Sample records for killer cell large
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One approach to cancer immunotherapy, as opposed to therapeutic vaccination, is the transfusion of large numbers of tumor-specific killer T cells (cytotoxic T cells or CTLs) into patients. The body’s own defense killer T cells are a subgroup of T lymphocytes (a type of white blood cells) that are capable of inducing death in tumor cells. CTLs can cause the death of target
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Chromatin organization as an indicator of glucocorticoid induced natural killer cell dysfunction.
Misale, Michael S; Witek Janusek, Linda; Tell, Dina; Mathews, Herbert L
2018-01-01
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 reserved.
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Agonist antibody that induces human malignant cells to kill one another
Yea, Kyungmoo; Zhang, Hongkai; Xie, Jia; Jones, Teresa M.; Lin, Chih-Wei; Francesconi, Walter; Berton, Fulvia; Fallahi, Mohammad; Sauer, Karsten; Lerner, Richard A.
2015-01-01
An attractive, but as yet generally unrealized, approach to cancer therapy concerns discovering agents that change the state of differentiation of the cancer cells. Recently, we discovered a phenomenon that we call “receptor pleiotropism” in which agonist antibodies against known receptors induce cell fates that are very different from those induced by the natural agonist to the same receptor. Here, we show that one can take advantage of this phenomenon to convert acute myeloblastic leukemic cells into natural killer cells. Upon induction with the antibody, these leukemic cells enter into a differentiation cascade in which as many as 80% of the starting leukemic cells can be differentiated. The antibody-induced killer cells make large amounts of perforin, IFN-γ, and granzyme B and attack and kill other members of the leukemic cell population. Importantly, induction of killer cells is confined to transformed cells, in that normal bone marrow cells are not induced to form killer cells. Thus, it seems possible to use agonist antibodies to change the differentiation state of cancer cells into those that attack and kill other members of the malignant clone from which they originate. PMID:26487683
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Blastic natural killer cell leukaemia in a dog--a case report.
Bonkobara, Makoto; Saito, Taro; Yamashita, Masahiro; Tamura, Kyoichi; Yagihara, Hiroko; Isotani, Mayu; Sato, Takashi; Washizu, Tsukimi
2007-11-01
A case of canine non-T, non-B lymphoid leukaemia was determined to be of natural killer (NK) cell lineage by detecting specific expression of canine CD56 mRNA by reverse transcriptase polymerase chain reaction analysis. Although NK cells are usually considered to be morphologically large granular lymphocytes, the malignant NK cells in this case were agranular and blast-like, resembling human blastic NK cell leukaemia. The prognosis of human NK cell leukaemia is usually poor. In this case, the dog died 10 days after initial presentation, despite chemotherapy.
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T-cell lymphomas in South america and europe.
Bellei, Monica; Chiattone, Carlos Sergio; Luminari, Stefano; Pesce, Emanuela Anna; Cabrera, Maria Elena; de Souza, Carmino Antonio; Gabús, Raul; Zoppegno, Lucia; Zoppegno, Lucia; Milone, Jorge; Pavlovsky, Astrid; Connors, Joseph Michael; Foss, Francine Mary; Horwitz, Steven Michael; Liang, Raymond; Montoto, Silvia; Pileri, Stefano Aldo; Polliack, Aaron; Vose, Julie Marie; Zinzani, Pier Luigi; Zucca, Emanuele; Federico, Massimo
2012-01-01
Peripheral T-cell lymphomas are a group of rare neoplasms originating from clonal proliferation of mature post-thymic lymphocytes with different entities having specific biological characteristics and clinical features. As natural killer cells are closely related to T-cells, natural killer-cell lymphomas are also part of the group. The current World Health Organization classification recognizes four categories of T/natural killer-cell lymphomas with respect to their presentation: disseminated (leukemic), nodal, extranodal and cutaneous. Geographic variations in the distribution of these diseases are well documented: nodal subtypes are more frequent in Europe and North America, while extranodal forms, including natural killer-cell lymphomas, occur almost exclusively in Asia and South America. On the whole, T-cell lymphomas are more common in Asia than in western countries, usually affect adults, with a higher tendency in men, and, excluding a few subtypes, usually have an aggressive course and poor prognosis. Apart from anaplastic lymphoma kinase-positive anaplastic large cell lymphoma, that have a good outcome, other nodal and extranodal forms have a 5-year overall survival of about 30%. According to the principal prognostic indexes, the majority of patients are allocated to the unfavorable subset. In the past, the rarity of these diseases prevented progress in the understanding of their biology and improvements in the efficaciousness of therapy. Recently, international projects devoted to these diseases created networks promoting investigations on T-cell lymphomas. These projects are the basis of forthcoming cooperative, large scale trials to detail biologic characteristics of each sub-entity and to possibly individuate targets for new therapies.
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T-Cell Lymphomas in South America and Europe
Bellei, Monica; Chiattone, Carlos Sergio; Luminari, Stefano; Pesce, Emanuela Anna; Cabrera, Maria Elena; de Souza, Carmino Antonio; Gabús, Raul; Zoppegno, Lucia; Zoppegno, Lucia; Milone, Jorge; Pavlovsky, Astrid; Connors, Joseph Michael; Foss, Francine Mary; Horwitz, Steven Michael; Liang, Raymond; Montoto, Silvia; Pileri, Stefano Aldo; Polliack, Aaron; Vose, Julie Marie; Zinzani, Pier Luigi; Zucca, Emanuele; Federico, Massimo
2012-01-01
Peripheral T-cell lymphomas are a group of rare neoplasms originating from clonal proliferation of mature post-thymic lymphocytes with different entities having specific biological characteristics and clinical features. As natural killer cells are closely related to T-cells, natural killer-cell lymphomas are also part of the group. The current World Health Organization classification recognizes four categories of T/natural killer-cell lymphomas with respect to their presentation: disseminated (leukemic), nodal, extranodal and cutaneous. Geographic variations in the distribution of these diseases are well documented: nodal subtypes are more frequent in Europe and North America, while extranodal forms, including natural killer-cell lymphomas, occur almost exclusively in Asia and South America. On the whole, T-cell lymphomas are more common in Asia than in western countries, usually affect adults, with a higher tendency in men, and, excluding a few subtypes, usually have an aggressive course and poor prognosis. Apart from anaplastic lymphoma kinase-positive anaplastic large cell lymphoma, that have a good outcome, other nodal and extranodal forms have a 5-year overall survival of about 30%. According to the principal prognostic indexes, the majority of patients are allocated to the unfavorable subset. In the past, the rarity of these diseases prevented progress in the understanding of their biology and improvements in the efficaciousness of therapy. Recently, international projects devoted to these diseases created networks promoting investigations on T-cell lymphomas. These projects are the basis of forthcoming cooperative, large scale trials to detail biologic characteristics of each sub-entity and to possibly individuate targets for new therapies. PMID:23049383
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One approach to cancer immunotherapy, as opposed to therapeutic vaccination, is the transfusion of large numbers of tumor-specific killer T cells (cytotoxic T cells or CTLs) into patients. The body’s own defense killer T cells are a subgroup of T lymphocytes (a type of white blood cells) that are capable of inducing death in tumor cells. CTLs can cause the death of target cells either by releasing granules containing toxic molecules including perforin, or by producing a membrane protein called Fas ligand (FasL) which on interaction with the tumor cell results in cell death.
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Natural killer T cells in health and disease
Wu, Lan; Van Kaer, Luc
2013-01-01
Natural killer T (NKT) cells are a subset of T lymphocytes that share surface markers and functional characteristics with both conventional T lymphocytes and natural killer cells. Most NKT cells express a semiinvariant T cell receptor that reacts with glycolipid antigens presented by the major histocompatibility complex class I-related protein CD1d on the surface of antigen-presenting cells. NKT cells become activated during a variety of infections and inflammatory conditions, rapidly producing large amounts of immunomodulatory cytokines. NKT cells can influence the activation state and functional properties of multiple other cell types in the immune system and, thus, modulate immune responses against infectious agents, autoantigens, tumors, tissue grafts and allergens. One attractive aspect of NKT cells is that their immunomodulatory activities can be readily harnessed with cognate glycolipid antigens, such as the marine sponge-derived glycosphingolipid alpha-galactosylceramide. These properties of NKT cells are being exploited for therapeutic intervention to prevent or treat cancer, infections, and autoimmune and inflammatory diseases. PMID:21196373
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View Point: Semaphorin-3E: An Emerging Modulator of Natural Killer Cell Functions?
Alamri, Abdulaziz; Soussi Gounni, Abdelilah; Kung, Sam K. P.
2017-01-01
Semaphorin-3E (Sema-3E) is a member of a large family of proteins originally identified as axon guidance cues in neural development. It is expressed in different cell types, such as immune cells, cancer cells, neural cells, and epithelial cells. Subsequently, dys-regulation of Sema-3E expression has been reported in various biological processes that range from cancers to autoimmune and allergic diseases. Recent work in our laboratories revealed a critical immunoregulatory role of Sema-3E in experimental allergic asthma. We further speculate possible immune modulatory function(s) of Sema-3E on natural killer (NK) cells. PMID:29113093
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Phototoxic effects of lysosome-associated genetically encoded photosensitizer KillerRed
NASA Astrophysics Data System (ADS)
Serebrovskaya, Ekaterina O.; Ryumina, Alina P.; Boulina, Maria E.; Shirmanova, Marina V.; Zagaynova, Elena V.; Bogdanova, Ekaterina A.; Lukyanov, Sergey A.; Lukyanov, Konstantin A.
2014-07-01
KillerRed is a unique phototoxic red fluorescent protein that can be used to induce local oxidative stress by green-orange light illumination. Here we studied phototoxicity of KillerRed targeted to cytoplasmic surface of lysosomes via fusion with Rab7, a small GTPase that is known to be attached to membranes of late endosomes and lysosomes. It was found that lysosome-associated KillerRed ensures efficient light-induced cell death similar to previously reported mitochondria- and plasma membrane-localized KillerRed. Inhibitory analysis demonstrated that lysosomal cathepsins play an important role in the manifestation of KillerRed-Rab7 phototoxicity. Time-lapse monitoring of cell morphology, membrane integrity, and nuclei shape allowed us to conclude that KillerRed-Rab7-mediated cell death occurs via necrosis at high light intensity or via apoptosis at lower light intensity. Potentially, KillerRed-Rab7 can be used as an optogenetic tool to direct target cell populations to either apoptosis or necrosis.
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The prognostic value of natural killer cell infiltration in resected pulmonary adenocarcinoma.
Takanami, I; Takeuchi, K; Giga, M
2001-06-01
Natural cytotoxicity caused by mediated natural killer cells is believed to play an important role in host-cancer defense mechanisms. Immunohistochemically, we have detected natural killer cells in tissue specimens from patients with pulmonary adenocarcinoma and have assessed their clinical characteristics. Using the monoclonal antibody for CD57 specific marker for natural killer cells, we quantified natural killer cell infiltration in 150 patients with pulmonary adenocarcinoma who underwent curative tumor resection to investigate the relationship between natural killer cell counts and clinicopathologic factors and prognosis. The natural killer cell count was significantly related to the regulation of tumor progression, involving T classification, N classification, and stage (P =.01 for T classification or stage; P =.02 for N classification). A significant difference in the rate of patient survival was detected between those patients whose tumors had either high or low natural killer cell counts in both the overall and stage I groups (P =.0002 for the overall group; P =.049 for the stage I group). These data indicate that natural killer infiltration may contribute to the regulation of tumor progression and that the natural killer cell count can serve as a useful prognostic marker in overall and stage I pulmonary adenocarcinoma.
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Siegler, Uwe; Meyer-Monard, Sandrine; Jörger, Simon; Stern, Martin; Tichelli, André; Gratwohl, Alois; Wodnar-Filipowicz, Aleksandra; Kalberer, Christian P
2010-10-01
Alloreactive natural killer (NK) cells are potent effectors of innate anti-tumor defense. The introduction of NK cell-based immunotherapy to current treatment options in acute myeloid leukemia (AML) requires NK cell products with high anti-leukemic efficacy optimized for clinical use. We describe a good manufacturing practice (GMP)-compliant protocol of large-scale ex vivo expansion of alloreactive NK cells suitable for multiple donor lymphocyte infusions (NK-DLI) in AML. CliniMACS-purified NK cells were cultured in closed air-permeable culture bags with certified culture medium and components approved for human use [human serum, interleukin (IL)-2, IL-15 and anti-CD3 antibody] and with autologous irradiated feeder cells. NK cells (6.0 ± 1.2 x 10(8)) were purified from leukaphereses (8.1 ± 0.8 L) of six healthy donors and cultured under GMP conditions. NK cell numbers increased 117.0 ± 20.0-fold in 19 days. To reduce the culture volume associated with expansion of bulk NK cells and to expand selectively the alloreactive NK cell subsets, GMP-certified cell sorting was introduced to obtain cells with single killer immunoglobulin-like receptor (KIR) specificities. The subsequent GMP-compliant expansion of single KIR+ cells was 268.3 ± 66.8-fold, with a contaminating T-cell content of only 0.006 ± 0.002%. The single KIR-expressing NK cells were cytotoxic against HLA-mismatched primary AML blasts in vitro and effectively reduced tumor cell load in vivo in NOD/SCID mice transplanted with human AML. The approach to generating large numbers of GMP-grade alloreactive NK cells described here provides the basis for clinical efficacy trials of NK-DLI to complement and advance therapeutic strategies against human AML.
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Shirmanova, Marina; Yuzhakova, Diana; Snopova, Ludmila; Perelman, Gregory; Serebrovskaya, Ekaterina; Lukyanov, Konstantin; Turchin, Ilya; Subochev, Pavel; Lukyanov, Sergey; Kamensky, Vladislav; Zagaynova, Elena
2015-01-01
The strong phototoxicity of the red fluorescent protein KillerRed allows it to be considered as a potential genetically encoded photosensitizer for the photodynamic therapy (PDT) of cancer. The advantages of KillerRed over chemical photosensitizers are its expression in tumor cells transduced with the appropriate gene and direct killing of cells through precise damage to any desired cell compartment. The ability of KillerRed to affect cell division and to induce cell death has already been demonstrated in cancer cell lines in vitro and HeLa tumor xenografts in vivo. However, the further development of this approach for PDT requires optimization of the method of treatment. In this study we tested the continuous wave (593 nm) and pulsed laser (584 nm, 10 Hz, 18 ns) modes to achieve an antitumor effect. The research was implemented on CT26 subcutaneous mouse tumors expressing KillerRed in fusion with histone H2B. The results showed that the pulsed mode provided a higher rate of photobleaching of KillerRed without any temperature increase on the tumor surface. PDT with the continuous wave laser was ineffective against CT26 tumors in mice, whereas the pulsed laser induced pronounced histopathological changes and inhibition of tumor growth. Therefore, we selected an effective regimen for PDT when using the genetically encoded photosensitizer KillerRed and pulsed laser irradiation.
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Veluchamy, John P.; Kok, Nina; van der Vliet, Hans J.; Verheul, Henk M. W.; de Gruijl, Tanja D.; Spanholtz, Jan
2017-01-01
Natural killer (NK) cells are critical immune effector cells in the fight against cancer. As NK cells in cancer patients are highly dysfunctional and reduced in number, adoptive transfer of large numbers of cytolytic NK cells and their potential to induce relevant antitumor responses are widely explored in cancer immunotherapy. Early studies from autologous NK cells have failed to demonstrate significant clinical benefit. In this review, the clinical benefits of adoptively transferred allogeneic NK cells in a transplant and non-transplant setting are compared and discussed in the context of relevant NK cell platforms that are being developed and optimized by various biotech industries with a special focus on augmenting NK cell functions. PMID:28620386
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Wu, Junjie; Waxman, David J.
2014-01-01
Metronomic cyclophosphamide (CPA) treatment activates robust innate anti-tumor immunity and induces major regression of large, implanted brain tumor xenografts when administered on an intermittent, every 6-day schedule, but not on a daily low-dose or a maximum-tolerated dose CPA schedule. Here, we used an implanted GL261 glioma model to compare five intermittent metronomic CPA schedules to elucidate the kinetics and schedule dependence of innate immune cell recruitment and tumor regression. Tumor-recruited natural killer cells induced by two every 6-day treatment cycles were significantly ablated one day after a third CPA treatment, but largely recovered several days later. Natural killer and other tumor-infiltrating innate immune cells peaked 12 days after the last CPA treatment on the every 6-day schedule, suggesting that drug-free intervals longer than 6 days may show increased efficacy. Metronomic CPA treatments spaced 9 or 12 days apart, or on an alternating 6 and 9 day schedule, induced extensive tumor regression, similar to the 6-day schedule, however, the tumor-infiltrating natural killer cell responses were not sustained, leading to rapid resumption of tumor regrowth after day 24, despite ongoing metronomic CPA treatment. Increasing the CPA dose prolonged the period of tumor regression on the every 9-day schedule, but natural killer cell activation was markedly decreased. Thus, while several intermittent metronomic CPA treatment schedules can activate innate immune cell recruitment leading to major tumor regression, sustained immune and anti-tumor responses are only achieved on the 6-day schedule. However, even with this schedule, some tumors eventually relapse, indicating a need for further improvements in immunogenic metronomic therapies. PMID:25069038
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Fasting Enhances TRAIL-Mediated Liver Natural Killer Cell Activity via HSP70 Upregulation
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. PMID:25356750
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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. © Society for Leukocyte Biology.
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Takehara, Kiyoto; Yano, Shuya; Tazawa, Hiroshi; Kishimoto, Hiroyuki; Narii, Nobuhiro; Mizuguchi, Hiroyuki; Urata, Yasuo; Kagawa, Shunsuke; Fujiwara, Toshiyoshi; Hoffman, Robert M
2017-08-18
Melanoma is a highly recalcitrant cancer and transformative therapy is necessary for the cure of this disease. We recently developed a telomerase-dependent adenovirus containing the fluorescent protein Killer-Red. In the present report, we first determined the efficacy of Killer-Red adenovirus combined with laser irradiation on human melanoma cell lines in vitro. Cell viability of human melanoma cells was reduced in a dose-dependent and irradiation-time-dependent manner. We used an intradermal xenografted melanoma model in nude mice to determine efficacy of the Killer-Red adenovirus. Intratumoral injection of Killer-Red adenovirus, combined with laser irradiation, eradicated the melanoma indicating the potential of a new paradigm of cancer therapy.
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Ocular anatomy, ganglion cell distribution and retinal resolution of a killer whale (Orcinus orca).
Mass, Alla M; Supin, Alexander Y; Abramov, Andrey V; Mukhametov, Lev M; Rozanova, Elena I
2013-01-01
Retinal topography, cell density and sizes of ganglion cells in the killer whale (Orcinus orca) were analyzed in retinal whole mounts stained with cresyl violet. A distinctive feature of the killer whale's retina is the large size of ganglion cells and low cell density compared to terrestrial mammals. The ganglion cell diameter ranged from 8 to 100 µm, with the majority of cells within a range of 20-40 µm. The topographic distribution of ganglion cells displayed two spots of high cell density located in the temporal and nasal quadrants, 20 mm from the optic disk. The high-density areas were connected by a horizontal belt-like area passing below the optic disk of the retina. Peak cell densities in these areas were evaluated. Mean peak cell densities were 334 and 288 cells/mm(2) in the temporal and nasal high-density areas, respectively. With a posterior nodal distance of 19.5 mm, these high-density data predict a retinal resolution of 9.6' (3.1 cycles/deg.) and 12.6' (2.4 cycles/deg.) in the temporal and nasal areas, respectively, in water. Copyright © 2012 S. Karger AG, Basel.
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Novakova, Lucie; Nevoralova, Zuzana; Novak, Jan
2012-01-01
Invariant natural killer T (iNKT) cells, CD1d restricted T cells, are involved in the immune responses against various infection agents. Here we describe their behavior during reactivation of human herpes simplex virus (HSV). iNKT cells exhibit only discrete changes, which however, reached statistically significant level due to the relatively large patient group. Higher percentage of iNKT cells express NKG2D. iNKT cells down-regulate NKG2A in a subset of patients. Finally, iNKT cells enhance their capacity to produce TNF-α. Our data suggests that iNKT cells are involved in the immune response against HSV and contribute mainly to its early, innate phase. Copyright © 2012 Elsevier Inc. All rights reserved.
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Large-Scale Culture and Genetic Modification of Human Natural Killer Cells for Cellular Therapy.
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.
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Chen, Xiaoyan; Mariee, Najat; Jiang, Lingming; Liu, Yingyu; Wang, Chi Chiu; Li, Tin Chiu; Laird, Susan
2017-12-01
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 Elsevier Inc. All rights reserved.
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A Novel Feeder-free System for Mass Production of Murine Natural Killer Cells In Vitro.
Tang, Patrick Ming-Kuen; Tang, Philip Chiu-Tsun; Chung, Jeff Yat-Fai; Hung, Jessica Shuk Chun; Wang, Qing-Ming; Lian, Guang-Yu; Sheng, Jingyi; Huang, Xiao-Ru; To, Ka-Fai; Lan, Hui-Yao
2018-01-09
Natural killer (NK) cells belong to the innate immune system and are a first-line anti-cancer immune defense; however, they are suppressed in the tumor microenvironment and the underlying mechanism is still largely unknown. The lack of a consistent and reliable source of NK cells limits the research progress of NK cell immunity. Here, we report an in vitro system that can provide high quality and quantity of bone marrow-derived murine NK cells under a feeder-free condition. More importantly, we also demonstrate that siRNA-mediated gene silencing successfully inhibits the E4bp4-dependent NK cell maturation by using this system. Thus, this novel in vitro NK cell differentiating system is a biomaterial solution for immunity research.
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Roberto, Alessandra; Di Vito, Clara; Zaghi, Elisa; Mazza, Emilia Maria Cristina; Capucetti, Arianna; Calvi, Michela; Tentorio, Paolo; Zanon, Veronica; Sarina, Barbara; Mariotti, Jacopo; Bramanti, Stefania; Tenedini, Elena; Tagliafico, Enrico; Bicciato, Silvio; Santoro, Armando; Roederer, Mario; Marcenaro, Emanuela; Castagna, Luca; Lugli, Enrico; Mavilio, Domenico
2018-04-26
Natural Killer cells are the first lymphocyte population to reconstitute early after non myelo-ablative and T cell-replete haploidentical hematopoietic stem cell transplantation with post-transplant infusion of cyclophosphamide. The present study characterizes the transient and predominant expansion starting from the 2nd week after haploidentical hematopoietic stem cell transplantation of a donor-derived unconventional subset of NKp46neg-low/CD56dim/CD16neg natural killer cells expressing remarkable high levels of CD94/NKG2A. Both transcription and phenotypic profiles indicated that unconventional NKp46neg-low/CD56dim/CD16neg natural killer cells are a distinct natural killer cell subpopulation with features of late stage differentiation, yet retaining proliferative capability and functional plasticity to generate conventional NKp46pos/CD56bright/CD16pos natural killer cells in response to interleukin-15 plus interleukin-18. While present at low frequency in healthy donors, unconventional NKp46neg-low/CD56dim/CD16neg natural killer cells are greatly expanded in the following 7 weeks after haploidentical hematopoietic stem cell transplantation and express high levels of the activating receptors NKGD and NKp30 as well as of the lytic granules Granzyme-B and Perforin. Nonetheless, NKp46neg-low/CD56dim/CD16neg natural killer cells displayed a markedly defective cytotoxicity that could be reversed by blocking the inhibitory receptor CD94/NKG2A. These data open new important perspectives to better understand the ontogenesis/homeostasis of human natural killer cells and to develop a novel immune-therapeutic approach that targets the inhibitory NKG2A check point, thus unleashing natural killer cell alloreactivity early after haploidentical hematopoietic stem cell transplantation. Copyright © 2018, Ferrata Storti Foundation.
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Jiang, Hong Ning; Li, Yuan; Jiang, Wen Yi; Cui, Zong Jie
2018-01-01
Plasma membrane-delimited generation of singlet oxygen by photodynamic action with photosensitizer sulfonated aluminum phthalocyanine (SALPC) activates cholecystokinin 1 receptor (CCK1R) in pancreatic acini. Whether CCK1R retains such photooxidative singlet oxygen activation properties in other environments is not known. Genetically encoded protein photosensitizers KillerRed or mini singlet oxygen generator (miniSOG) were expressed in pancreatic acinar tumor cell line AR4-2J, CCK1R, KillerRed or miniSOG were expressed in HEK293 or CHO-K1 cells. Cold light irradiation (87 mW⋅cm -2 ) was applied to photosensitizer-expressing cells to examine photodynamic activation of CCK1R by Fura-2 fluorescent calcium imaging. When CCK1R was transduced into HEK293 cells which lack endogenous CCK1R, photodynamic action with SALPC was found to activate CCK1R in CCK1R-HEK293 cells. When KillerRed or miniSOG were transduced into AR4-2J which expresses endogenous CCK1R, KillerRed or miniSOG photodynamic action at the plasma membrane also activated CCK1R. When fused KillerRed-CCK1R was transduced into CHO-K1 cells, light irradiation activated the fused CCK1R leading to calcium oscillations. Therefore KillerRed either expressed independently, or fused with CCK1R can both activate CCK1R photodynamically. It is concluded that photodynamic singlet oxygen activation is an intrinsic property of CCK1R, independent of photosensitizer used, or CCK1R-expressing cell types. Photodynamic singlet oxygen CCK1R activation after transduction of genetically encoded photosensitizer in situ may provide a convenient way to verify intrinsic physiological functions of CCK1R in multiple CCK1R-expressing cells and tissues, or to actuate CCK1R function in CCK1R-expressing and non-expressing cell types after transduction with fused KillerRed-CCK1R.
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IGF-1 promotes the development and cytotoxic activity of human NK cells
Ni, Fang; Sun, Rui; Fu, Binqing; Wang, Fuyan; Guo, Chuang; Tian, Zhigang; Wei, Haiming
2013-01-01
Insulin-like growth factor 1 (IGF-1) is a critical regulator of many physiological functions, ranging from longevity to immunity. However, little is known about the role of IGF-1 in natural killer cell development and function. Here, we identify an essential role for IGF-1 in the positive regulation of human natural killer cell development and cytotoxicity. Specifically, we show that human natural killer cells have the ability to produce IGF-1 and that differential endogenous IGF-1 expression leads to disparate cytotoxicity in human primary natural killer cells. Moreover, miR-483-3p is identified as a critical regulator of IGF-1 expression in natural killer cells. Overexpression of miR-483-3p has an effect similar to IGF-1 blockade and decreased natural killer cell cytotoxicity, whereas inhibition of miR-483-3p has the opposite effect, which is reversible with IGF-1 neutralizing antibody. These findings indicate that IGF-1 and miR-483-3p belong to a new class of natural killer cell functional modulators and strengthen the prominent role of IGF-1 in innate immunity. PMID:23403580
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Adoptive TReg Cell for Suppression of aGVHD After UCB HSCT for Heme Malignancies
2018-03-26
Acute Lymphoblastic Leukemia; Burkitt Lymphoma; Natural Killer Cell Malignancies; Chronic Myelogenous Leukemia; Myelodysplastic Syndromes; Large-cell Lymphoma; Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma; Marginal Zone B-Cell Lymphoma; Follicular Lymphoma; Lymphoplasmacytic Lymphoma; Mantle-Cell Lymphoma; Prolymphocytic Leukemia; Hodgkin Lymphoma; Multiple Myeloma; Acute Myelogenous Leukemia; Biphenotypic Leukemia; Undifferentiated Leukemia
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Medina, K; Carrau, F M; Gioia, O; Bracesco, N
1997-01-01
The competition between selected or commercial killer strains of type K2 and sensitive commercial strains of Saccharomyces cerevisiae was studied under various conditions in sterile grape juice fermentations. The focus of this study was the effect of yeast inoculation levels and the role of assimilable nitrogen nutrition on killer activity. A study of the consumption of free amino nitrogen (FAN) by pure and mixed cultures of killer and sensitive cells showed no differences between the profiles of nitrogen assimilation in all cases, and FAN was practically depleted in the first 2 days of fermentation. The effect of the addition of assimilable nitrogen and the size of inoculum was examined in mixed killer and sensitive strain competitions. Stuck and sluggish wine fermentations were observed to depend on nitrogen availability when the ratio of killer to sensitive cells was low (1:10 to 1:100). A relationship between the initial assimilable nitrogen content of must and the proportion of killer cells during fermentation was shown. An indirect relationship was found between inoculum size and the percentage of killer cells: a smaller inoculum resulted in a higher proportion of killer cells in grape juice fermentations. In all cases, wines obtained with pure-culture fermentations were preferred to mixed-culture fermentations by sensory analysis. The reasons why killer cells do not finish fermentation under competitive conditions with sensitive cells are discussed. PMID:9212430
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Baytak, Esra; Gong, Qiang; Akman, Burcu; Yuan, Hongling; Chan, Wing C; Küçük, Can
2017-05-01
Natural killer/T-cell lymphoma is a rare but aggressive neoplasm with poor prognosis. Despite previous reports that showed potential tumor suppressors, such as PRDM1 or oncogenes associated with the etiology of this malignancy, the role of long non-coding RNAs in natural killer/T-cell lymphoma pathobiology has not been addressed to date. Here, we aim to identify cancer-associated dysregulated long non-coding RNAs and signaling pathways or biological processes associated with these long non-coding RNAs in natural killer/T-cell lymphoma cases and to identify the long non-coding RNAs transcriptionally regulated by PRDM1. RNA-Seq analysis revealed 166 and 66 long non-coding RNAs to be significantly overexpressed or underexpressed, respectively, in natural killer/T-cell lymphoma cases compared with resting or activated normal natural killer cells. Novel long non-coding RNAs as well as the cancer-associated ones such as SNHG5, ZFAS1, or MIR155HG were dysregulated. Interestingly, antisense transcripts of many growth-regulating genes appeared to be transcriptionally deregulated. Expression of ZFAS1, which is upregulated in natural killer/T-cell lymphoma cases, showed association with growth-regulating pathways such as stabilization of P53, regulation of apoptosis, cell cycle, or nuclear factor-kappa B signaling in normal and neoplastic natural killer cell samples. Consistent with the tumor suppressive role of PRDM1, we identified MIR155HG and TERC to be transcriptionally downregulated by PRDM1 in two PRDM1-null NK-cell lines when it is ectopically expressed. In conclusion, this is the first study that identified long non-coding RNAs whose expression is dysregulated in natural killer/T-cell lymphoma cases. These findings suggest that ZFAS1 and other dysregulated long non-coding RNAs may be involved in natural killer/T-cell lymphoma pathobiology through regulation of cancer-related genes, and loss-of-PRDM1 expression in natural killer/T-cell lymphomas may contribute to overexpression of MIR155HG; thereby promoting tumorigenesis.
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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.
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Background Modified function of immune cells in nasal secretions may playa role in the enhanced susceptibility to resp iratory viruses that is seen in smokers. Innate immune cells in nasal secretions have largely been characterized by cellular differentials using morphologic c...
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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 dendritic cell. These data demonstrate that trauma-induced immunosuppression is characterized by an interleukin-10-dependent elimination of dendritic cell by natural killer cells and that hydrocortisone improves outcome by limiting this immunosuppressive feedback loop.
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Laouar, Yasmina; Sutterwala, Fayyaz S; Gorelik, Leonid; Flavell, Richard A
2005-06-01
Interferon-gamma and interleukin 12 produced by the innate arm of the immune system are important regulators of T helper type 1 (T(H)1) cell development, but signals that negatively regulate their expression remain controversial. Here we show that transforming growth factor-beta (TGF-beta) controlled T(H)1 differentiation through the regulation of interferon-gamma produced by natural killer (NK) cells. Blockade of TGF-beta signaling in NK cells caused the accumulation of a large pool of NK cells secreting copious interferon-gamma, responsible for T(H)1 differentiation and protection from leishmania infection. In contrast, blockade of TGF-beta signaling in dendritic cells did not affect dendritic cell homeostasis or interleukin 12 production, thus indicating a previously undescribed demarcation of the function of TGF-beta in NK cells versus dendritic cells.
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Cyclosporin a inhibits T cell-mediated augmentation of mouse natural killer activity.
