule. Therefore, understanding the biochemical basis for antigen recognition by NKT cells requires an understanding of how the trimolecular complex of CD1d, glycolipid, and the TCR is formed, which is in part a problem of carbohydrate recognition by the TCR. Recent investigations from our laboratories as well as studies from other groups have provided important information on the structural basis for NKT-cell specificity.

  14. Atypical natural killer T-cell receptor recognition of CD1d–lipid antigens

    PubMed Central

    Le Nours, Jérôme; Praveena, T.; Pellicci, Daniel G.; Gherardin, Nicholas A.; Ross, Fiona J.; Lim, Ricky T.; Besra, Gurdyal S.; Keshipeddy, Santosh; Richardson, Stewart K.; Howell, Amy R.; Gras, Stephanie; Godfrey, Dale I.; Rossjohn, Jamie; Uldrich, Adam P.

    2016-01-01

    Crucial to Natural Killer T (NKT) cell function is the interaction between their T-cell receptor (TCR) and CD1d-antigen complex. However, the diversity of the NKT cell repertoire and the ensuing interactions with CD1d-antigen remain unclear. We describe an atypical population of CD1d–α-galactosylceramide (α-GalCer)-reactive human NKT cells that differ markedly from the prototypical TRAV10-TRAJ18-TRBV25-1+ type I NKT cell repertoire. These cells express a range of TCR α- and β-chains that show differential recognition of glycolipid antigens. Two atypical NKT TCRs (TRAV21-TRAJ8-TRBV7–8 and TRAV12-3-TRAJ27-TRBV6-5) bind orthogonally over the A′-pocket of CD1d, adopting distinct docking modes that contrast with the docking mode of all type I NKT TCR-CD1d-antigen complexes. Moreover, the interactions with α-GalCer differ between the type I and these atypical NKT TCRs. Accordingly, diverse NKT TCR repertoire usage manifests in varied docking strategies and specificities towards CD1d–α-GalCer and related antigens, thus providing far greater scope for diverse glycolipid antigen recognition. PMID:26875526

  15. Two modes of lytic granule fusion during degranulation by natural killer cells.

    PubMed

    Liu, Dongfang; Martina, Jose A; Wu, Xufeng S; Hammer, John A; Long, Eric O

    2011-08-01

    Lytic granules in cytotoxic lymphocytes, which include T cells and natural killer (NK) cells, are secretory lysosomes that release their content upon fusion with the plasma membrane (PM), a process known as degranulation. Although vesicle exocytosis has been extensively studied in endocrine and neuronal cells, much less is known about the fusion of lytic granules in cytotoxic lymphocytes. Here, we used total internal reflection fluorescence microscopy to examine lytic granules labeled with fluorescently tagged Fas ligand (FasL) in the NK cell line NKL stimulated with phorbol ester and ionomycin and in primary NK cells activated by physiological receptor-ligand interactions. Two fusion modes were observed: complete fusion, characterized by loss of granule content and rapid diffusion of FasL at the PM; and incomplete fusion, characterized by transient fusion pore opening and retention of FasL at the fusion site. The pH-sensitive green fluorescence protein (pHluorin) fused to the lumenal domain of FasL was used to visualize fusion pore opening with a time resolution of 30 ms. Upon incomplete fusion, pHluorin emission lasted several seconds in the absence of noticeable diffusion. Thus, we conclude that lytic granules in NK cells undergo both complete and incomplete fusion with the PM, and propose that incomplete fusion may promote efficient recycling of lytic granule membrane after the release of cytotoxic effector molecules.

  16. Avian influenza virus directly infects human natural killer cells and inhibits cell activity.

    PubMed

    Mao, Huawei; Liu, Yinping; Sia, Sin Fun; Peiris, J S Malik; Lau, Yu-Lung; Tu, Wenwei

    2017-04-01

    Natural killer (NK) cell is a key component of innate immunity and plays an important role in host defense against virus infection by directly destroying infected cells. Influenza is a respiratory disease transmitted in the early phase of virus infection. Evasion of host innate immunity including NK cells is critical for the virus to expand and establish a successful acute infection. Previously, we showed that human influenza H1N1 virus infects NK cells and induces cell apoptosis, as well as inhibits NK cell activity. In this study, we further demonstrated that avian influenza virus also directly targeted NK cells as an immunoevasion strategy. The avian virus infected human NK cells and induced cell apoptosis. In addition, avian influenza virion and HA protein inhibited NK cell cytotoxicity. This novel strategy has obvious advantages for avian influenza virus, allowing the virus sufficient time to expand and subsequent spread before the onset of the specific immune response. Our findings provide an important clue for the immunopathogenesis of avian influenza, and also suggest that direct targeting NK cells may be a common strategy used by both human and avian influenza viruses to evade NK cell immunity.

  17. The phylogenetic origins of natural killer receptors and recognition:relationships, possibilities and realities

    PubMed Central

    Yoder, Jeffrey A.; Litman, Gary W.

    2013-01-01

    Natural killer (NK) cells effect a form of innate immunity that recognizes and eliminates cells that are infected with certain viruses or have undergone malignant transformation. In mammals, this recognition can be mediated through immunoglobulin- (Ig) and/or lectin-type NK receptors (NKRs). NKR genes in mammals range from minimally polymorphic single copy genes to complex multigene families that exhibit high levels of haplotypic complexity and exhibit significant interspecific variation. Certain single copy NKR genes that are present in one mammal are present as expanded multi-gene families in other mammals. These observations highlight NKRs as one of the most rapidly evolving eukaryotic gene families and likely reflect the influence of pathogens, especially viruses, on their evolution. Although well characterized in human and mice, cytotoxic cells that are functionally similar to NK cells have been identified in species ranging from birds to reptiles, amphibians and fish. Although numerous receptors have been identified in non-mammalian vertebrates that share structural relationships with mammalian NKRs, functionally defining these lower vertebrate molecules as NKRs is confounded by methodological and interpretive complexities. Nevertheless, several lines of evidence suggest that NK-type function or its equivalent has sustained a long evolutionary history throughout vertebrate species. PMID:21191578

  18. Ezh2 regulates differentiation and function of natural killer cells through histone methyltransferase activity.

    PubMed

    Yin, Jie; Leavenworth, Jianmei W; Li, Yang; Luo, Qi; Xie, Huafeng; Liu, Xinhua; Huang, Shan; Yan, Han; Fu, Zheng; Zhang, Liyun Y; Zhang, Litao; Hao, Junwei; Wu, Xudong; Deng, Xianming; Roberts, Charles W M; Orkin, Stuart H; Cantor, Harvey; Wang, Xi

    2015-12-29

    Changes of histone modification status at critical lineage-specifying gene loci in multipotent precursors can influence cell fate commitment. The contribution of these epigenetic mechanisms to natural killer (NK) cell lineage determination from common lymphoid precursors is not understood. Here we investigate the impact of histone methylation repressive marks (H3 Lys27 trimethylation; H3K27(me3)) on early NK cell differentiation. We demonstrate that selective loss of the histone-lysine N-methyltransferase Ezh2 (enhancer of zeste homolog 2) or inhibition of its enzymatic activity with small molecules unexpectedly increased generation of the IL-15 receptor (IL-15R) CD122(+) NK precursors and mature NK progeny from both mouse and human hematopoietic stem and progenitor cells. Mechanistic studies revealed that enhanced NK cell expansion and cytotoxicity against tumor cells were associated with up-regulation of CD122 and the C-type lectin receptor NKG2D. Moreover, NKG2D deficiency diminished the positive effects of Ezh2 inhibitors on NK cell commitment. Identification of the contribution of Ezh2 to NK lineage specification and function reveals an epigenetic-based mechanism that regulates NK cell development and provides insight into the clinical application of Ezh2 inhibitors in NK-based cancer immunotherapies.

  19. Characterization of Natural Killer Cells and Cytokines in Maternal Placenta and Fetus of Diabetic Mothers.

    PubMed

    Hara, Cristiane de Castro Pernet; França, Eduardo Luzía; Fagundes, Danny Laura Gomes; de Queiroz, Adriele Ataides; Rudge, Marilza Vieira Cunha; Honorio-França, Adenilda Cristina; Calderon, Iracema de Mattos Paranhos

    2016-01-01

    The present study characterized natural killer cells and cytokines in diabetic mothers, their placenta, and fetus. In the maternal blood from the hyperglycemic groups, the CD16(+)CD56(-) NK cells increased, whereas that of CD16(+)CD56(+) decreased in gestational diabetes mellitus [GDM] group. Cord blood from type 2 diabetes [DM-2] showed a higher proportion of CD16(+)CD56(-) and CD16(-)CD56(+). The placental extravillous layer of GDM and DM-2 showed an increase of CD16(+)CD56(-) cells and, irrespective of region, the proportion of CD16(-)CD56(+) cells was higher in mild gestational hyperglycemia [MGH] and GDM and lower in DM-2. IL-2 was lower in maternal blood and IFN-γ higher in maternal and cord blood from the GDM group. IL-17 was higher in maternal and cord blood from the DM-2 group. The placental extravillous layer of the MGH showed high levels of IL-4, IL-6, IL-10, IL-17, and IFN-γ and low levels of IL-1β and IL-8, whereas the placental villous layer contained high levels of IL-17 and IFN-γ. The GDM group, irrespective of region, showed higher levels of IL-8. The DM-2 group, irrespective of region, placenta showed high levels of TNF-α, IL-17, and IFN-γ. The hyperglycemia produces an inflammatory environment with a high content of inflammatory cytokines and cells expressing CD16(+).

  20. Natural Killer cells: Multi-faceted players with key roles in Hepatitis C immunity

    PubMed Central

    Golden-Mason, Lucy; Rosen, Hugo R.

    2013-01-01

    Summary Natural killer cells (NKs) are involved in every stage of hepatitis C viral (HCV) infection, from protection against HCV acquisition and resolution in the acute phase to treatment-induced clearance. In addition to their direct antiviral actions, NKs are involved in the induction and priming of appropriate downstream T-cell responses. In the setting of chronic HCV, overall NK cell levels are decreased, altered subset distribution is altered, and changes in NK receptor (NKR) expression have been demonstrated, although the contribution of individual NKRs to viral clearance or persistence remains to be clarified. Enhanced NK cell cytotoxicity accompanied by insufficient interferon-γ production may promote liver damage in the setting of chronic infection. Treatment-induced clearance is associated with activation of NK cells, and it will be of interest to monitor NK cell responses to triple therapy. Activated NK cells also have antifibrotic properties, and the same hepatic NK cell populations that are actively involved in control of HCV may also be involved in control of HCV-associated liver damage. We still have much to learn, in particular: how do liver-derived NKs influence the outcome of HCV infection? Do NK receptors recognize HCV-specific components? And, are HCV-specific memory NK populations generated? PMID:23947348

  1. Social support, psychological distress, and natural killer cell activity in ovarian cancer.

    PubMed

    Lutgendorf, Susan K; Sood, Anil K; Anderson, Barrie; McGinn, Stephanie; Maiseri, Heena; Dao, Minh; Sorosky, Joel I; De Geest, Koen; Ritchie, Justine; Lubaroff, David M

    2005-10-01

    Psychosocial stress has been related to impaired immunity in cancer patients. However, the extent to which these relationships exist in immune cells in the tumor microenvironment in humans has not been explored. We examined relationships among distress, social support, and natural killer (NK) cell activity in ovarian cancer patients in peripheral-blood mononuclear cells (PBMC), ascitic fluid, and tumor-infiltrating lymphocytes (TIL). Patients awaiting surgery for a pelvic mass suspected of being ovarian cancer completed psychological questionnaires and gave a presurgical sample of peripheral blood. Samples of tumor and ascites were taken during surgery, lymphocytes were then isolated, and NK cytotoxicity and percentage were determined. The final sample, which was confirmed by surgical diagnosis, included 42 patients with epithelial ovarian cancer and 23 patients with benign masses. Peripheral NK cell activity was significantly lower among ovarian cancer patients than in patients with benign masses. Among ovarian cancer patients, NK cytotoxicity in TIL was significantly lower than in PBMC or ascitic fluid. Social support was related to higher NK cytotoxicity in PBMC and TIL, adjusting for stage. Distress was related to lower NK cytotoxicity in TIL. A multivariate model indicated independent associations of both distress and social support with NK cell activity in TIL. Psychosocial factors, such as social support and distress, are associated with changes in the cellular immune response, not only in peripheral blood, but also at the tumor level. These relationships were more robust in TIL. These findings support the presence of stress influences in the tumor microenvironment.

  2. Natural killer cell populations in Egyptians infected with hepatitis C virus.

    PubMed

    Rafik, M; Sidhom, G; Mamdouh, R; Ellebedy, D; Mohamed, M

    2012-09-01

    Natural killer (NK) cells are key players in the immune response to viruses. This study examined the effect of hepatitis C virus (HCV) on the frequency of NK cells and their subsets in individuals with different clinical outcomes; 20 positive for anti-HCV and HCV-RNA (chronic hepatitis C), 20 positive for anti-HCV but negative for HCV-RNA (spontaneously resolved) and 20 healthy controls free of HCV. There was a significant reduction in the frequency of total NK cells in the chronic group compared to the control (P = 0.001) or resolved (P = 0.01) groups. The percentage of CD56(bright) cells was significantly higher than the control group (P = 0.04). While the percentages of CD56 (dim) cells and their CD16 expression were lower in the chronic group, this was not statistically significant. The frequency of CD3+CD56- T cells was significantly lower in both the chronic and resolved groups compared to the control group (P = 0.04). Our results confirm a potential role of NK cells and the different subsets in the pathogenesis of chronic HCV infection.