Yanagihara, R H; Adler, W H
1982-06-01
Cyclosporin A (CSA) in vitro inhibited the spontaneous cytotoxic activity of mouse spleen cells against YAC target cells in a 4 hr 51Cr release assay. While natural killer (NK) cells were inhibited directly by CSA, these suppressive effects were largely reversible by coculture of effector cells for an optimal period with polyinosinic-polycytidylic acid (Poly I:C) or lipopolysaccharide (LPS). In contrast concanavalin A (Con A), in the presence of CSA, was unable to augment NK activity. The supernatant, however, of mouse spleen cells cultured with Con A was fully able to augment the NK the activity by freshly cultured spleen cells in the presence of CSA. The results indicate that CSA inhibits NK activity by two distinct mechanisms: a) a direct inactivation of NK cells and b) a suppression of production or release of an NK-activating factor from T cells, but not B cells or macrophages.
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Natural killer cell function predicts severe infection in kidney transplant recipients.
Dendle, Claire; Gan, Poh-Yi; Polkinghorne, Kevan R; Ngui, James; Stuart, Rhonda L; Kanellis, John; Thursky, Karin; Mulley, William R; Holdsworth, Stephen
2018-04-30
The aim of this study was to determine if natural killer cell number (CD3 - /CD16 ± /CD56 ± ) and cytotoxic killing function predicts severity and frequency of infection in kidney transplant recipients. A cohort of 168 kidney transplant recipients with stable graft function underwent assessment of natural killer cell number and functional killing capacity immediately prior to entry into this prospective study. Participants were followed for 2 years for development of severe infection, defined as hospitalization for infection. Area under receiver operating characteristic (AUROC) curves were used to evaluate the accuracy of natural killer cell number and function for predicting severe infection. Adjusted odds ratios were determined by logistic regression. Fifty-nine kidney transplant recipients (35%) developed severe infection and 7 (4%) died. Natural killer cell function was a better predictor of severe infection than natural killer cell number: AUROC 0.84 and 0.75, respectively (P = .018). Logistic regression demonstrated that after adjustment for age, transplant function, transplant duration, mycophenolate use, and increasing natural killer function (odds ratio [OR] 0.82, 95% confidence interval [CI] 0.74-0.90; P < .0001) but not natural killer number (OR 0.96, 95% CI 0.93-1.00; P = .051) remained significantly associated with a reduced likelihood of severe infection. Natural killer cell function predicts severe infection in kidney transplant recipients. © 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.
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Rea, Delphine; Henry, Guylaine; Khaznadar, Zena; Etienne, Gabriel; Guilhot, François; Nicolini, Franck; Guilhot, Joelle; Rousselot, Philippe; Huguet, Françoise; Legros, Laurence; Gardembas, Martine; Dubruille, Viviane; Guerci-Bresler, Agnès; Charbonnier, Aude; Maloisel, Frédéric; Ianotto, Jean-Christophe; Villemagne, Bruno; Mahon, François-Xavier; Moins-Teisserenc, Hélène; Dulphy, Nicolas; Toubert, Antoine
2017-08-01
Despite persistence of leukemic stem cells, patients with chronic myeloid leukemia who achieve and maintain deep molecular responses may successfully stop the tyrosine kinase inhibitor imatinib. However, questions remain unanswered regarding the biological basis of molecular relapse after imatinib cessation. In IMMUNOSTIM, we monitored 51 patients from the French Stop IMatinib trial for peripheral blood T cells and natural killer cells. Molecular relapse-free survival at 24 months was 45.1% (95% CI: 31.44%-58.75%). At the time of imatinib discontinuation, non-relapsing patients had significantly higher numbers of natural killer cells of the cytotoxic CD56 dim subset than had relapsing patients, while CD56 bright natural killer cells, T cells and their subsets did not differ significantly. Furthermore, the CD56 dim natural killer-cell count was an independent prognostic factor of molecular-relapse free survival in a multivariate analysis. However, expression of natural killer-cell activating receptors, BCR-ABL1 + leukemia cell line K562-specific degranulation and cytokine-induced interferon-gamma secretion were decreased in non-relapsing and relapsing patients as compared with healthy individuals. After imatinib cessation, the natural killer-cell count increased significantly and stayed higher in non-relapsing patients than in relapsing patients, while receptor expression and functional properties remained unchanged. Altogether, our results suggest that natural killer cells may play a role in controlling leukemia-initiating cells at the origin of relapse after imatinib cessation, provided that these cells are numerous enough to compensate for their functional defects. Further research will decipher mechanisms underlying functional differences between natural killer cells from patients and healthy individuals and evaluate the potential interest of immunostimulatory approaches in tyrosine kinase inhibitor discontinuation strategies. (ClinicalTrial.gov Identifier NCT00478985) . Copyright© 2017 Ferrata Storti Foundation.
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Kim, Choon Kwan; Choi, Youn Mi; Bae, Eunsin; Jue, Mihn Sook; So, Hyung Seok; Hwang, Eung-Soo
2018-01-01
The pathogenesis of herpes zoster is closely linked to reduced varicella-zoster virus-specific cell-mediated immunity. However, little is known about the interplay between natural killer cells and psychological stress in the pathogenesis of herpes zoster. This study aimed to investigate possible associations among natural killer cells, T cells and psychological stress in herpes zoster. Interferon-gamma secretion from natural killer cell, psychological stress events, stress cognition scale scores and cytomegalovirus-specific cell-mediated immunity were compared between 44 patients with herpes zoster and 44 age- and gender-matched control subjects. A significantly lower median level of interferon-gamma secreted by natural killer cells was observed in patients with a recent diagnosis of herpes zoster than in control subjects (582.7 pg/ml vs. 1783 pg/ml; P = 0.004), whereas cytomegalovirus-specific cell-mediated immunity was not associated with herpes zoster. Psychological stress events and high stress cognition scale scores were significantly associated in patients with herpes zoster (P<0.001 and P = 0.037, respectively). However, reduced interferon-gamma secretion from natural killer cell and psychological stress were not associated. In conclusion, patients with a recent diagnosis of herpes zoster display reduced interferon-gamma secretion from natural killer cells and frequent previous psychological stress events compared with controls. However, reduced natural killer cell activity is not an immunological mediator between psychological stress and herpes zoster.
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Kim, Choon Kwan; Choi, Youn Mi; Bae, Eunsin; Jue, Mihn Sook; So, Hyung Seok
2018-01-01
The pathogenesis of herpes zoster is closely linked to reduced varicella-zoster virus-specific cell-mediated immunity. However, little is known about the interplay between natural killer cells and psychological stress in the pathogenesis of herpes zoster. This study aimed to investigate possible associations among natural killer cells, T cells and psychological stress in herpes zoster. Interferon-gamma secretion from natural killer cell, psychological stress events, stress cognition scale scores and cytomegalovirus-specific cell-mediated immunity were compared between 44 patients with herpes zoster and 44 age- and gender-matched control subjects. A significantly lower median level of interferon-gamma secreted by natural killer cells was observed in patients with a recent diagnosis of herpes zoster than in control subjects (582.7 pg/ml vs. 1783 pg/ml; P = 0.004), whereas cytomegalovirus-specific cell-mediated immunity was not associated with herpes zoster. Psychological stress events and high stress cognition scale scores were significantly associated in patients with herpes zoster (P<0.001 and P = 0.037, respectively). However, reduced interferon-gamma secretion from natural killer cell and psychological stress were not associated. In conclusion, patients with a recent diagnosis of herpes zoster display reduced interferon-gamma secretion from natural killer cells and frequent previous psychological stress events compared with controls. However, reduced natural killer cell activity is not an immunological mediator between psychological stress and herpes zoster. PMID:29466462
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Deficient natural killer cell function in preeclampsia
DOE Office of Scientific and Technical Information (OSTI.GOV)
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.
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The role of natural killer cells in chronic myeloid leukemia
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
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[Nasal type natural killer/T cell lymphoma: case series and literature review].
Düzlü, Mehmet; Ant, Ayça; Tutar, Hakan; Karamert, Recep; Şahin, Melih; Sayar, Erolcan; Cesur, Nesibe
2016-01-01
Nasal type natural killer/T-cell lymphoma is a rare type of extranodal non-Hodgkin lymphoma which originates from nasal cavity and paranasal sinuses. Exact diagnosis of nasal natural killer/T-cell lymphoma, which is a rapidly progressive clinical condition, may be established by immunohistochemical analysis on biopsy material after clinical suspicion. In this article, we report four cases of nasal natural killer/T-cell lymphoma who were followed-up in our clinic and discuss the diagnosis and treatment of the disease in light of the literature data.
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Decreased non-MHC-restricted (CD56+) killer cell cytotoxicity after spaceflight
NASA Technical Reports Server (NTRS)
Mehta, S. K.; Kaur, I.; Grimm, E. A.; Smid, C.; Feeback, D. L.; Pierson, D. L.
2001-01-01
Cytotoxic activity of non-major histocompatibility complex-restricted (CD56+) (NMHC) killer cells and cell surface marker expression of peripheral blood mononuclear cells were determined before and after spaceflight. Ten astronauts (9 men, 1 woman) from two space shuttle missions (9- and 10-day duration) participated in the study. Blood samples were collected 10 days before launch, within 3 h after landing, and 3 days after landing. All peripheral blood mononuclear cell preparations were cryopreserved and analyzed simultaneously in a 4-h cytotoxicity (51)Cr release assay using K562 target cells. NMHC killer cell lytic activity was normalized per 1,000 CD56+ cells. When all 10 subjects were considered as one study group, NMHC killer cell numbers did not change significantly during the three sampling periods, but at landing lytic activity had decreased by approximately 40% (P < 0.05) from preflight values. Nine of ten astronauts had decreased lytic activity immediately after flight. NMHC killer cell cytotoxicity of only three astronauts returned toward preflight values by 3 days after landing. Consistent with decreased NMHC killer cell cytotoxicity, urinary cortisol significantly increased after landing compared with preflight levels. Plasma cortisol and ACTH levels at landing were not significantly different from preflight values. No correlation of changes in NMHC killer cell function or hormone levels with factors such as age, gender, mission, or spaceflight experience was found. After landing, expression of the major lymphocyte surface markers (CD3, CD4, CD8, CD14, CD16, CD56), as determined by flow cytometric analysis, did not show any consistent changes from measurements made before flight.
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Endogenous cannabinoid receptor ligand induces the migration of human natural killer cells.
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.
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Espinoza, J. Luis; Takami, Akiyoshi; Yoshioka, Katsuji; Nakata, Katsuya; Sato, Tokiharu; Kasahara, Yoshihito; Nakao, Shinji
2012-01-01
Background NKG2D is an activating receptor expressed by natural killer and T cells, which have crucial functions in tumor and microbial immunosurveillance. Several cytokines have been identified as modulators of NKG2D receptor expression. However, little is known about NKG2D gene regulation. In this study, we found that microRNA 1245 attenuated the expression of NKG2D in natural killer cells. Design and Methods We investigated the potential interactions between the 3′-untranslated region of the NKG2D gene and microRNA as well as their functional roles in the regulation of NKG2D expression and cytotoxicity in natural killer cells. Results Transforming growth factor-β1, a major negative regulator of NKG2D expression, post-transcriptionally up-regulated mature microRNA-1245 expression, thus down-regulating NKG2D expression and impairing NKG2D-mediated immune responses in natural killer cells. Conversely, microRNA-1245 down-regulation significantly increased the expression of NKG2D expression in natural killer cells, resulting in more efficient NKG2D-mediated cytotoxicity. Conclusions These results reveal a novel NKG2D regulatory pathway mediated by microRNA-1245, which may represent one of the mechanisms used by transforming growth factor-β1 to attenuate NKG2D expression in natural killer cells. PMID:22491735
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Eidenschenk, Celine; Dunne, Jean; Jouanguy, Emmanuelle; Fourlinnie, Claire; Gineau, Laure; Bacq, Delphine; McMahon, Corrina; Smith, Owen; Casanova, Jean-Laurent; Abel, Laurent; Feighery, Conleth
2006-04-01
We describe four children with a novel primary immunodeficiency consisting of specific natural-killer (NK) cell deficiency and susceptibility to viral diseases. One child developed an Epstein-Barr virus-driven lymphoproliferative disorder; two others developed severe respiratory illnesses of probable viral etiology. The four patients are related and belong to a large inbred kindred of Irish nomadic descent, which suggests autosomal recessive inheritance of this defect. A genomewide scan identified a single 12-Mb region on chromosome 8p11.23-q11.21 that was linked to this immunodeficiency (maximum LOD score 4.51). The mapping of the disease-causing genomic region paves the way for the identification of a novel pathway governing NK cell differentiation in humans.
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Eidenschenk, Céline; Dunne, Jean; Jouanguy, Emmanuelle; Fourlinnie, Claire; Gineau, Laure; Bacq, Delphine; McMahon, Corrina; Smith, Owen; Casanova, Jean-Laurent; Abel, Laurent; Feighery, Conleth
2006-01-01
We describe four children with a novel primary immunodeficiency consisting of specific natural-killer (NK) cell deficiency and susceptibility to viral diseases. One child developed an Epstein-Barr virus–driven lymphoproliferative disorder; two others developed severe respiratory illnesses of probable viral etiology. The four patients are related and belong to a large inbred kindred of Irish nomadic descent, which suggests autosomal recessive inheritance of this defect. A genomewide scan identified a single 12-Mb region on chromosome 8p11.23-q11.21 that was linked to this immunodeficiency (maximum LOD score 4.51). The mapping of the disease-causing genomic region paves the way for the identification of a novel pathway governing NK cell differentiation in humans. PMID:16532402
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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.
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Preventing surgery-induced NK cell dysfunction and cancer metastases with influenza vaccination
Tai, Lee-Hwa; Zhang, Jiqing; Auer, Rebecca C
2013-01-01
Surgical resection is the mainstay of treatment for solid tumors, but the postoperative period is uniquely inclined to the formation of metastases, largely due to the suppression of natural killer (NK) cells. We found that preoperative influenza vaccination prevents postoperative NK-cell dysfunction, attenuating tumor dissemination in murine models and promoting the activation of NK cells in cancer patients. PMID:24404430
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Cancer Immunology at the Crossroads: Killer immunoglobulin-like receptors and tumor immunity
Benson, Don M; Caligiuri, Michael A
2014-01-01
Natural killer (NK) cells, large granular lymphocytes comprising a key cellular subset of innate immunity, were originally named for their capacity to elicit potent cytotoxicity against tumor cells independent of prior sensitization or gene rearrangement. This process is facilitated through the expression of activating and inhibitory receptors that provide for NK cell “education” and a subsequent ability to survey, recognize and lyse infected or transformed cells, especially those lacking or possessing mutated major histocompatibility complex (MHC) class I expression. Since these original observations were made, how NK cells recognize candidate target cells continues to be the topic of ongoing investigation. It is now appreciated that NK cells express a diverse repertoire of activating and inhibitory receptors of which killer immunoglobulin-like receptors (KIR) appear to play a critical role in mediating self-tolerance as well as facilitating cytotoxicity against infected or transformed cells. Additionally, in the presence of an activating signal, the absence or mismatch of MHC class I molecules on such targets (which serve as inhibitory KIR ligands) promotes NK cell-mediated lysis. An increasing understanding of the complexities of KIR biology has provided recent opportunities to leverage the NK cell versus tumor effect as a novel avenue of therapeutic immunotherapy for cancer. The present review seeks to summarize the current understanding of KIR expression and function and highlight ongoing efforts to translate these discoveries into novel NK cell-mediated immunotherapies for cancer. PMID:24592397
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Tubby, Carolyn; Negm, Ola H; Harrison, Timothy; Tighe, Patrick J; Todd, Ian; Fairclough, Lucy C
2017-06-01
The three main types of killer cells - CD8 + T cells, NK cells and NKT cells - have been linked to asthma and chronic obstructive pulmonary disease (COPD). However, their role in a small subset of asthma patients displaying fixed airway obstruction (FAO), similar to that seen in COPD, has not been explored. The objective of the present study was to investigate killer cell numbers, phenotype and function in peripheral blood from asthma patients with FAO, asthma patients without FAO, and healthy individuals. Peripheral CD8 + T cells (CD8 + CD3 + CD56 - ), NK cells (CD56 + CD3 - ) and NKT-like cells (CD56 + CD3 + ) of 14 asthma patients with FAO (post-bronchodilator FEV/FVC <0.7, despite clinician-optimised treatment), 7 asthma patients without FAO (post-bronchodilator FEV/FVC ≥ 0.7), and 9 healthy individuals were studied. No significant differences were seen between the number, receptor expression, MAPK signalling molecule expression, cytotoxic mediator expression, and functional cytotoxicity of peripheral killer cells from asthma patients with FAO, asthma patients without FAO and healthy individuals. Peripheral killer cell numbers or functions do not differentiate between asthma patients with or without fixed airway obstruction.
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Ebihara, Y; Manabe, A; Tanaka, R; Yoshimasu, T; Ishikawa, K; Iseki, T; Hayakawa, J; Maeda, M; Asano, S; Tsuji, K
2003-06-01
The optimal treatment for natural killer (NK) cell leukemia after chronic active Epstein-Barr virus (CAEBV) infection has not been determined. A 15-year-old boy presented with NK cell leukemia following CAEBV infection for 5 years. The peripheral blood and BM had an increased number of CD3(-)CD56(+) large granular lymphocytes and a monoclonal integration of the EBV genome was detected. Chemotherapy was not sufficiently effective to control the disease. Allogeneic BMT from an HLA-identical sister was performed using a conditioning regimen consisting of total body irradiation, cyclophosphamide and thiotepa. The patient is disease-free with a perfect performance status 24 months after BMT. This is the first report to show that allogeneic BMT is potentially able to cure NK cell leukemia after CAEBV infection.
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Large-scale ex vivo expansion and characterization of natural killer cells for clinical applications
LAPTEVA, NATALIA; DURETT, APRIL G.; SUN, JIALI; ROLLINS, LISA A.; HUYE, LESLIE L.; FANG, JIAN; DANDEKAR, VARADA; MEI, ZHUYONG; JACKSON, KIMBERLEY; VERA, JUAN; ANDO, JUN; NGO, MINHTRAN C.; COUSTAN-SMITH, ELAINE; CAMPANA, DARIO; SZMANIA, SUSANN; GARG, TARUN; MORENO-BOST, AMBERLY; VANRHEE, FRITS; GEE, ADRIAN P.; ROONEY, CLIONA M.
2016-01-01
Background aims Interest in natural killer (NK) cell-based immunotherapy has resurged since new protocols for the purification and expansion of large numbers of clinical-grade cells have become available. Methods We have successfully adapted a previously described NK expansion method that uses K562 cells expressing interleukin (IL)-15 and 4-1 BB Ligand (BBL) (K562-mb15-41BBL) to grow NK cells in novel gas-permeable static cell culture flasks (G-Rex). Results Using this system we produced up to 19 × 109 functional NK cells from unseparated apheresis products, starting with 15 × 107 CD3− CD56+ NK cells, within 8–10 days of culture. The G-Rex yielded a higher fold expansion of NK cells than conventional gas-permeable bags and required no cell manipulation or feeding during the culture period. We also showed that K562-mb15-41BBL cells up-regulated surface HLA class I antigen expression upon stimulation with the supernatants from NK cultures and stimulated alloreactive CD8+ T cells within the NK cultures. However, these CD3+ T cells could be removed successfully using the CliniMACS system. We describe our optimized NK cell cryopreservation method and show that the NK cells are viable and functional even after 12 months of cryopreservation. Conclusions We have successfully developed a static culture protocol for large-scale expansion of NK cells in the gas permeable G-Rex system under good manufacturing practice (GMP) conditions. This strategy is currently being used to produce NK cells for cancer immunotherapy. PMID:22900959
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Liu, Wenhua; Gao, Yang; Li, Haibo; Wang, Hongliang; Ye, Ming; Jiang, Guihua; Chen, Yongsheng; Liu, Yang; Kong, Junying; Liu, Wei; Sun, Meng; Hou, Meng; Yu, Kaijiang
2016-10-01
Transplantation of mesenchymal stromal cells is a promising strategy for treating sepsis. Natural killer cells are important in the development of sepsis, and their functions can be inhibited by mesenchymal stromal cells, we asked whether mesenchymal stromal cells exert their therapeutic effects through inhibiting the functions of natural killer cells in a septic mouse model generated with cecal ligation puncture method. Using co-cultures of cells, small interfering RNA, enzyme-linked immnuosorbent assays, fluorescence assays, western blotting, and pathological examination, we investigated the levels of inflammatory cytokines, proliferation of natural killer cells, inflammatory infiltration of important organs in mice, and activity of the Janus kinase/signal transducer and activator of transcription signaling pathway and found that mesenchymal stromal cells inhibited the function and proliferation of septic natural killer cells, increased interleukin-10 levels and increased the expression of components, such as Janus kinase 1, Janus kinase 2, and signal transducer and activator of transcription 3 in the Janus kinase/signal transducer and activator of transcription pathway both in vitro and in vivo. We conclude that mesenchymal stromal cells have their therapeutic effect in the septic mouse model through inhibiting the function and proliferation of septic natural killer cells. This biological process may involve interleukin-10 and suppressor of cytokine signaling 3 as well as other pathway components in the Janus kinase/signal transducer and activator of transcription pathway. Transplantation of mesenchymal stromal cells is an effective strategy to treat sepsis. Copyright © 2016. Published by Elsevier Ltd.
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Chieregato, Katia; Zanon, Cristina; Castegnaro, Silvia; Bernardi, Martina; Amati, Eliana; Sella, Sabrina; Rodeghiero, Francesco; Astori, Giuseppe
2017-01-01
Cytokine-induced killer cells are polyclonal T cells generated ex vivo and comprise two main subsets: the CD56- fraction, possessing an alloreactive potential caused by T cells (CD3+CD56-), and the CD56+ fraction, characterised by a strong antitumour capacity induced by natural killer-like T cells (NK-like T, CD3+CD56+) and natural killer cells (NK, CD3-CD56+ bright). We investigated the cytotoxic action of selected CD56+ cell subpopulations against a human chronic myeloid leukaemia (K562) cell line. After immunomagnetic selection of the CD56+ cell fraction, NK bright cells (CD3-CD56+ bright) and two subsets of NK-like T cells (CD3+CD56+), called NK-like T CD56 dim and NK-like T CD56 bright, could be identified. The cytotoxic effect against K562 cells was mainly exerted by the NK bright subpopulation and resulted to be inversely correlated with the percentage of NK-like T CD56 dim cells in the culture. The lytic action appeared to be independent of cell degranulation as suggested by the lack of change in the expression of CD107a. We conclude that the cytotoxic action of CD56+ cells against a K562 cell line is mainly due to the NK cells.
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K2 killer toxin-induced physiological changes in the yeast Saccharomyces cerevisiae.
Orentaite, Irma; Poranen, Minna M; Oksanen, Hanna M; Daugelavicius, Rimantas; Bamford, Dennis H
2016-03-01
Saccharomyces cerevisiae cells produce killer toxins, such as K1, K2 and K28, that can modulate the growth of other yeasts giving advantage for the killer strains. Here we focused on the physiological changes induced by K2 toxin on a non-toxin-producing yeast strain as well as K1, K2 and K28 killer strains. Potentiometric measurements were adjusted to observe that K2 toxin immediately acts on the sensitive cells leading to membrane permeability. This correlated with reduced respiration activity, lowered intracellular ATP content and decrease in cell viability. However, we did not detect any significant ATP leakage from the cells treated by killer toxin K2. Strains producing heterologous toxins K1 and K28 were less sensitive to K2 than the non-toxin producing one suggesting partial cross-protection between the different killer systems. This phenomenon may be connected to the observed differences in respiratory activities of the killer strains and the non-toxin-producing strain at low pH. This might also have practical consequences in wine industry; both as beneficial ones in controlling contaminating yeasts and non-beneficial ones causing sluggish fermentation. © FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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Martz, Eric; Burakoff, Steven J.; Benacerraf, Baruj
1974-01-01
Specific lysis of tumor cells by thymus-derived lymphocytes from alloimmunized mice (T-effector specific lysis) was studied with target cells labeled with isotopes attached to both small (14C-labeled nicotinamide) and large (51Cr-labeled) molecules. The results confirm and extend previous reports that target cells release small molecules considerably earlier than large molecules during T-effector specific lysis. After interruption of T-effector specific lysis by specific antibody and complement directed against the killer cells, or by ethylenediaminetetraacetic acid, release of both isotopes continued, eventually reaching identical levels of specific release, the value of which represents the fraction of the target cell population which had been committed to die at the time these treatments were applied. On the other hand, release of both isotopes during T-effector specific lysis stops immediately when the cultures are cooled to 0°. Thus, while ethylenediaminetetraacetic acid or specific complement-mediated lysis of the killer cells merely prevents the initiation of any new damage to target cells, cooling to 0° also stops the lytic process in already-damaged target cells. The colloid osmotic phase of target cell lysis induced by specific antibody and complement was similarly stopped at 0° in tumor cells, but not in erythrocytes. Thus, in tumor target cells, both T-effector specific lysis and complement cause a sequential release of progressively larger molecules which can be immediately stopped at any point by cooling to 0°. PMID:4359327
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Natural Killer Cells Promote Fetal Development through the Secretion of Growth-Promoting Factors.
Fu, Binqing; Zhou, Yonggang; Ni, Xiang; Tong, Xianhong; Xu, Xiuxiu; Dong, Zhongjun; Sun, Rui; Tian, Zhigang; Wei, Haiming
2017-12-19
Natural killer (NK) cells are present in large populations at the maternal-fetal interface during early pregnancy. However, the role of NK cells in fetal growth is unclear. Here, we have identified a CD49a + Eomes + subset of NK cells that secreted growth-promoting factors (GPFs), including pleiotrophin and osteoglycin, in both humans and mice. The crosstalk between HLA-G and ILT2 served as a stimulus for GPF-secreting function of this NK cell subset. Decreases in this GPF-secreting NK cell subset impaired fetal development, resulting in fetal growth restriction. The transcription factor Nfil3, but not T-bet, affected the function and the number of this decidual NK cell subset. Adoptive transfer of induced CD49a + Eomes + NK cells reversed impaired fetal growth and rebuilt an appropriate local microenvironment. These findings reveal properties of NK cells in promoting fetal growth. In addition, this research proposes approaches for therapeutic administration of NK cells in order to reverse restricted nourishments within the uterine microenvironment during early pregnancy. Copyright © 2017 Elsevier Inc. All rights reserved.
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van Rensburg, Ilana C; Loxton, Andre G
2018-01-01
Regulatory B cells (Bregs) have been shown to be present during several disease states. The phenotype of the cells is not completely defined and the function of these cells differ between disease. The presence of FASL expressing (killer) B cells during latent and successfully treated TB disease have been shown but whether these cells are similar to regulatory B cells remain unclear. We assessed the receptor expression of FASL/IL5 (killer B cells), CD24/CD38 (regulatory B cells) on whole peripheral blood of participants with untreated active TB and healthy controls. We then isolated B cells from a second cohort of M.tb exposed (Quantiferon (QFN) positive) and unexposed (Quantiferon negative) HIV negative participants, and evaluated the frequency of killer B cells induced following stimulation with BCG and/or CD40 and IL5. Our data reveal no difference in the expression on CD24 and CD38 between participants with active TB and the controls. There was also no difference in the frequency of regulatory B cells measured in the peripheral blood mononuclear cells (PBMC) fraction between latent TB and uninfected controls. We did however notice that regulatory B cells (CD24hiCD38hi) population express the FASL receptor. The expression of killer B cell phenotype (CD178+IL5RA+) was significantly higher in controls compared to those with active TB disease (1,06% vs 0,455%). Furthermore, we found that BCG restimulation significantly induced the FASL/IL5RA B cells but this was only evident in the QFN positive group. Our data suggest that both regulatory and killer B cells are present during latent and active TB disease but that the frequency of these populations are increased during latent disease. We also show that the FASL+IL5RA+ B killer B cells are induced in latent TB infection following BCG restimulation but whether these cells are indicative of protection remains unclear. Copyright © 2017 Elsevier Ltd. All rights reserved.
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NK cell-based immunotherapy for malignant diseases
Cheng, Min; Chen, Yongyan; Xiao, Weihua; Sun, Rui; Tian, Zhigang
2013-01-01
Natural killer (NK) cells play critical roles in host immunity against cancer. In response, cancers develop mechanisms to escape NK cell attack or induce defective NK cells. Current NK cell-based cancer immunotherapy aims to overcome NK cell paralysis using several approaches. One approach uses expanded allogeneic NK cells, which are not inhibited by self histocompatibility antigens like autologous NK cells, for adoptive cellular immunotherapy. Another adoptive transfer approach uses stable allogeneic NK cell lines, which is more practical for quality control and large-scale production. A third approach is genetic modification of fresh NK cells or NK cell lines to highly express cytokines, Fc receptors and/or chimeric tumor-antigen receptors. Therapeutic NK cells can be derived from various sources, including peripheral or cord blood cells, stem cells or even induced pluripotent stem cells (iPSCs), and a variety of stimulators can be used for large-scale production in laboratories or good manufacturing practice (GMP) facilities, including soluble growth factors, immobilized molecules or antibodies, and other cellular activators. A list of NK cell therapies to treat several types of cancer in clinical trials is reviewed here. Several different approaches to NK-based immunotherapy, such as tissue-specific NK cells, killer receptor-oriented NK cells and chemically treated NK cells, are discussed. A few new techniques or strategies to monitor NK cell therapy by non-invasive imaging, predetermine the efficiency of NK cell therapy by in vivo experiments and evaluate NK cell therapy approaches in clinical trials are also introduced. PMID:23604045
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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.
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Peixoto, António; Evaristo, César; Munitic, Ivana; Monteiro, Marta; Charbit, Alain; Rocha, Benedita; Veiga-Fernandes, Henrique
2007-01-01
To study in vivo CD8 T cell differentiation, we quantified the coexpression of multiple genes in single cells throughout immune responses. After in vitro activation, CD8 T cells rapidly express effector molecules and cease their expression when the antigen is removed. Gene behavior after in vivo activation, in contrast, was quite heterogeneous. Different mRNAs were induced at very different time points of the response, were transcribed during different time periods, and could decline or persist independently of the antigen load. Consequently, distinct gene coexpression patterns/different cell types were generated at the various phases of the immune responses. During primary stimulation, inflammatory molecules were induced and down-regulated shortly after activation, generating early cells that only mediated inflammation. Cytotoxic T cells were generated at the peak of the primary response, when individual cells simultaneously expressed multiple killer molecules, whereas memory cells lost killer capacity because they no longer coexpressed killer genes. Surprisingly, during secondary responses gene transcription became permanent. Secondary cells recovered after antigen elimination were more efficient killers than cytotoxic T cells present at the peak of the primary response. Thus, primary responses produced two transient effector types. However, after boosting, CD8 T cells differentiate into long-lived killer cells that persist in vivo in the absence of antigen. PMID:17485515
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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.
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UCB Transplant for Hematological Diseases Using a Non Myeloablative Prep
2017-12-03
Acute Leukemia; Acute Myeloid Leukemia; Acute Lymphoblastic Leukemia/Lymphoma; Burkitt's Lymphoma; Natural Killer Cell Malignancies; Chronic Myelogenous Leukemia; Myelodysplastic Syndrome; Large-cell Lymphoma; Hodgkin Lymphoma; Multiple Myeloma; Relapsed Chronic Lymphocytic Leukemia; Relapsed Small Lymphocytic Lymphoma; Marginal Zone B-cell Lymphoma; Follicular Lymphoma; Lymphoplasmacytic Lymphoma; Mantle-cell Lymphoma; Prolymphocytic Leukemia; Bone Marrow Failure Syndromes; Myeloproliferative Neoplasms/Myelofibrosis; Biphenotypic/Undifferentiated/Prolymphocytic Leukemias; MRD Positive Leukemia; Leukemia or MDS in Aplasia; Relapsed T-Cell Lymphoma; Relapsed Multiple Myeloma; Plasma Cell Leukemia
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Hemophagocytic lymphohistiocytosis secondary to T-cell/histiocyte-rich large B-cell lymphoma
Devitt, Katherine; Cerny, Jan; Switzer, Bradley; Ramanathan, Muthalagu; Nath, Rajneesh; Yu, Hongbo; Woda, Bruce A.; Chen, Benjamin J.
2014-01-01
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening clinical syndrome characterized by dysregulation of the immune system. Impaired function of cytotoxic T cells and natural killer cells is often seen, and T-cell malignancies represent most cases of lymphoma-associated HLH. HLH associated with B-cell lymphoma is rare. We describe a case of a 30-year-old man who presented with fever, splenomegaly, and hyperferritinemia. Bone marrow biopsy revealed T-cell/histiocyte-rich large B-cell lymphoma, a rare, aggressive B-cell malignancy. This case highlights the interplay between a pro-inflammatory cytokine microenvironment and tumor-mediated immune suppression, and addresses the importance of accurately diagnosing these entities for appropriate clinical management. PMID:24955327
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Hemophagocytic lymphohistiocytosis secondary to T-cell/histiocyte-rich large B-cell lymphoma.
Devitt, Katherine; Cerny, Jan; Switzer, Bradley; Ramanathan, Muthalagu; Nath, Rajneesh; Yu, Hongbo; Woda, Bruce A; Chen, Benjamin J
2014-01-01
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening clinical syndrome characterized by dysregulation of the immune system. Impaired function of cytotoxic T cells and natural killer cells is often seen, and T-cell malignancies represent most cases of lymphoma-associated HLH. HLH associated with B-cell lymphoma is rare. We describe a case of a 30-year-old man who presented with fever, splenomegaly, and hyperferritinemia. Bone marrow biopsy revealed T-cell/histiocyte-rich large B-cell lymphoma, a rare, aggressive B-cell malignancy. This case highlights the interplay between a pro-inflammatory cytokine microenvironment and tumor-mediated immune suppression, and addresses the importance of accurately diagnosing these entities for appropriate clinical management.
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Chang, Shang-Lin; Leu, Jun-Yi; Chang, Tien-Hsien
2015-08-01
Microbes have evolved ways of interference competition to gain advantage over their ecological competitors. The use of secreted killer toxins by yeast cells through acquiring double-stranded RNA viruses is one such prominent example. Although the killer behaviour has been well studied in laboratory yeast strains, our knowledge regarding how killer viruses are spread and maintained in nature and how yeast cells co-evolve with viruses remains limited. We investigated these issues using a panel of 81 yeast populations belonging to three Saccharomyces sensu stricto species isolated from diverse ecological niches and geographic locations. We found that killer strains are rare among all three species. In contrast, killer toxin resistance is widespread in Saccharomyces paradoxus populations, but not in Saccharomyces cerevisiae or Saccharomyces eubayanus populations. Genetic analyses revealed that toxin resistance in S. paradoxus is often caused by dominant alleles that have independently evolved in different populations. Molecular typing identified one M28 and two types of M1 killer viruses in those killer strains. We further showed that killer viruses of the same type could lead to distinct killer phenotypes under different host backgrounds, suggesting co-evolution between the viruses and hosts in different populations. Taken together, our data suggest that killer viruses vary in their evolutionary histories even within closely related yeast species. © 2015 John Wiley & Sons Ltd.
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Epstein–Barr virus-positive T/NK-cell lymphoproliferative disorders
Cai, Qingqing; Chen, Kailin; Young, Ken H
2015-01-01
Epstein–Barr virus, a ubiquitous human herpesvirus, can induce both lytic and latent infections that result in a variety of human diseases, including lymphoproliferative disorders. The oncogenic potential of Epstein–Barr virus is related to its ability to infect and transform B lymphocytes into continuously proliferating lymphoblastoid cells. However, Epstein–Barr virus has also been implicated in the development of T/natural killer cell lymphoproliferative diseases. Epstein–Barr virus encodes a series of products that mimic several growth, transcription and anti-apoptotic factors, thus usurping control of pathways that regulate diverse homeostatic cellular functions and the microenvironment. However, the exact mechanism by which Epstein–Barr virus promotes oncogenesis and inflammatory lesion development remains unclear. Epstein–Barr virus-associated T/natural killer cell lymphoproliferative diseases often have overlapping clinical symptoms as well as histologic and immunophenotypic features because both lymphoid cell types derive from a common precursor. Accurate classification of Epstein–Barr virus-associated T/natural killer cell lymphoproliferative diseases is a prerequisite for appropriate clinical management. Currently, the treatment of most T/natural killer cell lymphoproliferative diseases is less than satisfactory. Novel and targeted therapies are strongly required to satisfy clinical demands. This review describes our current knowledge of the genetics, oncogenesis, biology, diagnosis and treatment of Epstein–Barr virus-associated T/natural killer cell lymphoproliferative diseases. PMID:25613730
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Grosser, Katrin; Ramasamy, Pathmanaban; Amirabad, Azim Dehghani; Schulz, Marcel H; Gasparoni, Gilles; Simon, Martin
2018-01-01
Abstract Endosymbiosis is a widespread phenomenon and hosts of bacterial endosymbionts can be found all-over the eukaryotic tree of life. Likely, this evolutionary success is connected to the altered phenotype arising from a symbiotic association. The potential variety of symbiont’s contributions to new characteristics or abilities of host organisms are largely unstudied. Addressing this aspect, we focused on an obligate bacterial endosymbiont that confers an intraspecific killer phenotype to its host. The symbiosis between Paramecium tetraurelia and Caedibacter taeniospiralis, living in the host’s cytoplasm, enables the infected paramecia to release Caedibacter symbionts, which can simultaneously produce a peculiar protein structure and a toxin. The ingestion of bacteria that harbor both components leads to the death of symbiont-free congeners. Thus, the symbiosis provides Caedibacter-infected cells a competitive advantage, the “killer trait.” We characterized the adaptive gene expression patterns in symbiont-harboring Paramecium as a second symbiosis-derived aspect next to the killer phenotype. Comparative transcriptomics of infected P. tetraurelia and genetically identical symbiont-free cells confirmed altered gene expression in the symbiont-bearing line. Our results show up-regulation of specific metabolic and heat shock genes whereas down-regulated genes were involved in signaling pathways and cell cycle regulation. Functional analyses to validate the transcriptomics results demonstrated that the symbiont increases host density hence providing a fitness advantage. Comparative transcriptomics shows gene expression modulation of a ciliate caused by its bacterial endosymbiont thus revealing new adaptive advantages of the symbiosis. Caedibacter taeniospiralis apparently increases its host fitness via manipulation of metabolic pathways and cell cycle control. PMID:29390087
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Chennamadhavuni, Divya; Saavedra-Avila, Noemi Alejandra; Carreño, Leandro J; Guberman-Pfeffer, Matthew J; Arora, Pooja; Yongqing, Tang; Koay, Hui-Fern; Godfrey, Dale I; Keshipeddy, Santosh; Richardson, Stewart K; Sundararaj, Srinivasan; Lo, Jae Ho; Wen, Xiangshu; Gascón, José A; Yuan, Weiming; Rossjohn, Jamie; Le Nours, Jérôme; Porcelli, Steven A; Howell, Amy R
2018-05-17
Glycosylceramides that activate CD1d-restricted invariant natural killer T (iNKT) cells have potential therapeutic applications for augmenting immune responses against cancer and infections. Previous studies using mouse models identified sphinganine variants of α-galactosylceramide as promising iNKT cell activators that stimulate cytokine responses with a strongly proinflammatory bias. However, the activities of sphinganine variants in mice have generally not translated well to studies of human iNKT cell responses. Here, we show that strongly proinflammatory and anti-tumor iNKT cell responses were achieved in mice by a variant of α-galactosylceramide that combines a sphinganine base with a hydrocinnamoyl ester on C6″ of the sugar. Importantly, the activities observed with this variant were largely preserved for human iNKT cell responses. Structural and in silico modeling studies provided a mechanistic basis for these findings and suggested basic principles for capturing useful properties of sphinganine analogs of synthetic iNKT cell activators in the design of immunotherapeutic agents. Copyright © 2018 Elsevier Ltd. All rights reserved.
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Enhancing Natural Killer Cell Mediated Targeting and Responses to Myeloid Leukemias
2017-10-01
Syndromes , AML – Acute Myeloid Leukemia, BiKE – Bi-specific Killer Engager, TriKE – Tri-specific Killer E 16. SECURITY CLASSIFICATION OF: 17...Natural Killer CML – Chronic Myeloid Leukemia MDS – Myelodysplastic Syndromes AML – Acute Myeloid Leukemia BiKE – Bi-specific Killer Engager TriKE...incidence of myeloid malignancies is increased due to exposure to ionizing radiation , chemicals, and other agents during deployment. Although
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Lin, Mao; Liang, Shuzhen; Wang, Xiaohua; Liang, Yinqing; Zhang, Mingjie; Chen, Jibing; Niu, Lizhi; Xu, Kecheng
2017-10-10
In this study, the clinical efficacy of cryosurgery combined with allogenic natural killer cell immunotherapy for advanced hepatocellular cancer was evaluated. From October 2015 to March 2017, we enrolled 61 patients who met the enrollment criteria and divided them into two groups: 1) the simple cryoablation group (Cryo group, n = 26); and 2) the cryoablation combined with allogenic natural killer cells group (Cryo-NK group, n = 35), the safety and short-term effects were evaluated firstly, then the median progression-free survival, response rate and disease control rate were assessed. All adverse events experienced by the patients were recorded, and included local (e.g., pain, pleural effusion, and ascites) and systemic (e.g., chills, fatigue, and fever) reactions, fever was more frequent. Other possible seriously side effects (e.g., blood or bone marrow changes) were not detected. Combining allogeneic natural killer cells with cryoablation had a synergistic effect, not only enhancing the immune function, improving the quality of life of the patients, but also reducing the expression of AFP and significantly exhibiting good clinical efficacy of the patients. After a median follow-up of 8.7 months (3.9 -15.1months), median progression-free survival was higher in Cryo-NK (9.1 months) than in Cryo (7.6 months, P = 0.0107), median progression-free survival who received multiple natural killer was higher than who just received single natural killer (9.7 months vs.8.4 months, P = 0.0011, respectively), the response rate in Cryo-NK (60.0%) was higher than in Cryo (46.1%, P < 0.05), the disease control rate in Cryo-NK (85.7%) was higher than in Cryo group (69.2%, P < 0.01). Percutaneous cryoablation combined with allogeneic natural killer cell immunotherapy significantly increased median progression-free survival of advanced hepatocellular cancer patients. Multiple allogeneic natural killer cells infusion was associated with better prognosis to advanced hepatocellular cancer.
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Lin, Mao; Liang, Shuzhen; Wang, Xiaohua; Liang, Yinqing; Zhang, Mingjie; Chen, Jibing; Niu, Lizhi; Xu, Kecheng
2017-01-01
In this study, the clinical efficacy of cryosurgery combined with allogenic natural killer cell immunotherapy for advanced hepatocellular cancer was evaluated. From October 2015 to March 2017, we enrolled 61 patients who met the enrollment criteria and divided them into two groups: 1) the simple cryoablation group (Cryo group, n = 26); and 2) the cryoablation combined with allogenic natural killer cells group (Cryo-NK group, n = 35), the safety and short-term effects were evaluated firstly, then the median progression-free survival, response rate and disease control rate were assessed. All adverse events experienced by the patients were recorded, and included local (e.g., pain, pleural effusion, and ascites) and systemic (e.g., chills, fatigue, and fever) reactions, fever was more frequent. Other possible seriously side effects (e.g., blood or bone marrow changes) were not detected. Combining allogeneic natural killer cells with cryoablation had a synergistic effect, not only enhancing the immune function, improving the quality of life of the patients, but also reducing the expression of AFP and significantly exhibiting good clinical efficacy of the patients. After a median follow-up of 8.7 months (3.9 –15.1months), median progression-free survival was higher in Cryo-NK (9.1 months) than in Cryo (7.6 months, P = 0.0107), median progression-free survival who received multiple natural killer was higher than who just received single natural killer (9.7 months vs.8.4 months, P = 0.0011, respectively), the response rate in Cryo-NK (60.0%) was higher than in Cryo (46.1%, P < 0.05), the disease control rate in Cryo-NK (85.7%) was higher than in Cryo group (69.2%, P < 0.01). Percutaneous cryoablation combined with allogeneic natural killer cell immunotherapy significantly increased median progression-free survival of advanced hepatocellular cancer patients. Multiple allogeneic natural killer cells infusion was associated with better prognosis to advanced hepatocellular cancer. PMID:29137237
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Myeloablative Allo HSCT With Related or Unrelated Donor for Heme Disorders
2018-05-18
Acute Leukemia; Acute Myeloid Leukemia; Acute Lymphoblastic Leukemia; Lymphoma; Chronic Myelogenous Leukemia; Plasma Cell Leukemia; Myeloproliferative Neoplasms; Myelofibrosis; Myelodysplasia; Refractory Anemia; High Risk Anemia; Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma; Marginal Zone B-Cell Lymphoma; Follicular Lymphoma; Lymphoplasmacytic Lymphoma; Mantle-Cell Lymphoma; Prolymphocytic Leukemia; Diffuse Large Cell Non Hodgkins Lymphoma; Lymphoblastic Lymphoma; Burkitt Lymphoma; High Grade Non-Hodgkin's Lymphoma, Adult; Multiple Myeloma; Juvenile Myelomonocytic Leukemia; Biphenotypic/Undifferentiated/Prolymphocytic Leukemias; MRD Positive Leukemia; Natural Killer Cell Malignancies; Acquired Bone Marrow Failure Syndromes
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2017-11-08
Acute Lymphoblastic Leukemia; Acute Myeloid Leukemia; Aggressive Non-Hodgkin Lymphoma; Diffuse Large B-Cell Lymphoma; Previously Treated Myelodysplastic Syndrome; Recurrent Chronic Lymphocytic Leukemia; Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Recurrent Indolent Adult Non-Hodgkin Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Plasma Cell Myeloma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hodgkin Lymphoma; Refractory Plasma Cell Myeloma; Refractory Small Lymphocytic Lymphoma; Waldenstrom Macroglobulinemia
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[Methods for increasing the immunogenicity of vaccines].
Kündig, T M
2000-09-14
In the past years, enormous efforts have been undertaken to develop vaccine strategies against cancer. The aim is to have the immune system generate what are called killer cells that can specifically recognize the tumor. The surface of tumor cells contains MHC/HLA antigens which present short-chain peptides of tumor specific antigens. A large number of these oligopeptide antigens have been characterized in recent years. They are now available for use as tumor-specific vaccines. The problem is, however, that the immune response of producing T killer cells is very inefficient when these oligopeptide antigens are injected. As the physiological function of these killer cells virus-infected cells, a process associated with substantial tissue damage, the immune system has learned to use these killer cells with reticence over the course of evolution, in other words, when the life of the host is threatened. This does not happen until pathogens start to spread via lymphogenous or hematogenous pathways. And then it takes a certain amount of time after the invader is present for replication to take place. Since the oligopeptide antigens used as vaccines have a very short half-life in the tissue, not enough of them get to the lymph nodes and stay there for enough time to efficiently induce an immune response. Using a mouse model, we were able to show that the efficiency of the vaccine can be increased a million-fold by directly injecting the vaccine into a lymph node or the spleen which imitates lymphogenous or hematogenous spread. The efficiency of the "inactivated vaccine" can be enhanced even more by continuous administration of the vaccine over several days, simulating an especially dangerous virus replication. The evidence gathered in this mouse model was transferred to a clinical trial. The melanoma-specific inactivated vaccine is infused directly into a lymph node of tumor patients. The infusion is continued for several days. Booster vaccines are given every two weeks.
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The anti-canine distemper virus activities of ex vivo-expanded canine natural killer cells.
Park, Ji-Yun; Shin, Dong-Jun; Lee, Soo-Hyeon; Lee, Je-Jung; Suh, Guk-Hyun; Cho, Duck; Kim, Sang-Ki
2015-04-17
Natural killer (NK) cells play critical roles in induction of antiviral effects against various viruses of humans and animals. However, few data on NK cell activities during canine distemper virus (CDV) infections are available. Recently, we established a culture system allowing activation and expansion of canine non-B, non-T, large granular NK lymphocytes from PBMCs of normal dogs. In the present study, we explored the ability of such expanded NK cells to inhibit CDV infection in vitro. Cultured CD3-CD5-CD21- NK cells produced large amounts of IFN-γ, exhibited highly upregulated expression of mRNAs encoding NK-cell-associated receptors, and demonstrated strong natural killing activity against canine tumor cells. Although the expanded NK cells were dose-dependently cytotoxic to both normal and CDV-infected Vero cells, CDV infection rendered Vero cells more susceptible to NK cells. Pretreatment with anti-CDV serum from hyperimmunized dogs enhanced the antibody-dependent cellular cytotoxicity (ADCC) of NK cells against CDV-infected Vero cells. The culture supernatants of NK cells, added before or after infection, dose-dependently inhibited both CDV replication and development of CDV-induced cytopathic effects (CPEs) in Vero cells. Anti-IFN-γ antibody neutralized the inhibitory effects of NK cell culture supernatants on CDV replication and CPE induction in Vero cells. Such results emphasize the potential significance of NK cells in controlling CDV infection, and indicate that NK cells may play roles both during CDV infection and in combating such infections, under certain conditions. Copyright © 2015 Elsevier B.V. All rights reserved.
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Mouse natural killer cell development and maturation are differentially regulated by SHIP-1.
Banh, Cindy; Miah, S M Shahjahan; Kerr, William G; Brossay, Laurent
2012-11-29
The SH2-containing inositol phosphatase-1 (SHIP-1) is a 5' inositol phosphatase known to negatively regulate the product of phosphoinositide-3 kinase (PI3K), phosphatidylinositol-3.4,5-trisphosphate. SHIP-1 can be recruited to a large number of inhibitory receptors expressed on natural killer (NK) cells. However, its role in NK cell development, maturation, and functions is not well defined. In this study, we found that the absence of SHIP-1 results in a loss of peripheral NK cells. However, using chimeric mice we demonstrated that SHIP-1 expression is not required intrinsically for NK cell lineage development. In contrast, SHIP-1 is required cell autonomously for NK cell terminal differentiation. These findings reveal both a direct and indirect role for SHIP-1 at different NK cell development checkpoints. Notably, SHIP-1-deficient NK cells display an impaired ability to secrete IFN-γ during cytokine receptor-mediated responses, whereas immunoreceptor tyrosine-based activation motif containing receptor-mediated responses is not affected. Taken together, our results provide novel insights on how SHIP-1 participates in the development, maturation, and effector functions of NK cells.
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Lee, Sung Won; Park, Hyun Jung; Kim, Nayoung; Hong, Seokmann
2013-01-01
Natural killer dendritic cells (NKDCs) possess potent anti-tumor activity, but the cellular effect of NKDC interactions with other innate immune cells is unclear. In this study, we demonstrate that the interaction of NKDCs and natural killer T (NKT) cells is required for the anti-tumor immune responses that are elicited by α -galactosylceramide ( α -GC) in mice. The rapid and strong expression of interferon- γ by NKDCs after α -GC stimulation was dependent on NKT cells. Various NK and DC molecular markers and cytotoxic molecules were up-regulated following α -GC administration. This up-regulation could improve NKDC presentation of tumor antigens and increase cytotoxicity against tumor cells. NKDCs were required for the stimulation of DCs, NK cells, and NKT cells. The strong anti-tumor immune responses elicited by α -GC may be due to the down-regulation of regulatory T cells. Furthermore, the depletion of NKDCs dampened the tumor clearance mediated by α -GC-stimulated NKT cells in vivo. Taken together, these results indicate that complex interactions of innate immune cells might be required to achieve optimal anti-tumor immune responses during the early stages of tumorigenesis.
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(1-->6)-beta-D-glucan as cell wall receptor for Pichia membranifaciens killer toxin.
Santos, A; Marquina, D; Leal, J A; Peinado, J M
2000-05-01
The killer toxin from Pichia membranifaciens CYC 1106, a yeast isolated from fermenting olive brines, binds primarily to the (1-->6)-beta-D-glucan of the cell wall of a sensitive yeast (Candida boidinii IGC 3430). The (1-->6)-beta-D-glucan was purified from cell walls of C. boidinii by alkali and hot-acetic acid extraction, a procedure which solubilizes glucans. The major fraction of receptor activity remained with the alkali-insoluble (1-->6)-beta- and (1-->3)-beta-D-glucans. The chemical (gas-liquid chromatography) and structural (periodate oxidation, infrared spectroscopy, and (1)H nuclear magnetic resonance) analyses of the fractions obtained showed that (1-->6)-beta-D-glucan was a receptor. Adsorption of most of the killer toxin to the (1-->6)-beta-D-glucan was complete within 2 min. Killer toxin adsorption to the linear (1-->6)-beta-D-glucan, pustulan, and a glucan from Penicillium allahabadense was observed. Other polysaccharides with different linkages failed to bind the killer toxin. The specificity of the killer toxin for its primary receptor provides an effective means to purify the killer toxin, which may have industrial applications for fermentations in which salt is present as an adjunct, such as olive brines. This toxin shows its maximum killer activity in the presence of NaCl. This report is the first to identify the (1-->6)-beta-D-glucan as a receptor for this novel toxin.
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Spicer, Julie A; Huttunen, Kristiina M; Miller, Christian K; Denny, William A; Ciccone, Annette; Browne, Kylie A; Trapani, Joseph A
2012-02-01
An aryl-substituted isobenzofuran-1(3H)-one lead compound was identified from a high throughput screen designed to find inhibitors of the lymphocyte pore-forming protein perforin. A series of analogs were then designed and prepared, exploring structure-activity relationships through variation of 2-thioxoimidazolidin-4-one and furan subunits on an isobenzofuranone core. The ability of the resulting compounds to inhibit the lytic activity of both isolated perforin protein and perforin delivered in situ by intact KHYG-1 natural killer effector cells was determined. Several compounds showed excellent activity at concentrations that were non-toxic to the killer cells. This series represents a significant improvement on previous classes of compounds, being substantially more potent and largely retaining activity in the presence of serum. Copyright © 2011 Elsevier Ltd. All rights reserved.
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Genetically Engineered Natural Killer Cells as a Means for Adoptive Tumor Immunotherapy.
Michen, Susanne; Temme, Achim
2016-01-01
Natural killer (NK) cells are lymphoid cells of the innate immune system; they stand at the first defense line against viruses and transformed cells. NK cells use an array of germline-encoded activating and inhibitory receptors that sense virus-infected cells or malignant cells displaying altered surface expression of activating and inhibitory NK cell ligands. They exert potent cytotoxic responses to cellular targets and thus are candidate effector cells for immunotherapy of cancer. In particular, the genetic engineering of NK cells with chimeric antigen receptors (CARs) against surface-expressed tumor-associated antigens (TAAs) seems promising. In the allogeneic context, gene-modified NK cells compared to T cells may be superior because they are short-lived effector cells and do not cause graft-versus-host disease. Furthermore, their anti-tumoral activity can be augmented by combinatorial use with therapeutic antibodies, chemotherapeutics, and radiation. Today, efforts are being undertaken for large-scale NK-cell expansion and their genetic engineering for adoptive cell transfer. With the recent advances in understanding the complex biological interactions that regulate NK cells, it is expected that the genetic engineering of NK cells and a combinatorial blockade of immune evasion mechanisms are required to exploit the full potential of NK-cell-based immunotherapies.
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The Biology of Pichia membranifaciens Killer Toxins
Belda, Ignacio; Ruiz, Javier; Alonso, Alejandro; Marquina, Domingo; Santos, Antonio
2017-01-01
The killer phenomenon is defined as the ability of some yeast to secrete toxins that are lethal to other sensitive yeasts and filamentous fungi. Since the discovery of strains of Saccharomyces cerevisiae capable of secreting killer toxins, much information has been gained regarding killer toxins and this fact has substantially contributed knowledge on fundamental aspects of cell biology and yeast genetics. The killer phenomenon has been studied in Pichia membranifaciens for several years, during which two toxins have been described. PMKT and PMKT2 are proteins of low molecular mass that bind to primary receptors located in the cell wall structure of sensitive yeast cells, linear (1→6)-β-d-glucans and mannoproteins for PMKT and PMKT2, respectively. Cwp2p also acts as a secondary receptor for PMKT. Killing of sensitive cells by PMKT is characterized by ionic movements across plasma membrane and an acidification of the intracellular pH triggering an activation of the High Osmolarity Glycerol (HOG) pathway. On the contrary, our investigations showed a mechanism of killing in which cells are arrested at an early S-phase by high concentrations of PMKT2. However, we concluded that induced mortality at low PMKT2 doses and also PMKT is indeed of an apoptotic nature. Killer yeasts and their toxins have found potential applications in several fields: in food and beverage production, as biocontrol agents, in yeast bio-typing, and as novel antimycotic agents. Accordingly, several applications have been found for P. membranifaciens killer toxins, ranging from pre- and post-harvest biocontrol of plant pathogens to applications during wine fermentation and ageing (inhibition of Botrytis cinerea, Brettanomyces bruxellensis, etc.). PMID:28333108
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Natural killer T-cell lymphoma of the tongue.
Cho, Kwang-Jae; Cho, Seok-Goo; Lee, Dong-Hee
2005-01-01
Lymphoma, which represents about 5.4% of all neoplasms and, more significantly, 19% to 28% of malignant neoplasms, is the most common nonepithelial malignancy of the head and neck area in Koreans. Natural killer T-cell (NK/T-cell) lymphoma is a lymphoma of putative natural killer cell lineage. NK/T-cell neoplasms are generally rare, but they are more common in people of East Asian, Mexican, or South American descent. These neoplasms are highly aggressive and show a strong association with Epstein-Barr virus. The preferential site of extranodal NK/T-cell lymphoma is the nasal cavity, and there has been no report of NK/T-cell lymphoma developing from the tongue. We encountered a rare case of NK/T-cell lymphoma of the tongue, which we report with a review of the literature.
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Bollino, Dominique; Webb, Tonya J
2017-09-01
Natural killer (NK) cells of the innate immune system and natural killer T (NKT) cells, which have roles in both the innate and adaptive responses, are unique lymphocyte subsets that have similarities in their functions and phenotypes. Both cell types can rapidly respond to the presence of tumor cells and participate in immune surveillance and antitumor immune responses. This has incited interest in the development of novel cancer therapeutics based on NK and NKT cell manipulation. Chimeric antigen receptors (CARs), generated through the fusion of an antigen-binding region of a monoclonal antibody or other ligand to intracellular signaling domains, can enhance lymphocyte targeting and activation toward diverse malignancies. Most of the CAR studies have focused on their expression in T cells; however, the functional heterogeneity of CAR T cells limits their therapeutic potential and is associated with toxicity. CAR-modified NK and NKT cells are becoming more prevalent because they provide a method to direct these cells more specifically to target cancer cells, with less risk of adverse effects. This review will outline current NK and NKT cell CAR constructs and how they compare to conventional CAR T cells, and discuss future modifications that can be explored to advance adoptive cell transfer of NK and NKT cells. Copyright © 2017 Elsevier Inc. All rights reserved.
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Hughes, Tiffany; Becknell, Brian; McClory, Susan; Briercheck, Edward; Freud, Aharon G.; Zhang, Xiaoli; Mao, Hsiaoyin; Nuovo, Gerard; Yu, Jianhua
2009-01-01
Considerable functional heterogeneity within human natural killer (NK) cells has been revealed through the characterization of distinct NK-cell subsets. Accordingly, a small subset of CD56+NKp44+NK cells, termed NK-22 cells, was recently described within secondary lymphoid tissue (SLT) as IL-22− when resting, with a minor fraction of this population becoming IL-22+ when activated. Here we discover that the vast majority of stage 3 immature NK (iNK) cells in SLT constitutively and selectively express IL-22, a TH17 cytokine important for mucosal immunity, whereas earlier and later stages of NK developmental intermediates do not express IL-22. These iNK cells have a surface phenotype of CD34−CD117+CD161+CD94−, largely lack expression of NKp44 and CD56, and do not produce IFN-γ or possess cytolytic activity. In summary, stage 3 iNK cells are highly enriched for IL-22 and IL-26 messenger RNA, and IL-22 protein production, but do not express IL-17A or IL-17F. PMID:19244159
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The up side of decidual natural killer cells: new developments in immunology of pregnancy.
Jabrane-Ferrat, Nabila; Siewiera, Johan
2014-04-01
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. © 2013 John Wiley & Sons Ltd.
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Gunge, N; Murata, K; Sakaguchi, K
1982-01-01
Protoplasts of Saccharomyces cerevisiae were mixed with linear DNA plasmids, pGKl1 and pGKl2, isolated from a Kluyveromyces lactis killer strain and treated with polyethylene glycol. Out of 2,000 colonies regenerated on a nonselective medium, two killer transformants were obtained. The pGKl plasmids and the killer character were stably maintained in one (Pdh-1) of them. Another transformant, Pdl-1, was a weak killer, and the subclones consisted of a mixture of weak and nonkiller cells. The weak killers were characterized by the presence of pGKl1 in a decreased amount, and nonkillers were characterized by the absence of pGKl1. The occurrence of two new plasmids which migrated faster than pGKl1 in an agarose gel was observed in Pdl-1 and its subclones, whether weak or nonkillers. Staining with 4',6-diamidino-2-phenylindole revealed that the pGKl plasmids exist in the cytosol of transformant cells with numerous copy numbers. Images PMID:7045080
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Cruz, C. Russell; Bollard, Catherine M.
2015-01-01
Hematopoietic stem cell transplantation has revolutionized the treatment of hematologic malignancies, but infection, graft-versus-host disease and relapse are still important problems. Calcineurin inhibitors, T-cell depletion strategies, and immunomodulators have helped to prevent graft-versus-host disease, but have a negative impact on the graft-versus-leukemia effect. T cells and natural killer cells are both thought to be important in the graft-versus-leukemia effect, and both cell types are amenable to ex vivo manipulation and clinical manufacture, making them versatile immunotherapeutics. We provide an overview of these immunotherapeutic strategies following hematopoietic stem cell transplantation, with discussions centered on natural killer and T-cell biology. We discuss the contributions of each cell type to graft-versus-leukemia effects, as well as the current research directions in the field as related to adoptive cell therapy after hematopoietic stem cell transplantation. PMID:26034113
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"Killer" Microcapsules That Can Selectively Destroy Target Microparticles in Their Vicinity.
Arya, Chandamany; Oh, Hyuntaek; Raghavan, Srinivasa R
2016-11-02
We have developed microscale polymer capsules that are able to chemically degrade a certain type of polymeric microbead in their immediate vicinity. The inspiration here is from the body's immune system, where killer T cells selectively destroy cancerous cells or cells infected by pathogens while leaving healthy cells alone. The "killer" capsules are made from the cationic biopolymer chitosan by a combination of ionic cross-linking (using multivalent tripolyposphate anions) and subsequent covalent cross-linking (using glutaraldehyde). During capsule formation, the enzyme glucose oxidase (GOx) is encapsulated in these capsules. The target beads are made by ionic cross-linking of the biopolymer alginate using copper (Cu 2+ ) cations. The killer capsules harvest glucose from their surroundings, which is then enzymatically converted by GOx into gluconate ions. These ions are known for their ability to chelate Cu 2+ cations. Thus, when a killer capsule is next to a target alginate bead, the gluconate ions diffuse into the bead and extract the Cu 2+ cross-links, causing the disintegration of the target bead. Such destruction is visualized in real-time using optical microscopy. The destruction is specific, i.e., other microparticles that do not contain Cu 2+ are left undisturbed. Moreover, the destruction is localized, i.e., the targets destroyed in the short term are the ones right next to the killer beads. The time scale for destruction depends on the concentration of encapsulated enzyme in the capsules.
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Education of human natural killer cells by activating killer cell immunoglobulin-like receptors.
Fauriat, Cyril; Ivarsson, Martin A; Ljunggren, Hans-Gustaf; Malmberg, Karl-Johan; Michaëlsson, Jakob
2010-02-11
Expression of inhibitory killer cell immunoglobulin-like receptors (KIRs) specific for self-major histocompatibility complex (MHC) class I molecules provides an educational signal that generates functional natural killer (NK) cells. However, the effects of activating KIRs specific for self-MHC class I on NK-cell education remain elusive. Here, we provide evidence that the activating receptor KIR2DS1 tunes down the responsiveness of freshly isolated human NK cells to target cell stimulation in donors homozygous for human leukocyte antigen (HLA)-C2, the ligand of KIR2DS1. The tuning was apparent in KIR2DS1(+) NK cells lacking expression of inhibitory KIRs and CD94/NKG2A, as well as in KIR2DS1(+) NK cells coexpressing the inhibitory MHC class I-specific receptors CD94/NKG2A and KIR2DL3, but not KIR2DL1. However, the tuning of responsiveness was restricted to target cell recognition because KIR2DS1(+) NK cells responded well to stimulation with exogenous cytokines. Our results provide the first example of human NK-cell education by an activating KIR and suggest that the education of NK cells via activating KIRs is a mechanism to secure tolerance that complements education via inhibitory KIRs.