  3. Cell cycle progression dictates the requirement for BCL2 in natural killer cell survival.

    PubMed

    Viant, Charlotte; Guia, Sophie; Hennessy, Robert J; Rautela, Jai; Pham, Kim; Bernat, Claire; Goh, Wilford; Jiao, Yuhao; Delconte, Rebecca; Roger, Michael; Simon, Vanina; Souza-Fonseca-Guimaraes, Fernando; Grabow, Stephanie; Belz, Gabrielle T; Kile, Benjamin T; Strasser, Andreas; Gray, Daniel; Hodgkin, Phillip D; Beutler, Bruce; Vivier, Eric; Ugolini, Sophie; Huntington, Nicholas D

    2017-02-01

    Natural killer (NK) cells are innate lymphoid cells with antitumor functions. Using an N-ethyl-N-nitrosourea (ENU)-induced mutagenesis screen in mice, we identified a strain with an NK cell deficiency caused by a hypomorphic mutation in the Bcl2 (B cell lymphoma 2) gene. Analysis of these mice and the conditional deletion of Bcl2 in NK cells revealed a nonredundant intrinsic requirement for BCL2 in NK cell survival. In these mice, NK cells in cycle were protected against apoptosis, and NK cell counts were restored in inflammatory conditions, suggesting a redundant role for BCL2 in proliferating NK cells. Consistent with this, cycling NK cells expressed higher MCL1 (myeloid cell leukemia 1) levels in both control and BCL2-null mice. Finally, we showed that deletion of BIM restored survival in BCL2-deficient but not MCL1-deficient NK cells. Overall, these data demonstrate an essential role for the binding of BCL2 to BIM in the survival of noncycling NK cells. They also favor a model in which MCL1 is the dominant survival protein in proliferating NK cells.

  4. Role of cortactin homolog HS1 in transendothelial migration of natural killer cells.

    PubMed

    Mukherjee, Suranjana; Kim, Joanna; Mooren, Olivia L; Shahan, Stefanie T; Cohan, Megan; Cooper, John A

    2015-01-01

    Natural Killer (NK) cells perform many functions that depend on actin assembly, including adhesion, chemotaxis, lytic synapse assembly and cytolysis. HS1, the hematopoietic homolog of cortactin, binds to Arp2/3 complex and promotes actin assembly by helping to form and stabilize actin filament branches. We investigated the role of HS1 in transendothelial migration (TEM) by NK cells. Depletion of HS1 led to a decrease in the efficiency of TEM by NK cells, as measured by transwell assays with endothelial cell monolayers on porous filters. Transwell assays involve chemotaxis of NK cells across the filter, so to examine TEM more specifically, we imaged live-cell preparations and antibody-stained fixed preparations, with and without the chemoattractant SDF-1α. We found small to moderate effects of HS1 depletion on TEM, including whether the NK cells migrated via the transcellular or paracellular route. Expression of HS1 mutants indicated that phosphorylation of HS1 tyrosines at positions 222, 378 and 397 was required for rescue in the transwell assay, but HS1 mutations affecting interaction with Arp2/3 complex or SH3-domain ligands had no effect. The GEF Vav1, a ligand of HS1 phosphotyrosine, influenced NK cell transendothelial migration. HS1 and Vav1 also affected the speed of NK cells migrating across the surface of the endothelium. We conclude that HS1 has a role in transendothelial migration of NK cells and that HS1 tyrosine phosphorylation may signal through Vav1.

  5. Optimal effector functions in human natural killer cells rely upon autocrine bone morphogenetic protein signaling.

    PubMed

    Robson, Neil C; Hidalgo, Laura; McAlpine, Tristan; Wei, Heng; Martínez, Víctor G; Entrena, Ana; Melen, Gustavo J; MacDonald, Andrew S; Phythian-Adams, Alexander; Sacedón, Rosa; Maraskovsky, Eugene; Cebon, Jonathan; Ramírez, Manuel; Vicente, Angeles; Varas, Alberto

    2014-09-15

    Natural killer (NK) cells are critical for innate tumor immunity due to their specialized ability to recognize and kill neoplastically transformed cells. However, NK cells require a specific set of cytokine-mediated signals to achieve optimal effector function. Th1-associated cytokines promote effector functions that are inhibited by the prototypic Th2 cytokine IL4 and the TGFβ superfamily members TGFβ1 and activin-A. Interestingly, the largest subgroup of the TGFβ superfamily are the bone morphogenetic proteins (BMP), but the effects of BMP signaling on NK cell effector functions have not been evaluated. Here, we demonstrate that blood-circulating NK cells express type I and II BMP receptors, BMP-2 and BMP-6 ligands, and phosphorylated isoforms of Smad-1/-5/-8, which mediate BMP family member signaling. In opposition to the inhibitory effects of TGFβ1 or activin-A, autocrine BMP signaling was supportive to NK cell function. Mechanistic investigations in cytokine and TLR-L-activated NK cells revealed that BMP signaling optimized IFNγ and global cytokine and chemokine production, phenotypic activation and proliferation, and autologous dendritic cell activation and target cytotoxicity. Collectively, our findings identify a novel auto-activatory pathway that is essential for optimal NK cell effector function, one that might be therapeutically manipulated to help eradicate tumors. Cancer Res; 74(18); 5019-31. ©2014 AACR.

  6. Natural Killer Cell Function and Dysfunction in Hepatitis C Virus Infection

    PubMed Central

    Holder, Kayla A.; Russell, Rodney S.; Grant, Michael D.

    2014-01-01

    Viruses must continually adapt against dynamic innate and adaptive responses of the host immune system to establish chronic infection. Only a small minority (~20%) of those exposed to hepatitis C virus (HCV) spontaneously clear infection, leaving approximately 200 million people worldwide chronically infected with HCV. A number of recent research studies suggest that establishment and maintenance of chronic HCV infection involve natural killer (NK) cell dysfunction. This relationship is illustrated in vitro by disruption of typical NK cell responses including both cell-mediated cytotoxicity and cytokine production. Expression of a number of activating NK cell receptors in vivo is also affected in chronic HCV infection. Thus, direct in vivo and in vitro evidence of compromised NK function in chronic HCV infection in conjunction with significant epidemiological associations between the outcome of HCV infection and certain combinations of NK cell regulatory receptor and class I human histocompatibility linked antigen (HLA) genotypes indicate that NK cells are important in the immune response against HCV infection. In this review, we highlight evidence suggesting that selective impairment of NK cell activity is related to establishment of chronic HCV infection. PMID:25057504

  7. Co-Activation of Cultured Human Natural Killer Cells: Enhanced Function and Decreased Inhibition.

    PubMed

    Urlaub, Doris; Bhat, Rauf; Messmer, Birgitta; Watzl, Carsten

    2016-01-01

    Natural killer (NK) cells are important immune effector cells that protect the organism against viral infections and cancer. The cytotoxic activity of NK cells is induced by the engagement of a number of different activating surface receptors and controlled by inhibitory receptors to ensure self-tolerance. Resting NK cells need to be co-activated by involvement of at least two distinct activating receptors in order to induce their functional activity. However, in cultured NK cells, which have been expanded in cytokines such as interleukin (IL)-2, the engagement of a single activating receptor may be sufficient to induce their function. Data demonstrated that also cultured NK cells may be co-activated by involvement of certain combinations of activating receptors. This co-activation results in enhanced activation of Vav-1 and ERK signaling pathways and produces greater degranulation. In addition to enhanced functionality, co-activation makes NK cells more resistant to the effect of inhibitory receptors, thereby inducing more potent and efficient NK cell responses.

  8. The effect of different anesthetics on tumor cytotoxicity by natural killer cells.

    PubMed

    Tazawa, Kazumasa; Koutsogiannaki, Sophia; Chamberlain, Matthew; Yuki, Koichi

    2017-01-15

    A number of retrospective studies have suggested that choice of anesthetic drugs during surgical tumor resection might affect tumor recurrence/metastasis, or outcome of patients. The recent study showed that volatile anesthetics-based general anesthesia was associated with the worse outcomes than intravenous anesthetics-based general anesthesia. However, the underlying mechanism is yet to be determined. Because natural killer (NK) cells are implicated as important immune cells for tumor recurrence/metastasis in the perioperative period, we examined the effect of different anesthetics on NK cell-mediated tumor cytotoxicity. Because adhesion molecule leukocyte function-associated antigen-1 (LFA-1) is functionally important in NK cells and is inhibited by commonly used volatile anesthetics isoflurane and sevoflurane, we hypothesized that these anesthetics would attenuate NK cell-mediated cytotoxicity. Using human NK cell line NK92-MI cells and tumor cell line K562 cells as a model system, we performed cytotoxicity, proliferation, conjugation and degranulation assays. Lytic granule polarization was also assessed. We showed that isoflurane, sevoflurane and LFA-1 inhibitor BIRT377 attenuated cytotoxicity, and reduced conjugation and polarization, but not degranulation of NK cells. Our data suggest that isoflurane and sevoflurane attenuated NK cell-mediated cytotoxicity at least partly by their LFA-1 inhibition in vitro. Whether or not isoflurane and sevoflurane attenuate NK cell-mediated tumor cytotoxicity in patients needs to be determined in the future. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  9. Therapeutic Potential and Challenges of Natural Killer Cells in Treatment of Solid Tumors

    PubMed Central

    Gras Navarro, Andrea; Björklund, Andreas T.; Chekenya, Martha

    2015-01-01

    Natural killer (NK) cells are innate lymphoid cells that hold tremendous potential for effective immunotherapy for a broad range of cancers. Due to the mode of NK cell killing, requiring one-to-one target engagement and site-directed release of cytolytic granules, the therapeutic potential of NK cells has been most extensively explored in hematological malignancies. However, their ability to precisely kill antibody coated cells, cancer stem cells, and genotoxically altered cells, while maintaining tolerance to healthy cells makes them appealing therapeutic effectors for all cancer forms, including metastases. Due to their release of pro-inflammatory cytokines, NK cells may potently reverse the anti-inflammatory tumor microenvironment (TME) and augment adaptive immune responses by promoting differentiation, activation, and/or recruitment of accessory immune cells to sites of malignancy. Nevertheless, integrated and coordinated mechanisms of subversion of NK cell activity against the tumor and its microenvironment exist. Although our understanding of the receptor ligand interactions that regulate NK cell functionality has evolved remarkably, the diversity of ligands and receptors is complex, as is their mechanistic foundations in regulating NK cell function. In this article, we review the literature and highlight how the TME manipulates the NK cell phenotypes, genotypes, and tropism to evade tumor recognition and elimination. We discuss counter strategies that may be adopted to augment the efficacy of NK cell anti-tumor surveillance, the clinical trials that have been undertaken so far in solid malignancies, critically weighing the challenges and opportunities with this approach. PMID:25972872

  10. Nfil3-independent lineage maintenance and antiviral response of natural killer cells.

    PubMed

    Firth, Matthew A; Madera, Sharline; Beaulieu, Aimee M; Gasteiger, Georg; Castillo, Eliseo F; Schluns, Kimberly S; Kubo, Masato; Rothman, Paul B; Vivier, Eric; Sun, Joseph C

    2013-12-16

    Development of the natural killer (NK) cell lineage is dependent on the transcription factor Nfil3 (or E4BP4), which is thought to act downstream of IL-15 signaling. Nfil3-deficient mice lack NK cells, whereas other lymphocyte lineages (B, T, and NKT cells) remain largely intact. We report the appearance of Ly49H-expressing NK cells in Nfil3(-/-) mice infected with mouse cytomegalovirus (MCMV) or recombinant viruses expressing the viral m157 glycoprotein. Nfil3(-/-) NK cells at the peak of antigen-driven expansion were functionally similar to NK cells from infected wild-type mice with respect to IFN-γ production and cytotoxicity, and could comparably produce long-lived memory NK cells that persisted in lymphoid and nonlymphoid tissues for >60 d. We demonstrate that generation and maintenance of NK cell memory is an Nfil3-independent but IL-15-dependent process. Furthermore, specific ablation of Nfil3 in either immature NK cells in the bone marrow or mature peripheral NK cells had no observable effect on NK cell lineage maintenance or homeostasis. Thus, expression of Nfil3 is crucial only early in the development of NK cells, and signals through activating receptors and proinflammatory cytokines during viral infection can bypass the requirement for Nfil3, promoting the proliferation and long-term survival of virus-specific NK cells.

  11. Nfil3-independent lineage maintenance and antiviral response of natural killer cells

    PubMed Central

    Firth, Matthew A.; Madera, Sharline; Beaulieu, Aimee M.; Gasteiger, Georg; Castillo, Eliseo F.; Schluns, Kimberly S.; Kubo, Masato; Rothman, Paul B.; Vivier, Eric

    2013-01-01

    Development of the natural killer (NK) cell lineage is dependent on the transcription factor Nfil3 (or E4BP4), which is thought to act downstream of IL-15 signaling. Nfil3-deficient mice lack NK cells, whereas other lymphocyte lineages (B, T, and NKT cells) remain largely intact. We report the appearance of Ly49H-expressing NK cells in Nfil3−/− mice infected with mouse cytomegalovirus (MCMV) or recombinant viruses expressing the viral m157 glycoprotein. Nfil3−/− NK cells at the peak of antigen-driven expansion were functionally similar to NK cells from infected wild-type mice with respect to IFN-γ production and cytotoxicity, and could comparably produce long-lived memory NK cells that persisted in lymphoid and nonlymphoid tissues for >60 d. We demonstrate that generation and maintenance of NK cell memory is an Nfil3-independent but IL-15–dependent process. Furthermore, specific ablation of Nfil3 in either immature NK cells in the bone marrow or mature peripheral NK cells had no observable effect on NK cell lineage maintenance or homeostasis. Thus, expression of Nfil3 is crucial only early in the development of NK cells, and signals through activating receptors and proinflammatory cytokines during viral infection can bypass the requirement for Nfil3, promoting the proliferation and long-term survival of virus-specific NK cells. PMID:24277151

  12. The Transcription Factors T-bet and Eomes Control Key Checkpoints of Natural Killer Cell Maturation

    PubMed Central

    Gordon, Scott M.; Chaix, Julie; Rupp, Levi J.; Wu, Junmin; Madera, Sharline; Sun, Joseph C.; Lindsten, Tullia; Reiner, Steven L.