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Yajing, Sun; Rajput, Imran Rashid; Ying, Huang; Fei, Yu; Sanganyado, Edmond; Ping, Li; Jingzhen, Wang; Wenhua, Liu
2018-01-01
The pygmy killer whale (Feresa attenuata) (PKW) is a tropical and subtropical marine mammal commonly found in the Atlantic, Indian and Pacific oceans. Since the PKWs live in offshore protected territories, they are rarely seen onshore. Hence, PKW are one of the most poorly understood oceanic species of odontocetes. The dermal tissue comes primarily from stranding events that occur along the coast of the Shantou, Guangdong, China. The sampled tissues were immediately processed and attached on collagen-coated 6-well tissue culture plate. The complete medium (DMEM and Ham's F12, fetal bovine serum, antibiotic and essential amino acids) was added to the culture plates. The primary culture (PKW-LWH) cells were verified as fibroblast by vimentin and karyotype analyses, which revealed 42 autosomes and two sex chromosomes X and Y. Following transfection of PKW-LWH cells with a plasmid encoding, the SV40 large T-antigens and the transfected cells were isolated and expanded. Using RT-PCR, western blot, immunofluorescence analysis and SV40 large T-antigen stability was confirmed. The cell proliferation rate of the fibroblast cells, PKW-LWHT was faster than the primary cells PKW-LWH with the doubling time 68.9h and 14.4h, respectively. In this study, we established PKW dermal fibroblast cell line for the first time, providing a unique opportunity for in vitro studies on the effects of environmental pollutants and pathogens that could be determined in PKW and/or Cetaceans.
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Yagita, M; Huang, C L; Umehara, H; Matsuo, Y; Tabata, R; Miyake, M; Konaka, Y; Takatsuki, K
2000-05-01
We present the establishment of a natural killer (NK) leukemia cell line, designated KHYG-1, from the blood of a patient with aggressive NK leukemia, which both possessed the same p53 point mutation. The immunophenotype of the primary leukemia cells was CD2+, surface CD3-, cytoplasmic CD3epsilon+, CD7+, CD8alphaalpha+, CD16+, CD56+, CD57+ and HLA-DR+. A new cell line (KHYG-1) was established by culturing peripheral leukemia cells with 100 units of recombinant interleukin (IL)-2. The KHYG-1 cells showed LGL morphology with a large nucleus, coarse chromatin, conspicuous nucleoli, and abundant basophilic cytoplasm with many azurophilic granules. The immunophenotype of KHYG-1 cells was CD1-, CD2+, surface CD3-, cytoplasmic CD3epsilon+, CD7+, CD8alphaalpha+, CD16-, CD25-, CD33+, CD34-, CD56+, CD57-, CD122+, CD132+, and TdT-. Southern blot analysis of these cells revealed a normal germline configuration for the beta, delta, and gamma chains of the T cell receptor and the immunoglobulin heavy-chain genes. Moreover, the KHYG-1 cells displayed NK cell activity and IL-2-dependent proliferation in vitro, suggesting that they are of NK cell origin. Epstein-Barr virus (EBV) DNA was not detected in KHYG-1 cells by Southern blot analysis with a terminal repeat probe from an EBV genome. A point mutation in exon 7 of the p53 gene was detected in the KHYG-1 cells by PCR/SSCP analysis, and direct sequencing revealed the conversion of C to T at nucleotide 877 in codon 248. The primary leukemia cells also carried the same point mutation. Although the precise role of the p53 point mutation in leukemogenesis remains to be clarified, the establishment of an NK leukemia cell line with a p53 point mutation could be valuable in the study of leukemogenesis.
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2012-01-01
Background Killer whales (Orcinus orca) are the most widely distributed cetacean, occurring in all oceans worldwide, and within ocean regions different ecotypes are defined based on prey preferences. Prey items are largely unknown in the eastern Canadian Arctic and therefore we conducted a survey of Inuit Traditional Ecological Knowledge (TEK) to provide information on the feeding ecology of killer whales. We compiled Inuit observations on killer whales and their prey items via 105 semi-directed interviews conducted in 11 eastern Nunavut communities (Kivalliq and Qikiqtaaluk regions) from 2007-2010. Results Results detail local knowledge of killer whale prey items, hunting behaviour, prey responses, distribution of predation events, and prey capture techniques. Inuit TEK and published literature agree that killer whales at times eat only certain parts of prey, particularly of large whales, that attacks on large whales entail relatively small groups of killer whales, and that they hunt cooperatively. Inuit observations suggest that there is little prey specialization beyond marine mammals and there are no definitive observations of fish in the diet. Inuit hunters and elders also documented the use of sea ice and shallow water as prey refugia. Conclusions By combining TEK and scientific approaches we provide a more holistic view of killer whale predation in the eastern Canadian Arctic relevant to management and policy. Continuing the long-term relationship between scientists and hunters will provide for successful knowledge integration and has resulted in considerable improvement in understanding of killer whale ecology relevant to management of prey species. Combining scientists and Inuit knowledge will assist in northerners adapting to the restructuring of the Arctic marine ecosystem associated with warming and loss of sea ice. PMID:22520955
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Ferguson, Steven H; Higdon, Jeff W; Westdal, Kristin H
2012-01-30
Killer whales (Orcinus orca) are the most widely distributed cetacean, occurring in all oceans worldwide, and within ocean regions different ecotypes are defined based on prey preferences. Prey items are largely unknown in the eastern Canadian Arctic and therefore we conducted a survey of Inuit Traditional Ecological Knowledge (TEK) to provide information on the feeding ecology of killer whales. We compiled Inuit observations on killer whales and their prey items via 105 semi-directed interviews conducted in 11 eastern Nunavut communities (Kivalliq and Qikiqtaaluk regions) from 2007-2010. Results detail local knowledge of killer whale prey items, hunting behaviour, prey responses, distribution of predation events, and prey capture techniques. Inuit TEK and published literature agree that killer whales at times eat only certain parts of prey, particularly of large whales, that attacks on large whales entail relatively small groups of killer whales, and that they hunt cooperatively. Inuit observations suggest that there is little prey specialization beyond marine mammals and there are no definitive observations of fish in the diet. Inuit hunters and elders also documented the use of sea ice and shallow water as prey refugia. By combining TEK and scientific approaches we provide a more holistic view of killer whale predation in the eastern Canadian Arctic relevant to management and policy. Continuing the long-term relationship between scientists and hunters will provide for successful knowledge integration and has resulted in considerable improvement in understanding of killer whale ecology relevant to management of prey species. Combining scientists and Inuit knowledge will assist in northerners adapting to the restructuring of the Arctic marine ecosystem associated with warming and loss of sea ice.
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Natural killer/T-cell lymphoma invading the orbit and globe.
Lyons, Lance J; Vrcek, Ivan; Somogyi, Marie; Taheri, Kevin; Admirand, Joan H; Chexal, Saradha; Loukas, Demetrius F; Nakra, Tanuj
2017-10-01
Natural killer/T-cell lymphomas are extremely rare and carry high mortality rates. Epidemiologically, these cancers tend to affect mainly Asian and South American patients and are associated with Epstein-Barr virus seropositivity. This report details a 78-year-old Vietnamese woman who presented initially with vitritis of unknown cause, but later developed proptosis and conjunctival involvement as her disease spread. Biopsies of the orbit, ethmoid sinus, and conjunctiva were found to be significant for natural killer/T-cell lymphoma. The case highlights the diagnostic difficulty of this tumor given its rarity and ability to mimic other disorders.
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Natural killer/T-cell lymphoma invading the orbit and globe
Lyons, Lance J.; Somogyi, Marie; Taheri, Kevin; Admirand, Joan H.; Chexal, Saradha; Loukas, Demetrius F.; Nakra, Tanuj
2017-01-01
Natural killer/T-cell lymphomas are extremely rare and carry high mortality rates. Epidemiologically, these cancers tend to affect mainly Asian and South American patients and are associated with Epstein-Barr virus seropositivity. This report details a 78-year-old Vietnamese woman who presented initially with vitritis of unknown cause, but later developed proptosis and conjunctival involvement as her disease spread. Biopsies of the orbit, ethmoid sinus, and conjunctiva were found to be significant for natural killer/T-cell lymphoma. The case highlights the diagnostic difficulty of this tumor given its rarity and ability to mimic other disorders. PMID:28966461
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TdKT, a new killer toxin produced by Torulaspora delbrueckii effective against wine spoilage yeasts.
Villalba, María Leticia; Susana Sáez, Julieta; Del Monaco, Silvana; Lopes, Christian Ariel; Sangorrín, Marcela Paula
2016-01-18
Microbiological spoilage is a major concern throughout the wine industry, and control tools are limited. This paper addresses the identification and partial characterization of a new killer toxin from Torulaspora delbrueckii with potential biocontrol activity of Brettanomyces bruxellensis, Pichia guilliermondii, Pichia manshurica and Pichia membranifaciens wine spoilage. A panel of 18 different wine strains of T. delbrueckii killer yeasts was analysed, and the strain T. delbrueckii NPCC 1033 (TdKT producer) showed a significant inhibitory effect on the growth of all different spoilage yeasts evaluated. The TdKT toxin was then subjected to a partial biochemical characterization. Its estimated molecular weight was N30 kDa and it showed glucanase and chitinase enzymatic activities. The killer activity was stable between pH 4.2 and 4.8 and inactivated at temperature above 40 °C. Pustulan and chitin — but not other cell wall polysaccharides — prevented sensitive yeast cells from being killed by TdKT, suggesting that those may be the first toxin targets in the cell wall. TdKT provoked an increase in necrosis cell death after 3 h treatment and apoptotic cell death after 24 h showing time dependence in its mechanisms of action. Killer toxin extracts were active at oenological conditions, confirming their potential use as a biocontrol tool in winemaking.
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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.
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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...
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Conry, Sara J; Milkovich, Kimberly A; Yonkers, Nicole L; Rodriguez, Benigno; Bernstein, Helene B; Asaad, Robert; Heinzel, Frederick P; Tary-Lehmann, Magdalena; Lederman, Michael M; Anthony, Donald D
2009-11-01
Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections impair plasmacytoid dendritic cell (PDC) and natural killer (NK) cell subset numbers and functions, though little is known about PDC-NK cell interactions during these infections. We evaluated PDC-dependent NK cell killing and gamma interferon (IFN-gamma) and granzyme B production, using peripheral blood mononuclear cell (PBMC)-based and purified cell assays of samples from HCV- and HIV-infected subjects. CpG-enhanced PBMC killing and IFN-gamma and granzyme B activity (dependent on PDC and NK cells) were impaired in viremic HIV infection. In purified PDC-NK cell culture experiments, CpG-enhanced, PDC-dependent NK cell activity was cell contact and IFN-alpha dependent, and this activity was impaired in viremic HIV infection but not in HCV infection. In heterologous PDC-NK cell assays, impaired PDC-NK cell killing activity was largely attributable to an NK cell defect, while impaired PDC-NK cell IFN-gamma-producing activity was attributable to both PDC and NK cell defects. Additionally, the response of NK cells to direct IFN-alpha stimulation was defective in viremic HIV infection, and this defect was not attributable to diminished IFN-alpha receptor expression, though IFN-alpha receptor and NKP30 expression was closely associated with killer activity in viremic HIV infection but not in healthy controls. These data indicate that during uncontrolled HIV infection, PDC-dependent NK cell function is impaired, which is in large part attributable to defective IFN-alpha-induced NK cell activity and not to altered IFN-alpha receptor, NKP30, NKP44, NKP46, or NKG2D expression.
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Recognition of peptide–MHC class I complexes by activating killer immunoglobulin-like receptors
Stewart, C. Andrew; Laugier-Anfossi, Fanny; Vély, Frédéric; Saulquin, Xavier; Riedmuller, Jenifer; Tisserant, Agnès; Gauthier, Laurent; Romagné, François; Ferracci, Géraldine; Arosa, Fernando A.; Moretta, Alessandro; Sun, Peter D.; Ugolini, Sophie; Vivier, Eric
2005-01-01
Inhibitory receptors for MHC class I molecules increase the threshold of lymphocyte activation. Natural Killer (NK) cells express a large number of such inhibitory receptors, including the human killer Ig-like receptors (KIR). However, activating members of the KIR family have poorly defined ligands and functions. Here we describe the use of activating KIR tetramer reagents as probes to detect their ligands. Infection of cells with Epstein–Barr virus leads to expression of a detectable ligand for the activating receptor KIR2DS1. In this case, KIR2DS1 interacts with up-regulated peptide–MHC class I complexes on Epstein–Barr virus-infected cells in a transporter associated with antigen processing (TAP)-dependent manner. In tetramer-based cellular assays and direct affinity measurements, this interaction with MHC class I is facilitated by a broad spectrum of peptides. KIR2DS1 and its inhibitory homologue, KIR2DL1, share sensitivity to peptide sequence alterations at positions 7 and 8. These results fit a model in which activating and inhibitory receptors recognize the same sets of self-MHC class I molecules, differing only in their binding affinities. Importantly, KIR2DS1 is not always sufficient to trigger NK effector responses when faced with cognate ligand, consistent with fine control during NK cell activation. We discuss how our results for KIR2DS1 and parallel studies on KIR2DS2 relate to the association between activating KIR genes and susceptibility to autoimmune disorders. PMID:16141329
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Recognition of peptide-MHC class I complexes by activating killer immunoglobulin-like receptors.
Stewart, C Andrew; Laugier-Anfossi, Fanny; Vély, Frédéric; Saulquin, Xavier; Riedmuller, Jenifer; Tisserant, Agnès; Gauthier, Laurent; Romagné, François; Ferracci, Géraldine; Arosa, Fernando A; Moretta, Alessandro; Sun, Peter D; Ugolini, Sophie; Vivier, Eric
2005-09-13
Inhibitory receptors for MHC class I molecules increase the threshold of lymphocyte activation. Natural Killer (NK) cells express a large number of such inhibitory receptors, including the human killer Ig-like receptors (KIR). However, activating members of the KIR family have poorly defined ligands and functions. Here we describe the use of activating KIR tetramer reagents as probes to detect their ligands. Infection of cells with Epstein-Barr virus leads to expression of a detectable ligand for the activating receptor KIR2DS1. In this case, KIR2DS1 interacts with up-regulated peptide-MHC class I complexes on Epstein-Barr virus-infected cells in a transporter associated with antigen processing (TAP)-dependent manner. In tetramer-based cellular assays and direct affinity measurements, this interaction with MHC class I is facilitated by a broad spectrum of peptides. KIR2DS1 and its inhibitory homologue, KIR2DL1, share sensitivity to peptide sequence alterations at positions 7 and 8. These results fit a model in which activating and inhibitory receptors recognize the same sets of self-MHC class I molecules, differing only in their binding affinities. Importantly, KIR2DS1 is not always sufficient to trigger NK effector responses when faced with cognate ligand, consistent with fine control during NK cell activation. We discuss how our results for KIR2DS1 and parallel studies on KIR2DS2 relate to the association between activating KIR genes and susceptibility to autoimmune disorders.
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Velickovic, M; Velickovic, Z; Panigoro, R; Dunckley, H
2009-01-01
Killer cell immunoglobulin-like receptors (KIRs) regulate the activity of natural killer and T cells through interactions with specific human leucocyte antigen class I molecules on target cells. Population studies performed over the last several years have established that KIR gene frequencies (GFs) and genotype content vary considerably among different ethnic groups, indicating the extent of KIR diversity, some of which have also shown the effect of the presence or absence of specific KIR genes in human disease. We have determined the frequencies of 16 KIR genes and pseudogenes and genotypes in 193 Indonesian individuals from Java, East Timor, Irian Jaya (western half of the island of New Guinea) and Kalimantan provinces of Indonesian Borneo. All 16 KIR genes were observed in all four populations. Variation in GFs between populations was observed, except for KIR2DL4, KIR3DL2, KIR3DL3, KIR2DP1 and KIR3DP1 genes, which were present in every individual tested. When comparing KIR GFs between populations, both principal component analysis and a phylogenetic tree showed close clustering of the Kalimantan and Javanese populations, while Irianese populations were clearly separated from the other three populations. Our results indicate a high level of KIR polymorphism in Indonesian populations that probably reflects the large geographical spread of the Indonesian archipelago and the complex evolutionary history and population migration in this region.
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USDA-ARS?s Scientific Manuscript database
Chicken natural killer (NK) cells are not well defined, so little is known about the molecular interactions controlling their activity. At day 14 of embryonic development, chick spleens are a rich source of T-cellfree CD8aa+, CD3_ cells with natural killing activity. Cell-mediated cytotoxicity assay...
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Silva-Santos, Bruno; Strid, Jessica
2018-01-01
Natural killer cell receptors (NKRs) are germline-encoded transmembrane proteins that regulate the activation and homeostasis of NK cells as well as other lymphocytes. For γδ T cells, NKRs play critical roles in discriminating stressed (transformed or infected) cells from their healthy counterparts, as proposed in the "lymphoid stress-surveillance" theory. Whereas the main physiologic role is seemingly fulfilled by natural killer group 2 member D, constitutively expressed by γδ T cells, enhancement of their therapeutic potential may rely on natural cytotoxicity receptors (NCRs), like NKp30 or NKp44, that can be induced selectively on human Vδ1 + T cells. Here, we review the contributions of NCRs, NKG2D, and their multiple ligands, to γδ T cell biology in mouse and human.
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Kim, Bo Kyung; Hong, Kyung Taek; Kang, Hyoung Jin; An, Hong Yul; Choi, Jung Yoon; Hong, Che Ry; Park, Kyung Duk; Lee, Dong Soon; Shin, Hee Young
2018-06-08
Epstein-Barr virus (EBV)-positive aggressive natural killer-cell leukemia (ANKL) is a rare malignancy of mature natural killer cells, with a very poor survival rate. Patients have a rapidly declining clinical course and a poor prognosis, with a median survival of only a few months. Herein, we describe a 16-year-old boy who was diagnosed with EBV-positive ANKL and successfully treated using combination chemotherapy and a subsequent allogeneic hematopoietic stem cell transplantation (alloHSCT). The patient is disease free 4 years and 9 months after alloHSCT. Thus, combination chemotherapy followed by alloHSCT seems to be a promising therapeutic option for EBV-positive ANKL.
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Kuśnierczyk, Piotr
2013-01-01
Killer cell immunoglobulin-like receptors (KIRs) are a family of cell surface inhibitory or activating receptors expressed on natural killer cells and some subpopulations of T lymphocytes. KIR genes are clustered in the 19q13.4 region and are characterized by both allelic (high numbers of variants) and haplotypic (different numbers of genes for inhibitory and activating receptors on individual chromosomes) polymorphism. This contributes to diverse susceptibility to diseases and other clinical situations. Associations of KIR genes, as well as of genes for their ligands, with selected diseases such as psoriasis vulgaris and atopic dermatitis, rheumatoid arthritis, recurrent spontaneous abortion, and non-small cell lung cancer are discussed in the context of NK and T cell functions. PMID:23372569
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Malova, E S; Balmasova, I P; Iuschuk, N D; Shmeleva, E V; Eremina, O F
2010-01-01
To study functional activity of natural killers on different stages of fibrosis during chronic hepatitis C. Functional activity of CD3-/CD56+/CD16+ lymphocytes measured as expression of natural killers receptors (NKR) and natural cytotoxicity receptors (NCR) was assessed by flow cytometry. At stage I of fibrosis, decrease of number of CD3-/CD56+/NKG2D+ cells was observed, whereas at precirrhotic stage III--sharp decrease of CD3-/CD56+/CD94+ and CD3-/ CD56+/NKG2D+ populations, and at cirrhotic stage--decrease of number of CD3-/CD56+/ NKG2D+ cells and increase of cytolytic activity of natural killers carrying CD107a marker compared to precirrhotic stage. Obtained data demonstrate that natural killers during chronic hepatitis C receive regulatory signals mainly through lectin type receptors (CD94 and NKG2D).
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Velázquez, Rocío; Zamora, Emiliano; Álvarez, Manuel; Álvarez, María L; Ramírez, Manuel
2016-10-01
The quality of traditional sparkling-wine depends on the aging process in the presence of dead yeast cells. These cells undergo a slow autolysis process thereby releasing some compounds, mostly colloidal polymers such as polysaccharides and mannoproteins, which influence the wine's foam properties and mouthfeel. Saccharomyces cerevisiae killer yeasts were tested to increase cell death and autolysis during mixed-yeast-inoculated second fermentation and aging. These yeasts killed sensitive strains in killer plate assays done under conditions of low pH and temperature similar to those used in sparkling-wine making, although some strains showed a different killer behaviour during the second fermentation. The fast killer effect improved the foam quality and mouthfeel of the mixed-inoculated wines, while the slow killer effect gave small improvements over single-inoculated wines. The effect was faster under high-pressure than under low-pressure conditions. Wine quality improvement did not correlate with the polysaccharide, protein, mannan, or aromatic compound concentrations, suggesting that the mouthfeel and foaming quality of sparkling wine are very complex properties influenced by other wine compounds and their interactions, as well as probably by the specific chemical composition of a given wine. Copyright © 2016 Elsevier Ltd. All rights reserved.
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Cui, Junqing; Watanabe, Naohiro; Kawano, Tetsu; Yamashita, Masakatsu; Kamata, Tohru; Shimizu, Chiori; Kimura, Motoko; Shimizu, Eiko; Koike, Jyunzo; Koseki, Haruhiko; Tanaka, Yujiro; Taniguchi, Masaru; Nakayama, Toshinori
1999-01-01
Murine Vα14 natural killer T (NKT) cells are thought to play a crucial role in various immune responses, including infectious, allergic, and autoimmune diseases. Because Vα14 NKT cells produce large amounts of both interleukin (IL)-4 and interferon (IFN)-γ upon in vivo stimulation with a specific ligand, α-galactosylceramide (α-GalCer), or after treatment with anti-CD3 antibody, a regulatory role on helper T (Th) cell differentiation has been proposed for these cells. However, the identity of the cytokine produced by Vα14 NKT cells that play a dominant role on the Th cell differentiation still remains controversial. Here, we demonstrate by using Vα14 NKT-deficient mice that Vα14 NKT cells are dispensable for the induction of antigen-specific immunoglobulin (Ig)E responses induced by ovalbumin immunization or Nippostrongylus brasiliensis infection. However, upon in vivo activation with α-GalCer, Vα14 NKT cells are found to suppress antigen-specific IgE production. The suppression appeared to be IgE specific, and was not detected in either Vα14 NKT– or IFN-γ–deficient mice. Consistent with these results, we also found that ligand-activated Vα14 NKT cells inhibited Th2 cell differentiation in an in vitro induction culture system. Thus, it is likely that activated Vα14 NKT cells exert a potent inhibitory effect on Th2 cell differentiation and subsequent IgE production by producing a large amount of IFN-γ. In marked contrast, our studies have revealed that IL-4 produced by Vα14 NKT cells has only a minor effect on Th2 cell differentiation. PMID:10499917
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USDA-ARS?s Scientific Manuscript database
Natural killer (NK) cells are a diverse population of lymphocytes with a range of biological roles including essential immune functions. NK cell diversity is created by the differential expression of cell surface receptors which modulate activation and function, including multiple subfamilies of C-t...
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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
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Natural Killer Cells for Therapy of Leukemia
Suck, Garnet; Linn, Yeh Ching; Tonn, Torsten
2016-01-01
Summary Clinical application of natural killer (NK) cells against leukemia is an area of intense investigation. In human leukocyte antigen-mismatched allogeneic hematopoietic stem cell transplantations (HSCT), alloreactive NK cells exert powerful anti-leukemic activity in preventing relapse in the absence of graft-versus-host disease, particularly in acute myeloid leukemia patients. Adoptive transfer of donor NK cells post-HSCT or in non-transplant scenarios may be superior to the currently widely used unmanipulated donor lymphocyte infusion. This concept could be further improved through transfusion of activated NK cells. Significant progress has been made in good manufacturing practice (GMP)-compliant large-scale production of stimulated effectors. However, inherent limitations remain. These include differing yields and compositions of the end-product due to donor variability and inefficient means for cryopreservation. Moreover, the impact of the various novel activation strategies on NK cell biology and in vivo behavior are barely understood. In contrast, reproduction of the third-party NK-92 drug from a cryostored GMP-compliant master cell bank is straightforward and efficient. Safety for the application of this highly cytotoxic cell line was demonstrated in first clinical trials. This novel ‘off-the-shelf’ product could become a treatment option for a broad patient population. For specific tumor targeting chimeric-antigen-receptor-engineered NK-92 cells have been designed. PMID:27226791
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Killer whales and whaling: the scavenging hypothesis.
Whitehead, Hal; Reeves, Randall
2005-12-22
Killer whales (Orcinus orca) frequently scavenged from the carcasses produced by whalers. This practice became especially prominent with large-scale mechanical whaling in the twentieth century, which provided temporally and spatially clustered floating carcasses associated with loud acoustic signals. The carcasses were often of species of large whale preferred by killer whales but that normally sink beyond their diving range. In the middle years of the twentieth century floating whaled carcasses were much more abundant than those resulting from natural mortality of whales, and we propose that scavenging killer whales multiplied through diet shifts and reproduction. During the 1970s the numbers of available carcasses fell dramatically with the cessation of most whaling (in contrast to a reasonably stable abundance of living whales), and the scavenging killer whales needed an alternative source of nutrition. Diet shifts may have triggered declines in other prey species, potentially affecting ecosystems, as well as increasing direct predation on living whales.
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Domogala, Anna; Madrigal, J Alejandro; Saudemont, Aurore
2016-06-01
Natural killer (NK) cells offer the potential for a powerful cellular immunotherapy because they can target malignant cells without being direct effectors of graft-versus-host disease. We have previously shown that high numbers of functional NK cells can be differentiated in vitro from umbilical cord blood (CB) CD34(+) cells. To develop a readily available, off-the-shelf cellular product, it is essential that NK cells differentiated in vitro can be frozen and thawed while maintaining the same phenotype and functions. We evaluated the phenotype and function of fresh and frozen NK cells differentiated in vitro. We also assessed whether the concentration of NK cells at the time of freezing had an impact on cell viability. We found that cell concentration of NK cells at the time of freezing did not have an impact on their viability and on cell recovery post-thaw. Moreover, freezing of differentiated NK cells in vitro did not affect their phenotype, cytotoxicity and degranulation capacity toward K562 cells, cytokine production and proliferation. We are therefore able to generate large numbers of functional NK cells from CB CD34(+) cells that maintain the same phenotype and function post-cryopreservation, which will allow for multiple infusions of a highly cytotoxic NK cell product. Copyright © 2016 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.
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Hercend, T; Griffin, J D; Bensussan, A; Schmidt, R E; Edson, M A; Brennan, A; Murray, C; Daley, J F; Schlossman, S F; Ritz, J
1985-01-01
The initial characterization of two monoclonal antibodies directed at antigens selectively expressed on large granular lymphocytes (LGL) is reported in the present paper. These two reagents, anti-natural killer (NK) H1A and anti-NKH2, were obtained following immunization of mouse spleen cells with a cloned human NK cell line termed JT3. In fresh human peripheral blood, both anti-NKH1A and anti-NKH2 selectively reacted with cells that appeared morphologically as large granular lymphocytes. However, complement lysis studies and two color fluorescence analysis demonstrated that some LGL express both antigens and other cells express only NKH1A or NKH2. Functional analysis of these subsets indicated that the population of NKH1A+ cells contains the entire pool of NK active lymphocytes, whereas expression of NKH2 antigen appeared to delineate a unique subpopulation of LGL which, in a resting state, display a low degree of spontaneous cytotoxicity. Expression of NKH1A and NKH2 was also investigated using a series of nine well characterized human NK clones. All NK clones were found to be NKH1A+ and four out of nine also expressed NKH2. These results strongly supported the view that NKH1A is a "pan-NK" associated antigen, and indicated that at least a fraction of cloned NKH2 + LGL are strongly cytotoxic. Anti-NKH1A was shown to have the same specificity as the previously described N901 antibody and was found here to precipitate a 200,000-220,000-mol wt molecule in SDS-polyacrylamide gel electrophoresis (PAGE) analysis. Anti-NKH2 was specific for a structure that migrates at 60,000 mol wt in SDS-PAGE analysis under reducing conditions. Two color immunofluorescence analysis of NKH1A, NKH2, and other NK-associated antigens (Leu7 and B73.1) demonstrated variable degrees of coexpression of these antigens, which confirmed that NKH1A and NKH2 define distinct cell surface structures. Anti-NKH1A and anti-NKH2 appear to be useful reagents for characterizing LGL present in human peripheral blood and for identifying functionally relevant subsets within this heterogeneous population of cytotoxic lymphocytes. Images PMID:3884668
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Rapidly fatal nasal natural killer/T-cell lymphoma: orbital and ocular adnexal presentations.
Yousuf, Salman J; Kumar, Nitin; Kidwell, Earl D; Copeland, Robert A
2011-03-01
Nasal natural killer/T-cell lymphoma (NKTL) is an aggressive malignancy that may initially present with orbital and/or ocular adnexal symptoms. We describe the case of a 27-year-old female with nasal NKTL, who initially presented with epiphora and died 4 months thereafter.
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Impaired natural killer cell self-education and "missing-self" responses in Ly49-deficient mice.
Bélanger, Simon; Tu, Megan M; Rahim, Mir Munir Ahmed; Mahmoud, Ahmad B; Patel, Rajen; Tai, Lee-Hwa; Troke, Angela D; Wilhelm, Brian T; Landry, Josette-Renée; Zhu, Qinzhang; Tung, Kenneth S; Raulet, David H; Makrigiannis, Andrew P
2012-07-19
Ly49-mediated recognition of MHC-I molecules on host cells is considered vital for natural killer (NK)-cell regulation and education; however, gene-deficient animal models are lacking because of the difficulty in deleting this large multigene family. Here, we describe NK gene complex knockdown (NKC(KD)) mice that lack expression of Ly49 and related MHC-I receptors on most NK cells. NKC(KD) NK cells exhibit defective killing of MHC-I-deficient, but otherwise normal, target cells, resulting in defective rejection by NKC(KD) mice of transplants from various types of MHC-I-deficient mice. Self-MHC-I immunosurveillance by NK cells in NKC(KD) mice can be rescued by self-MHC-I-specific Ly49 transgenes. Although NKC(KD) mice display defective recognition of MHC-I-deficient tumor cells, resulting in decreased in vivo tumor cell clearance, NKG2D- or antibody-dependent cell-mediated cytotoxicity-induced tumor cell cytotoxicity and cytokine production induced by activation receptors was efficient in Ly49-deficient NK cells, suggesting MHC-I education of NK cells is a single facet regulating their total potential. These results provide direct genetic evidence that Ly49 expression is necessary for NK-cell education to self-MHC-I molecules and that the absence of these receptors leads to loss of MHC-I-dependent "missing-self" immunosurveillance by NK cells.
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Models to Study NK Cell Biology and Possible Clinical Application.
Zamora, Anthony E; Grossenbacher, Steven K; Aguilar, Ethan G; Murphy, William J
2015-08-03
Natural killer (NK) cells are large granular lymphocytes of the innate immune system, responsible for direct targeting and killing of both virally infected and transformed cells. NK cells rapidly recognize and respond to abnormal cells in the absence of prior sensitization due to their wide array of germline-encoded inhibitory and activating receptors, which differs from the receptor diversity found in B and T lymphocytes that is due to the use of recombination-activation gene (RAG) enzymes. Although NK cells have traditionally been described as natural killers that provide a first line of defense prior to the induction of adaptive immunity, a more complex view of NK cells is beginning to emerge, indicating they may also function in various immunoregulatory roles and have the capacity to shape adaptive immune responses. With the growing appreciation for the diverse functions of NK cells, and recent technological advancements that allow for a more in-depth understanding of NK cell biology, we can now begin to explore new ways to manipulate NK cells to increase their clinical utility. In this overview unit, we introduce the reader to various aspects of NK cell biology by reviewing topics ranging from NK cell diversity and function, mouse models, and the roles of NK cells in health and disease, to potential clinical applications. © 2015 by John Wiley & Sons, Inc. Copyright © 2015 John Wiley & Sons, Inc.
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Classification of human natural killer cells based on migration behavior and cytotoxic response.
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.
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Oliveira, Sofia A.; Park, Se-Ho; Lee, Peter; Bendelac, Albert; Shenk, Thomas E.