    2012-01-01

    Summary Natural killer (NK) cells play critical roles defending against tumors and pathogens. We show that mice lacking both transcription factors Eomesodermin (Eomes) and T-bet failed to develop NK cells. Developmental stability of immature NK cells constitutively expressing the death ligand TRAIL depended on T-bet. Conversely, maturation characterized by loss of constitutive TRAIL expression and induction of Ly49 receptor diversity and integrin CD49b (DX5+) required Eomes. Mature NK cells from which Eomes was deleted reverted to phenotypic immaturity if T-bet was present or downregulated NK lineage antigens if T-bet was absent, despite retaining expression of Ly49 receptors. Adult, hepatic and fetal hematopoiesis restricted Eomes expression and limited NK development to the T-bet-dependent, immature stage, whereas medullary hematopoiesis permitted Eomes-dependent NK maturation in adult mice. These findings reveal two sequential, genetically separable checkpoints of NK cell maturation, the progression of which is metered largely by the anatomic localization of hematopoiesis. PMID:22261438

  13. The transcription factors T-bet and Eomes control key checkpoints of natural killer cell maturation.

    PubMed

    Gordon, Scott M; Chaix, Julie; Rupp, Levi J; Wu, Junmin; Madera, Sharline; Sun, Joseph C; Lindsten, Tullia; Reiner, Steven L

    2012-01-27

    Natural killer (NK) cells play critical roles defending against tumors and pathogens. We show that mice lacking both transcription factors Eomesodermin (Eomes) and T-bet failed to develop NK cells. Developmental stability of immature NK cells constitutively expressing the death ligand TRAIL depended on T-bet. Conversely, maturation characterized by loss of constitutive TRAIL expression and induction of Ly49 receptor diversity and integrin CD49b (DX5(+)) required Eomes. Mature NK cells from which Eomes was deleted reverted to phenotypic immaturity if T-bet was present or downregulated NK lineage antigens if T-bet was absent, despite retaining expression of Ly49 receptors. Fetal and adult hepatic hematopoiesis restricted Eomes expression and limited NK development to the T-bet-dependent, immature stage, whereas medullary hematopoiesis permitted Eomes-dependent NK maturation in adult mice. These findings reveal two sequential, genetically separable checkpoints of NK cell maturation, the progression of which is metered largely by the anatomic localization of hematopoiesis. Copyright © 2012 Elsevier Inc. All rights reserved.

  14. Proinflammatory cytokine signaling required for the generation of natural killer cell memory

    PubMed Central

    Sun, Joseph C.; Madera, Sharline; Bezman, Natalie A.; Beilke, Joshua N.; Kaplan, Mark H.

    2012-01-01

    Although natural killer (NK) cells are classified as innate immune cells, recent studies demonstrate that NK cells can become long-lived memory cells and contribute to secondary immune responses. The precise signals that promote generation of long-lived memory NK cells are unknown. Using cytokine receptor-deficient mice, we show that interleukin-12 (IL-12) is indispensible for mouse cytomegalovirus (MCMV)-specific NK cell expansion and generation of memory NK cells. In contrast to wild-type NK cells that proliferated robustly and resided in lymphoid and nonlymphoid tissues for months after MCMV infection, IL-12 receptor–deficient NK cells failed to expand and were unable to mediate protection after MCMV challenge. We further demonstrate that a STAT4-dependent IFN-γ–independent mechanism contributes toward the generation of memory NK cells during MCMV infection. Understanding the full contribution of inflammatory cytokine signaling to the NK cell response against viral infection will be of interest for the development of vaccines and therapeutics. PMID:22493516

  15. Proinflammatory cytokine signaling required for the generation of natural killer cell memory.

    PubMed

    Sun, Joseph C; Madera, Sharline; Bezman, Natalie A; Beilke, Joshua N; Kaplan, Mark H; Lanier, Lewis L

    2012-05-07

    Although natural killer (NK) cells are classified as innate immune cells, recent studies demonstrate that NK cells can become long-lived memory cells and contribute to secondary immune responses. The precise signals that promote generation of long-lived memory NK cells are unknown. Using cytokine receptor-deficient mice, we show that interleukin-12 (IL-12) is indispensible for mouse cytomegalovirus (MCMV)-specific NK cell expansion and generation of memory NK cells. In contrast to wild-type NK cells that proliferated robustly and resided in lymphoid and nonlymphoid tissues for months after MCMV infection, IL-12 receptor-deficient NK cells failed to expand and were unable to mediate protection after MCMV challenge. We further demonstrate that a STAT4-dependent IFN-γ-independent mechanism contributes toward the generation of memory NK cells during MCMV infection. Understanding the full contribution of inflammatory cytokine signaling to the NK cell response against viral infection will be of interest for the development of vaccines and therapeutics.

  16. Natural killer cells and HLA-G expression in the basal decidua of human placenta adhesiva.

    PubMed

    van Beekhuizen, H J; Joosten, I; Lotgering, F K; Bulten, J; van Kempen, L C

    2010-12-01

    Retained placenta is caused by abnormal adherence of the placenta to the uterine wall, leading to delayed expulsion of the placenta and causing postpartum haemorrhage. The mildest form of retained placenta is the placenta adhesiva (PA), of which the cause is unknown. The aim of our study was to explore possible differences in immune response in the basal decidua between PA and control placentas (CP). We performed a descriptive analysis of immunohistochemical differences in 17 PA and 10 CP. Our results show that in PA the amount of uterine natural killer (uNK) cells is significantly reduced (0.2 uNK cell/standardised area) as compared to CP (9.8 uNK cell/standardised area, p < 0.001) whereas the number of trophoblast cells and the expression of HLA-G by trophoblast are similar in the decidua of PA and CP. We speculate that adequate numbers of uNK cells in the basal decidua are needed for normal expulsion of the placenta.

  17. Targeting natural killer cell reactivity by employing antibody to NKp46: implications for type 1 diabetes.

    PubMed

    Yossef, Rami; Gur, Chamutal; Shemesh, Avishai; Guttman, Ofer; Hadad, Uzi; Nedvetzki, Shlomo; Miletić, Antonija; Nalbandyan, Karen; Cerwenka, Adelheid; Jonjic, Stipan; Mandelboim, Ofer; Porgador, Angel

    2015-01-01

    Natural killer (NK) cells belong to the innate lymphoid cells. Their cytotoxic activity is regulated by the delicate balance between activating and inhibitory signals. NKp46 is a member of the primary activating receptors of NK cells. We previously reported that the NKp46 receptor is involved in the development of type 1 diabetes (T1D). Subsequently, we hypothesized that blocking this receptor could prevent or hinder disease development. To address this goal, we developed monoclonal antibodies for murine NKp46. One mAb, named NCR1.15, recognizes the mouse homologue protein of NKp46, named Ncr1, and was able to down-regulate the surface expression of NKp46 on primary murine NK cells following antibody injection in vivo. Additionally, NCR1.15 treatments were able to down-regulate cytotoxic activity mediated by NKp46, but not by other NK receptors. To test our primary assumption, we examined T1D development in two models, non-obese diabetic mice and low-dose streptozotocin. Our results show a significantly lower incidence of diabetic mice in the NCR1.15-treated group compared to control groups. This study directly demonstrates the involvement of NKp46 in T1D development and suggests a novel treatment strategy for early insulitis.

  18. HIV Latency-Reversing Agents Have Diverse Effects on Natural Killer Cell Function

    PubMed Central

    Garrido, Carolina; Spivak, Adam M.; Soriano-Sarabia, Natalia; Checkley, Mary Ann; Barker, Edward; Karn, Jonathan; Planelles, Vicente; Margolis, David M.

    2016-01-01

    In an effort to clear persistent HIV infection and achieve a durable therapy-free remission of HIV disease, extensive pre-clinical studies and early pilot clinical trials are underway to develop and test agents that can reverse latent HIV infection and present viral antigen to the immune system for clearance. It is, therefore, critical to understand the impact of latency-reversing agents (LRAs) on the function of immune effectors needed to clear infected cells. We assessed the impact of LRAs on the function of natural killer (NK) cells, the main effector cells of the innate immune system. We studied the effects of three histone deacetylase inhibitors [SAHA or vorinostat (VOR), romidepsin, and panobinostat (PNB)] and two protein kinase C agonists [prostratin (PROST) and ingenol] on the antiviral activity, cytotoxicity, cytokine secretion, phenotype, and viability of primary NK cells. We found that ex vivo exposure to VOR had minimal impact on all parameters assessed, while PNB caused a decrease in NK cell viability, antiviral activity, and cytotoxicity. PROST caused non-specific NK cell activation and, interestingly, improved antiviral activity. Overall, we found that LRAs can alter the function and fate of NK cells, and these effects must be carefully considered as strategies are developed to clear persistent HIV infection. PMID:27708642

  19. CD20-Positive nodal natural killer/T-cell lymphoma with cutaneous involvement.

    PubMed

    Tsai, Yi-Chiun; Chen, Chi-Kuan; Wu, Yu-Hung

    2015-09-01

    CD20-positive natural killer (NK)/T-cell lymphoma is extremely rare. We describe a case of a CD20-positive nodal NK/T-cell lymphoma with cutaneous involvement in a 32-year-old man. The patient presented with fever, night sweats, right inguinal lymphadenopathy and multiple violaceous to erythematous nodules and plaques on the back and bilateral legs. Immunohistochemical analysis showed diffusely and strongly positive staining for CD3, CD3 epsilon, CD43, CD56, TIA-1 and CD20 but negative staining for other B-cell markers, including CD79a and PAX-5 and T-cell markers CD5 and CD7. The tumor cell nuclei were diffusely positive for Epstein-Barr virus-encoded RNA in situ hybridization. A partial clinical response was observed after chemotherapy, indicated by the decreased size of the lymph nodes and skin lesions. It is a diagnostic challenge to deal with lymphoma cells that present with the surface proteins of both T- and B-cells.

  20. Adipose Natural Killer Cells Regulate Adipose Tissue Macrophages to Promote Insulin Resistance in Obesity.

    PubMed

    Lee, Byung-Cheol; Kim, Myung-Sunny; Pae, Munkyong; Yamamoto, Yasuhiko; Eberlé, Delphine; Shimada, Takeshi; Kamei, Nozomu; Park, Hee-Sook; Sasorith, Souphatta; Woo, Ju Rang; You, Jia; Mosher, William; Brady, Hugh J M; Shoelson, Steven E; Lee, Jongsoon

    2016-04-12

    Obesity-induced inflammation mediated by immune cells in adipose tissue appears to participate in the pathogenesis of insulin resistance. We show that natural killer (NK) cells in adipose tissue play an important role. High-fat diet (HFD) increases NK cell numbers and the production of proinflammatory cytokines, notably TNFα, in epididymal, but not subcutaneous, fat depots. When NK cells were depleted either with neutralizing antibodies or genetic ablation in E4bp4(+/-) mice, obesity-induced insulin resistance improved in parallel with decreases in both adipose tissue macrophage (ATM) numbers, and ATM and adipose tissue inflammation. Conversely, expansion of NK cells following IL-15 administration or reconstitution of NK cells into E4bp4(-/-) mice increased both ATM numbers and adipose tissue inflammation and exacerbated HFD-induced insulin resistance. These results indicate that adipose NK cells control ATMs as an upstream regulator potentially by producing proinflammatory mediators, including TNFα, and thereby contribute to the development of obesity-induced insulin resistance. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Natural killer cells: multifaceted players with key roles in hepatitis C immunity.

    PubMed

    Golden-Mason, Lucy; Rosen, Hugo R

    2013-09-01

    Natural killer cells (NKs) are involved in every stage of hepatitis C viral (HCV) infection, from protection against HCV acquisition and resolution in the acute phase to treatment-induced clearance. In addition to their direct antiviral actions, NKs are involved in the induction and priming of appropriate downstream T-cell responses. In the setting of chronic HCV, overall NK cell levels are decreased, subset distribution is altered, and changes in NK receptor (NKR) expression have been demonstrated, although the contribution of individual NKRs to viral clearance or persistence remains to be clarified. Enhanced NK cell cytotoxicity accompanied by insufficient interferon-γ production may promote liver damage in the setting of chronic infection. Treatment-induced clearance is associated with activation of NK cells, and it will be of interest to monitor NK cell responses to triple therapy. Activated NK cells also have anti-fibrotic properties, and the same hepatic NK cell populations that are actively involved in control of HCV may also be involved in control of HCV-associated liver damage. We still have much to learn, in particular: how do liver-derived NKs influence the outcome of HCV infection? Do NK receptors recognize HCV-specific components? And, are HCV-specific memory NK populations generated? © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. Natural killer cells and malignant haemopathies: a model for the interaction of cancer with innate immunity.

    PubMed

    Sanchez, C J; Le Treut, T; Boehrer, A; Knoblauch, B; Imbert, J; Olive, D; Costello, R T

    2011-01-01

    Despite recent progress in the therapeutic approach of malignant haemopathies, their prognoses remain frequently poor. Immunotherapy offers an alternative of great interest in this context but defect or abnormal expression of human leukocyte antigens (HLA), frequently observed in cancer cells, limits its efficiency. Natural killer (NK) cells, which are able to kill target cells in a HLA-independent way, represent a novel tool in the treatment of haematological malignancies. Abnormal NK cytolytic function is observed in all the haematological malignancies studied, such as acute leukaemia, myelodysplastic syndromes or chronic myeloid/lymphoid leukaemia. Several mechanisms are involved in the alterations of NK cytotoxicity: decreased expression of activating receptors, increased expression of inhibitory receptors or defective expression of NK ligands on target cells. Further studies are needed to identify how each type of haematological malignancy escapes from the innate immune response. Attempts to increase the expression of activating receptors, to counteract inhibitory receptors expression, or to increase NK cell cytotoxic capacities could overcome tumour escape from innate immunity. These therapies are based on monoclonal antibodies or culture of NK cells in presence of cytokines or dendritic cells. Moreover, many novel drugs used in haematological malignancies [tyrosine kinase inhibitors, IMIDs(®), proteasome inhibitors, demethylating agents, histone deacetylase inhibitors (HDACis), histamine dihydrochloride] display interesting immunomodulatory properties that affect NK cells. These data suggest that combined modalities associating cytotoxic drugs with innate immunity modulators may represent a major breakthrough in tumour eradication.

  3. Invariant natural killer T cells: boon or bane in immunity to intracellular bacterial infections?

    PubMed

    Shekhar, Sudhanshu; Joyee, Antony George; Yang, Xi

    2014-01-01

    Invariant natural killer T (iNKT) cells represent a specialized subset of innate lymphocytes that recognize lipid and glycolipid antigens presented to them by nonclassical MHC-I CD1d molecules and are able to rapidly secrete copious amounts of a variety of cytokines. iNKT cells possess the ability to modulate innate as well as adaptive immune responses against various pathogens. Intracellular bacteria are one of the most clinically significant human pathogens that effectively evade the immune system and cause a myriad of diseases of public health concern globally. Emerging evidence suggests that iNKT cells can confer immunity to intracellular bacteria but also inflict pathology in certain cases. We summarize the current knowledge on the contribution of iNKT cells in the host defense against intracellular bacterial infections, with a focus on the underlying mechanisms by which these cells induce protective or pathogenic reactions including the pathways of direct action (acting on infected cells) and indirect action (modulating dendritic, NK and T cells). The rational exploitation of iNKT cells for prophylactic and therapeutic purposes awaits a profound understanding of their functional biology.

  4. Generation of cellular immune memory and B-cell immunity is impaired by natural killer cells.

    PubMed

    Rydyznski, Carolyn; Daniels, Keith A; Karmele, Erik P; Brooks, Taylor R; Mahl, Sarah E; Moran, Michael T; Li, Caimei; Sutiwisesak, Rujapak; Welsh, Raymond M; Waggoner, Stephen N

    2015-02-27

    The goal of most vaccines is the induction of long-lived memory T and B cells capable of protecting the host from infection by cytotoxic mechanisms, cytokines and high-affinity antibodies. However, efforts to develop vaccines against major human pathogens such as HIV and HCV have not been successful, thereby highlighting the need for novel approaches to circumvent immunoregulatory mechanisms that limit the induction of protective immunity. Here, we show that mouse natural killer (NK) cells inhibit generation of long-lived virus-specific memory T- and B cells as well as virus-specific antibody production after acute infection. Mechanistically, NK cells suppressed CD4 T cells and follicular helper T cells (T(FH)) in a perforin-dependent manner during the first few days of infection, resulting in a weaker germinal centre (GC) response and diminished immune memory. We anticipate that innovative strategies to relieve NK cell-mediated suppression of immunity should facilitate development of efficacious new vaccines targeting difficult-to-prevent infections.

  5. A Viral Immunoevasin Controls Innate Immunity by Targeting the Prototypical Natural Killer Cell Receptor Family.

    PubMed

    Aguilar, Oscar A; Berry, Richard; Rahim, Mir Munir A; Reichel, Johanna J; Popović, Branka; Tanaka, Miho; Fu, Zhihui; Balaji, Gautham R; Lau, Timothy N H; Tu, Megan M; Kirkham, Christina L; Mahmoud, Ahmad Bakur; Mesci, Aruz; Krmpotić, Astrid; Allan, David S J; Makrigiannis, Andrew P; Jonjić, Stipan; Rossjohn, Jamie; Carlyle, James R

    2017-03-23

    Natural killer (NK) cells play a key role in innate immunity by detecting alterations in self and non-self ligands via paired NK cell receptors (NKRs). Despite identification of numerous NKR-ligand interactions, physiological ligands for the prototypical NK1.1 orphan receptor remain elusive. Here, we identify a viral ligand for the inhibitory and activating NKR-P1 (NK1.1) receptors. This murine cytomegalovirus (MCMV)-encoded protein, m12, restrains NK cell effector function by directly engaging the inhibitory NKR-P1B receptor. However, m12 also interacts with the activating NKR-P1A/C receptors to counterbalance m12 decoy function. Structural analyses reveal that m12 sequesters a large NKR-P1 surface area via a "polar claw" mechanism. Polymorphisms in, and ablation of, the viral m12 protein and host NKR-P1B/C alleles impact NK cell responses in vivo. Thus, we identify the long-sought foreign ligand for this key immunoregulatory NKR family and reveal how it controls the evolutionary balance of immune recognition during host-pathogen interplay. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Decreased TIM-3 expression of peripheral blood natural killer cells in patients with severe aplastic anemia.

    PubMed

    Zhang, Tian; Yuan, Xin; Liu, Chunyan; Li, Yi; Liu, Hui; Li, Lijuan; Ding, Kai; Wang, Ting; Wang, Honglei; Shao, Zonghong; Fu, Rong

    2017-08-01

    Severe aplastic anemia (SAA) is an autoimmune disease characterized by severe pancytopenia and bone marrow failure. In our previous studies, we found natural killer (NK) cells were aberrant in SAA patients. T cell immunoglobulin mucin-3 (TIM-3), an important regulator of immunity, is widely detected on NK cells and may contribute as a marker of activation and maturation of NK cells. In this study, we found that SAA untreated patients had lower TIM-3 expression on NK cells and CD56(dim) NK subsets compared with normal controls, and were correlated with the severity of pancytopenia of SAA. After immunosuppressive therapy (IST), TIM-3 expression recovered to normal level. Moreover, the TIM-3 mRNA levels in NK cells significantly increased in SAA remission patients after IST. We inferred that low expression of TIM-3 on NK cells might lead to NK cells dysfunction and involve in the progress of bone marrow failure in SAA. Copyright © 2017. Published by Elsevier Inc.

  7. Natural killer cell deficiencies in a consecutive series of children with herpetic encephalitis.

    PubMed

    Almerigogna, F; Fassio, F; Giudizi, M G; Biagiotti, R; Manuelli, C; Chiappini, E; Galli, L; Romagnani, S; De Martino, M

    2011-01-01

    Natural killer (NK) cells play a fundamental role in innate and early phases of adaptive immunity against viral infections, both in humans and in animal models. To date, NK cell deficiencies in patients with severe herpetic infections have been reported in single cases, and their role as predisposing factor is still controversial. Five children affected by herpetic encephalitis were consecutively admitted to the Anna Meyer Children's Hospital in Florence (Italy) between 2003 and 2005. We therefore investigated the presence of NK cell deficiencies in a consecutive series of children with herpetic encephalitis. Five healthy children were included in the study as controls. Differential WBC counts, main Ig and IgE class serum analysis, cytofluorimetric analysis of circulating T, B and NK cells were performed on our study population. Sequencing of a selected region of CD16A gene transcript was carried out in two patients. All patients resulted to be affected by deficiencies related to NK cells in respect to controls. One patient was also affected by lymphopenia, while no other significant deficits of immunity were detected in the study population. To date, this is the first survey that demonstrates isolated NK cell deficiencies in a cohort of consecutive patients affected by severe herpes simplex infections. These findings suggest a role for NK cell deficiencies as a predisposing factor for increased susceptibility and severe course of disease in these patients.

  8. Prognostic significance of peripheral monocyte count in patients with extranodal natural killer/T-cell lymphoma

    PubMed Central

    2013-01-01

    Background Extranodal natural killer/T-cell lymphoma (ENKL) has heterogeneous clinical manifestations and prognosis. This study aims to evaluate the prognostic impact of absolute monocyte count (AMC) in ENKL, and provide some immunologically relevant information for better risk stratification in patients with ENKL. Methods Retrospective data from 163 patients newly diagnosed with ENKL were analyzed. The absolute monocyte count (AMC) at diagnosis was analyzed as continuous and dichotomized variables. Independent prognostic factors of survival were determined by Cox regression analysis. Results The AMC at diagnosis were related to overall survival (OS) and progression-free survival (PFS) in patients with ENKL. Multivariate analysis identified AMC as independent prognostic factors of survival, independent of International Prognostic Index (IPI) and Korean prognostic index (KPI). The prognostic index incorporating AMC and absolute lymphocyte count (ALC), another surrogate factor of immune status, could be used to stratify all 163 patients with ENKL into different prognostic groups. For patients who received chemotherapy followed by radiotherapy (102 cases), the three AMC/ALC index categories identified patients with significantly different survivals. When superimposed on IPI or KPI categories, the AMC/ALC index was better able to identify high-risk patients in the low-risk IPI or KPI category. Conclusion The baseline peripheral monocyte count is shown to be an effective prognostic indicator of survival in ENKL patients. The prognostic index related to tumor microenvironment might be helpful to identify high-risk patients with ENKL. PMID:23638998

  9. Interleukin-12- and interferon-gamma-mediated natural killer cell activation by Agaricus blazei Murill.

    PubMed

    Yuminamochi, Eri; Koike, Taisuke; Takeda, Kazuyoshi; Horiuchi, Isao; Okumura, Ko

    2007-06-01

    Dried fruiting bodies of Agaricus blazei Murill (A. blazei) and its extracts have generally used as complementary and alternative medicines (CAMs). Here, we report that the oral administration of A. blazei augmented cytotoxicity of natural killer (NK) cells in wild-type (WT) C57BL/6, C3H/HeJ, and BALB/c mice. Augmented cytotoxicity was demonstrated by purified NK cells from treated wild-type (WT) and RAG-2-deficient mice, but not from interferon-gamma (IFN-gamma) deficient mice. NK cell activation and IFN-gamma production was also observed in vitro when dendritic cell (DC)-rich splenocytes of WT mice were coincubation with an extract of A. blazei. Both parameters were largely inhibited by neutralizing anti-interleukin-12 (IL-12) monoclonal antibody (mAb) and completely inhibited when anti-IL-12 mAb and anti-IL-18 mAb were used in combination. An aqueous extract of the hemicellulase-digested compound of A. blazei particle; (ABPC) induced IFN-gamma production more effectively, and this was completely inhibited by anti-IL-12 mAb alone. NK cell cytotoxicty was augmented with the same extracts, again in an IL-12 and IFN-gamma-dependent manner. These results clearly demonstrated that A. blazei and ABPC augmented NK cell activation through IL-12-mediated IFN-gamma production.