2002-01-01
The murine cytomegalovirus m02 gene family encodes putative type I membrane glycoproteins named m02 through m16. A subset of these genes were fused to an epitope tag and cloned into an expression vector. In transfected and murine cytomegalovirus-infected cells, m02, m04, m05, m06, m07, m09, m10, and m12 localized to cytoplasmic structures near the nucleus, whereas m08 and m13 localized to a filamentous structure surrounding the nucleus. Substitution mutants lacking the m02 gene (SMsubm02) or the entire m02 gene family (SMsubm02-16) grew like their wild-type parent in cultured cells. However, whereas SMsubm02 was as pathogenic as the wild-type virus, SMsubm02-16 was markedly less virulent. SMsubm02-16 produced less infectious virus in most organs compared to wild-type virus in BALB/c and C57BL/6J mice, but it replicated to wild-type levels in the organs of immunodeficient γc/Rag2 mice, lacking multiple cell types including natural killer cells, and in C57BL/6J mice depleted of natural killer cells. These results argue that one or more members of the m02 gene family antagonize natural killer cell-mediated immune surveillance. PMID:11752177
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Morimoto, K; Takeshita, T; Inoue-Sakurai, C; Maruyama, S
2001-04-10
We investigated the association of lifestyle and mental health status with natural killer (NK) cell and lymphokine-activated killer (LAK) cell activities in healthy males. NK cell activity was determined in 105 male workers and LAK cell activity was determined in 54 male workers. Peripheral blood was obtained from each subject and peripheral blood mononuclear cells (PBMC) were isolated from the blood. These PBMC were used as effector cells. LAK cells were generated by incubation of PBMC with interleukin-2 for 72 h. NK cell activity against NK-sensitive K562 cells and LAK cell activity against NK-resistant Raji cells were examined by 51Cr release assay. Overall lifestyles were evaluated according to the answers on a questionnaire regarding eight health practices (cigarette smoking, alcohol consumption, eating breakfast, hours of sleep, hours of work, physical exercise, nutritional balance, mental stress). Subjects with a good overall lifestyle showed significantly higher NK cell (P < 0.05) and LAK cell (P < 0.05) activities than those with a poor overall lifestyles. Among eight lifestyle factors, cigarette smoking has relatively strong effects on NK cell and LAK cell activities. Subjects who complained of unstable mental status had significantly lower NK cell activity than those who reported stable mental status. When subjects were divided into four groups by lifestyle and mental health status, subjects who had poor or moderate lifestyle and reported unstable mental status showed the lowest NK cell activity and subjects who had good lifestyle and reported stable mental status showed the highest NK cell activity among four groups.
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Invariant natural killer T cells trigger adaptive lymphocytes to churn up bile.
Joyce, Sebastian; Van Kaer, Luc
2008-05-15
How innate immune response causes autoimmunity has remained an enigma. In this issue of Cell Host & Microbe, Mattner et al. demonstrate that invariant natural killer T cells activated by the mucosal commensal Novosphingobium aromaticivorans precipitate chronic T cell-mediated autoimmunity against small bile ducts that mirrors human primary biliary cirrhosis. These findings provide a mechanistic understanding of the role of innate immunity toward a microbe in the development of autoimmunity.
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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.
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Colotta, F.; Rambaldi, A.; Colombo, N.; Tabacchi, L.; Introna, M.; Mantovani, A.
1983-01-01
The streptococcal preparation OK432 was studied for its effects on natural killer (NK) activity of peripheral blood lymphocytes (PBL) from normal donors and from ovarian cancer patients, and of tumour-associated lymphocytes (TAL) from peritoneal effusions. OK432 augmented NK activity against the susceptible K562 line and induced killing of the relatively resistant Raji line. Freshly isolated ovarian carcinoma cells were relatively resistant to killing by unstimulated PBL and TAL. OK432 induced significant, though low, levels of cytotoxicity against 51Cr-labelled ovarian carcinoma cells. Augmentation of killing of fresh tumour cells by OK432 was best observed in a 20 h assay and both autologous and allogeneic targets were lysed. PBL were separated on discontinuous Percoll gradients. Unstimulated and OK432-boosted activity were enriched in the lower density fractions where large granular lymphocytes (LGL) and activity against K562 were found. Thus, OK432 augments NK activity of PBL and TAL in human ovarian carcinomas and induces low, but significant, levels of killing of fresh tumour cells. Effector cells involved in killing of fresh ovarian tumours copurify with LGL on discontinuous gradients of Percoll. PMID:6626452
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Buer, J; Hilse, R; Dallmann, I; Grosse, J; Kirchner, H; Zorn, U; Hänninen, E L; Franzke, A; Duensing, S; Poliwoda, H
1995-03-01
In this study, effective antitumour immunity was transferred by autologous short activated killer (SHAK) cells induced over four hours with lymphocyte conditioned medium (LCM) and recombinant interleukin-2 (rIL-2). Among eight patients with progressive metastatic renal cell carcinoma refractory to standard therapy, there were six objective tumour responses to SHAKs. Progression-free survival ranged from 0 to 8+ months, and overall survival ranged from 2 to 14+ months, with a median of 9+ months. Systemic toxicity of SHAKs was limited to flulike symptoms. Patient SHAKs provided a tumour-specific immunity, both cellular and humoral (expression and secretion of secondary cytokines, including IL-2, GM-CSF, INF-gamma and TNF-alpha), far superior to rIL-2 activated killer cells.
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NASA Technical Reports Server (NTRS)
Chapes, S. K.; Hoynowski, S. M.; Woods, K. M.; Armstrong, J. W.; Beharka, A. A.; Iandolo, J. J.; Spooner, B. S. (Principal Investigator)
1993-01-01
We used major histocompatibility complex class II antigen-deficient transgenic mice to show that in vitro natural killer cell cytotoxicity and T-cell activation by staphylococcal exotoxins (superantigens) are not dependent upon the presence of major histocompatibility complex class II molecules. T cells can be activated by exotoxins in the presence of exogenously added interleukin 1 or 2 or in the presence of specific antibody without exogenously added cytokines.
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Rajalingam, Raja
2016-01-01
Natural killer (NK) cells of the innate immune system are cytotoxic lymphocytes that play an important roles following transplantation of solid organs and hematopoietic stem cells. Recognition of self-human leukocyte antigen (HLA) class I molecules by inhibitory killer cell immunoglobulin-like receptors (KIRs) is involved in the calibration of NK cell effector capacities during the developmental stage, allowing the subsequent recognition and elimination of target cells with decreased expression of self-HLA class I (due to virus infection or tumor transformation) or HLA class I disparities (in the setting of allogeneic transplantation). NK cells expressing an inhibitory KIR-binding self-HLA can be activated when confronted with allografts lacking a ligand for the inhibitory receptor. Following the response of the adaptive immune system, NK cells can further destroy allograft endothelium by antibody-dependent cell-mediated cytotoxicity (ADCC), triggered through cross-linking of the CD16 Fc receptor by donor-specific antibodies bound to allograft. Upon recognizing allogeneic target cells, NK cells also secrete cytokines and chemokines that drive maturation of dendritic cells to promote cellular and humoral adaptive immune responses against the allograft. The cumulative activating and inhibitory signals generated by ligation of the receptors regulates mature NK cell killing of target cells and their production of cytokines and chemokines. This review summarizes the role of NK cells in allograft rejection and proposes mechanistic concepts that indicate a prominent role for KIR-HLA interactions in facilitating NK cells for Fc receptor-mediated ADCC effector function involved in antibody-mediated rejection of solid organ transplants.
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The role of the maternal immune system in the regulation of human birthweight.
Moffett, Ashley; Hiby, Susan E; Sharkey, Andrew M
2015-03-05
Human birthweight is subject to stabilizing selection. Large babies are at risk of obstetric complications such as obstructed labour, which endangers both mother and child. Small babies are also at risk with reduced survival. Fetal growth requires remodelling of maternal spiral arteries to provide an adequate maternal blood supply to the placenta. This arterial transformation is achieved by placental trophoblast cells, which invade into the uterine wall. Under-invasion is associated with fetal growth restriction; but if invasion is excessive large babies can result. A growing body of evidence suggests that this process is controlled by interactions between killer-cell immunoglobulin-like receptors (KIRs) expressed on maternal uterine natural killer cells (uNK) and their corresponding human leukocyte antigen-C (HLA-C) ligands on invading trophoblast. Mothers with the KIR AA genotype and a fetus with a paternal HLA-C2 allele tend to have small babies, because this combination inhibits cytokine secretion by uNK. Mothers with the activating KIR2DS1 gene and an HLA-C2 fetus are more likely to have large babies. When KIR2DS1 binds to HLA-C2 this increases secretion of cytokines that enhance trophoblast invasion. We conclude that specific combinations of the highly polymorphic gene systems, KIR and HLA-C, contribute to successful reproduction by maintaining birthweight between two extremes. © 2015 The Author(s) Published by the Royal Society. All rights reserved.
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Thio-isoglobotrihexosylceramide, an agonist for activating invariant natural killer T cells.
Xia, Chengfeng; Zhou, Dapeng; Liu, Chengwen; Lou, Yanyan; Yao, Qingjia; Zhang, Wenpeng; Wang, Peng George
2006-11-23
Thio-isoglobotrihexosylceramide (S-iGb3) might be resistant to alpha-galactosidases in antigen-presenting cells and have a longer retaining time in the lysosome before being loaded to CD1d. The biological assay showed that S-iGb3 demonstrates a much higher increase as a stimulatory ligand toward invariant natural killer T (iNKT) cells as compared to iGb3. [structure: see text].
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Linking killer whale survival and prey abundance: food limitation in the oceans' apex predator?
Ford, John K. B.; Ellis, Graeme M.; Olesiuk, Peter F.; Balcomb, Kenneth C.
2010-01-01
Killer whales (Orcinus orca) are large predators that occupy the top trophic position in the world's oceans and as such may have important roles in marine ecosystem dynamics. Although the possible top-down effects of killer whale predation on populations of their prey have received much recent attention, little is known of how the abundance of these predators may be limited by bottom-up processes. Here we show, using 25 years of demographic data from two populations of fish-eating killer whales in the northeastern Pacific Ocean, that population trends are driven largely by changes in survival, and that survival rates are strongly correlated with the availability of their principal prey species, Chinook salmon (Oncorhynchus tshawytscha). Our results suggest that, although these killer whales may consume a variety of fish species, they are highly specialized and dependent on this single salmonid species to an extent that it is a limiting factor in their population dynamics. Other ecologically specialized killer whale populations may be similarly constrained to a narrow range of prey species by culturally inherited foraging strategies, and thus are limited in their ability to adapt rapidly to changing prey availability. PMID:19755531
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Linking killer whale survival and prey abundance: food limitation in the oceans' apex predator?
Ford, John K B; Ellis, Graeme M; Olesiuk, Peter F; Balcomb, Kenneth C
2010-02-23
Killer whales (Orcinus orca) are large predators that occupy the top trophic position in the world's oceans and as such may have important roles in marine ecosystem dynamics. Although the possible top-down effects of killer whale predation on populations of their prey have received much recent attention, little is known of how the abundance of these predators may be limited by bottom-up processes. Here we show, using 25 years of demographic data from two populations of fish-eating killer whales in the northeastern Pacific Ocean, that population trends are driven largely by changes in survival, and that survival rates are strongly correlated with the availability of their principal prey species, Chinook salmon (Oncorhynchus tshawytscha). Our results suggest that, although these killer whales may consume a variety of fish species, they are highly specialized and dependent on this single salmonid species to an extent that it is a limiting factor in their population dynamics. Other ecologically specialized killer whale populations may be similarly constrained to a narrow range of prey species by culturally inherited foraging strategies, and thus are limited in their ability to adapt rapidly to changing prey availability.
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Natural Killer T Cells in Cancer Immunotherapy
Nair, Shiny; Dhodapkar, Madhav V.
2017-01-01
Natural killer T (NKT) cells are specialized CD1d-restricted T cells that recognize lipid antigens. Following stimulation, NKT cells lead to downstream activation of both innate and adaptive immune cells in the tumor microenvironment. This has impelled the development of NKT cell-targeted immunotherapies for treating cancer. In this review, we provide a brief overview of the stimulatory and regulatory functions of NKT cells in tumor immunity as well as highlight preclinical and clinical studies based on NKT cells. Finally, we discuss future perspectives to better harness the potential of NKT cells for cancer therapy. PMID:29018445
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Wang, Liming; Huang, Shigao; Dang, Yazheng; Li, Ming; Bai, Wen; Zhong, Zhanqiang; Zhao, Hongliang; Li, Yang; Liu, Yongjun; Wu, Mingyuan
2014-12-01
Esophageal cancer is a serious malignancy with regards to mortality and prognosis. Current treatment options include multimodality therapy mainstays of current treatment including surgery, radiation, and chemotherapy. Cell therapy for esophageal cancer is an advancing area of research. We report a case of esophageal cancer following cord blood-derived cytokine-induced killer cell infusion and adjuvant radiotherapy. Initially, she presented with poor spirit, full liquid diets, and upper abdominal pain. Through cell therapy plus adjuvant radiotherapy, the patient remitted and was self-reliant. Recognition of this curative effect of sequent therapy for esophageal cancer is important to enable appropriate treatment. This case highlights cord blood-derived cytokine-induced killer cell therapy significantly alleviates the adverse reaction of radiation and improves the curative effect. Cell therapy plus adjuvant radiotherapy can be a safe and effective treatment for esophageal cancer.
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Swift, Brenna E; Williams, Brent A; Kosaka, Yoko; Wang, Xing-Hua; Medin, Jeffrey A; Viswanathan, Sowmya; Martinez-Lopez, Joaquin; Keating, Armand
2012-07-01
Novel therapies capable of targeting drug resistant clonogenic MM cells are required for more effective treatment of multiple myeloma. This study investigates the cytotoxicity of natural killer cell lines against bulk and clonogenic multiple myeloma and evaluates the tumor burden after NK cell therapy in a bioluminescent xenograft mouse model. The cytotoxicity of natural killer cell lines was evaluated against bulk multiple myeloma cell lines using chromium release and flow cytometry cytotoxicity assays. Selected activating receptors on natural killer cells were blocked to determine their role in multiple myeloma recognition. Growth inhibition of clonogenic multiple myeloma cells was assessed in a methylcellulose clonogenic assay in combination with secondary replating to evaluate the self-renewal of residual progenitors after natural killer cell treatment. A bioluminescent mouse model was developed using the human U266 cell line transduced to express green fluorescent protein and luciferase (U266eGFPluc) to monitor disease progression in vivo and assess bone marrow engraftment after intravenous NK-92 cell therapy. Three multiple myeloma cell lines were sensitive to NK-92 and KHYG-1 cytotoxicity mediated by NKp30, NKp46, NKG2D and DNAM-1 activating receptors. NK-92 and KHYG-1 demonstrated 2- to 3-fold greater inhibition of clonogenic multiple myeloma growth, compared with killing of the bulk tumor population. In addition, the residual colonies after treatment formed significantly fewer colonies compared to the control in a secondary replating for a cumulative clonogenic inhibition of 89-99% at the 20:1 effector to target ratio. Multiple myeloma tumor burden was reduced by NK-92 in a xenograft mouse model as measured by bioluminescence imaging and reduction in bone marrow engraftment of U266eGFPluc cells by flow cytometry. This study demonstrates that NK-92 and KHYG-1 are capable of killing clonogenic and bulk multiple myeloma cells. In addition, multiple myeloma tumor burden in a xenograft mouse model was reduced by intravenous NK-92 cell therapy. Since multiple myeloma colony frequency correlates with survival, our observations have important clinical implications and suggest that clinical studies of NK cell lines to treat MM are warranted.
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Kusumi, Maki; Yamashita, Takahiro; Fujii, Tomoyuki; Nagamatsu, Takeshi; Kozuma, Shiro; Taketani, Yuji
2006-06-01
The balance of inhibitory and activating natural killer (NK) receptors on maternal decidual NK cells, most of which are CD56bright, is thought to be crucial for the proper growth of trophoblasts in placenta. A lectin-like NK receptor, CD94/NKG2, is the receptor for human leukocyte antigen (HLA)-E, which is expressed on trophoblasts. To clarify the mechanism regulating the activity of decidual NK cells during pregnancy, we investigated the expression patterns of inhibitory NK receptor, CD94/NKG2A, and activating receptor, CD94/NKG2C, on decidual NK cells in an early stage of normal pregnancy and compared them with those on peripheral NK cells, most of which are CD56dim. The rate of NKG2A-positive cells was significantly higher for decidual CD56bright NK cells than for peripheral CD56dim NK cells, but the rates of NKG2C-positive cells were comparable between the two cell types. Interestingly, peripheral CD56dim NK cells reciprocally expressed inhibitory NKG2A and activating NKG2C, but decidual CD56bright NK cells that expressed activating NKG2C simultaneously expressed inhibitory NKG2A. The co-expression of inhibitory and activating NKG2 receptors may fine-tune the immunoregulatory functions of the decidual NK cells to control the trophoblast invasion in constructing placenta.
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Neely, Harold R; Mazo, Irina B; Gerlach, Carmen; von Andrian, Ulrich H
2017-12-18
Natural killer (NK) cells have historically been considered to be a part of the innate immune system, exerting a rapid response against pathogens and tumors in an antigen (Ag)-independent manner. However, over the past decade, evidence has accumulated suggesting that at least some NK cells display certain characteristics of adaptive immune cells. Indeed, NK cells can learn and remember encounters with a variety of Ags, including chemical haptens and viruses. Upon rechallenge, memory NK cells mount potent recall responses selectively to those Ags. This phenomenon, traditionally termed "immunological memory," has been reported in mice, nonhuman primates, and even humans and appears to be concentrated in discrete NK cell subsets. Because immunological memory protects against recurrent infections and is the central goal of active vaccination, it is crucial to define the mechanisms and consequences of NK cell memory. Here, we summarize the different kinds of memory responses that have been attributed to specific NK cell subsets and discuss the possibility to harness NK cell memory for vaccination purposes. Copyright © 2017 Cold Spring Harbor Laboratory Press; all rights reserved.
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Lidocaine Stimulates the Function of Natural Killer Cells in Different Experimental Settings.
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.
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Oelsner, Sarah; Wagner, Juliane; Friede, Miriam E; Pfirrmann, Verena; Genßler, Sabrina; Rettinger, Eva; Buchholz, Christian J; Pfeifer, Heike; Schubert, Ralf; Ottmann, Oliver G; Ullrich, Evelyn; Bader, Peter; Wels, Winfried S
2016-10-15
Pre-emptive cancer immunotherapy by donor lymphocyte infusion (DLI) using cytokine-induced killer (CIK) cells may be beneficial to prevent relapse with a reduced risk of causing graft-versus-host-disease. CIK cells are a heterogeneous effector cell population including T cells (CD3(+) CD56(-) ), natural killer (NK) cells (CD3(-) CD56(+) ) and natural killer T (T-NK) cells (CD3(+) CD56(+) ) that exhibit non-major histocompatibility complex (MHC)-restricted cytotoxicity and are generated by ex vivo expansion of peripheral blood mononuclear cells in the presence of interferon (IFN)-γ, anti-CD3 antibody, interleukin-2 (IL-2) and interleukin-15 (IL-15). To facilitate selective target-cell recognition and enhance specific cytotoxicity against B-cell acute lymphoblastic leukemia (B-ALL), we transduced CIK cells with a lentiviral vector encoding a chimeric antigen receptor (CAR) that carries a composite CD28-CD3ζ domain for signaling and a CD19-specific scFv antibody fragment for cell binding (CAR 63.28.z). In vitro analysis revealed high and specific cell killing activity of CD19-targeted CIK/63.28.z cells against otherwise CIK-resistant cancer cell lines and primary B-ALL blasts, which was dependent on CD19 expression and CAR signaling. In a xenograft model in immunodeficient mice, treatment with CIK/63.28.z cells in contrast to therapy with unmodified CIK cells resulted in complete and durable molecular remissions of established primary pre-B-ALL. Our results demonstrate potent antileukemic activity of CAR-engineered CIK cells in vitro and in vivo, and suggest this strategy as a promising approach for adoptive immunotherapy of refractory pre-B-ALL. © 2016 UICC.
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Natural killer cell dysfunction in hepatocellular carcinoma and NK cell-based immunotherapy
Sun, Cheng; Sun, Hao-yu; Xiao, Wei-hua; Zhang, Cai; Tian, Zhi-gang
2015-01-01
The mechanisms linking hepatitis B virus (HBV) and hepatitis C virus (HCV) infection to hepatocellular carcinoma (HCC) remain largely unknown. Natural killer (NK) cells account for 25%–50% of the total number of liver lymphocytes, suggesting that NK cells play an important role in liver immunity. The number of NK cells in the blood and tumor tissues of HCC patients is positively correlated with their survival and prognosis. Furthermore, a group of NK cell-associated genes in HCC tissues is positively associated with the prolonged survival. These facts suggest that NK cells and HCC progression are strongly associated. In this review, we describe the abnormal NK cells and their functional impairment in patients with chronic HBV and HCV infection, which contribute to the progression of HCC. Then, we summarize the association of NK cells with HCC based on the abnormalities in the numbers and phenotypes of blood and liver NK cells in HCC patients. In particular, the exhaustion of NK cells that represents lower cytotoxicity and impaired cytokine production may serve as a predictor for the occurrence of HCC. Finally, we present the current achievements in NK cell immunotherapy conducted in mouse models of liver cancer and in clinical trials, highlighting how chemoimmunotherapy, NK cell transfer, gene therapy, cytokine therapy and mAb therapy improve NK cell function in HCC treatment. It is conceivable that NK cell-based anti-HCC therapeutic strategies alone or in combination with other therapies will be great promise for HCC treatment. PMID:26073325
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Shah, Nina; Martin-Antonio, Beatriz; Yang, Hong; Ku, Stephanie; Lee, Dean A; Cooper, Laurence J N; Decker, William K; Li, Sufang; Robinson, Simon N; Sekine, Takuya; Parmar, Simrit; Gribben, John; Wang, Michael; Rezvani, Katy; Yvon, Eric; Najjar, Amer; Burks, Jared; Kaur, Indreshpal; Champlin, Richard E; Bollard, Catherine M; Shpall, Elizabeth J
2013-01-01
Natural killer (NK) cells are important mediators of anti-tumor immunity and are active against several hematologic malignancies, including multiple myeloma (MM). Umbilical cord blood (CB) is a promising source of allogeneic NK cells but large scale ex vivo expansion is required for generation of clinically relevant CB-derived NK (CB-NK) cell doses. Here we describe a novel strategy for expanding NK cells from cryopreserved CB units using artificial antigen presenting feeder cells (aAPC) in a gas permeable culture system. After 14 days, mean fold expansion of CB-NK cells was 1848-fold from fresh and 2389-fold from cryopreserved CB with >95% purity for NK cells (CD56(+)/CD3(-)) and less than 1% CD3(+) cells. Though surface expression of some cytotoxicity receptors was decreased, aAPC-expanded CB-NK cells exhibited a phenotype similar to CB-NK cells expanded with IL-2 alone with respect to various inhibitory receptors, NKG2C and CD94 and maintained strong expression of transcription factors Eomesodermin and T-bet. Furthermore, CB-NK cells formed functional immune synapses with and demonstrated cytotoxicity against various MM targets. Finally, aAPC-expanded CB-NK cells showed significant in vivo activity against MM in a xenogenic mouse model. Our findings introduce a clinically applicable strategy for the generation of highly functional CB-NK cells which can be used to eradicate MM.
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Watanabe, T; Fathman, C G; Coutinho, A
1977-09-01
Selection in long-term culture of alloreactive T cells, by successive in vitro restimulation with semi-allogeneic cells, results in primed responder cell populations which maintain full proliferative reactivity to allogeneic cells as well as to the T cell mitogens concanavalin A (Con A) and phytohemagglutinin (PHA) but are depleted of cells which can effect target cell destruction in either a specific or nonspecific manner. Con A-induced T cell blasts (selected by velocity sedimentation) can revert to small resting lymphocytes in the presence of inert "filler" cells. Con A blasts which have reverted, readily proliferate in response to Con A or allogeneic stimulator cells but are largely depleted of effector killer cells and PHA-responsive cells.
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Perry, Anamarija M; Diebold, Jacques; Nathwani, Bharat N; MacLennan, Kenneth A; Müller-Hermelink, Hans K; Bast, Martin; Boilesen, Eugene; Armitage, James O; Weisenburger, Dennis D
2016-10-01
The distribution of non-Hodgkin lymphoma subtypes varies around the world, but a large systematic comparative study has never been done. In this study, we evaluated the clinical features and relative frequencies of non-Hodgkin lymphoma subtypes in five developing regions of the world and compared the findings to the developed world. Five expert hematopathologists classified 4848 consecutive cases of lymphoma from 26 centers in 24 countries using the World Health Organization classification, and 4539 (93.6%) were confirmed to be non-Hodgkin lymphoma, with a significantly greater number of males than females in the developing regions compared to the developed world (P<0.05). The median age at diagnosis was significantly lower for both low- and high-grade B-cell lymphoma in the developing regions. The developing regions had a significantly lower frequency of B-cell lymphoma (86.6%) and a higher frequency of T- and natural killer-cell lymphoma (13.4%) compared to the developed world (90.7% and 9.3%, respectively). Also, the developing regions had significantly more cases of high-grade B-cell lymphoma (59.6%) and fewer cases of low-grade B-cell lymphoma (22.7%) compared to the developed world (39.2% and 32.7%, respectively). Among the B-cell lymphomas, diffuse large B-cell lymphoma was the most common subtype (42.5%) in the developing regions. Burkitt lymphoma (2.2%), precursor B- and T-lymphoblastic leukemia/lymphoma (1.1% and 2.9%, respectively) and extranodal natural killer/T-cell lymphoma (2.2%) were also significantly increased in the developing regions. These findings suggest that differences in etiologic and host risk factors are likely responsible, and more detailed epidemiological studies are needed to better understand these differences. Copyright© Ferrata Storti Foundation.
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Yu, Jian-Bo; Zuo, Zhuo; Zhang, Wen-Yan; Yang, Qun-Pei; Zhang, Ying-Chun; Tang, Yuan; Zhao, Sha; Mo, Xian-Ming; Liu, Wei-Ping
2014-11-01
To analyze the differentiation characteristics of extranodal natural killer/T-cell lymphoma, nasal type, one nude mouse model, cell lines SNK6 and SNT8, and 16 fresh human samples were analyzed by flow cytometry immunophenotyping and immunohistochemistry staining; and 115 archived cases were used for phenotypic detection and prognostic analysis. We found that CD25 was expressed by most tumor cells in all samples, and CD56(+)CD25(+) cells were the predominant population in the mouse model, the 2 cell lines, and 10 of the 16 fresh tumor samples; in the other 6 fresh tumor samples, the predominant cell population was of the CD16(+)CD25(+) phenotype, and only a minor population showed the CD56(+)CD25(+) phenotype. The phenotype detected by immunohistochemistry staining generally was consistent with the phenotype found by flow cytometry immunophenotyping. According to the expression of CD56 and CD16, 115 cases could be classified into 3 phenotypic subtypes: CD56(-)CD16(-), CD56(+)CD16(-), and CD56(dim/-)CD16(+). Patients with tumors of the CD56(dim/-)CD16(+) phenotype had a poorer prognosis than patients with tumors of the other phenotypes. Differentiation of extranodal natural killer/T-cell lymphoma, nasal type apparently resembles the normal natural killer cell developmental pattern, and these tumors can be classified into 3 phenotypic subtypes of different aggressiveness. Expression of CD56(dim/-)CD16(+) implies a poorer prognosis. Copyright © 2014 Elsevier Inc. All rights reserved.
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Rajalingam, Raja
2016-01-01
Natural killer (NK) cells of the innate immune system are cytotoxic lymphocytes that play an important roles following transplantation of solid organs and hematopoietic stem cells. Recognition of self-human leukocyte antigen (HLA) class I molecules by inhibitory killer cell immunoglobulin-like receptors (KIRs) is involved in the calibration of NK cell effector capacities during the developmental stage, allowing the subsequent recognition and elimination of target cells with decreased expression of self-HLA class I (due to virus infection or tumor transformation) or HLA class I disparities (in the setting of allogeneic transplantation). NK cells expressing an inhibitory KIR-binding self-HLA can be activated when confronted with allografts lacking a ligand for the inhibitory receptor. Following the response of the adaptive immune system, NK cells can further destroy allograft endothelium by antibody-dependent cell-mediated cytotoxicity (ADCC), triggered through cross-linking of the CD16 Fc receptor by donor-specific antibodies bound to allograft. Upon recognizing allogeneic target cells, NK cells also secrete cytokines and chemokines that drive maturation of dendritic cells to promote cellular and humoral adaptive immune responses against the allograft. The cumulative activating and inhibitory signals generated by ligation of the receptors regulates mature NK cell killing of target cells and their production of cytokines and chemokines. This review summarizes the role of NK cells in allograft rejection and proposes mechanistic concepts that indicate a prominent role for KIR–HLA interactions in facilitating NK cells for Fc receptor-mediated ADCC effector function involved in antibody-mediated rejection of solid organ transplants. PMID:28066408
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Lee, Soo-Hyeon; Shin, Dong-Jun; Kim, Yoseop; Kim, Cheol-Jung; Lee, Je-Jung; Yoon, Mee Sun; Uong, Tung Nguyen Thanh; Yu, Dohyeon; Jung, Ji-Youn; Cho, Duck; Jung, Bock-Gie; Kim, Sang-Ki; Suh, Guk-Hyun
2018-01-01
Natural killer (NK) cells play a pivotal role in the immune response against infections and malignant transformation, and adopted transfer of NK cells is thought to be a promising therapeutic approach for cancer patients. Previous reports describing the phenotypic features of canine NK cells have produced inconsistent results. Canine NK cells are still defined as non-B and non-T (CD3 - CD21 - ) large granular lymphocytes. However, a few reports have demonstrated that canine NK cells share the phenotypic characteristics of T lymphocytes, and that CD3 + CD5 dim CD21 - lymphocytes are putative canine NK cells. Based on our previous reports, we hypothesized that phenotypic modulation could occur between these two populations during activation. In this study, we investigated the phenotypic and functional differences between CD3 + CD5 dim CD21 - (cytotoxic large granular lymphocytes) and CD3 - CD5 - CD21 - NK lymphocytes before and after culture of peripheral blood mononuclear cells isolated from normal dogs. The results of this study show that CD3 + CD5 dim CD21 - lymphocytes can be differentiated into non-B, non-T NK (CD3 - CD5 - CD21 - TCRαβ - TCRγδ - GranzymeB + ) lymphocytes through phenotypic modulation in response to cytokine stimulation. In vitro studies of purified CD3 + CD5 dim CD21 - cells showed that CD3 - CD5 - CD21 - cells are derived from CD3 + CD5 dim CD21 - cells through phenotypic modulation. CD3 + CD5 dim CD21 - cells share more NK cell functional characteristics compared with CD3 - CD5 - CD21 - cells, including the expression of T-box transcription factors (Eomes, T-bet), the production of granzyme B and interferon-γ, and the expression of NK cell-related molecular receptors such as NKG2D and NKp30. In conclusion, the results of this study suggest that CD3 + CD5 dim CD21 - and CD3 - CD5 - CD21 - cells both contain a subset of putative NK cells, and the difference between the two populations may be due to the degree of maturation.
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Lapteva, Natalia; Aldrich, Melissa; Weksberg, David; Rollins, Lisa; Goltsova, Tatiana; Chen, Si-Yi; Huang, Xue F.
2014-01-01
Summary Dendritic cells (DCs) are professional antigen (Ag)-presenting cells capable of inducing immune responses to tumor Ags and, therefore, play a central role in the induction of antitumor immunity. There is a large amount of evidence, however, about paucity of tumor-associated DCs and that DCs’ immunogenic functions are suppressed in a tumor environment. Here we describe a potent in situ vaccine targeting tumoral DCs in vivo. This vaccine comprised of an oncolytic adenovirus expressing RANTES (regulated upon activation, normally T expressed, and presumably secreted) (Ad-RANTES-E1A), enhanced tumor infiltration, and maturation of Ag-presenting cells in vivo. In this study, we show that intratumoral vaccinations with Ad-RANTES-E1A induced significant primary tumor growth regression and blocked metastasis formation in JC and E.G-7 murine tumor models. This vaccine recruited DCs, macrophages, natural killer cells, and CD8+ T cells to the tumor site, and thus enhanced Ag-specific cytotoxic T lymphocyte responses and natural killer cell responses. DCs purified from the Ad-RANTES-E1A–treated E.G-7 tumors secreted significantly higher levels of interferon-γ and interleukin-12, as compared with control groups and more efficiently enhanced CD8+ T-cell response. This in situ immunization strategy could be a potent antitumor immunotherapy approach for aggressive established tumors. PMID:19238013
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Viral Evasion of Natural Killer Cell Activation
Ma, Yi; Li, Xiaojuan; Kuang, Ersheng
2016-01-01
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. PMID:27077876
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Viral Evasion of Natural Killer Cell Activation.