  10. Interferon-γ-Mediated Natural Killer Cell Activation by an Aqueous Panax ginseng Extract

    PubMed Central

    Takeda, Kazuyoshi; Okumura, Ko

    2015-01-01

    Panax ginseng extracts are used in traditional herbal medicines, particularly in eastern Asia, but their effect on natural killer (NK) cell activity is not completely understood. This study aimed to examine the effects of P. ginseng extracts on the cytotoxic activity of NK cells. We orally administered P. ginseng extracts or ginsenosides to wild-type (WT) C57BL/6 (B6) and BALB/c mice and to B6 mice deficient in either recombination activating gene 2 (RAG-2) or interferon-γ (IFN-γ). We then tested the cytotoxic activity of NK cells (of spleen and liver mononuclear cells) against NK-sensitive YAC-1 cells. Oral administration of P. ginseng aqueous extract augmented the cytotoxicity of NK cells in WT B6 and BALB/c mice and in RAG-2-deficient B6 mice, but not in IFN-γ-deficient B6 mice. This effect was only observed with the aqueous extract of P. ginseng. Interestingly, the ginsenosides Rb1 and Rg1 did not augment NK cell cytotoxicity. These results demonstrated that the aqueous P. ginseng extract augmented NK cell activation in vivo via an IFN-γ-dependent pathway. PMID:26649061

  11. Natural killer T cell defects in multiple myeloma and the impact of lenalidomide therapy

    PubMed Central

    Chan, A C; Neeson, P; Leeansyah, E; Tainton, K; Quach, H; Prince, H M; Harrison, S J; Godfrey, D I; Ritchie, D; Berzins, S P

    2014-01-01

    The causes of multiple myeloma (MM) remain obscure and there are few known risk factors; however, natural killer T (NKT) cell abnormalities have been reported in patients with MM, and therapeutic targeting of NKT cells is promoted as a potential treatment. We characterized NKT cell defects in treated and untreated patients with MM and determined the impact of lenalidomide therapy on the NKT cell pool. Lenalidomide is an immunomodulatory drug with co-stimulatory effects on NKT cells in vitro and is an approved treatment for MM, although its mode of action in that context is not well defined. We find that patients with relapsed/progressive MM had a marked deficiency in NKT cell numbers. In contrast, newly diagnosed patients had relatively normal NKT cell frequency and function prior to treatment, although a specific NKT cell deficiency emerged after high-dose melphalan and autologous stem cell transplantation (ASCT) regimen. This also impacted NK cells and conventional T cells, but the recovery of NKT cells was considerably delayed, resulting in a prolonged, treatment-induced NKT cell deficit. Longitudinal analysis of individual patients revealed that lenalidomide therapy had no in-vivo impact on NKT cell numbers or cytokine production, either as induction therapy, or as maintenance therapy following ASCT, indicating that its clinical benefits in this setting are independent of NKT cell modulation. PMID:24032527

  12. Primary natural killer/T cell lymphoma of the cervix: case report and clinicopathological analysis.

    PubMed

    Wang, Guan-Nan; Zhao, Wu-Gan; Gao, Xian-Zheng; Zhang, Dan-Dan; Wang, Guan-Jun; Li, Wen-Cai

    2015-02-01

    To present pathological and molecular characterizations of a rare case that was diagnosed as nasal-type natural killer (NK)/T cell lymphoma primarily arising in the cervix. An Asian woman was admitted to hospital with a hysteromyoma, and laparotomy was performed. A large tumor of the uterus was found, which was limited to the cervix. Pathological examination showed NK/T cell lymphoma, which was supported by histological and immunohistochemical studies and was confirmed by evidence of Epstein-Barr virus infection. Less commonly, this case concerned a cytotoxic T cell phenotype, as molecular studies showed evidence of a clonal T cell receptor γ chain gene rearrangement. Microscopically, prominent and extensive necrosis was the distinctive feature of this case, which reminded us of considering it as a tumor. Primary NK/T lymphoma of the cervix is rare. Our experience in this case provided variable information on both pathological and molecular studies. This case may be of value in the differential diagnosis of lymphoid lesions and other small cell tumors of the cervix. Copyright © 2014. Published by Elsevier B.V.

  13. Post-transplantation lymphoproliferative disease of natural killer cell lineage: a clinicopathological and molecular analysis.

    PubMed

    Kwong, Y L; Lam, C C; Chan, T M

    2000-07-01

    Post-transplantation lymphoproliferative disorders (PTLD) occur after solid organ and bone marrow transplantation. They are predominantly of B-cell and occasionally of T-cell lineage. We report a case of PTLD of natural killer (NK) cell lineage. A renal allograft recipient developed progressive pancytopenia 1 year after transplantation. Serial bone marrow biopsies showed an increasing infiltration by large granular lymphoid cells. A subsequent leukaemic phase also developed with systemic infiltration of other organs. Immunophenotyping showed that these cells were CD2+, CD3-, CD3epsilon+, CD56+, CD94+, CD158a- and CD158b-. In situ hybridization showed Epstein-Barr virus (EBV) infection of the neoplastic cells. Genotypical analysis showed the T-cell receptor gene in germline configuration and clonal EBV episomal integration. The overall features were consistent with NK cell lymphoma/leukaemia. The patient did not respond to cessation of immunosuppression or anti-EBV treatment. Combination chemotherapy was given, but the patient died ultimately of disseminated fungal infection. In conclusion, we have demonstrated that NK cell lymphoma is another rare type of PTLD that appears to be highly aggressive and therefore may require early chemotherapy to improve treatment outcome.

  14. Serious foetal growth restriction is associated with reduced proportions of natural killer cells in decidua basalis.

    PubMed

    Eide, Irina P; Rolfseng, Toril; Isaksen, Christina V; Mecsei, Reidun; Roald, Borghild; Lydersen, Stian; Salvesen, Kjell A; Harsem, Nina K; Austgulen, Rigmor

    2006-03-01

    Extravillous trophoblasts are major participants in placental development and remodelling of spiral arteries. Trophoblast invasion is regulated by maternal immune cells, and abnormal leucocyte subpopulation composition has been reported in implantation failure. In pre-eclampsia (PE), with or without foetal growth restriction (FGR), superficial trophoblast invasion and insufficient remodelling of spiral arteries are common findings. In the present study, we have compared spiral artery remodelling and leucocyte composition in decidual tissue from 30 cases (PE=8, FGR=5, PE + FGR=17) and 31 controls. Six histological remodelling criteria were established, and each pregnancy obtained a remodelling score. Numbers of natural killer (NK) cells (CD56+), T cells (CD3+) and activated (CD25+ or CD69+) leucocytes were determined and related to total leucocyte (CD45+) numbers in serial sections. Cases demonstrated significantly impaired spiral artery remodelling, inappropriate placental growth and reduced NK cell proportions, as compared to controls (P=0.02, P<0.001 and P=0.01, respectively). Reduced NK cell proportion was primarily found in pregnancies complicated by FGR, with or without PE, and a significant positive correlation was observed between NK cell proportion, trophoblast infiltration and placental growth. Our in vivo observations support the hypothesized association between NK cells, impaired placental development and pathogenesis of PE/FGR.

  15. Natural Killer Cell Evasion Is Essential for Infection by Rhesus Cytomegalovirus

    PubMed Central

    Sturgill, Elizabeth R.; Malouli, Daniel; Hansen, Scott G.; Burwitz, Benjamin J.; Schneider, Christine L.; Womack, Jennie L.; Verweij, Marieke C.; Ventura, Abigail B.; Bhusari, Amruta; Jeffries, Krystal M.; Legasse, Alfred W.; Axthelm, Michael K.; Hudson, Amy W.; Sacha, Jonah B.; Picker, Louis J.; Früh, Klaus

    2016-01-01

    The natural killer cell receptor NKG2D activates NK cells by engaging one of several ligands (NKG2DLs) belonging to either the MIC or ULBP families. Human cytomegalovirus (HCMV) UL16 and UL142 counteract this activation by retaining NKG2DLs and US18 and US20 act via lysomal degradation but the importance of NK cell evasion for infection is unknown. Since NKG2DLs are highly conserved in rhesus macaques, we characterized how NKG2DL interception by rhesus cytomegalovirus (RhCMV) impacts infection in vivo. Interestingly, RhCMV lacks homologs of UL16 and UL142 but instead employs Rh159, the homolog of UL148, to prevent NKG2DL surface expression. Rh159 resides in the endoplasmic reticulum and retains several NKG2DLs whereas UL148 does not interfere with NKG2DL expression. Deletion of Rh159 releases human and rhesus MIC proteins, but not ULBPs, from retention while increasing NK cell stimulation by infected cells. Importantly, RhCMV lacking Rh159 cannot infect CMV-naïve animals unless CD8+ cells, including NK cells, are depleted. However, infection can be rescued by replacing Rh159 with HCMV UL16 suggesting that Rh159 and UL16 perform similar functions in vivo. We therefore conclude that cytomegaloviral interference with NK cell activation is essential to establish but not to maintain chronic infection. PMID:27580123

  16. Molecular Imaging: A Useful Tool for the Development of Natural Killer Cell-Based Immunotherapies.

    PubMed

    Gangadaran, Prakash; Ahn, Byeong-Cheol

    2017-01-01

    Molecular imaging is a relatively new discipline that allows visualization, characterization, and measurement of the biological processes in living subjects, including humans, at a cellular and molecular level. The interaction between cancer cells and natural killer (NK) cells is complex and incompletely understood. Despite our limited knowledge, progress in the search for immune cell therapies against cancer could be significantly improved by dynamic and non-invasive visualization and tracking of immune cells and by visualization of the response of cancer cells to therapies in preclinical and clinical studies. Molecular imaging is an essential tool for these studies, and a multimodal molecular imaging approach can be applied to monitor immune cells in vivo, for instance, to visualize therapeutic effects. In this review, we discuss the usefulness of NK cells in cancer therapies and the preclinical and clinical usefulness of molecular imaging in NK cell-based therapies. Furthermore, we discuss different molecular imaging modalities for use with NK cell-based therapies, and their preclinical and clinical applications in animal and human subjects. Molecular imaging has contributed to the development of NK cell-based therapies against cancers in animal models and to the refinement of current cell-based cancer immunotherapies. Developing sensitive and reproducible non-invasive molecular imaging technologies for in vivo NK cell monitoring and for real-time assessment of therapeutic effects will accelerate the development of NK cell therapies.

  17. Linking CD11b+ Dendritic Cells and Natural Killer T Cells to Plaque Inflammation in Atherosclerosis

    PubMed Central

    Rombouts, Miche; Ammi, Rachid; Van Brussel, Ilse; Roth, Lynn; De Winter, Benedicte Y.; Vercauteren, Sven R.; Hendriks, Jeroen M. H.; Lauwers, Patrick; Van Schil, Paul E.; De Meyer, Guido R. Y.; Fransen, Erik; Cools, Nathalie; Schrijvers, Dorien M.

    2016-01-01

    Atherosclerosis remains the leading cause of death and disability in our Western society. To investigate whether the dynamics of leukocyte (sub)populations could be predictive for plaque inflammation during atherosclerosis, we analyzed innate and adaptive immune cell distributions in blood, plaques, and lymphoid tissue reservoirs in apolipoprotein E-deficient (ApoE−/−) mice and in blood and plaques from patients undergoing endarterectomy. Firstly, there was predominance of the CD11b+ conventional dendritic cell (cDC) subset in the plaque. Secondly, a strong inverse correlation was observed between CD11b+ cDC or natural killer T (NKT) cells in blood and markers of inflammation in the plaque (including CD3, T-bet, CCR5, and CCR7). This indicates that circulating CD11b+ cDC and NKT cells show great potential to reflect the inflammatory status in the atherosclerotic plaque. Our results suggest that distinct changes in inflammatory cell dynamics may carry biomarker potential reflecting atherosclerotic lesion progression. This not only is crucial for a better understanding of the immunopathogenesis but also bares therapeutic potential, since immune cell-based therapies are emerging as a promising novel strategy in the battle against atherosclerosis and its associated comorbidities. The cDC-NKT cell interaction in atherosclerosis serves as a good candidate for future investigations. PMID:27051078

  18. Imaging burst kinetics and spatial coordination during serial killing by single natural killer cells.

    PubMed

    Choi, Paul J; Mitchison, Timothy J

    2013-04-16

    Cytotoxic lymphocytes eliminate virus-infected and cancerous cells by immune recognition and killing through the perforin-granzyme pathway. Traditional killing assays measure average target cell lysis at fixed times and high effector:target ratios. Such assays obscure kinetic details that might reveal novel physiology. We engineered target cells to report on granzyme activity, used very low effector:target ratios to observe potential serial killing, and performed low magnification time-lapse imaging to reveal time-dependent statistics of natural killer (NK) killing at the single-cell level. Most kills occurred during serial killing, and a single NK cell killed up to 10 targets over a 6-h assay. The first kill was slower than subsequent kills, especially on poor targets, or when NK signaling pathways were partially inhibited. Spatial analysis showed that sequential kills were usually adjacent. We propose that NK cells integrate signals from the previous and current target, possibly by simultaneous contact. The resulting burst kinetics and spatial coordination may control the activity of NK cells in tissues.

  19. The effects of dexamethasone, betamethasone, flunixin and phenylbutazone on bovine natural-killer-cell cytotoxicity.

    PubMed

    O'Brien, M A; Duffus, W P

    1990-09-01

    A series of in-vitro experiments was performed utilizing the ability of bovine peripheral-blood mononuclear cells (PBMC) to induce lysis of Madin-Darby bovine kidney (MDBK) cells infected with bovine herpesvirus 1 (BHV1), in an antibody-independent natural-killer(NK)-cell cytotoxic assay. The effects of dexamethasone (dexamethasone sodium phosphate), betamethasone (betamethasone sodium phosphate), flunixin (flunixin meglumine) and phenylbutazone on this NK cytolysis were studied using concentrations of the drugs ranging from well below to well above those normally attained in plasma at recommended therapeutic doses. All four drugs inhibited NK activity. For each agent a minimum inhibitory concentration (MIC50) required to inhibit NK activity by approximately 50% was calculated. For dexamethasone, betamethasone and flunixin the MIC50 was lower after a 24-h pre-incubation of PBMC with each drug, although a marked inhibition was seen when the drug was only present during the 5-h NK assay itself. In contrast the MIC50 for phenylbutazone rose after a 24-h pre-incubation with PBMC.

  20. Natural killer cellular cytotoxicity against herpes simplex virus-infected cells in Igh-1-disparate mice.

    PubMed

    Tamesis, R R; Foster, C S

    1990-11-01

    Susceptibility to Herpes simplex virus type 1 (HSV-1) stromal keratitis (HSK) in the mouse has previously been linked to the Igh-1 locus. The role of natural killer cells (NK) in resistance to viral infections is controversial. The authors studied the influence of the Igh-1 locus on in vitro murine NK activity against HSV-1 infected cell lines. The HSV-1 infected targets were lysed better than uninfected cells by murine splenic lymphocytes. Strain had no influence on virus-augmented cell lysis. Spleen cells from naive HSK-susceptible CAL-20 (Igh-1d) and BALB/c (Igh-1a) mice lysed YAC-1 targets better than HSK-resistant C.B-17 (Igh-1b) mice. The reverse was seen 24 hours after in vivo infection intraperitoneally with HSV-1. In contrast, CAL-20 splenocytes lysed PU5-1R targets better than BALB/c and C.B-17 splenocytes 24 hours after intraperitoneal (IP) infection. No significant differences were detected in interferon (IFN) levels after IP challenge with HSV-1 among the Igh-1 congenics. The data show that differences in NK activity were determined by both the Igh-1 genotype and the uninfected target cell. Susceptibility to HSK in these Igh-1-disparate congenics thus cannot be explained simply by differences in NK activity against HSV-1-infected targets.

  1. Dibutyltin activates MAP kinases in human natural killer cells, in vitro.

    PubMed

    Odman-Ghazi, Sabah O; Abraha, Abraham; Isom, Erica Taylor; Whalen, Margaret M

    2010-10-01

    Previous studies have shown that dibutyltin (DBT) interferes with the function of human natural killer (NK) cells, diminishing their capacity to destroy tumor cells, in vitro. DBT is a widespread environmental contaminant and has been found in human blood. As NK cells are our primary immune defense against tumor cells, it is important to understand the mechanism by which DBT interferes with their function. The current study examines the effects of DBT exposures on key enzymes in the signaling pathway that regulates NK responsiveness to tumor cells. These include several protein tyrosine kinases (PTKs), mitogen-activated protein kinases (MAPKs), and mitogen-activated protein kinase kinases (MAP2Ks). The results showed that in vitro exposures of NK cells to DBT had no effect on PTKs. However, exposures to DBT for as little as 10 min were able to increase the phosphorylation (activation) of the MAPKs. The DBT-induced activations of these MAPKs appear to be due to DBT-induced activations of the immediate upstream activators of the MAPKs, MAP2Ks. The results suggest that DBT-interference with the MAPK signaling pathway is a consequence of DBT exposures, which could account for DBT-induced decreases in NK function.

  2. Serum supplementation modulates the effects of dibutyltin on human natural killer cell function.

    PubMed

    Whalen, Margaret M; DeWitt, Jamie C; Luebke, Robert W

    2008-08-01

    Natural killer (NK) cells are a subset of lymphocytes capable of killing tumor cells, virally infected cells and antibody-coated cells. Dibutyltin (DBT) dichloride is an organotin used as a stabilizer in polyvinylchloride (PVC) plastics and as a deworming product in poultry. DBT may leach from PVC water supply pipes and therefore poses a potential risk to human health. We previously reported diminished NK cells lysis of tumor cells following exposure to DBT in serum-free cell culture medium. However, under in vivo conditions, circulating cells will be exposed to DBT in the presence of 100% plasma; thus we investigated whether serum supplementation and incubation time modulates DBT effects on NK cell killing and the accumulation of DBT in freshly isolated NK cells, to determine whether a serum-free model accurately predicts possible effects of DBT on human NK cells under in vivo conditions. Lytic function was decreased by approximately 35% at an intracellular DBT (DBTi) concentration of 200 microM and nearly complete loss of lytic function was observed at DBTi above 300 microM for one h. However, an intracellular concentration of 50 microM DBT, achieved over 24 h of exposure in 50% serum, reduced lytic function by 50%. Thus, conditions that reflect prolonged contact with circulating DBT, in the presence of serum, suggest that NK cell activity is decreased at lower DBTi. These data indicate that the model is useful in predicting potential human effects of relatively low DBTi concentrations.

  3. Dibutyltin exposure decreases granzyme B and perforin in human natural killer cells.

    PubMed

    Catlin, Reetta; Shah, Hemangini; Bankhurst, Arthur D; Whalen, Margaret M

    2005-11-01

    Natural killer (NK) cells are a subset of lymphocytes that are capable of killing tumor and virally-infected cells. Dibutyltin (DBT) is a catalyst in the production of PVC plastics and a breakdown product of tributyltin (TBT). DBT is a significant environmental contaminant. This study investigates the mechanism by which DBT exposure decreases the immune function of human NK cells. NK cells destroy their target cells by releasing cytotoxic proteins, perforin, and granzyme B. We examined the effect of DBT exposures on the levels of cytotoxic proteins and their mRNAs. Exposure of NK cells to DBT for 1h caused significant decreases in the mRNAs for granzyme B and perforin but not in protein levels. A 24h exposure to DBT decreased mRNAs as well as protein levels for both granzyme B and perforin. Exposure to DBT for 1h followed by either a 24 or 48h period in DBT-free media, decreased levels of granzyme B and perforin. The results indicate that decreases in granzyme B and perforin levels in NK cells are consequences of DBT exposure. Additionally, DBT causes rapid decreases in mRNAs for perforin and granzyme B, suggesting decreases in transcription and/or increases in mRNA degradation.

  4. Natural killer cells regulate Th1/Treg and Th17/Treg balance in chlamydial lung infection.

    PubMed

    Li, Jing; Dong, Xiaojing; Zhao, Lei; Wang, Xiao; Wang, Yan; Yang, Xi; Wang, Hong; Zhao, Weiming

    2016-07-01

    Natural killer (NK) cell is an important component in innate immunity, playing a critical role in bridging innate and adaptive immunity by modulating the function of other immune cells including T cells. In this study, we focused on the role of NK cells in regulating Th1/Treg and Th17/Treg balance during chlamydial lung infection. We found that NK cell-depleted mice showed decreased Th1 and Th17 cells, which was correlated with reduced interferon-γ, interleukin (IL)-12, IL-17 and IL-22 production as well as T-bet and receptor-related orphan receptor gamma t expression compared with mice treated with the isotype control antibody. In contrast, NK cell depletion significantly increased Treg in cell number and related transcription factor (Foxp3) expression. The opposite trends of changes of Th1/Th17 and Treg led to significant reduction in the Th1/Treg and Th17/Treg ratios. The data implicate that NK cells play an important role in host defence against chlamydial lung infection, mainly through maintaining Th1/Treg and Th17/Treg balance.

  5. Reduced number of peripheral natural killer cells in schizophrenia but not in bipolar disorder.

    PubMed

    Karpiński, Paweł; Frydecka, Dorota; Sąsiadek, Maria M; Misiak, Błażej

    2016-05-01

    Overwhelming evidence indicates that subthreshold inflammatory state might be implicated in the pathophysiology of schizophrenia (SCZ) and bipolar disorder (BPD). It has been reported that both groups of patients might be characterized by abnormal lymphocyte counts. However, little is known about alterations in lymphocyte proportions that may differentiate SCZ and BPD patients. Therefore, in this study we investigated blood cell proportions quantified by means of microarray expression deconvolution using publicly available data from SCZ and BPD patients. We found significantly lower counts of natural killer (NK) cells in drug-naïve and medicated SCZ patients compared to healthy controls across all datasets. In one dataset from SCZ patients, there were no significant differences in the number of NK cells between acutely relapsed and remitted SCZ patients. No significant difference in the number of NK cells between BPD patients and healthy controls was observed in all datasets. Our results indicate that SCZ patients, but not BPD patients, might be characterized by reduced counts of NK cells. Future studies looking at lymphocyte counts in SCZ should combine the analysis of data obtained using computational deconvolution and flow cytometry techniques. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Suppression of natural killer cell cytotoxicity in postpartum women: time course and potential mechanisms.

    PubMed

    Groer, Maureen W; El-Badri, Nagwa; Djeu, Julie; Williams, S Nicole; Kane, Bradley; Szekeres, Karoly

    2014-07-01

    Little is known about the recovery of the immune system from normal pregnancy and whether the postpartum period is a uniquely adapted immune state. This report extends previous observations from our group of decreased natural killer (NK) cell cytotoxicity in the postpartum period. NK cytotoxicity was measured from 1 week through 9 months postpartum. In addition, NK cytotoxicity was assayed in the presence or absence of pooled plasmas collected from either postpartum or nonpostpartum women. Samples of cells were stained for inhibitory receptors and analyzed by flow cytometry. NK cytotoxicity remained decreased in postpartum women compared to controls through the first 6 postpartum months, returned to normal levels by 9 months, and remained normal at 12 months. NK cytotoxicity during the first 6 months was further inhibited by the addition of pooled plasma to NK cultures from postpartum women, but the addition of pooled plasma from the control group did not affect that group's NK cultures. There were differences in inhibitory receptor staining between the two groups, with decreased CD158a and CD158b and increased NKG2A expression on postpartum NK cells during the first 3 postpartum months. These data suggest that NK cytotoxicity postpartum inhibition lasts 6 months and is influenced by unidentified postpartum plasma components. The effect may also involve receptors on NK cells.

  7. Natural killer cell-mediated cytotoxicity is increased by a type II arabinogalactan from Anoectochilus formosanus.

    PubMed

    Yang, Li-Chan; Lai, Ching-Yi; Lin, Wen-Chuan

    2017-01-02

    This study investigated the effects of a type II arabinogalactan from Anoectochilus formosanus (AGAF) on natural killer (NK) cell-mediated cytotoxicity and the possible underlying mechanisms. This study reported that sustained exposure to AGAF increased NK-92MI cell-mediated cytotoxicity in a time- and concentration-dependent manner, as characterized according to the cellular lactic dehydrogenase leakage from K562 leukemia cells. Additionally, antibody neutralization studies have reported that interferon (IFN)-γ, but not perforin or tumor necrosis factor-α, released by NK-92MI NK cells is crucial in enhancing cytotoxicity through an autocrine loop. In this study, AGAF was further demonstrated to induce IFN-γ expression, increasing the susceptibility to NK-92MI cell-mediated cytotoxicity through the toll-like receptor (TLR)-2, TLR4, extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, and nuclear factor-κB pathways. A pharmacological study revealed that Janus kinase 2/signal transducers and activators of the signal transducers and of transcription 3 signaling are involved in IFN-γ-induced NK cell-mediated cytotoxicity.

  8. Designing multivalent proteins based on natural killer cell receptors and their ligands as immunotherapy for cancer.

    PubMed

    Smits, Nicole C; Coupet, Tiffany A; Godbersen, Claire; Sentman, Charles L

    2016-09-01

    Natural killer (NK) cells are an important component of the innate immune system that play a key role in host immunity against cancer. NK cell recognition and activation is based on cell surface receptors recognizing specific ligands that are expressed on many types of tumor cells. Some of these receptors are capable of activating NK cell function while other receptors inhibit NK cell function. Therapeutic approaches to treat cancer have been developed based on preventing NK cell inhibition or using NK cell receptors and their ligands to activate NK cells or T cells to destroy tumor cells. This article describes the various strategies for targeting NK cell receptors and NK cell receptor ligands using multivalent proteins to activate immunity against cancer. NK cell receptors work in synergy to activate NK cell effector responses. Effective anti-cancer strategies will need to not only kill tumor cells but must also lead to the destruction of the tumor microenvironment. Immunotherapy based on NK cells and their receptors has the capacity to accomplish this through triggering lymphocyte cytotoxicity and cytokine production.

  9. Cell cycle progression dictates the requirement for BCL2 in natural killer cell survival

    PubMed Central

    Viant, Charlotte; Guia, Sophie; Hennessy, Robert J.; Rautela, Jai; Pham, Kim; Bernat, Claire; Goh, Wilford; Jiao, Yuhao; Delconte, Rebecca; Roger, Michael; Simon, Vanina; Souza-Fonseca-Guimaraes, Fernando; Grabow, Stephanie; Belz, Gabrielle T.; Kile, Benjamin T.; Strasser, Andreas; Gray, Daniel; Hodgkin, Phillip D.; Beutler, Bruce; Vivier, Eric

    2017-01-01

    Natural killer (NK) cells are innate lymphoid cells with antitumor functions. Using an N-ethyl-N-nitrosourea (ENU)–induced mutagenesis screen in mice, we identified a strain with an NK cell deficiency caused by a hypomorphic mutation in the Bcl2 (B cell lymphoma 2) gene. Analysis of these mice and the conditional deletion of Bcl2 in NK cells revealed a nonredundant intrinsic requirement for BCL2 in NK cell survival. In these mice, NK cells in cycle were protected against apoptosis, and NK cell counts were restored in inflammatory conditions, suggesting a redundant role for BCL2 in proliferating NK cells. Consistent with this, cycling NK cells expressed higher MCL1 (myeloid cell leukemia 1) levels in both control and BCL2-null mice. Finally, we showed that deletion of BIM restored survival in BCL2-deficient but not MCL1-deficient NK cells. Overall, these data demonstrate an essential role for the binding of BCL2 to BIM in the survival of noncycling NK cells. They also favor a model in which MCL1 is the dominant survival protein in proliferating NK cells. PMID:28057804

  10. Characterization of Natural Killer Cells and Cytokines in Maternal Placenta and Fetus of Diabetic Mothers

    PubMed Central

    Hara, Cristiane de Castro Pernet; França, Eduardo Luzía; Fagundes, Danny Laura Gomes; de Queiroz, Adriele Ataides; Rudge, Marilza Vieira Cunha; Honorio-França, Adenilda Cristina; Calderon, Iracema de Mattos Paranhos