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.
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The role of natural killer cells in autoimmune blistering diseases.
Zakka, L R; Fradkov, E; Keskin, D B; Tabansky, I; Stern, J N H; Ahmed, A R
2012-02-01
The major focus of this paper is to describe and evaluate current information on the role of natural killer cells (NK cells) in the pathogenesis of blistering diseases. Until now, only pemphigus vulgaris (PV) has been studied. One co-culture study demonstrated that CD4+ T cells from the peripheral blood or perilesional skin of patients with active disease proliferate and secrete cytokines in the presence of major histocompatibility class II-expressing NK cells loaded with antigenic desmoglein self-peptides. Another study showed that NK cells can contribute to a T helper type 2-biased immune response through impaired interleukins (IL)-12 signaling and upregulation of IL, IL-10 and IL-5. Although significant data on other blistering diseases are unavailable at present, some studies implicate NK cells in disease progression. For instance, information on the role of NK cells in psoriasis and their production of tumor necrosis factor-α (TNF-α) will be provided since several TNF-α-inhibitors are used in its treatment. Studies on alopecia areata are also included in this paper because NK cells seem to play a key role in its pathogenesis. This review highlights the potential importance of NK cells and NKT cells as members of the large repertoire of cells and soluble mediators that play a critical role in pathogenesis of blistering diseases and other autoimmune diseases involving the skin. Therefore, the authors advocate a greater focus and interest on the study of the interaction of NK cells and the skin.
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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. © 2016 John Wiley & Sons Ltd.
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A large gene family in fission yeast encodes spore killers that subvert Mendel’s law
Hu, Wen; Jiang, Zhao-Di; Suo, Fang; Zheng, Jin-Xin; He, Wan-Zhong; Du, Li-Lin
2017-01-01
Spore killers in fungi are selfish genetic elements that distort Mendelian segregation in their favor. It remains unclear how many species harbor them and how diverse their mechanisms are. Here, we discover two spore killers from a natural isolate of the fission yeast Schizosaccharomyces pombe. Both killers belong to the previously uncharacterized wtf gene family with 25 members in the reference genome. These two killers act in strain-background-independent and genome-location-independent manners to perturb the maturation of spores not inheriting them. Spores carrying one killer are protected from its killing effect but not that of the other killer. The killing and protecting activities can be uncoupled by mutation. The numbers and sequences of wtf genes vary considerably between S. pombe isolates, indicating rapid divergence. We propose that wtf genes contribute to the extensive intraspecific reproductive isolation in S. pombe, and represent ideal models for understanding how segregation-distorting elements act and evolve. DOI: http://dx.doi.org/10.7554/eLife.26057.001 PMID:28631610
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Psychosocial predictors of natural killer cell mobilization during marital conflict.
Miller, G E; Dopp, J M; Myers, H F; Stevens, S Y; Fahey, J L
1999-05-01
This study examined how specific emotions relate to autonomic nervous and immune system parameters and whether cynical hostility moderates this relationship. Forty-one married couples participated in a 15-min discussion about a marital problem. Observers recorded spouses' emotional expressions during the discussion, and cardiovascular, neuroendocrine, and immunologic parameters were assessed throughout the laboratory session. Among men high in cynical hostility, anger displayed during the conflict was associated with greater elevations in systolic and diastolic blood pressure, cortisol, and increases in natural killer cell numbers and cytotoxicity. Among men low in cynical hostility, anger was associated with smaller increases in heart rate and natural killer cell cytotoxicity. These findings suggest that models describing the impact of stress on physiology should be refined to reflect the joint contribution of situational and dispositional variables.
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2014-05-14
microsatellite loci from 206 individuals to examine levels of differentiation among the 2 island-associated populations and offshore animals from the...they are from offshore animals . The patterns of differentiation revealed by the 2 marker types suggest that the island-associated false killer whale...False killer whales (Pseudorca crassidens) are large delphinids typically found in deep water far offshore . However, in the Hawaiian Archipelago
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Restoration of Immune Surveillance in Lung Cancer by Natural Killer Cells
2016-10-01
and had no dramatic effects on NK cell, unlike TGFb, although this product had been effective in the past. However, the pathway that Nicotine and... effects of nicotine on NK function in vivo in smokers and have proceeded to conduct the clinical protocol in Aim 2. Aim 2. To verify that use of...molecule, DAP12, that controls tumoricidal function in human Natural Killer (NK) Cells and to understand how nicotine , contained in tobacco smoke
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Copy Number Variation of KIR Genes Influences HIV-1 Control
Shianna, Kevin V.; Feng, Sheng; Urban, Thomas J.; Ge, Dongliang; De Luca, Andrea; Martinez-Picado, Javier; Wolinsky, Steven M.; Martinson, Jeremy J.; Jamieson, Beth D.; Bream, Jay H.; Martin, Maureen P.; Borrow, Persephone; Letvin, Norman L.; McMichael, Andrew J.; Haynes, Barton F.; Telenti, Amalio; Carrington, Mary; Goldstein, David B.; Alter, Galit
2011-01-01
A genome-wide screen for large structural variants showed that a copy number variant (CNV) in the region encoding killer cell immunoglobulin-like receptors (KIR) associates with HIV-1 control as measured by plasma viral load at set point in individuals of European ancestry. This CNV encompasses the KIR3DL1-KIR3DS1 locus, encoding receptors that interact with specific HLA-Bw4 molecules to regulate the activation of lymphocyte subsets including natural killer (NK) cells. We quantified the number of copies of KIR3DS1 and KIR3DL1 in a large HIV-1 positive cohort, and showed that an increase in KIR3DS1 count associates with a lower viral set point if its putative ligand is present (p = 0.00028), as does an increase in KIR3DL1 count in the presence of KIR3DS1 and appropriate ligands for both receptors (p = 0.0015). We further provide functional data that demonstrate that NK cells from individuals with multiple copies of KIR3DL1, in the presence of KIR3DS1 and the appropriate ligands, inhibit HIV-1 replication more robustly, and associated with a significant expansion in the frequency of KIR3DS1+, but not KIR3DL1+, NK cells in their peripheral blood. Our results suggest that the relative amounts of these activating and inhibitory KIR play a role in regulating the peripheral expansion of highly antiviral KIR3DS1+ NK cells, which may determine differences in HIV-1 control following infection. PMID:22140359
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Interleukin-12- and interferon-γ-mediated natural killer cell activation by Agaricus blazei Murill
Yuminamochi, Eri; Koike, Taisuke; Takeda, Kazuyoshi; Horiuchi, Isao; Okumura, Ko
2007-01-01
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-γ (IFN-γ) deficient mice. NK cell activation and IFN-γ 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-γ 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-γ-dependent manner. These results clearly demonstrated that A. blazei and ABPC augmented NK cell activation through IL-12-mediated IFN-γ production. PMID:17346284
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Generation of natural killer cells from hematopoietic stem cells in vitro for immunotherapy
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
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Ghiringhelli, Francois; Ménard, Cédric; Martin, Francois; Zitvogel, Laurence
2006-12-01
Tumor immunosurveillance relies on cognate immune effectors [lymphocytes and interferon-gamma (IFN-gamma)] and innate immunity [natural killer (NK) cells, natural killer group 2, member D (NKG2D) ligands, perforin/granzyme, and tumor necrosis factor-related apoptosis-inducing ligand]. In parallel, tumor cells promote the expansion of CD4(+)CD25(+) regulatory T cells (Tregs) that counteract T-cell-based anti-tumor immunity. Moreover, accumulating evidence points to a critical role for Tregs in dampening NK cell immune responses. This review summarizes the findings showing that Tregs suppress NK cell effector functions in vitro and in vivo, i.e. homeostatic proliferation, cytotoxicity, and interleukin-12-mediated IFN-gamma production. The molecular mechanism involve selective expression of membrane-bound transforming growth factor-beta on Tregs, which downregulate NKG2D expression on NK cells in vitro and in vivo. The regulatory events dictating NK cell suppression by Tregs have been studied and are discussed. The pathological relevance of the Treg-NK cell interaction has been brought up in tumor models and in patients with cancer. Consequently, inhibition of Tregs through pharmacological interventions should be considered during NK-cell-based immunotherapy of cancer.
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Bárcena, Paloma; Jara-Acevedo, María; Tabernero, María Dolores; López, Antonio; Sánchez, María Luz; García-Montero, Andrés C.; Muñoz-García, Noemí; Vidriales, María Belén; Paiva, Artur; Lecrevisse, Quentin; Lima, Margarida; Langerak, Anton W.; Böttcher, Sebastian; van Dongen, Jacques J.M.
2015-01-01
Currently, the lack of a universal and specific marker of clonality hampers the diagnosis and classification of chronic expansions of natural killer (NK) cells. Here we investigated the utility of flow cytometric detection of aberrant/altered NK-cell phenotypes as a surrogate marker for clonality, in the diagnostic work-up of chronic lymphoproliferative disorders of NK cells (CLPD-NK). For this purpose, a large panel of markers was evaluated by multiparametric flow cytometry on peripheral blood (PB) CD56low NK cells from 60 patients, including 23 subjects with predefined clonal (n = 9) and polyclonal (n = 14) CD56low NK-cell expansions, and 37 with CLPD-NK of undetermined clonality; also, PB samples from 10 healthy adults were included. Clonality was established using the human androgen receptor (HUMARA) assay. Clonal NK cells were found to show decreased expression of CD7, CD11b and CD38, and higher CD2, CD94 and HLADR levels vs. normal NK cells, together with a restricted repertoire of expression of the CD158a, CD158b and CD161 killer-associated receptors. In turn, NK cells from both clonal and polyclonal CLPD-NK showed similar/overlapping phenotypic profiles, except for high and more homogeneous expression of CD94 and HLADR, which was restricted to clonal CLPD-NK. We conclude that the CD94hi/HLADR+ phenotypic profile proved to be a useful surrogate marker for NK-cell clonality. PMID:26556869
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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
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Swine in biomedical research. Vol. 3
DOE Office of Scientific and Technical Information (OSTI.GOV)
Tumbleson, M.E.
This volume presents information on the following topics: hemodynamic characteristics of the conscious resting pig; cardiovascular and metabolic responses to acute and chronic exercise in swine (ILLEGIBLE) a large animal model for studies (ILLEGIBLE) effects of heparin-protamine interaction in swine - intravenous vs. intraarterial; swine as animal models in cardiovascular research; studies of coronary thrombosis in swine with von Willebrand's disease; role of plasma intermediate and low density lipoproteins in early atherogenesis in hyperlipidemic swine; swine as a model in renal physiology and nephrology; the pig as a model for studying kidney disease in man; hypertension of renal origin andmore » the effects of Captopril in miniature pigs; porcine natural killer/killer cell system; the behavior of pig lymphocyte populations in vivo; a review of spontaneous and experimental porcine eperythrozoonosis; and Sinclair swine melanoma.« less
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Tracking the Response of Natural Killer T Cells to a Glycolipid Antigen Using Cd1d Tetramers
Matsuda, Jennifer L.; Naidenko, Olga V.; Gapin, Laurent; Nakayama, Toshinori; Taniguchi, Masaru; Wang, Chyung-Ru; Koezuka, Yasuhiko; Kronenberg, Mitchell
2000-01-01
A major group of natural killer (NK) T cells express an invariant Vα14+ T cell receptor (TCR) specific for the lipoglycan α-galactosylceramide (α-GalCer), which is presented by CD1d. These cells may have an important immune regulatory function, but an understanding of their biology has been hampered by the lack of suitable reagents for tracking them in vivo. Here we show that tetramers of mouse CD1d loaded with α-GalCer are a sensitive and highly specific reagent for identifying Vα14+ NK T cells. Using these tetramers, we find that α-GalCer–specific T lymphocytes are more widely distributed than was previously appreciated, with populations of largely NK1.1− but tetramer-binding T cells present in the lymph nodes and the intestine. Injection of α-GalCer leads to the production of both interferon γ and interleukin 4 by nearly all NK T cells in the liver and the majority of the spleen within 2 h. These cells mostly disappear by 5 h, and they do not reappear after 1 wk. Curiously, tetramer-positive thymocytes do not rapidly synthesize cytokines, nor do they undergo decreases in cell number after lipid antigen stimulation, although they express equivalent TCR levels. In summary, the data presented here demonstrate that α-GalCer–specific NK T cells undergo a unique and highly compartmentalized response to antigenic stimulation. PMID:10974039
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Alava, Juan José; Ross, Peter S; Gobas, Frank A P C
2016-01-01
Resident killer whale populations in the NE Pacific Ocean are at risk due to the accumulation of pollutants, including polybrominated diphenyl ethers (PBDEs). To assess the impact of PBDEs in water and sediments in killer whale critical habitat, we developed a food web bioaccumulation model. The model was designed to estimate PBDE concentrations in killer whales based on PBDE concentrations in sediments and the water column throughout a lifetime of exposure. Calculated and observed PBDE concentrations exceeded the only toxicity reference value available for PBDEs in marine mammals (1500 μg/kg lipid) in southern resident killer whales but not in northern resident killer whales. Temporal trends (1993-2006) for PBDEs observed in southern resident killer whales showed a doubling time of ≈5 years. If current sediment quality guidelines available in Canada for polychlorinated biphenyls are applied to PBDEs, it can be expected that PBDE concentrations in killer whales will exceed available toxicity reference values by a large margin. Model calculations suggest that a PBDE concentration in sediments of approximately 1.0 μg/kg dw produces PBDE concentrations in resident killer whales that are below the current toxicity reference value for 95 % of the population, with this value serving as a precautionary benchmark for a management-based approach to reducing PBDE health risks to killer whales. The food web bioaccumulation model may be a useful risk management tool in support of regulatory protection for killer whales.
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Suppressing the killer instinct.
Campbell, Kerry S
2016-05-24
Natural killer (NK) cells are innate lymphoid cells that have adopted activating and inhibitory signaling mechanisms enabling them to be tolerant of normal cells but to distinguish and eliminate tumor cells and virus-infected cells. In this issue of Science Signaling, Matalon et al show how inhibitory receptors disrupt NK cell activation by stimulating dephosphorylation of the adaptor protein LAT (linker of activated T cells) and phospholipase C-γ by the phosphatase SHP-1 [Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 1], as well as ubiquitylation of LAT by Cbl family E3 ubiquitin ligases. Copyright © 2016, American Association for the Advancement of Science.
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Retroviral expression screening of oncogenes in natural killer cell leukemia.
Choi, Young Lim; Moriuchi, Ryozo; Osawa, Mitsujiro; Iwama, Atsushi; Makishima, Hideki; Wada, Tomoaki; Kisanuki, Hiroyuki; Kaneda, Ruri; Ota, Jun; Koinuma, Koji; Ishikawa, Madoka; Takada, Shuji; Yamashita, Yoshihiro; Oshimi, Kazuo; Mano, Hiroyuki
2005-08-01
Aggressive natural killer cell leukemia (ANKL) is an intractable malignancy that is characterized by the outgrowth of NK cells. To identify transforming genes in ANKL, we constructed a retroviral cDNA expression library from an ANKL cell line KHYG-1. Infection of 3T3 cells with recombinant retroviruses yielded 33 transformed foci. Nucleotide sequencing of the DNA inserts recovered from these foci revealed that 31 of them encoded KRAS2 with a glycine-to-alanine mutation at codon 12. Mutation-specific PCR analysis indicated that the KRAS mutation was present only in KHYG-1 cells, not in another ANKL cell line or in clinical specimens (n=8).
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Oligosaccharide ligands for NKR-P1 protein activate NK cells and cytotoxicity
NASA Astrophysics Data System (ADS)
Bezouška, Karel; Yuen, Chun-Ting; O'Brien, Jacqui; Childs, Robert A.; Chai, Wengang; Lawson, Alexander M.; Drbal, Karel; Fišerová, Anna; Posíšil, Miloslav; Feizi, Ten
1994-11-01
A diversity of high-affinity Oligosaccharide ligands are identified for NKR-P1, a membrane protein on natural killer (NK) cells which contains an extracellular Ca2+-dependent lectin domain. Interactions of such oligosaccharides on the target cell surface with NKR-P1 on the killer cell surface are crucial both for target cell recognition and for delivery of stimulatory or inhibitory signals linked to the NK cytolytic machinery. NK-resistant tumour cells are rendered susceptible by preincubation with liposomes expressing NKR-P1 ligands, suggesting that purging of tumour or virally infected cells in vivo may be a therapeutic possibility.
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α-Galactosylceramide-activated Vα14 natural killer T cells mediate protection against murine malaria
Gonzalez-Aseguinolaza, Gloria; de Oliveira, Camila; Tomaska, Margaret; Hong, Seokmann; Bruna-Romero, Oscar; Nakayama, Toshinori; Taniguchi, Masaru; Bendelac, Albert; Van Kaer, Luc; Koezuka, Yasuhiko; Tsuji, Moriya
2000-01-01
Natural killer T (NKT) cells are a unique population of lymphocytes that coexpress a semiinvariant T cell and natural killer cell receptors, which are particularly abundant in the liver. To investigate the possible effect of these cells on the development of the liver stages of malaria parasites, a glycolipid, α-galactosylceramide (α-GalCer), known to selectively activate Vα14 NKT cells in the context of CD1d molecules, was administered to sporozoite-inoculated mice. The administration of α-GalCer resulted in rapid, strong antimalaria activity, inhibiting the development of the intrahepatocytic stages of the rodent malaria parasites Plasmodium yoelii and Plasmodium berghei. The antimalaria activity mediated by α-GalCer is stage-specific, since the course of blood-stage-induced infection was not inhibited by administration of this glycolipid. Furthermore, it was determined that IFN-γ is essential for the antimalaria activity mediated by the glycolipid. Taken together, our results provide the clear evidence that NKT cells can mediate protection against an intracellular microbial infection. PMID:10900007
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A novel system of polymorphic and diverse NK cell receptors in primates.
Averdam, Anne; Petersen, Beatrix; Rosner, Cornelia; Neff, Jennifer; Roos, Christian; Eberle, Manfred; Aujard, Fabienne; Münch, Claudia; Schempp, Werner; Carrington, Mary; Shiina, Takashi; Inoko, Hidetoshi; Knaust, Florian; Coggill, Penny; Sehra, Harminder; Beck, Stephan; Abi-Rached, Laurent; Reinhardt, Richard; Walter, Lutz
2009-10-01
There are two main classes of natural killer (NK) cell receptors in mammals, the killer cell immunoglobulin-like receptors (KIR) and the structurally unrelated killer cell lectin-like receptors (KLR). While KIR represent the most diverse group of NK receptors in all primates studied to date, including humans, apes, and Old and New World monkeys, KLR represent the functional equivalent in rodents. Here, we report a first digression from this rule in lemurs, where the KLR (CD94/NKG2) rather than KIR constitute the most diverse group of NK cell receptors. We demonstrate that natural selection contributed to such diversification in lemurs and particularly targeted KLR residues interacting with the peptide presented by MHC class I ligands. We further show that lemurs lack a strict ortholog or functional equivalent of MHC-E, the ligands of non-polymorphic KLR in "higher" primates. Our data support the existence of a hitherto unknown system of polymorphic and diverse NK cell receptors in primates and of combinatorial diversity as a novel mechanism to increase NK cell receptor repertoire.
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A Novel System of Polymorphic and Diverse NK Cell Receptors in Primates
Rosner, Cornelia; Neff, Jennifer; Roos, Christian; Eberle, Manfred; Aujard, Fabienne; Münch, Claudia; Schempp, Werner; Carrington, Mary; Shiina, Takashi; Inoko, Hidetoshi; Knaust, Florian; Coggill, Penny; Sehra, Harminder; Beck, Stephan; Abi-Rached, Laurent; Reinhardt, Richard; Walter, Lutz
2009-01-01
There are two main classes of natural killer (NK) cell receptors in mammals, the killer cell immunoglobulin-like receptors (KIR) and the structurally unrelated killer cell lectin-like receptors (KLR). While KIR represent the most diverse group of NK receptors in all primates studied to date, including humans, apes, and Old and New World monkeys, KLR represent the functional equivalent in rodents. Here, we report a first digression from this rule in lemurs, where the KLR (CD94/NKG2) rather than KIR constitute the most diverse group of NK cell receptors. We demonstrate that natural selection contributed to such diversification in lemurs and particularly targeted KLR residues interacting with the peptide presented by MHC class I ligands. We further show that lemurs lack a strict ortholog or functional equivalent of MHC-E, the ligands of non-polymorphic KLR in “higher” primates. Our data support the existence of a hitherto unknown system of polymorphic and diverse NK cell receptors in primates and of combinatorial diversity as a novel mechanism to increase NK cell receptor repertoire. PMID:19834558
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Swift, Brenna E.; Williams, Brent A.; Kosaka, Yoko; Wang, Xing-Hua; Medin, Jeffrey A.; Viswanathan, Sowmya; Martinez-Lopez, Joaquin; Keating, Armand
2012-01-01
Background Novel therapies capable of targeting drug resistant clonogenic MM cells are required for more effective treatment of multiple myeloma. This study investigates the cytotoxicity of natural killer cell lines against bulk and clonogenic multiple myeloma and evaluates the tumor burden after NK cell therapy in a bioluminescent xenograft mouse model. Design and Methods The cytotoxicity of natural killer cell lines was evaluated against bulk multiple myeloma cell lines using chromium release and flow cytometry cytotoxicity assays. Selected activating receptors on natural killer cells were blocked to determine their role in multiple myeloma recognition. Growth inhibition of clonogenic multiple myeloma cells was assessed in a methylcellulose clonogenic assay in combination with secondary replating to evaluate the self-renewal of residual progenitors after natural killer cell treatment. A bioluminescent mouse model was developed using the human U266 cell line transduced to express green fluorescent protein and luciferase (U266eGFPluc) to monitor disease progression in vivo and assess bone marrow engraftment after intravenous NK-92 cell therapy. Results Three multiple myeloma cell lines were sensitive to NK-92 and KHYG-1 cytotoxicity mediated by NKp30, NKp46, NKG2D and DNAM-1 activating receptors. NK-92 and KHYG-1 demonstrated 2- to 3-fold greater inhibition of clonogenic multiple myeloma growth, compared with killing of the bulk tumor population. In addition, the residual colonies after treatment formed significantly fewer colonies compared to the control in a secondary replating for a cumulative clonogenic inhibition of 89–99% at the 20:1 effector to target ratio. Multiple myeloma tumor burden was reduced by NK-92 in a xenograft mouse model as measured by bioluminescence imaging and reduction in bone marrow engraftment of U266eGFPluc cells by flow cytometry. Conclusions This study demonstrates that NK-92 and KHYG-1 are capable of killing clonogenic and bulk multiple myeloma cells. In addition, multiple myeloma tumor burden in a xenograft mouse model was reduced by intravenous NK-92 cell therapy. Since multiple myeloma colony frequency correlates with survival, our observations have important clinical implications and suggest that clinical studies of NK cell lines to treat MM are warranted. PMID:22271890
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Petrov, R V; Saidov, M Z; Koval'chuk, L V; Sorokin, A M; Kaganov, B S
1984-04-01
The activity of natural killers was examined in peripheral blood of healthy subjects and patients with chronic hepatitis and disseminated sclerosis. An attempt was made to correct natural killer activity by human leukocyte interferon in vitro. To assess the activity of natural killers, use was made of the method of serial dilutions. An optimal effector/target ratio was employed in experiments. The patients with chronic hepatitis and disseminated sclerosis demonstrated a reduction in the activity of natural killers whatever the effector/target ratio. The action of interferon in vitro is specific immunomodulatory in nature. Administration of interferon in a dose of 250 Units/ml raises the magnitude of the cytotoxic index in healthy donors and in patients with chronic hepatitis and disseminated sclerosis, making the shape of the killer activity curve approach that of normal. Such an approach can be used for preliminary assessment of the sensitivity of natural killers to interferon in viral diseases of man. The potentialities and efficacy of interferon in clinical medicine are discussed.
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Synergistic inhibition of natural killer cells by the nonsignaling molecule CD94.
Cheent, Kuldeep S; Jamil, Khaleel M; Cassidy, Sorcha; Liu, Mengya; Mbiribindi, Berenice; Mulder, Arend; Claas, Frans H J; Purbhoo, Marco A; Khakoo, Salim I
2013-10-15
Peptide selectivity is a feature of inhibitory receptors for MHC class I expressed by natural killer (NK) cells. CD94-NKG2A operates in tandem with the polymorphic killer cell Ig-like receptors (KIR) and Ly49 systems to inhibit NK cells. However, the benefits of having two distinct inhibitory receptor-ligand systems are not clear. We show that noninhibitory peptides presented by HLA-E can augment the inhibition of NKG2A(+) NK cells mediated by MHC class I signal peptides through the engagement of CD94 without a signaling partner. Thus, CD94 is a peptide-selective NK cell receptor, and NK cells can be regulated by nonsignaling interactions. We also show that KIR(+) and NKG2A(+) NK cells respond with differing stoichiometries to MHC class I down-regulation. MHC-I-bound peptide functions as a molecular rheostat controlling NK cell function. Selected peptides which in isolation do not inhibit NK cells can have different effects on KIR and NKG2A receptors. Thus, these two inhibitory systems may complement each other by having distinct responses to bound peptide and surface levels of MHC class I.
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Synergistic inhibition of natural killer cells by the nonsignaling molecule CD94
Cheent, Kuldeep S.; Jamil, Khaleel M.; Cassidy, Sorcha; Liu, Mengya; Mbiribindi, Berenice; Mulder, Arend; Claas, Frans H. J.; Purbhoo, Marco A.; Khakoo, Salim I.
2013-01-01
Peptide selectivity is a feature of inhibitory receptors for MHC class I expressed by natural killer (NK) cells. CD94–NKG2A operates in tandem with the polymorphic killer cell Ig-like receptors (KIR) and Ly49 systems to inhibit NK cells. However, the benefits of having two distinct inhibitory receptor–ligand systems are not clear. We show that noninhibitory peptides presented by HLA-E can augment the inhibition of NKG2A+ NK cells mediated by MHC class I signal peptides through the engagement of CD94 without a signaling partner. Thus, CD94 is a peptide-selective NK cell receptor, and NK cells can be regulated by nonsignaling interactions. We also show that KIR+ and NKG2A+ NK cells respond with differing stoichiometries to MHC class I down-regulation. MHC-I–bound peptide functions as a molecular rheostat controlling NK cell function. Selected peptides which in isolation do not inhibit NK cells can have different effects on KIR and NKG2A receptors. Thus, these two inhibitory systems may complement each other by having distinct responses to bound peptide and surface levels of MHC class I. PMID:24082146
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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.
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Morales-Menchén, Ana; Navarro-García, Federico; Guirao-Abad, José P.; Román, Elvira; Prieto, Daniel; Coman, Ioana V.; Pla, Jesús; Alonso-Monge, Rebeca
2018-01-01
Certain yeasts secrete peptides known as killer toxins or mycocins with a deleterious effect on sensitive yeasts or filamentous fungi, a common phenomenon in environmental species. In a recent work, different Debaryomyces hansenii (Dh) strains isolated from a wide variety of cheeses were identified as producing killer toxins active against Candida albicans and Candida tropicalis. We have analyzed the killer activity of these toxins in C. albicans mutants defective in MAPK signaling pathways and found that the lack of the MAPK Hog1 (but not Cek1 or Mkc1) renders cells hypersensitive to Dh mycocins while mutants lacking other upstream elements of the pathway behave as the wild type strain. Point mutations in the phosphorylation site (T174A-176F) or in the kinase domain (K52R) of HOG1 gene showed that both activities were relevant for the survival of C. albicans to Dh killer toxins. Moreover, Hog1 phosphorylation was also required to sense and adapt to osmotic and oxidative stress while the kinase activity was somehow dispensable. Although the addition of supernatant from the killer toxin- producing D. hansenii 242 strain (Dh-242) induced a slight intracellular increase in Reactive Oxygen Species (ROS), overexpression of cytosolic catalase did not protect C. albicans against this mycocin. This supernatant induced an increase in intracellular glycerol concentration suggesting that this toxin triggers an osmotic stress. We also provide evidence of a correlation between sensitivity to Dh-242 killer toxin and resistance to Congo red, suggesting cell wall specific alterations in sensitive strains. PMID:29774204
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Relationship of aging and nutritional status to innate immunity in tube-fed bedridden patients.
Takeuchi, Yoshiaki; Tashiro, Tomoe; Yamamura, Takuya; Takahashi, Seiichiro; Katayose, Kozo; Kohga, Shin; Takase, Mitsunori; Imawari, Michio
2017-01-01
Aging and malnutrition are known to influence immune functions. The aim of this study was to investigate the relationship of aging and malnutrition to innate immune functions in tube-fed bedridden patients. A cross-sectional survey was performed in 71 tube-fed bedridden patients aged 50-95 years (mean age±SD, 80.2±8.5 years) with serum albumin concentrations between 2.5 and 3.5 g/dL. We evaluated associations of age and nutritional variables with natural-killer cell activity, neutrophilphagocytic activity, and neutrophil-sterilizing activity. Nutritional variables included body mass index, weightadjusted energy intake, total lymphocyte count, and serum concentrations of albumin, transferrin, prealbumin, total cholesterol, C-reactive protein, and zinc. Natural-killer cell activity, neutrophil-phagocytic activity, and neutrophil-sterilizing activity were normal or increased in 67 (94%), 63 (89%), and 69 (97%) patients, respectively. Multiple linear regression analysis with a backward elimination method showed that natural-killer cell activity correlated negatively with aging and lymphocyte counts (p<0.01 for both) but positively with body mass index and transferrin (p<0.01 for both). Neutrophil-phagocytic and neutrophil-sterilizing activities were not associated with any variables. In tube-fed bedridden patients with hypo-albuminemia, natural-killer cell activity may be associated with aging, body mass index, transferrin, and lymphocyte counts.
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[Morphofunctional characteristics of immunocompetent cells in dysplasia of the breast].
Dikshteĭn, E A; Burlak, Iu P; Shevchenko, N I
1985-01-01
Immunocompetent cells were studied in the stroma and epithelium of 34 cases of mammary gland dysplasia. The following stainings were used for light microscopy: hematoxylin and eosin, methods of Brachet, van Gieson, Romanovsky-Giemsa, hallocyanine alums, Gomori, PAS-reaction as well as the determination of acid and alkaline phosphatases, glucose-6-phosphate and succinate dehydrogenase were used. 14 cases were studied ultrastructurally. Two types of small B lymphocytes and one type of large lymphocytes, stromal macrophages are described. Their morphofunctional characteristics is given and their properties in proliferating and non-proliferating fibroadenomatosis are shown. Interaction of intraepithelial large granular lymphocytes (normal killers) with immature epithelial cells resulting in the death of these epitheliocytes is described. The results obtained are regarded as a morphological manifestation of the immune surveillance.
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Hodge, Greg; Mukaro, Violet; Holmes, Mark; Reynolds, Paul N; Hodge, Sandra
2013-02-01
Natural killer (NK) and natural killer T (NKT)-like cells represent a small but important proportion of effector lymphocytes that we have previously shown to be major sources of pro-inflammatory cytokines and granzymes. We hypothesized that these cells would be increased in the airway in chronic obstructive pulmonary disease (COPD), accompanied by reduced expression of the inhibitory receptor CD94 (Kp43) and increased expression of cytotoxic mediators granzyme B and perforin. We measured NK and NKT-like cells and their expression of CD94 in the blood of COPD patients (n = 71; 30 current and 41 ex-smokers), smokers (16) and healthy controls (25), and bronchoalveolar lavage fluid (BALF) from a cohort of subjects (19 controls, 12 smokers, 33 COPD). Activation was assessed by measuring CD69 in blood and the cytotoxic potential of NK cells by measuring granzymes A and B, and using a cytotoxicity assay in blood and BALF. In blood in COPD, there were no significant changes in the proportion of NK or NKT-like cells or expression of granzyme A or NK cytotoxic potential versus controls. There was, however, increased expression of granzyme B and decreased expression of CD94 by both cell types versus controls. The proportion of NK and NKT-like cells were increased in BALF in COPD, associated with increased NK cytotoxicity, increased expression of granzyme B and decreased expression of the inhibitory receptor CD94 by both cell types. Treatment strategies that target NK and NKT-like cells, their cytotoxicity and production of inflammatory mediators in the airway may improve COPD morbidity. © 2012 The Authors. Respirology © 2012 Asian Pacific Society of Respirology.