    2016-01-01

    The present study characterized natural killer cells and cytokines in diabetic mothers, their placenta, and fetus. In the maternal blood from the hyperglycemic groups, the CD16+CD56− NK cells increased, whereas that of CD16+CD56+ decreased in gestational diabetes mellitus [GDM] group. Cord blood from type 2 diabetes [DM-2] showed a higher proportion of CD16+CD56− and CD16−CD56+. The placental extravillous layer of GDM and DM-2 showed an increase of CD16+CD56− cells and, irrespective of region, the proportion of CD16−CD56+ cells was higher in mild gestational hyperglycemia [MGH] and GDM and lower in DM-2. IL-2 was lower in maternal blood and IFN-γ higher in maternal and cord blood from the GDM group. IL-17 was higher in maternal and cord blood from the DM-2 group. The placental extravillous layer of the MGH showed high levels of IL-4, IL-6, IL-10, IL-17, and IFN-γ and low levels of IL-1β and IL-8, whereas the placental villous layer contained high levels of IL-17 and IFN-γ. The GDM group, irrespective of region, showed higher levels of IL-8. The DM-2 group, irrespective of region, placenta showed high levels of TNF-α, IL-17, and IFN-γ. The hyperglycemia produces an inflammatory environment with a high content of inflammatory cytokines and cells expressing CD16+. PMID:27294162

  11. Mucormycosis or extranodal natural killer/T cell lymphoma, similar symptoms but different diagnosis.

    PubMed

    Zhang, Y; Wang, T; Liu, G-L; Li, J; Gao, S-Q; Wan, L

    2016-09-01

    Facial mucormycosis and extranodal natural killer/T cell lymphoma (NK/TCL) are characterized by facial progressive swelling, ulceration and destruction. Patient one was a 58-year-old woman, who had typical clinical-pathological symptoms of tumor. She was hospitalized in order to remove the tumor. But the diagnosis turned out to be primary mucor infection, which was corrected by positive tissue culture and fungal elements in histology. She was also diagnosed with type 2 diabetes mellitus and acute myelocytic leukemia M2a. With the antifungal therapy, her symptoms, signs and general conditions improved. Regrettably, she gave up the treatment, and died three months later for unknown reason. Patient two was a 60-year-old woman, with the complaints of chronic sinusitis, swelling and necrotic lesion in the right temporal area. Although the mycelium was recovered in biopsy tissues from the necrotic lesion, the diagnosis was revised to extranodal NK/TCL by reviewing the histopathological features and immunophenotypic analysis. The patient also voluntarily abandoned treatment, and died at home for unknown reason. The differential diagnosis of facial mucormycosis and extranodal NK/TCL is usually perplexing. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  12. High-dose chemotherapy with peripheral blood stem cell rescue in blastoid natural killer cell lymphoma.

    PubMed

    Mukai, H Y; Kojima, H; Suzukawa, K; Hori, M; Komeno, T; Hasegawa, Y; Ninomiya, H; Mori, N; Nagasawa, T

    1999-02-01

    A 25-year-old man was referred because of skin rash, lymphadenopathy and anemia. Laboratory examinations revealed severe anemia (Hb, 4.8 g/dl) and elevated levels of GOT, GPT, LDH and soluble interleukin-2 receptor. Work-up studies disclosed the involvement of lymphoma cells in lymph nodes, skin, bilateral kidneys and bone marrow. Lymph node biopsy revealed diffuse proliferation of medium- to large-sized lymphoblastic cells. Bone marrow aspiration showed massive infiltration of large blastic cells with no cytoplasmic granules. The lymphoma cells in bone marrow and lymph node showed surface CD3-, cytoplasmic CD3epsilon+, CD4+, CD8-, CD56+, CD57-, CD16- and CD43 (MT-1)+ phenotype. Analyses of T cell receptor beta and gamma genes showed germ line configurations. EBER-1 was not detectable in the lymphoma cells. He was diagnosed as having blastoid natural killer (NK) cell lymphoma. In spite of several courses of combination chemotherapy, the lymphoma was progressive. He was then treated with high-dose chemotherapy and peripheral blood stem cell rescue, achieving remission which has now lasted for more than 12 months. We consider that blastoid NK cell lymphoma is an extremely aggressive subtype of CD56-positive lymphomas, and high-dose chemotherapy with peripheral blood stem cell rescue should be included for the choice of the treatment.

  13. Partial MCM4 deficiency in patients with growth retardation, adrenal insufficiency, and natural killer cell deficiency

    PubMed Central

    Gineau, Laure; Cognet, Céline; Kara, Nihan; Lach, Francis Peter; Dunne, Jean; Veturi, Uma; Picard, Capucine; Trouillet, Céline; Eidenschenk, Céline; Aoufouchi, Said; Alcaïs, Alexandre; Smith, Owen; Geissmann, Frédéric; Feighery, Conleth; Abel, Laurent; Smogorzewska, Agata; Stillman, Bruce; Vivier, Eric; Casanova, Jean-Laurent; Jouanguy, Emmanuelle

    2012-01-01

    Natural killer (NK) cells are circulating cytotoxic lymphocytes that exert potent and nonredundant antiviral activity and antitumoral activity in the mouse; however, their function in host defense in humans remains unclear. Here, we investigated 6 related patients with autosomal recessive growth retardation, adrenal insufficiency, and a selective NK cell deficiency characterized by a lack of the CD56dim NK subset. Using linkage analysis and fine mapping, we identified the disease-causing gene, MCM4, which encodes a component of the MCM2-7 helicase complex required for DNA replication. A splice-site mutation in the patients produced a frameshift, but the mutation was hypomorphic due to the creation of two new translation initiation methionine codons downstream of the premature termination codon. The patients’ fibroblasts exhibited genomic instability, which was rescued by expression of WT MCM4. These data indicate that the patients’ growth retardation and adrenal insufficiency likely reflect the ubiquitous but heterogeneous impact of the MCM4 mutation in various tissues. In addition, the specific loss of the NK CD56dim subset in patients was associated with a lower rate of NK CD56bright cell proliferation, and the maturation of NK CD56bright cells toward an NK CD56dim phenotype was tightly dependent on MCM4-dependent cell division. Thus, partial MCM4 deficiency results in a genetic syndrome of growth retardation with adrenal insufficiency and selective NK deficiency. PMID:22354167

  14. Optimal effector functions in human natural killer cells rely upon autocrine bone morphogenetic protein signaling

    PubMed Central

    Mc Alpine, Tristan; Wei, Heng; Martínez, Víctor G.; Entrena, Ana; Melen, Gustavo J; MacDonald, Andrew S.; Phythian-Adams, Alexander; Sacedón, Rosa; Maraskovsky, Eugene; Cebon, Jonathan; Ramírez, Manuel

    2014-01-01

    Natural killer (NK) cells are critical for innate tumor immunity due to their specialized ability to recognize and kill neoplastically transformed cells. However, NK cells require a specific set of cytokine-mediated signals to achieve optimal effector function. Th1-associated cytokines promote effector functions which are inhibited by the prototypic Th-2 cytokine IL-4 and the TGF-β superfamily members TGF-β1 and activin-A. Interestingly, the largest subgroup of the TGF-β superfamily are the bone morphogenetic proteins (BMP), but the effects of BMP signaling to NK cell effector functions have not been evaluated. Here we demonstrate that blood-circulating NK cells express type I and II BMP receptors, BMP-2 and BMP-6 ligands, and phosphorylated isoforms of Smad-1/-5/-8 which mediate BMP family member signaling. In opposition to the inhibitory effects of TGF-β1 or activin-A, autocrine BMP signaling was supportive to NK cell function. Mechanistic investigations in cytokine and TLR-L activated NK cells revealed that BMP signaling optimized IFN-γ and global cytokine and chemokine production; phenotypic activation and proliferation; autologous DC activation and target cytotoxicity. Collectively, our findings identify a novel auto-activatory pathway that is essential for optimal NK cell effector function, one which might be therapeutically manipulated to help eradicate tumors. PMID:25038228

  15. Role for early-differentiated natural killer cells in infectious mononucleosis

    PubMed Central

    Azzi, Tarik; Lünemann, Anna; Murer, Anita; Ueda, Seigo; Béziat, Vivien; Malmberg, Karl-Johan; Staubli, Georg; Gysin, Claudine; Berger, Christoph; Münz, Christian

    2014-01-01

    A growing body of evidence suggests that the human natural killer (NK)-cell compartment is phenotypically and functionally heterogeneous and is composed of several differentiation stages. Moreover, NK-cell subsets have been shown to exhibit adaptive immune features during herpes virus infection in experimental mice and to expand preferentially during viral infections in humans. However, both phenotype and role of NK cells during acute symptomatic Epstein-Barr virus (EBV) infection, termed infectious mononucleosis (IM), remain unclear. Here, we longitudinally assessed the kinetics, the differentiation, and the proliferation of subsets of NK cells in pediatric IM patients. Our results indicate that acute IM is characterized by the preferential proliferation of early-differentiated CD56dim NKG2A+ immunoglobulin-like receptor- NK cells. Moreover, this NK-cell subset exhibits features of terminal differentiation and persists at higher frequency during at least the first 6 months after acute IM. Finally, we demonstrate that this NK-cell subset preferentially degranulates and proliferates on exposure to EBV-infected B cells expressing lytic antigens. Thus, early-differentiated NK cells might play a key role in the immune control of primary infection with this persistent tumor-associated virus. PMID:25205117

  16. Natural killer cells facilitate PRAME-specific T-cell reactivity against neuroblastoma.

    PubMed

    Spel, Lotte; Boelens, Jaap-Jan; van der Steen, Dirk M; Blokland, Nina J G; van Noesel, Max M; Molenaar, Jan J; Heemskerk, Mirjam H M; Boes, Marianne; Nierkens, Stefan

    2015-11-03

    Neuroblastoma is the most common solid tumor in children with an estimated 5-year progression free survival of 20-40% in stage 4 disease. Neuroblastoma actively avoids recognition by natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). Although immunotherapy has gained traction for neuroblastoma treatment, these immune escape mechanisms restrain clinical results. Therefore, we aimed to improve neuroblastoma immunogenicity to further the development of antigen-specific immunotherapy against neuroblastoma. We found that neuroblastoma cells significantly increase surface expression of MHC I upon exposure to active NK cells which thereby readily sensitize neuroblastoma cells for recognition by CTLs. We show that oncoprotein PRAME serves as an immunodominant antigen for neuroblastoma as NK-modulated neuroblastoma cells are recognized by PRAMESLLQHLIGL/A2-specific CTL clones. Furthermore, NK cells induce MHC I upregulation in neuroblastoma through contact-dependent secretion of IFNγ. Our results demonstrate remarkable plasticity in the peptide/MHC I surface expression of neuroblastoma cells, which is reversed when neuroblastoma cells experience innate immune attack by sensitized NK cells. These findings support the exploration of NK cells as adjuvant therapy to enforce neuroblastoma-specific CTL responses.

  17. Virus-Infected Human Mast Cells Enhance Natural Killer Cell Functions.

    PubMed

    Portales-Cervantes, Liliana; Haidl, Ian D; Lee, Patrick W; Marshall, Jean S

    2017-01-01

    Mucosal surfaces are protected from infection by both structural and sentinel cells, such as mast cells. The mast cell's role in antiviral responses is poorly understood; however, they selectively recruit natural killer (NK) cells following infection. Here, the ability of virus-infected mast cells to enhance NK cell functions was examined. Cord blood-derived human mast cells infected with reovirus (Reo-CBMC) and subsequent mast cell products were used for the stimulation of human NK cells. NK cells upregulated the CD69 molecule and cytotoxicity-related genes, and demonstrated increased cytotoxic activity in response to Reo-CBMC soluble products. NK cell interferon (IFN)-γ production was also promoted in the presence of interleukin (IL)-18. In vivo, SCID mice injected with Reo-CBMC in a subcutaneous Matrigel model, could recruit and activate murine NK cells, a property not shared by normal human fibroblasts. Soluble products of Reo-CBMC included IL-10, TNF, type I and type III IFNs. Blockade of the type I IFN receptor abrogated NK cell activation. Furthermore, reovirus-infected mast cells expressed multiple IFN-α subtypes not observed in reovirus-infected fibroblasts or epithelial cells. Our data define an important mast cell IFN response, not shared by structural cells, and a subsequent novel mast cell-NK cell immune axis in human antiviral host defense.

  18. Ezh2 regulates differentiation and function of natural killer cells through histone methyltransferase activity

    PubMed Central

    Yin, Jie; Leavenworth, Jianmei W.; Li, Yang; Luo, Qi; Xie, Huafeng; Liu, Xinhua; Huang, Shan; Yan, Han; Fu, Zheng; Zhang, Liyun Y.; Zhang, Litao; Hao, Junwei; Wu, Xudong; Deng, Xianming; Roberts, Charles W. M.; Orkin, Stuart H.; Cantor, Harvey; Wang, Xi

    2015-01-01

    Changes of histone modification status at critical lineage-specifying gene loci in multipotent precursors can influence cell fate commitment. The contribution of these epigenetic mechanisms to natural killer (NK) cell lineage determination from common lymphoid precursors is not understood. Here we investigate the impact of histone methylation repressive marks (H3 Lys27 trimethylation; H3K27me3) on early NK cell differentiation. We demonstrate that selective loss of the histone-lysine N-methyltransferase Ezh2 (enhancer of zeste homolog 2) or inhibition of its enzymatic activity with small molecules unexpectedly increased generation of the IL-15 receptor (IL-15R) CD122+ NK precursors and mature NK progeny from both mouse and human hematopoietic stem and progenitor cells. Mechanistic studies revealed that enhanced NK cell expansion and cytotoxicity against tumor cells were associated with up-regulation of CD122 and the C-type lectin receptor NKG2D. Moreover, NKG2D deficiency diminished the positive effects of Ezh2 inhibitors on NK cell commitment. Identification of the contribution of Ezh2 to NK lineage specification and function reveals an epigenetic-based mechanism that regulates NK cell development and provides insight into the clinical application of Ezh2 inhibitors in NK-based cancer immunotherapies. PMID:26668377

  19. Improving efficacy of cancer immunotherapy by genetic modification of natural killer cells.

    PubMed

    Burga, Rachel A; Nguyen, Tuongvan; Zulovich, Jane; Madonna, Sarah; Ylisastigui, Loyda; Fernandes, Rohan; Yvon, Eric

    2016-11-01

    Natural killer (NK) cells are members of the innate immune system that recognize target cells via activating and inhibitory signals received through cell receptors. Derived from the lymphoid lineage, NK cells are able to produce cytokines and exert a cytotoxic effect on viral infected and malignant cells. It is their unique ability to lyse target cells rapidly and without prior education that renders NK cells a promising effector cell for adoptive cell therapy. However, both viruses and tumors employ evasion strategies to avoid attack by NK cells, which represent biological challenges that need to be harnessed to fully exploit the cytolytic potential of NK cells. Using genetic modification, the function of NK cells can be enhanced to improve their homing, cytolytic activity, in vivo persistence and safety. Examples include gene modification to express chemokine, high-affinity Fc receptor and chimeric antigen receptors, suicide genes and the forced expression of cytokines such as interleukin (IL)-2 and IL-15. Preclinical studies have clearly demonstrated that such approaches are effective in improving NK-cell function, homing and safety. In this review, we summarize the recent advances in the genetic manipulations of NK cells and their application for cellular immunotherapeutic strategies. Copyright © 2016 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  20. Connecting the Dots: Artificial Antigen Presenting Cell-Mediated Modulation of Natural Killer T Cells

    PubMed Central

    Sun, Wenji; Subrahmanyam, Priyanka B.; East, James E.

    2012-01-01

    Natural killer T (NKT) cells constitute an important subset of T cells that can both directly and indirectly mediate antitumor immunity. However, we and others have reported that cancer patients have a reduction in both NKT cell number and function. NKT cells can be stimulated and expanded with α-GalCer and cytokines and these expanded NKT cells retain their phenotype, remain responsive to antigenic stimulation, and display cytotoxic function against tumor cell lines. These data strongly favor the use of ex vivo expanded NKT cells in adoptive immunotherapy. NKT cell based-immunotherapy has been limited by the use of autologous antigen-presenting cells, which can vary substantially in their quantity and quality. A standardized system that relies on artificial antigen-presenting cells (aAPCs) could produce the stimulating effects of dendritic cell (DC) without the pitfalls of allo- or xenogeneic cells. In this review, we discuss the progress that has been made using CD1d-based aAPC and how this acellular antigen presenting system can be used in the future to enhance our understanding of NKT cell biology and to develop NKT cell-specific adoptive immunotherapeutic strategies. PMID:23050947

  1. Peripheral natural killer cell maturation depends on the transcription factor Aiolos

    PubMed Central

    Holmes, Melissa L; Huntington, Nicholas D; Thong, Rebecca PL; Brady, Jason; Hayakawa, Yoshihiro; Andoniou, Christopher E; Fleming, Peter; Shi, Wei; Smyth, Gordon K; Degli-Esposti, Mariapia A; Belz, Gabrielle T; Kallies, Axel; Carotta, Sebastian; Smyth, Mark J; Nutt, Stephen L

    2014-01-01

    Natural killer (NK) cells are an innate lymphoid cell lineage characterized by their capacity to provide rapid effector functions, including cytokine production and cytotoxicity. Here, we identify the Ikaros family member, Aiolos, as a regulator of NK-cell maturation. Aiolos expression is initiated at the point of lineage commitment and maintained throughout NK-cell ontogeny. Analysis of cell surface markers representative of distinct stages of peripheral NK-cell maturation revealed that Aiolos was required for the maturation in the spleen of CD11bhighCD27− NK cells. The differentiation block was intrinsic to the NK-cell lineage and resembled that found in mice lacking either T-bet or Blimp1; however, genetic analysis revealed that Aiolos acted independently of all other known regulators of NK-cell differentiation. NK cells lacking Aiolos were strongly hyper-reactive to a variety of NK-cell-mediated tumor models, yet impaired in controlling viral infection, suggesting a regulatory function for CD27− NK cells in balancing these two arms of the immune response. These data place Aiolos in the emerging gene regulatory network controlling NK-cell maturation and function. PMID:25319415

  2. The immunostatus of natural killer cells in people exposed to sulfur mustard.

    PubMed

    Ghotbi, Ladan; Hassan, Zuhair

    2002-06-01

    Sulfur mustard (2,2-dichloroethyl sulfide, SM) has been documented as an alkylating agent. It has been widely used as a chemical weapon during the last two decades. Despite extensive worldwide research, no effective therapy has yet been devised for the treatment of patients exposed to SM. A severe suppression of the immune system still remains as the major cause of opportunistic infections, septicemia and death in such patients. The aim of this study was to determine the possible effect of SM on natural killer (NK) cells in patients suffering from SM injuries. Patients were classified into three groups: mild, moderate and severe. Blood sample obtained from each patient was examined using flowcytometric technique. Results showed that the percentage of NK cells (CD45+/CD56+) is significantly lower in severe patients than that of the control group (P<0.05). It was also observed that the activity of NK cells (CD56+/CD25+) in severe alkylating group is noticeably higher compared with the control group (P<0.1).

  3. beta. -endorphin augments the cytolytic activity and interferon production of natural killer cells

    SciTech Connect

    Mandler, R.N.; Biddison, W.E.; Mandler, R.; Serrate, S.A.

    1986-02-01

    The in vitro effects of the neurohormone ..beta..-endorphin (b-end) on natural killer (NK) activity and interferon (IFN) production mediated by large granular lymphocytes (LGL) were investigated. LGL-enriched fractions from peripheral blood mononuclear cells (PBMC) from normal human volunteers were obtained by fractionation over discontinuous Percoll gradients. LGL were preincubated with or without various concentrations of b-end or the closely related peptides ..cap alpha..-endorphin (a-end), ..gamma..-endorphin (g-end), or D-ALA/sub 2/-..beta..-endorphin (D-ALA/sub 2/-b-end), a synthetic b-end analogue. NK activity was assayed on /sup 51/Cr-labeled K562 target cells. Preincubation of LGL effectors (but not K562 targets) for 2 to 18 hr with concentrations of b-end between 10/sup -7/ M and 10/sup -10/ M produced significant augmentation of NK cytolytic activity (mean percentage increase: 63%). The classic opiate antagonist naloxone blocked the enhancing effect when used at a 100-fold molar excess relative to b-end. These findings demonstrate that b-end enhances NK activity and IFN production of purified LGL, and suggests that b-end might bind to an opioid receptor on LGL that can be blocked by naloxone. These results lend support to the concepts of regulation of the immune response by neurohormones and the functional relationship between the nervous and immune systems.

  4. Multiple Myeloma Impairs Bone Marrow Localization of Effector Natural Killer Cells by Altering the Chemokine Microenvironment.

    PubMed

    Ponzetta, Andrea; Benigni, Giorgia; Antonangeli, Fabrizio; Sciumè, Giuseppe; Sanseviero, Emilio; Zingoni, Alessandra; Ricciardi, Maria Rosaria; Petrucci, Maria Teresa; Santoni, Angela; Bernardini, Giovanni

    2015-11-15

    Natural killer (NK) cells are key innate immune effectors against multiple myeloma, their activity declining in multiple myeloma patients with disease progression. To identify the mechanisms underlying NK cell functional impairment, we characterized the distribution of functionally distinct NK cell subsets in the bone marrow of multiple myeloma-bearing mice. Herein we report that the number of KLRG1(-) NK cells endowed with potent effector function rapidly and selectively decreases in bone marrow during multiple myeloma growth, this correlating with decreased bone marrow NK cell degranulation in vivo. Altered NK cell subset distribution was dependent on skewed chemokine/chemokine receptor axes in the multiple myeloma microenvironment, with rapid downmodulation of the chemokine receptor CXCR3 on NK cells, increased CXCL9 and CXCL10, and decreased CXCL12 expression in bone marrow. Similar alterations in chemokine receptor/chemokine axes were observed in patients with multiple myeloma. Adoptive transfer experiments demonstrated that KLRG1(-) NK cell migration to the bone marrow was more efficient in healthy than multiple myeloma-bearing mice. Furthermore, bone marrow localization of transferred CXCR3-deficient NK cells with respect to wild type was enhanced in healthy and multiple myeloma-bearing mice, suggesting that CXCR3 restrains bone marrow NK cell trafficking. Our results indicate that multiple myeloma-promoted CXCR3 ligand upregulation together with CXCL12 downmodulation act as exit signals driving effector NK cells outside the bone marrow, thus weakening the antitumor immune response at the primary site of tumor growth.

  5. Primitive neuroectodermal tumor in an ovarian cystic teratoma: natural killer and neuroblastoma cell analysis.

    PubMed

    Tabellini, Giovanna; Benassi, Marzia; Marcenaro, Emanuela; Coltrini, Daniela; Patrizi, Ornella; Ricotta, Doris; Rampinelli, Fabio; Moretta, Alessandro; Parolini, Silvia

    2014-01-01

    In the present study, we report an extremely rare case of a 31-year-old woman with neuroblastoma arising in an ovarian cystic teratoma. We analyzed the expression of activating receptors on natural killer (NK) cells derived from the patient's peripheral blood and peritoneal fluid. In addition, we investigated the presence of specific ligands recognized by different NK cell receptors on tumor cells. We show that NK cells isolated from peritoneal fluid expressed certain triggering receptors including DNAM-1 (CD226) and CD16 with lower intensity as compared to peripheral blood NK cells. Remarkably, at variance with most cases of childhood neuroblastoma, the tumor cells from this patient expressed substantial amounts of HLA class-I molecules. These molecules are known to be protective against NK cell-mediated lysis. In addition, neuroblastoma cells expressed B7-H3 (CD276), another surface molecule that inhibits NK cell function. Finally, this tumor did not express the PVR (CD155) and nectin-2 (CD112) ligands for the DNAM-1 activating NK receptor, which plays a crucial role in NK/neuroblastoma interactions. Altogether, these findings indicate that the neuroblastoma cells of this patient express an NK-resistant surface phenotype, which is at least in part similar to that previously described in a fraction of childhood neuroblastoma.

  6. Synthetic glycolipid activators of natural killer T cells as immunotherapeutic agents.

    PubMed

    Carreño, Leandro J; Saavedra-Ávila, Noemí A; Porcelli, Steven A

    2016-04-01

    Certain types of glycolipids have been found to have remarkable immunomodulatory properties as a result of their ability to activate specific T lymphocyte populations with an extremely wide range of immune effector properties. The most extensively studied glycolipid reactive T cells are known as invariant natural killer T (iNKT) cells. The antigen receptors of these cells specifically recognize certain glycolipids, most notably glycosphingolipids with α-anomeric monosaccharides, presented by the major histocompatibility complex class I-like molecule CD1d. Once activated, iNKT cells can secrete a very diverse array of pro- and anti-inflammatory cytokines to modulate innate and adaptive immune responses. Thus, glycolipid-mediated activation of iNKT cells has been explored for immunotherapy in a variety of disease states, including cancer and a range of infections. In this review, we discuss the design of synthetic glycolipid activators for iNKT cells, their impact on adaptive immune responses and their use to modulate iNKT cell responses to improve immunity against infections and cancer. Current challenges in translating results from preclinical animal studies to humans are also discussed.

  7. Identification of a cell-surface antigen selectively expressed on the natural killer cell

    PubMed Central

    1977-01-01

    We have studied the cell-surface phenotype of natural killer (NK) cells of NZB and B6 mice which react to an MuLV+ lymphoid tumor. (a) NK cells do not express Thy1, Ly2, or Ig surface markers. (b) NK cells express an antigen recognized by C3H anti-CE antiserum ('anti-Ly1.2 antiserum'). Inasmuch as NK activity of spleen cells from B6 and B6/Ly1.1 congenic strains were both equally sensitive to C3H anti-CE antiserum, the NK antigen is distinct from Ly1.2. This point was confirmed by the observation that alphaNK activity was removed by absorption of C3H anti-CE antiserum with spleen cells from either B6 or B6/Ly1.1 congenic strains. Absorption of C3H alphaCE serum with BALB/c thymocytes and spleen cells (which are Ly1.2+NK-) removed anti-Ly1.2 activity and left anti-NK activity intact. This absorption step could be circumvented by inserting the BALB/c genotype into the recipient immunized to CE cells (i.e., (C3H X BALB/c)F1 alphaCE spleen cells). This antiserum, provisionally termed 'anti-NK', defines a new subclass of lymphocytes which may play a central role in the immunosurveillance against tumors. PMID:187714

  8. Enhanced mesenchymal stromal cell recruitment via natural killer cells by incorporation of inflammatory signals in biomaterials

    PubMed Central

    Almeida, Catarina R.; Vasconcelos, Daniela P.; Gonçalves, Raquel M.; Barbosa, Mário A.

    2012-01-01

    An exacerbated inflammatory response questions biomaterial biocompatibility, but on the other hand, inflammation has a central role in the regulation of tissue regeneration. Therefore, it may be argued that an ‘ideal’ inflammatory response is crucial to achieve efficient tissue repair/regeneration. Natural killer (NK) cells, being one of the first populations arriving at an injury site, can have an important role in regulating bone repair/regeneration, particularly through interactions with mesenchymal stem/stromal cells (MSCs). Here, we studied how biomaterials