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André, Pascale; Spertini, Olivier; Guia, Sophie; Rihet, Pascal; Dignat-George, Françoise; Brailly, Hervé; Sampol, José; Anderson, Paul J.; Vivier, Eric
2000-01-01
Natural killer (NK) cells are components of the innate immune system that can recognize and kill virally infected cells, tumor cells, and allogeneic cells without prior sensitization. NK cells also elaborate cytokines (e.g., interferon-γ and tumor necrosis factor-α) and chemokines (e.g., macrophage inflammatory protein-1α) that promote the acquisition of antigen-specific immunity. NK cell differentiation is accompanied by the cell surface expression of a mucin-like glycoprotein bearing an NK cell-restricted keratan sulfate-related lactosamine carbohydrate, the PEN5 epitope. Here, we report that PEN5 is a post-translational modification of P-selectin glycoprotein ligand-1 (PSGL-1). The PEN5 epitope creates on PSGL-1 a unique binding site for L-selectin, which is independent of PSGL-1 tyrosine sulfation. On the surface of NK cells, the expression of PEN5 is coordinated with the disappearance of L-selectin and the up-regulation of Killer cell Ig-like Receptors (KIR). These results indicate that NK cell differentiation is accompanied by the acquisition of a unique carbohydrate, PEN5, that can serve as part of a combination code to deliver KIR+ NK cells to specific tissues. PMID:10725346
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Lee, Woo-Yong; Sanz, Maria-Jesus; Wong, Connie H Y; Hardy, Pierre-Olivier; Salman-Dilgimen, Aydan; Moriarty, Tara J; Chaconas, George; Marques, Adriana; Krawetz, Roman; Mody, Christopher H; Kubes, Paul
2014-09-23
CXCR6-GFP(+) cells, which encompass 70% invariant natural killer T cells (iNKT cells), have been found primarily patrolling inside blood vessels in the liver. Although the iNKT cells fail to interact with live pathogens, they do respond to bacterial glycolipids presented by CD1d on liver macrophage that have caught the microbe. In contrast, in this study using dual laser multichannel spinning-disk intravital microscopy of joints, the CXCR6-GFP, which also made up 60-70% iNKT cells, were not found in the vasculature but rather closely apposed to and surrounding the outside of blood vessels, and to a lesser extent throughout the extravascular space. These iNKT cells also differed in behavior, responding rapidly and directly to joint-homing pathogens like Borrelia burgdorferi, which causes Lyme disease. These iNKT cells interacted with B. burgdorferi at the vessel wall and disrupted dissemination attempts by these microbes into joints. Successful penetrance of B. burgdorferi out of the vasculature and into the joint tissue was met by a lethal attack by extravascular iNKT cells through a granzyme-dependent pathway, an observation also made in vitro for iNKT cells from joint but not liver or spleen. These results suggest a novel, critical extravascular iNKT cell immune surveillance in joints that functions as a cytotoxic barrier and explains a large increase in pathogen burden of B. burgdorferi in the joint of iNKT cell-deficient mice, and perhaps the greater susceptibility of humans to this pathogen because of fewer iNKT cells in human joints.
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Natural killer cells attack tumor cells expressing high levels of sialyl Lewis x oligosaccharides
Ohyama, Chikara; Kanto, Satoru; Kato, Kazunori; Nakano, Osamu; Arai, Yoichi; Kato, Tetsuro; Chen, Shihao; Fukuda, Michiko N.; Fukuda, Minoru
2002-01-01
Epithelial carcinoma and leukemia cells express sialyl Lewis x oligosaccharides as tumor-associated carbohydrate antigens. To determine the role of sialyl Lewis x oligosaccharides in tumor dissemination, human melanoma MeWo cells, which do not express sialyl Lewis x, were transfected with α1,3-fucosyltransferase III (FTIII), and cell lines expressing different amounts of sialyl Lewis x were isolated. When these cells were injected into the tail vein of nude mice, cells expressing moderate amounts of sialyl Lewis x (MeWo-FTIII⋅M) produced a significantly greater number of lung tumor foci than did parental MeWo cells. In contrast, cells expressing large amounts of sialyl Lewis x (MeWo-FTIII⋅H) produced few lung tumor foci in nude mice but were highly tumorigenic in beige mice, which have defective natural killer (NK) cells. In vitro assays demonstrated that MeWo-FTIII⋅H cells are much more sensitive to NK cell-mediated cytotoxicity than are MeWo-FTIII⋅M cells or parental MeWo cells and the susceptibility of MeWo-FTIII⋅H cells to NK cell-mediated cytolysis can be inhibited by preincubating MeWo-FTIII⋅H cells with anti-sialyl Lewis x antibody. Moreover, we discovered that NK cell-mediated cytolysis of MeWo-FTIII⋅H cells can be inhibited by the addition of an antibody against the NK cell receptor CD94 or sialyl Lewis x oligosaccharides. These results, combined with structural analysis of MeWo-FTIII⋅H cell carbohydrates, indicate that moderate amounts of sialyl Lewis x lead to tumor metastasis, whereas expression of high levels of sialyl Lewis x leads to an NK cell attack on tumor cells, demonstrating that expression of different amounts of sialyl Lewis x results in entirely different biological consequences. PMID:12370411
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Screening the Budding Yeast Genome Reveals Unique Factors Affecting K2 Toxin Susceptibility
Servienė, Elena; Lukša, Juliana; Orentaitė, Irma
2012-01-01
Background Understanding how biotoxins kill cells is of prime importance in biomedicine and the food industry. The budding yeast (S. cerevisiae) killers serve as a convenient model to study the activity of biotoxins consistently supplying with significant insights into the basic mechanisms of virus-host cell interactions and toxin entry into eukaryotic target cells. K1 and K2 toxins are active at the cell wall, leading to the disruption of the plasma membrane and subsequent cell death by ion leakage. K28 toxin is active in the cell nucleus, blocking DNA synthesis and cell cycle progression, thereby triggering apoptosis. Genome-wide screens in the budding yeast S. cerevisiae identified several hundred effectors of K1 and K28 toxins. Surprisingly, no such screen had been performed for K2 toxin, the most frequent killer toxin among industrial budding yeasts. Principal Findings We conducted several concurrent genome-wide screens in S. cerevisiae and identified 332 novel K2 toxin effectors. The effectors involved in K2 resistance and hypersensitivity largely map in distinct cellular pathways, including cell wall and plasma membrane structure/biogenesis and mitochondrial function for K2 resistance, and cell wall stress signaling and ion/pH homeostasis for K2 hypersensitivity. 70% of K2 effectors are different from those involved in K1 or K28 susceptibility. Significance Our work demonstrates that despite the fact that K1 and K2 toxins share some aspects of their killing strategies, they largely rely on different sets of effectors. Since the vast majority of the host factors identified here is exclusively active towards K2, we conclude that cells have acquired a specific K2 toxin effectors set. Our work thus indicates that K1 and K2 have elaborated different biological pathways and provides a first step towards the detailed characterization of K2 mode of action. PMID:23227207
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Screening the budding yeast genome reveals unique factors affecting K2 toxin susceptibility.
Servienė, Elena; Lukša, Juliana; Orentaitė, Irma; Lafontaine, Denis L J; Urbonavičius, Jaunius
2012-01-01
Understanding how biotoxins kill cells is of prime importance in biomedicine and the food industry. The budding yeast (S. cerevisiae) killers serve as a convenient model to study the activity of biotoxins consistently supplying with significant insights into the basic mechanisms of virus-host cell interactions and toxin entry into eukaryotic target cells. K1 and K2 toxins are active at the cell wall, leading to the disruption of the plasma membrane and subsequent cell death by ion leakage. K28 toxin is active in the cell nucleus, blocking DNA synthesis and cell cycle progression, thereby triggering apoptosis. Genome-wide screens in the budding yeast S. cerevisiae identified several hundred effectors of K1 and K28 toxins. Surprisingly, no such screen had been performed for K2 toxin, the most frequent killer toxin among industrial budding yeasts. We conducted several concurrent genome-wide screens in S. cerevisiae and identified 332 novel K2 toxin effectors. The effectors involved in K2 resistance and hypersensitivity largely map in distinct cellular pathways, including cell wall and plasma membrane structure/biogenesis and mitochondrial function for K2 resistance, and cell wall stress signaling and ion/pH homeostasis for K2 hypersensitivity. 70% of K2 effectors are different from those involved in K1 or K28 susceptibility. Our work demonstrates that despite the fact that K1 and K2 toxins share some aspects of their killing strategies, they largely rely on different sets of effectors. Since the vast majority of the host factors identified here is exclusively active towards K2, we conclude that cells have acquired a specific K2 toxin effectors set. Our work thus indicates that K1 and K2 have elaborated different biological pathways and provides a first step towards the detailed characterization of K2 mode of action.
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Cooper, Megan A; Fehniger, Todd A; Colonna, Marco
2017-12-18
Studies over the last decade have decisively shown that innate immune natural killer (NK) cells exhibit enhanced long-lasting functional responses following a single activation event. With the increased recognition of memory and memory-like properties of NK cells, questions have arisen with regard to their ability to effectively mediate vaccination responses in humans. Moreover, recently discovered innate lymphoid cells (ILCs) could also potentially exhibit memory-like functions. Here, we review different forms of NK cell memory, and speculate about the ability of these cells and ILCs to meaningfully contribute to vaccination responses. Copyright © 2017 Cold Spring Harbor Laboratory Press; all rights reserved.
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Nabatanzi, Rose; Cose, Stephen; Joloba, Moses; Jones, Sarah Rowland; Nakanjako, Damalie
2018-03-15
HIV infection causes upregulation of markers of inflammation, immune activation and apoptosis of host adaptive, and innate immune cells particularly monocytes, natural killer (NK) and innate lymphoid cells (ILCs). Although antiretroviral therapy (ART) restores CD4 T-cell counts, the persistent aberrant activation of monocytes, NK and ILCs observed likely contributes to the incomplete recovery of T-cell effector functions. A better understanding of the effects of HIV infection and ART on the phenotype and function of circulating monocytes, NK, and ILCs is required to guide development of novel therapeutic interventions to optimize immune recovery.
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Preethy, Senthilkumar; Dedeepiya, Vidyasagar Devaprasad; Senthilkumar, Rajappa; Rajmohan, Mathaiyan; Karthick, Ramalingam; Terunuma, Hiroshi; Abraham, Samuel J K
2017-07-04
Immune cell-based therapies are emerging as a promising tool to tackle malignancies, both solid tumors and selected hematological tumors. Vast experiences in literature have documented their safety and added survival benefits when such cell-based therapies are combined with the existing treatment options. Numerous methodologies of processing and in vitro expansion protocols of immune cells, such as the dendritic cells, natural killer (NK) cells, NKT cells, αβ T cells, so-called activated T lymphocytes, γδ T cells, cytotoxic T lymphocytes, and lymphokine-activated killer cells, have been reported for use in cell-based therapies. Among this handful of immune cells of significance, the NK cells stand apart from the rest for not only their direct cytotoxic ability against cancer cells but also their added advantage, which includes their capability of (i) action through both innate and adaptive immune mechanism, (ii) tackling viruses too, giving benefits in conditions where viral infections culminate in cancer, and (iii) destroying cancer stem cells, thereby preventing resistance to chemotherapy and radiotherapy. This review thoroughly analyses the sources of such NK cells, methods for expansion, and the future potentials of taking the in vitro expanded allogeneic NK cells with good cytotoxic ability as a drug for treating cancer and/or viral infection and even as a prophylactic tool for prevention of cancer after initial remission.
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McIlvried, Lisa A; Cruz, J Agustin; Borghesi, Lisa A; Gold, Michael S
2017-01-01
Aim of investigation Due to compelling evidence in support of links between sex, stress, sympathetic post-ganglionic innervation, dural immune cells, and migraine, our aim was to characterize the impacts of these factors on the type and proportion of immune cells in the dura. Methods Dural immune cells were obtained from naïve or stressed adult male and female Sprague Dawley rats for flow cytometry. Rats with surgical denervation of sympathetic post-ganglionic neurons of the dura were also studied. Results Immune cells comprise ∼17% of all cells in the dura. These included: macrophages/granulocytes ("Macs"; 63.2% of immune cells), dendritic cells (0.88%), T-cells (4.51%), natural killer T-cells (0.51%), natural killer cells (3.08%), and B-cells (20.0%). There were significantly more Macs and fewer B- and natural killer T-cells in the dura of females compared with males. Macs and dendritic cells were significantly increased by stress in males, but not females. In contrast, T-cells were significantly increased in females with a 24-hour delay following stress. Lastly, Macs, dendritic cells, and T-cells were significantly higher in sympathectomized-naïve males, but not females. Conclusions It may not only be possible, but necessary to use different strategies for the most effective treatment of migraine in men and women.
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Natural killer cell-type body cavity lymphoma following chronic active Epstein-Barr virus infection.
Ogata, Masao; Imamura, Tomoyuki; Mizunoe, Syunji; Ohtsuka, Eiichi; Kikuchi, Hiroshi; Nasu, Masaru
2003-06-01
We describe a 69-year-old female who developed natural killer cell-type body cavity lymphoma following chronic active Epstein-Barr virus (CAEBV) infection. Examination of the patient's pleural effusion revealed large abnormal lymphocytes, which were CD2(+), CD7(+), CD30(+), CD56(+), CD3(-), and CD4(-). No rearrangement of T cell receptor genes was detected. Clonal proliferation of Epstein-Barr virus (EBV)-infected cells in pleural effusion was demonstrated by Southern blot hybridization analysis. Human herpesvirus type-8 (HHV-8) DNA was not detected in these cells. The patient achieved a complete remission with combination chemotherapy. Prior to the clinical onset of lymphoma, high fever of unknown origin had persisted for 21 months. IgG antibodies to EBV-viral capsid antigen and to EBV-early antigens, types D and R were not high (1:160 and less than 1:10, respectively). Two months after the onset of fever, however, retrospective quantitative PCR assay revealed a high EBV DNA load in plasma, indicating that CAEBV infection had been the cause of the patient's recurrent fever. The remarkable features of this case are (i) the development of lymphoma following CAEBV infection that demonstrated a normal pattern of EBV-specific antibodies, (ii) the development of HHV-8-negative body cavity lymphoma, and (iii) the effectiveness of combination chemotherapy. Copyright 2003 Wiley-Liss, Inc.
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Kill and spread the word: stimulation of antitumor immune responses in the context of radiotherapy.
Gaipl, Udo S; Multhoff, Gabriele; Scheithauer, Heike; Lauber, Kirsten; Hehlgans, Stefanie; Frey, Benjamin; Rödel, Franz
2014-01-01
Besides the direct, targeted effects of ionizing irradiation (x-ray) on cancer cells, namely DNA damage and cell death induction, indirect, nontargeted ones exist, which are mediated in large part by the immune system. Immunogenic forms of tumor cell death induced by x-ray, including immune modulating danger signals like the heat shock protein 70, adenosine triphosphate, and high-mobility group box 1 protein are presented. Further, antitumor effects exerted by cells of the innate (natural killer cells) as well as adaptive immune system (T cells activated by dendritic cells) are outlined. Tumor cell death inhibiting molecules such as survivin are introduced as suitable target for molecularly tailored therapies in combination with x-ray. Finally, reasonable combinations of immune therapies with radiotherapy are discussed.
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Expression of killer inhibitory receptors on cytotoxic cells from HIV-1-infected individuals
Galiani, M D; Aguado, E; Tarazona, R; Romero, P; Molina, I; Santamaria, M; Solana, R; PeñA, J
1999-01-01
Dysfunction of cytotoxic activity of T and natural killer (NK) lymphocytes is a main immunological feature in patients with AIDS, but its basis are not well understood. It has been recently described that T and NK cell-mediated cytotoxicity can be regulated by HLA killer inhibitory receptors (KIR). In this work, we have determined on cytotoxic T cells and NK cells from HIV-1-infected individuals the expression of the following KIR molecules: p58, p70, and ILT2 (immunoglobulin-like family KIR) as well as CD94 and NKG2A (C-lectin-type family KIR). With some exceptions, no significant changes were found on the expression of immunoglobulin-like KIR in either CD8+ or CD56+ cells. Interestingly, the percentages of CD8+ and CD56+ cells expressing CD94 were significantly increased in these individuals. We also show that, in vitro, IL-10 up-regulates CD94 expression on CD8+ and CD56+ cells obtained from normal individuals, suggesting that the augmented expression observed in HIV-infected individuals could be related to the high levels of IL-10 previously described in HIV-1-infected individuals. PMID:10193420
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Crystal structure of the human natural killer cell inhibitory receptor KIR2DL1-HLA-Cw4 complex.
Fan, Q R; Long, E O; Wiley, D C
2001-05-01
Inhibitory natural killer (NK) cell receptors down-regulate the cytotoxicity of NK cells upon recognition of specific class I major histocompatibility complex (MHC) molecules on target cells. We report here the crystal structure of the inhibitory human killer cell immunoglobulin-like receptor 2DL1 (KIR2DL1) bound to its class I MHC ligand, HLA-Cw4. The KIR2DL1-HLA-Cw4 interface exhibits charge and shape complementarity. Specificity is mediated by a pocket in KIR2DL1 that hosts the Lys80 residue of HLA-Cw4. Many residues conserved in HLA-C and in KIR2DL receptors make different interactions in KIR2DL1-HLA-Cw4 and in a previously reported KIR2DL2-HLA-Cw3 complex. A dimeric aggregate of KIR-HLA-C complexes was observed in one KIR2DL1-HLA-Cw4 crystal. Most of the amino acids that differ between human and chimpanzee KIRs with HLA-C specificities form solvent-accessible clusters outside the KIR-HLA interface, which suggests undiscovered interactions by KIRs.
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Panthong, Sumalee; Itharat, Arunporn
2014-08-01
Immune system is the most important system ofhuman body. Thaifolk doctors have used some medicinal plants as an adaptogenic drug or immunomodulatory agent. Piper chaba Hunter, Piper sarmentosum Roxb. and Piper interruptum Opiz. are used by folk doctors to activate immune response in cancer patients. To investigate the effect on natural killer cell activity and on lymphocyte proliferation activity of water extract of P chaba Hunter P. sarmentosum Roxb. and P interruptum Opiz. MATERIAL ANDMETHOD: Plant materials were extracted by decoction method. All extracts were testedfor an immunomodulatory effect using PBMCs from twelve healthy donors by chromium release assay. Lymphocyte proliferation was also determined by 3H-thymidine uptake assay. The degree of activation was expressed as the stimulation index. The water extract of P chaba Hunter significantly increased lymphocyte proliferation at concentrations ofl ng/ml, 10 ng/ml, 1 μg/ml, 5 μg/ml, 10 μg/ml and 100 μg/ml. P sarmentosum Roxb., and P interruptum Opiz. extracts at those concentrations significantly stimulated lymphocyteproliferation. P sarmentosum Roxb. extractsignificantly increased natural killer (NK) cell activity at a concentration of 100 μg/ml but P chaba Hunter and P interruptum Opiz. extracts did not significantly stimulate natural killer cell activity. P chaba Hunter, P interruptum Opiz. andP sarmentosum Roxb. have an immunomodulatory effect especially for P sarmentosum Roxb. extract which can activate both lymphocyte proliferation and NK cell activity.
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1990-12-20
and infectious mononucleosis , as well as outbreaks of herpes simplex (Ishigami, 1919; Hinkle and Plummer, 1952; McClelland, Alexander, and Marks, 1982...Evans, A., and Neiderman, J., (1979). Psychosocial risk factors in the development of infectious mononucleosis . Psychosomatic Medicine, 41, 445-466...34Stress, Coping, and Infectious Illness: Persistently Low Natural Killer Cell Activity as a Host Ri-k Fa.ctor" 2. PERSONAL AUTHOR(S) Sandra M. Lev
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Wallace, Alison E.; Goulwara, Sonu S.; Whitley, Guy S.; Cartwright, Judith E.
2014-01-01
Decidual natural killer (dNK) cells have been shown to both promote and inhibit trophoblast behavior important for decidual remodeling in pregnancy and have a distinct phenotype compared to peripheral blood NK cells. We investigated whether different levels of oxygen tension, mimicking the physiological conditions of the decidua in early pregnancy, altered cell surface receptor expression and activity of dNK cells and their interactions with trophoblast. dNK cells were isolated from terminated first-trimester pregnancies and cultured in oxygen tensions of 3%, 10%, and 21% for 24 h. Cell surface receptor expression was examined by flow cytometry, and the effects of secreted factors in conditioned medium (CM) on the trophoblast cell line SGHPL-4 were assessed in vitro. SGHPL-4 cells treated with dNK cell CM incubated in oxygen tensions of 10% were significantly more invasive (P < 0.05) and formed endothelial-like networks to a greater extent (P < 0.05) than SGHPL-4 cells treated with dNK cell CM incubated in oxygen tensions of 3% or 21%. After 24 h, a lower percentage of dNK cells expressed CD56 at 21% oxygen (P < 0.05), and an increased percentage of dNK cells expressed NKG2D at 10% oxygen (P < 0.05) compared to other oxygen tensions, with large patient variation. This study demonstrates dNK cell phenotype and secreted factors are modulated by oxygen tension, which induces changes in trophoblast invasion and endovascular-like differentiation. Alterations in dNK cell surface receptor expression and secreted factors at different oxygen tensions may represent regulation of function within the decidua during the first trimester of pregnancy. PMID:25232021
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Adoptive cell transfer therapy for malignant gliomas.
Ishikawa, Eiichi; Takano, Shingo; Ohno, Tadao; Tsuboi, Koji
2012-01-01
To date, various adoptive immunotherapies have been attempted for treatment of malignant gliomas using nonspecific and/or specific effector cells. Since the late 1980s, with the development of rIL-2, the efficacy of lymphokine-activated killer (LAK) cell therapy with or without rIL-2 for malignant gliomas had been tested with some modifications in therapeutic protocols. With advancements in technology, ex vivo expanded tumor specific cytotoxic T-lymphocytes (CTL) or those lineages were used in clinical trials with higher tumor response rates. In addition, combinations of those adoptive cell transfer using LAK cells, CTLs or natural killer (NK) cells with autologous tumor vaccine (ATV) therapy were attempted. Also, a strategy of high-dose (or lymphodepleting) chemotherapy followed by adoptive cell transfer has been drawing attentions recently. The most important role of these clinical studies using cell therapy was to prove that these ex vivo expanded effector cells could kill tumor cells in vivo. Although recent clinical results could demonstrate radiologic tumor shrinkage in a number of cases, cell transfer therapy alone has been utilized less frequently, because of the high cost of ex vivo cell expansion, the short duration of antitumor activity in vivo, and the recent shift of interest to vaccine immunotherapy. Nevertheless, NK cell therapy using specific feeder cells or allergenic NK cell lines have potentials to be a good choice of treatment because of easy ex vivo expansion and their efficacy especially when combined with vaccine therapy as they are complementary to each other. Also, further studies are expected to clarify the efficacy of the high-dose chemotherapy followed by a large scale cell transfer therapy as a new therapeutic strategy for malignant gliomas.
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Komatsu, M; Yee, L; Carraway, K L
1999-05-01
Sialomucin complex (SMC) is a large heterodimeric glycoprotein complex composed of a mucin subunit ascites sialoglycoprotein-1 and a transmembrane subunit ascites sialoglycoprotein-2. It is a rat homologue of human mucin gene MUC4 and is abundantly expressed on the cell surface of highly metastatic ascites 13762 rat mammary adenocarcinoma cells. Because of their extended and rigid structures, mucin-type glycoproteins are suggested to have suppressing effects on cell-cell and cell-matrix interactions. During the metastatic process, these effects presumably cause tumor cell detachment from the primary tumor mass and facilitate escape of the tumor cells from immunosurveillance. Analyses of human breast cancer cells in solid tumors and tumor effusions showed that the more aggressive cells in effusions are stained with polyclonal antibodies against SMC more frequently than cells in solid tumors, suggesting a role for MUC4/SMC in tumor progression and metastasis. Previously, we generated recombinant cDNAs for SMC that vary in the number of mucin repeats to study the putative functions of SMC in tumor metastasis. These cDNAs were transfected into human cancer cell lines and tested for the effect of the expression of this gene. Here, using a tetracycline-responsive inducible expression system, we demonstrate that overexpression of SMC masks the surface antigens on target tumor cells and effectively suppresses tumor cell killing by cytotoxic lymphocytes. This effect results from the ability of SMC to block killer cell binding to the tumor cells and is dependent on both overexpression of the mucin and the number of mucin repeats in the expressed SMC. These results provide an explanation for the proposed role of SMC/MUC4 in tumor progression.
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The eyeball killer: serial killings with postmortem globe enucleation.
Coyle, Julie; Ross, Karen F; Barnard, Jeffrey J; Peacock, Elizabeth; Linch, Charles A; Prahlow, Joseph A
2015-05-01
Although serial killings are relatively rare, they can be the cause of a great deal of anxiety while the killer remains at-large. Despite the fact that the motivations for serial killings are typically quite complex, the psychological analysis of a serial killer can provide valuable insight into how and why certain individuals become serial killers. Such knowledge may be instrumental in preventing future serial killings or in solving ongoing cases. In certain serial killings, the various incidents have a variety of similar features. Identification of similarities between separate homicidal incidents is necessary to recognize that a serial killer may be actively killing. In this report, the authors present a group of serial killings involving three prostitutes who were shot to death over a 3-month period. Scene and autopsy findings, including the unusual finding of postmortem enucleation of the eyes, led investigators to recognize the serial nature of the homicides. © 2015 American Academy of Forensic Sciences.
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Using Behavior Sequence Analysis to Map Serial Killers' Life Histories.
Keatley, David A; Golightly, Hayley; Shephard, Rebecca; Yaksic, Enzo; Reid, Sasha
2018-03-01
The aim of the current research was to provide a novel method for mapping the developmental sequences of serial killers' life histories. An in-depth biographical account of serial killers' lives, from birth through to conviction, was gained and analyzed using Behavior Sequence Analysis. The analyses highlight similarities in behavioral events across the serial killers' lives, indicating not only which risk factors occur, but the temporal order of these factors. Results focused on early childhood environment, indicating the role of parental abuse; behaviors and events surrounding criminal histories of serial killers, showing that many had previous convictions and were known to police for other crimes; behaviors surrounding their murders, highlighting differences in victim choice and modus operandi; and, finally, trial pleas and convictions. The present research, therefore, provides a novel approach to synthesizing large volumes of data on criminals and presenting results in accessible, understandable outcomes.
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Current Status of Gene Engineering Cell Therapeutics
Saudemont, Aurore; Jespers, Laurent; Clay, Timothy
2018-01-01
Ex vivo manipulations of autologous patient’s cells or gene-engineered cell therapeutics have allowed the development of cell and gene therapy approaches to treat otherwise incurable diseases. These modalities of personalized medicine have already shown great promises including product commercialization for some rare diseases. The transfer of a chimeric antigen receptor or T cell receptor genes into autologous T cells has led to very promising outcomes for some cancers, and particularly for hematological malignancies. In addition, gene-engineered cell therapeutics are also being explored to induce tolerance and regulate inflammation. Here, we review the latest gene-engineered cell therapeutic approaches being currently explored to induce an efficient immune response against cancer cells or viruses by engineering T cells, natural killer cells, gamma delta T cells, or cytokine-induced killer cells and to modulate inflammation using regulatory T cells. PMID:29459866
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Zulu, Michael Z; Naidoo, Kewreshini K; Mncube, Zenele; Jaggernath, Manjeetha; Goulder, Philip J R; Ndung'u, Thumbi; Altfeld, Marcus; Thobakgale, Christina F
2017-12-01
HIV-1 viremia has been shown to induce several phenotypic and functional abnormalities in natural killer (NK) cells. To assess immune defects associated with HIV viremia, we examined NK cell function, differentiation status, and phenotypic alterations based on expression of inhibitory and activating receptors on NK cells in HIV-1 subtype C chronically infected participants from Durban, South Africa. NK cell phenotypic profiles were characterized by assessing sialic acid-binding immunoglobulin-like lectin-7 (Siglec-7), NKG2A, and NKG2C markers on frozen peripheral blood mononuclear cells from viremic, antiretroviral therapy (ART)-naive HIV-1 chronically infected participants (n = 23), HIV-1 chronically infected participants who had been on combination antiretroviral therapy (cART) for at least 12 months (n = 23) compared with healthy donors (n = 23). NK cell differentiation was assessed by measurement of killer immunoglobulin receptor (KIR) and NKG2A expression; CD57 and CD107a measurements were carried out in HIV viremic and healthy donors. All phenotypic and functional assessments were analyzed by using multicolor flow cytometry. HIV-1-infected participants displayed greater frequencies of the CD56 - CD16 + (CD56negative) NK cell subset compared with healthy donors (p < .0001). Downregulation of Siglec-7 and NKG2A and upregulation of NKG2C were more pronounced in the CD56negative NK cell subset of viremic participants. The CD56negative subset demonstrated a differentiated (KIR + NKG2A - ) phenotype with reduced CD57 expression and lower degranulation capacity in HIV-1-infected participants compared with healthy donors. HIV-1 infection induces the expansion of the CD56negative NK cell subset marked by altered receptor expression profiles that are indicative of impaired function and may explain the overall NK cell dysfunction observed in chronic HIV-1 infection.
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Liu, Yin; Wu, Hong-Wei; Sheard, Michael A; Sposto, Richard; Somanchi, Srinivas S; Cooper, Laurence J N; Lee, Dean A; Seeger, Robert C
2013-04-15
Adoptive transfer of natural killer (NK) cells combined with tumor-specific monoclonal antibodies (mAb) has therapeutic potential for malignancies. We determined if large numbers of activated NK (aNK) cells can be grown ex vivo from peripheral blood mononuclear cells (PBMC) of children with high-risk neuroblastoma using artificial antigen-presenting cells (aAPC). Irradiated K562-derived Clone 9.mbIL21 aAPC were cocultured with PBMC, and propagated NK cells were characterized with flow cytometry, cytotoxicity assays, Luminex multicytokine assays, and a nonobese diabetic/severe combined immunodeficient (NOD/SCID) mouse model of disseminated neuroblastoma. Coculturing patient PBMC with aAPC for 14 days induced 2,363- ± 443-fold expansion of CD56(+)CD3(-)CD14(-) NK cells with 83% ± 3% purity (n = 10). Results were similar to PBMC from normal donors (n = 5). Expression of DNAM-1, NKG2D, FcγRIII/CD16, and CD56 increased 6- ± 3-, 10- ± 2-, 21- ± 20-, and 18- ± 3-fold, respectively, on day 14 compared with day 0, showing activation of NK cells. In vitro, aNK cells were highly cytotoxic against neuroblastoma cell lines and killing was enhanced with GD2-specific mAb ch14.18. When mediating cytotoxicity with ch14.18, release of TNF-α, granulocyte macrophage colony-stimulating factor, IFN-γ, sCD40L, CCL2/MCP-1, CXCL9/MIG, and CXCL11/I-TAC by aNK cells increased 4-, 5-, 6-, 15-, 265-, 917-, and 363-fold (151-9,121 pg/mL), respectively, compared with aNK cells alone. Survival of NOD/SCID mice bearing disseminated neuroblastoma improved when treated with thawed and immediately intravenously infused cryopreserved aNK cells compared with untreated mice and was further improved when ch14.18 was added. Propagation of large numbers of aNK cells that maintain potent antineuroblastoma activities when cryopreserved supports clinical testing of adoptive cell therapy with ch14.18.
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Szmania, Susann; Lapteva, Natalia; Garg, Tarun; Greenway, Amy; Lingo, Joshuah; Nair, Bijay; Stone, Katie; Woods, Emily; Khan, Junaid; Stivers, Justin; Panozzo, Susan; Campana, Dario; Bellamy, William T.; Robbins, Molly; Epstein, Joshua; Yaccoby, Shmuel; Waheed, Sarah; Gee, Adrian; Cottler-Fox, Michele; Rooney, Cliona; Barlogie, Bart; van Rhee, Frits
2015-01-01
Highly activated/expanded natural killer (NK) cells can be generated via stimulation with the HLA-deficient cell line K562 genetically modified to express 41BB-ligand and membrane-bound interleukin (IL)15. We tested the safety, persistence and activity of expanded NK cells generated from myeloma patients (auto-NK) or haplo-identical family donors (allo-NK) in heavily pretreated patients with high-risk relapsing myeloma. The preparative regimen comprised bortezomib only or bortezomib and immunosuppression with cyclophosphamide, dexamethasone and fludarabine. NK cells were shipped overnight either cryopreserved or fresh. In 8 patients, up to 1×108 NK cells/kg were infused on day 0 and followed by daily administrations of IL2. Significant in vivo expansion was observed only in the 5 patients receiving fresh products, peaking at or near day 7, with the highest NK cell counts in 2 subjects who received cells produced in a high concentration of IL2 (500 units/mL). Seven days after infusion, donor NK cells comprised > 90% of circulating leukocytes in fresh allo-NK cell recipients, and cytolytic activity against allogeneic myeloma targets was retained in vitro. Among the 7 evaluable patients, there were no serious adverse events that could be related to NK cell infusion. One patient had a partial response and in another the tempo of disease progression decreased; neither patient required further therapy for 6 months. In the 5 remaining patients, disease progression was not affected by NK cell infusion. In conclusion, infusion of large numbers of expanded NK cells was feasible and safe; infusing fresh cells was critical to their expansion in vivo. PMID:25415285
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Dok1 and Dok2 proteins regulate natural killer cell development and function
Celis-Gutierrez, Javier; Boyron, Marilyn; Walzer, Thierry; Pandolfi, Pier Paolo; Jonjić, Stipan; Olive, Daniel; Dalod, Marc; Vivier, Eric; Nunès, Jacques A
2014-01-01
Natural killer (NK) cells are involved in immune responses against tumors and microbes. NK-cell activation is regulated by intrinsic and extrinsic mechanisms that ensure NK tolerance and efficacy. Here, we show that the cytoplasmic signaling molecules Dok1 and Dok2 are tyrosine phosphorylated upon NK-cell activation. Overexpression of Dok proteins in human NK cells reduces cell activation induced by NK-cell-activating receptors. Dok1 and Dok2 gene ablation in mice induces an NK-cell maturation defect and leads to increased IFN-γ production induced by activating receptors. Taken together, these results reveal that Dok1 and Dok2 proteins are involved in an intrinsic negative feedback loop downstream of NK-cell-activating receptors in mouse and human. PMID:24963146
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ERAP1 regulates natural killer cell function by controlling the engagement of inhibitory receptors.
Cifaldi, Loredana; Romania, Paolo; Falco, Michela; Lorenzi, Silvia; Meazza, Raffaella; Petrini, Stefania; Andreani, Marco; Pende, Daniela; Locatelli, Franco; Fruci, Doriana
2015-03-01
The endoplasmic reticulum aminopeptidase ERAP1 regulates innate and adaptive immune responses by trimming peptides for presentation by MHC class I (MHC-I) molecules. Herein, we demonstrate that genetic or pharmacological inhibition of ERAP1 on human tumor cell lines perturbs their ability to engage several classes of inhibitory receptors by their specific ligands, including killer cell Ig-like receptors (KIR) by classical MHC-I-peptide (pMHC-I) complexes and the lectin-like receptor CD94-NKG2A by nonclassical pMHC-I complexes, in each case leading to natural killer (NK) cell killing. The protective effect of pMHC-I complexes could be restored in ERAP1-deficient settings by the addition of known high-affinity peptides, suggesting that ERAP1 was needed to positively modify the affinity of natural ligands. Notably, ERAP1 inhibition enhanced the ability of NK cells to kill freshly established human lymphoblastoid cell lines from autologous or allogeneic sources, thereby promoting NK cytotoxic activity against target cells that would not be expected because of KIR-KIR ligand matching. Overall, our results identify ERAP1 as a modifier to leverage immune functions that may improve the efficacy of NK cell-based approaches for cancer immunotherapy. ©2015 American Association for Cancer Research.
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Killer whale call frequency is similar across the oceans, but varies across sympatric ecotypes.
Filatova, Olga A; Miller, Patrick J O; Yurk, Harald; Samarra, Filipa I P; Hoyt, Erich; Ford, John K B; Matkin, Craig O; Barrett-Lennard, Lance G
2015-07-01
Killer whale populations may differ in genetics, morphology, ecology, and behavior. In the North Pacific, two sympatric populations ("resident" and "transient") specialize on different prey (fish and marine mammals) and retain reproductive isolation. In the eastern North Atlantic, whales from the same populations have been observed feeding on both fish and marine mammals. Fish-eating North Pacific "residents" are more genetically related to eastern North Atlantic killer whales than to sympatric mammal-eating "transients." In this paper, a comparison of frequency variables in killer whale calls recorded from four North Pacific resident, two North Pacific transient, and two eastern North Atlantic populations is reported to assess which factors drive the large-scale changes in call structure. Both low-frequency and high-frequency components of North Pacific transient killer whale calls have significantly lower frequencies than those of the North Pacific resident and North Atlantic populations. The difference in frequencies could be related to ecological specialization or to the phylogenetic history of these populations. North Pacific transient killer whales may have genetically inherited predisposition toward lower frequencies that may shape their learned repertoires.
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Zhao, Yan-Jie; Jiang, Ni; Song, Qing-Kun; Wu, Jiang-Ping; Song, Yu-Guang; Zhang, Hong-Mei; Chen, Feng; Zhou, Lei; Wang, Xiao-Li; Zhou, Xin-Na; Yang, Hua-Bing; Ren, Jun; Lyerly, Herbert Kim
2015-01-01
There are few choices for treatment of advanced cancer patients who do not respond to or tolerate conventional anti-cancer treatments. Therefore this study aimed to deploy the benefits and clinical efficacy of continuous dendritic cell-cytokine induced killer cell infusions in such patients. A total of 381 infusions (from 67 advanced cases recruited) were included in this study. All patients underwent peripheral blood mononuclear cell apheresis for the following cellular therapy and dendritic cells-cytokine induced killer cells were expanded in vitro. Peripheral blood T lymphocyte subsets were quantified through flow cytometry to address the cellular immunity status. Clinical efficacy and physical activities were evaluated by RECIST criteria and Eastern Cooperative Oncology Group scores respectively. Logistic regression model was used to estimate the association between cellular infusions and clinical benefits. An average of 5.7±2.94x10(9) induced cells were infused each time and patients were exposed to 6 infusions. Cellular immunity was improved in that cytotoxic CD8+CD28+T lymphocytes were increased by 74% and suppressive CD8+CD28-T lymphocytes were elevated by 16% (p<0.05). Continuous infusion of dendritic cells-cytokine induced killer cells was associated with improvement of both patient status and cellular immunity. A median of six infusions were capable of reducing risk of progression by 70% (95%CI 0.10-0.91). Every elevation of one ECOG score corresponded to a 3.90-fold higher progression risk (p<0.05) and 1% increase of CD8+CD28- T cell proportion reflecting a 5% higher risk of progression (p<0.05). In advanced cancer patients, continuous dendritic cell-cytokine induced killer cell infusions are capable of recovering cellular immunity, improving patient status and quality of life in those who are unresponsive to conventional cancer treatment.
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Imaging immune surveillance of individual natural killer cells confined in microwell arrays.
Guldevall, Karolin; Vanherberghen, Bruno; Frisk, Thomas; Hurtig, Johan; Christakou, Athanasia E; Manneberg, Otto; Lindström, Sara; Andersson-Svahn, Helene; Wiklund, Martin; Önfelt, Björn
2010-11-12
New markers are constantly emerging that identify smaller and smaller subpopulations of immune cells. However, there is a growing awareness that even within very small populations, there is a marked functional heterogeneity and that measurements at the population level only gives an average estimate of the behaviour of that pool of cells. New techniques to analyze single immune cells over time are needed to overcome this limitation. For that purpose, we have designed and evaluated microwell array systems made from two materials, polydimethylsiloxane (PDMS) and silicon, for high-resolution imaging of individual natural killer (NK) cell responses. Both materials were suitable for short-term studies (<4 hours) but only silicon wells allowed long-term studies (several days). Time-lapse imaging of NK cell cytotoxicity in these microwell arrays revealed that roughly 30% of the target cells died much more rapidly than the rest upon NK cell encounter. This unexpected heterogeneity may reflect either separate mechanisms of killing or different killing efficiency by individual NK cells. Furthermore, we show that high-resolution imaging of inhibitory synapse formation, defined by clustering of MHC class I at the interface between NK and target cells, is possible in these microwells. We conclude that live cell imaging of NK-target cell interactions in multi-well microstructures are possible. The technique enables novel types of assays and allow data collection at a level of resolution not previously obtained. Furthermore, due to the large number of wells that can be simultaneously imaged, new statistical information is obtained that will lead to a better understanding of the function and regulation of the immune system at the single cell level.
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Inflammation-induced formation of fat-associated lymphoid clusters
Bénézech, Cécile; Kruglov, Andrei A.; Loo, Yunhua; Nakamura, Kyoko; Zhang, Yang; Nayar, Saba; Jones, Lucy H.; Flores-Langarica, Adriana; McIntosh, Alistair; Marshall, Jennifer; Barone, Francesca; Besra, Gurdyal; Miles, Katherine; Allen, Judith E.; Gray, Mohini; Kollias, George; Cunningham, Adam F.; Withers, David R.; Toellner, Kai Michael; Jones, Nick D.; Veldhoen, Marc; Nedospasov, Sergei A.; McKenzie, Andrew N.J.; Caamaño, Jorge H.
2015-01-01
Fat-associated lymphoid clusters (FALCs) are a recently discovered type of lymphoid tissue associated with visceral fat. Here we show that distribution of FALCs was heterogeneous with the pericardium containing large numbers of these clusters. FALCs contributed to the retention of B-1 B cells in the peritoneal cavity through high expression of the chemokine CXCL13 and supported B cell proliferation and germinal center differentiation during peritoneal immune challenges. FALC formation was induced by inflammation, which triggered recruitment of myeloid cells that express tumor necrosis factor (TNF) necessary for TNF receptor-signaling in stromal cells. CD1d-restricted Natural killer T (NKT) cells were likewise required for inducible formation of FALCs. Thus, FALCs support and coordinate innate B and T cell activation during serosal immune responses. PMID:26147686
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Cancer killers in the human gut microbiota: diverse phylogeny and broad spectra
Zhou, Yu-Jie; Zhao, Dan-Dan; Liu, Huidi; Chen, Hao-Ting; Li, Jia-Jing; Mu, Xiao-Qin; Liu, Zheng; Li, Xia; Tang, Le; Zhao, Zhan-Yi; Wu, Ji-Heng; Cai, Yu-Xuan; Huang, Ya-Zhuo; Wang, Peng-Ge; Jia, Yi-Yue; Liang, Pei-Qiang; Peng, Xue; Chen, Si-Yu; Yue, Zhi-Lin; Yuan, Xin-Yuan; Lu, Tammy; Yao, Bing-Qing; Li, Yong-Guo; Liu, Gui-Rong; Liu, Shu-Lin
2017-01-01
Cancer as a large group of complex diseases is believed to result from the interactions of numerous genetic and environmental factors but may develop in people without any known genetic or environmental risks, suggesting the existence of other powerful factors to influence the carcinogenesis process. Much attention has been focused recently on particular members of the intestinal microbiota for their potential roles in promoting carcinogenesis. Here we report the identification and characterization of intestinal bacteria that exhibited potent anti-malignancy activities on a broad range of solid cancers and leukemia. We collected fecal specimens from healthy individuals of different age groups (preschool children and university students), inspected their effects on cancer cells, and obtained bacteria with potent anti-malignancy activities. The bacteria mostly belonged to Actinobacteria but also included lineages of other phyla such as Proteobacteria and Firmicutes. In animal cancer models, sterile culture supernatant from the bacteria highly effectively inhibited tumor growth. Remarkably, intra-tumor administration of the bacterial products prevented metastasis and even cleared cancer cells at remote locations from the tumor site. This work demonstrates the prevalent existence of potent malignancy-killers in the human intestinal microbiota, which may routinely clear malignant cells from the body before they form cancers. PMID:28484095
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Ferromagnetic nickel silicide nanowires for isolating primary CD4+ T lymphocytes
NASA Astrophysics Data System (ADS)
Kim, Dong-Joo; Seol, Jin-Kyeong; Lee, Mi-Ri; Hyung, Jung-Hwan; Kim, Gil-Sung; Ohgai, Takeshi; Lee, Sang-Kwon
2012-04-01
Direct CD4+ T lymphocytes were separated from whole mouse splenocytes using 1-dimensional ferromagnetic nickel silicide nanowires (NiSi NWs). NiSi NWs were prepared by silver-assisted wet chemical etching of silicon and subsequent deposition and annealing of Ni. This method exhibits a separation efficiency of ˜93.5%, which is comparable to that of the state-of-the-art superparamagnetic bead-based cell capture (˜96.8%). Furthermore, this research shows potential for separation of other lymphocytes, B, natural killer and natural killer T cells, and even rare tumor cells simply by changing the biotin-conjugated antibodies.
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Emmer, P M; Nelen, W L; Steegers, E A; Hendriks, J C; Veerhoek, M; Joosten, I
2000-05-01
For diagnostic purposes we assessed peripheral natural killer (NK) cell cytotoxicity and NK and T cell numbers to assess their putative predictive value in recurrent spontaneous abortion (RSA). A total of 43 women with subsequent pregnancy, 37 healthy controls and 39 women successfully partaking in an in-vitro fertilization (IVF) procedure, were included in the study. We show that before pregnancy, levels of NK cytotoxicity and numbers of both single CD56(pos) and double CD56(pos)CD16(pos) cells were similar between RSA women and controls. But notably, within the RSA group, NK cell numbers of <12% were strongly associated with a subsequent pregnancy carried to term. Supplementation of folic acid led to an increase of single CD56(pos) cells, but cytotoxic function appeared unaffected. The expression pattern of killer inhibitory receptors on CD56(pos) cells was not different between patients and controls. A longitudinal study revealed that, compared with controls, in RSA women higher numbers of double CD56(pos)CD16(pos) cells were present during early pregnancy, paralleled by an increase in cytotoxic NK cell reactivity. The single CD56(pos) population decreased in number. In conclusion, the analysis of peripheral NK cell characteristics appears a suitable diagnostic tool in RSA. Immunomodulation aimed at NK cell function appears a promising therapeutic measure.
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Growth and apoptosis of human natural killer cell neoplasms: role of interleukin-2/15 signaling.
Yamasaki, Satoshi; Maeda, Motoi; Ohshima, Koichi; Kikuchi, Masahiro; Otsuka, Teruhisa; Harada, Mine
2004-10-01
Interleukin (IL)-15 plays an important role in the survival of human natural killer (NK) cells. We investigated IL-2/15 signaling in NK cell neoplasms from five patients and in five cell lines (NK-92, KHYG-1, SNK-6, HANK1 and MOTN-1) compared to mature peripheral NK cells from 10 healthy subjects. Apoptosis of NK cell lines was prevented by addition of IL-15 in vitro. Blocking IL-2/15Rbeta on IL-2-stimulated NK-92 cells resulted in reduced expression of Bcl-X(L) and phosphorylated Stat5, which paralleled early apoptosis without altering Bcl-2 expression. These data add IL-2/15Rbeta to the list of factors important for the survival of NK cell neoplasms.
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Building tolerance by dismantling synapses: inhibitory receptor signaling in natural killer cells.
Huse, Morgan; Catherine Milanoski, S; Abeyweera, Thushara P
2013-01-01
Cell surface receptors bearing immunotyrosine-based inhibitory motifs (ITIMs) maintain natural killer (NK) cell tolerance to normal host tissues. These receptors are difficult to analyze mechanistically because they block activating responses in a rapid and comprehensive manner. The advent of high-resolution single cell imaging techniques has enabled investigators to explore the cell biological basis of the inhibitory response. Recent studies using these approaches indicate that ITIM-containing receptors function at least in part by structurally undermining the immunological synapse between the NK cell and its target. In this review, we discuss these new advances and how they might relate to what is known about the biochemistry of inhibitory signaling in NK cells and other cell types. © 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.
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Natural killer cells: In health and disease.
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. Copyright © 2015. Published by Elsevier B.V.
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Nguyen-Pham, Thanh-Nhan; Im, Chang-Min; Nguyen, Truc-Anh Thi; Lim, Mi-Seon; Hong, Cheol Yi; Kim, Mi-Hyun; Lee, Hyun Ju; Lee, Youn-Kyung; Cho, Duck; Ahn, Jae-Sook; Yang, Deok-Hwan; Kim, Yeo-Kyeoung; Chung, Ik-Joo; Kim, Hyeoung-Joon; Lee, Je-Jung
2011-09-01
The interaction between dendritic cells (DCs) and natural killer (NK) cells plays a key role in inducing DC maturation for subsequent T-cell priming. We investigated to generate potent DCs by stimulated with NK cells to induce myeloma-specific cytotoxic T lymphocytes (CTLs). NK cells-stimulated-DCs exhibited high expression of costimulatory molecules and high production of IL-12p70. These DCs induce high potency of Th1 polarization and exhibit a high ability to generate myeloma-specific CTLs responses. These results suggest that functionally potent DCs can be generated by stimulation with NK cells and may provide an effective source of DC-based immunotherapy in multiple myeloma. Copyright © 2011 Elsevier Ltd. All rights reserved.
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Boosting Natural Killer Cell-Based Immunotherapy with Anticancer Drugs: a Perspective.
Cifaldi, Loredana; Locatelli, Franco; Marasco, Emiliano; Moretta, Lorenzo; Pistoia, Vito
2017-12-01
Natural killer (NK) cells efficiently recognize and kill tumor cells through several mechanisms including the expression of ligands for NK cell-activating receptors on target cells. Different clinical trials indicate that NK cell-based immunotherapy represents a promising antitumor treatment. However, tumors develop immune-evasion strategies, including downregulation of ligands for NK cell-activating receptors, that can negatively affect antitumor activity of NK cells, which either reside endogenously, or are adoptively transferred. Thus, restoration of the expression of NK cell-activating ligands on tumor cells represents a strategic therapeutic goal. As discussed here, various anticancer drugs can fulfill this task via different mechanisms. We envision that the combination of selected chemotherapeutic agents with NK cell adoptive transfer may represent a novel strategy for cancer immunotherapy. Copyright © 2017 Elsevier Ltd. All rights reserved.
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Theoretical immunology, Part 2: Proceedings
DOE Office of Scientific and Technical Information (OSTI.GOV)
Perelson, A.S.
1988-01-01
This document contains 43 papers on current topics in immunology. Topics include cell chemotaxis, killer cells, AIDS, antigen reactivity, t-cells, crosslinking, cell-cell adhesion, immune response, and the regulation of lymphocyte proliferation. (TEM)
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Mechanisms of diminished natural killer cell activity in pregnant women and neonates
DOE Office of Scientific and Technical Information (OSTI.GOV)
Baley, J.E.; Schacter, B.Z.
1985-05-01
Because alterations in natural killer (NK) activity in the perinatal period may be important in the maintenance of a healthy pregnancy, the mechanisms by which these alterations are mediated in neonates and in pregnant and postpartum women was examined. NK activity, as measured in a 4-hr /sup 51/Cr-release assay and compared with adult controls, is significantly diminished in all three trimesters of pregnancy and in immediately postpartum women. In postpartum women, NK activity appears to be higher than in pregnant women, although this does not reach statistical significance. Pregnant and postpartum women have normal numbers of large granular lymphocytes andmore » normal target cell binding in an agarose single cell assay but decreased lysis of the bound target cells. NK activity of mononuclear cells from postpartum women, in addition, demonstrate a shift in distribution to higher levels of resistance to gamma-irradiation. Further, sera from postpartum women cause a similar shift to increased radioresistance in mononuclear cells from adult controls. Because radioresistance is a property of interleukin 2-stimulated NK, the shift to radioresistance may represent lymphokine-mediated stimulation occurring during parturition. In contrast, cord blood cells have a more profound decrease in NK activity as determined by /sup 51/Cr-release assay and decreases in both binding and lysis of bound target cells in the single cell assay. The resistance of NK activity in cord cells to gamma-irradiation is also increased, as seen in postpartum women. Cord blood serum, however, did not alter radioresistance or inhibit NK activity. The results suggest that the observed diminished NK activity in pregnant women and neonates arise by different mechanisms: an absence of mature NK cells in the neonate and an alteration of the NK cell in pregnancy leading to decreased killing.« less
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Genßler, Sabrina; Burger, Michael C; Zhang, Congcong; Oelsner, Sarah; Mildenberger, Iris; Wagner, Marlies; Steinbach, Joachim P; Wels, Winfried S
2016-04-01
Epidermal growth factor receptor (EGFR) and its mutant form EGFRvIII are overexpressed in a large proportion of glioblastomas (GBM). Immunotherapy with an EGFRvIII-specific vaccine has shown efficacy against GBM in clinical studies. However, immune escape by antigen-loss variants and lack of control of EGFR wild-type positive clones limit the usefulness of this approach. Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells may represent an alternative immunotherapeutic strategy. For targeting to GBM, we generated variants of the clinically applicable human NK cell line NK-92 that express CARs carrying a composite CD28-CD3ζ domain for signaling, and scFv antibody fragments for cell binding either recognizing EGFR, EGFRvIII, or an epitope common to both antigens. In vitro analysis revealed high and specific cytotoxicity of EGFR-targeted NK-92 against established and primary human GBM cells, which was dependent on EGFR expression and CAR signaling. EGFRvIII-targeted NK-92 only lysed EGFRvIII-positive GBM cells, while dual-specific NK cells expressing a cetuximab-based CAR were active against both types of tumor cells. In immunodeficient mice carrying intracranial GBM xenografts either expressing EGFR, EGFRvIII or both receptors, local treatment with dual-specific NK cells was superior to treatment with the corresponding monospecific CAR NK cells. This resulted in a marked extension of survival without inducing rapid immune escape as observed upon therapy with monospecific effectors. Our results demonstrate that dual targeting of CAR NK cells reduces the risk of immune escape and suggest that EGFR/EGFRvIII-targeted dual-specific CAR NK cells may have potential for adoptive immunotherapy of glioblastoma.
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Gamliel, Moriya; Anderson, Karen L; Ebstein, Richard P; Yirmiya, Nurit; Mankuta, David
2016-01-01
Killer-cell immunoglobulin-like receptors (KIRs) are a family of cell surface proteins found on natural killer cells, which are components of the innate immune system. KIRs recognize MHC class I proteins, mainly HLA-C and are further divided into two groups: short-tailed 2/3DS activating receptors and long-tailed 2/3DL inhibitory receptors. Based on the Barker Hypothesis, the origins of illness can be traced back to embryonic development in the uterus, and since KIR:HLA interaction figures prominently in the maternal-fetal interface, we investigated whether specific KIR:HLA combinations may be found in autism spectrum disorders (ASD) children compared with their healthy parents. This study enrolled 49 ASD children from different Israeli families, and their healthy parents. Among the parents, a higher frequency of HLA-C2 allotypes was found in the fathers, while its corresponding ligand 2DS1 was found in higher percentage in the maternal group. However, such skewing in KIR:HLA frequencies did not appear in the ASD children. Additionally, analysis of "overall activation" indicated higher activation in maternal than in paternal cohorts.
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Protein Kinase C-θ (PKC-θ) in Natural Killer Cell Function and Anti-Tumor Immunity
Anel, Alberto; Aguiló, Juan I.; Catalán, Elena; Garaude, Johan; Rathore, Moeez G.; Pardo, Julián; Villalba, Martín
2012-01-01
The protein kinase C-θ (PKCθ), which is essential for T cell function and survival, is also required for efficient anti-tumor immune surveillance. Natural killer (NK) cells, which express PKCθ, play a prominent role in this process, mainly by elimination of tumor cells with reduced or absent major histocompatibility complex class-I (MHC-I) expression. This justifies the increased interest of the use of activated NK cells in anti-tumor immunotherapy in the clinic. The in vivo development of MHC-I-deficient tumors is much favored in PKCθ−/− mice compared with wild-type mice. Recent data offer some clues on the mechanism that could explain the important role of PKCθ in NK cell-mediated anti-tumor immune surveillance: some studies show that PKCθ is implicated in signal transduction and anti-tumoral activity of NK cells elicited by interleukin (IL)-12 or IL-15, while others show that it is implicated in NK cell functional activation mediated by certain killer-activating receptors. Alternatively, the possibility that PKCθ is involved in NK cell degranulation is discussed, since recent data indicate that it is implicated in microtubule-organizing center polarization to the immune synapse in CD4+ T cells. The implication of PKC isoforms in degranulation has been more extensively studied in cytotoxic T lymphocyte, and these studies will be also summarized. PMID:22783260
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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
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Lactic Acid Bacteria from Kefir Increase Cytotoxicity of Natural Killer Cells to Tumor Cells.
Yamane, Takuya; Sakamoto, Tatsuji; Nakagaki, Takenori; Nakano, Yoshihisa
2018-03-27
The Japanese fermented beverage, homemade kefir, contains six lactic acid bacteria: Lactococcus. lactis subsp. Lactis , Lactococcus . lactis subsp. Cremoris , Lactococcus. Lactis subsp. Lactis biovar diacetylactis , Lactobacillus plantarum , Leuconostoc meseuteroides subsp. Cremoris and Lactobacillus casei . In this study, we found that a mixture of the six lactic acid bacteria from kefir increased the cytotoxicity of human natural killer KHYG-1 cells to human chronic myelogenous leukemia K562 cells and colorectal tumor HCT116 cells. Furthermore, levels of mRNA expression and secretion of IFN-γ (interferon gamma) increased in KHYG-1 cells that had been treated with the six lactic acid bacteria mixture from kefir. The results suggest that the six lactic acid bacteria mixture from kefir has strong effects on natural immunity and tumor cell cytotoxicity.
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Lactic Acid Bacteria from Kefir Increase Cytotoxicity of Natural Killer Cells to Tumor Cells
Yamane, Takuya; Sakamoto, Tatsuji; Nakagaki, Takenori; Nakano, Yoshihisa
2018-01-01
The Japanese fermented beverage, homemade kefir, contains six lactic acid bacteria: Lactococcus. lactis subsp. Lactis, Lactococcus. lactis subsp. Cremoris, Lactococcus. Lactis subsp. Lactis biovar diacetylactis, Lactobacillus plantarum, Leuconostoc meseuteroides subsp. Cremoris and Lactobacillus casei. In this study, we found that a mixture of the six lactic acid bacteria from kefir increased the cytotoxicity of human natural killer KHYG-1 cells to human chronic myelogenous leukemia K562 cells and colorectal tumor HCT116 cells. Furthermore, levels of mRNA expression and secretion of IFN-γ (interferon gamma) increased in KHYG-1 cells that had been treated with the six lactic acid bacteria mixture from kefir. The results suggest that the six lactic acid bacteria mixture from kefir has strong effects on natural immunity and tumor cell cytotoxicity. PMID:29584690
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TCRαβ+/CD4+ Large Granular Lymphocytosis
Lima, Margarida; Almeida, Julia; dos Anjos Teixeira, Maria; Alguero, Maria del Carmen; Santos, Ana Helena; Balanzategui, Ana; Queirós, Maria Luís; Bárcena, Paloma; Izarra, Antonio; Fonseca, Sónia; Bueno, Clara; Justiça, Benvindo; Gonzalez, Marcos; San Miguel, Jesús F.; Orfao, Alberto
2003-01-01
Large granular lymphocyte (LGL) leukemia is a well-recognized disease of mature T-CD8+ or less frequently natural killer cells; in contrast, monoclonal expansions of CD4+ T-LGL have only been sporadically reported in the literature. In the present article we have explored throughout a period of 56 months the incidence of monoclonal expansions of CD4+ T-LGL in a population of 2.2 million inhabitants and analyzed the immunophenotype and the pattern of cytokine production of clonal CD4+ T cells of a series of 34 consecutive cases. Like CD8+ T-LGL leukemias, CD4+ T-LGL leukemia patients have an indolent disease; however, in contrast to CD8+ T-LGL leukemias, they do not show cytopenias and autoimmune phenomena and they frequently have associated neoplasias, which is usually determining the clinical course of the disease. Monoclonal CD4+ T-LGLshowed expression of TCRαβ, variable levels of CD8 (CD8−/+dim) and a homogeneous typical cytotoxic (granzyme B+, CD56+, CD57+, CD11b+/−) and activated/memory T cell (CD2+bright, CD7−/+dim, CD11a+bright, CD28−, CD62L− HLA-DR+) immunophenotype. In addition, they exhibited a Th1 pattern of cytokine production [interferon-γ++, tumor necrosis factor-α++, interleukin (IL-2)−/+, IL-4−, IL-10−, IL-13−]. Phenotypic analysis of the TCR-Vβ repertoire revealed large monoclonal TCR-Vβ expansions; only a restricted number of TCR-Vβ families were represented in the 34 cases analyzed. These findings suggest that monoclonal TCRαβ+/CD4+/NKa+/CD8−/+dim T-LGL represent a subgroup of monoclonal LGL lymphoproliferative disorders different from both CD8+ T-LGL and natural killer cell-type LGL leukemias. Longer follow-up periods are necessary to determine the exact significance of this clonal disorder. PMID:12875995
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Kinome Analysis of Receptor-Induced Phosphorylation in Human Natural Killer Cells
König, Sebastian; Nimtz, Manfred; Scheiter, Maxi; Ljunggren, Hans-Gustaf; Bryceson, Yenan T.; Jänsch, Lothar
2012-01-01
Background Natural killer (NK) cells contribute to the defense against infected and transformed cells through the engagement of multiple germline-encoded activation receptors. Stimulation of the Fc receptor CD16 alone is sufficient for NK cell activation, whereas other receptors, such as 2B4 (CD244) and DNAM-1 (CD226), act synergistically. After receptor engagement, protein kinases play a major role in signaling networks controlling NK cell effector functions. However, it has not been characterized systematically which of all kinases encoded by the human genome (kinome) are involved in NK cell activation. Results A kinase-selective phosphoproteome approach enabled the determination of 188 kinases expressed in human NK cells. Crosslinking of CD16 as well as 2B4 and DNAM-1 revealed a total of 313 distinct kinase phosphorylation sites on 109 different kinases. Phosphorylation sites on 21 kinases were similarly regulated after engagement of either CD16 or co-engagement of 2B4 and DNAM-1. Among those, increased phosphorylation of FYN, KCC2G (CAMK2), FES, and AAK1, as well as the reduced phosphorylation of MARK2, were reproducibly observed both after engagement of CD16 and co-engagement of 2B4 and DNAM-1. Notably, only one phosphorylation on PAK4 was differentally regulated. Conclusions The present study has identified a significant portion of the NK cell kinome and defined novel phosphorylation sites in primary lymphocytes. Regulated phosphorylations observed in the early phase of NK cell activation imply these kinases are involved in NK cell signaling. Taken together, this study suggests a largely shared signaling pathway downstream of distinct activation receptors and constitutes a valuable resource for further elucidating the regulation of NK cell effector responses. PMID:22238634
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Jung, Yoon Suk; Park, Jung Ho; Park, Dong Il; Sohn, Chong Il; Lee, Jae Myun; Kim, Tae Il
2018-06-01
Several studies have reported relationships among physical activity, healthy metabolic status, and increased natural killer (NK) cell activity. However, large-scale data thereon are lacking. Thus, the present study aimed to assess NK cell activity according to physical activity and metabolic status. A cross-sectional study was performed on 12014 asymptomatic examinees. Using a patented stimulatory cytokine, NK cell activity was quantitated by the amount of interferon-γ secreted into the plasma by NK cells. Physical activity levels were assessed using the validated Korean version of the International Physical Activity Questionnaire Short Form. The physically inactive group showed lower NK cell activity than the minimally active group (median, 1461 vs. 1592 pg/mL, p<0.001) and health-enhancing physically active group (median, 1461 vs. 1712 pg/mL, p=0.001). Compared to women with a body mass index (BMI) of 18.5-27.5 kg/m², those with a BMI <18.5 kg/m² had significantly lower NK cell activity (1356 vs. 1024 g/mL, p<0.001), and those with a BMI ≥27.5 kg/m² tended to have lower NK cell activity (1356 vs. 1119 g/mL, p=0.070). Subjects with high hemoglobin A1c levels and low high-density lipoprotein cholesterol levels, as well as men with high blood pressure and women with high triglyceride levels, exhibited lower NK cell activity. Moreover, physical inactivity and metabolic abnormalities were independently associated with low NK cell activity, even after adjusting for confounders. Physical inactivity and metabolic abnormalities are associated with reduced NK cell activity. Immune systems may become altered depending on physical activity and metabolic status. © Copyright: Yonsei University College of Medicine 2018.
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SHAN, CHAN-CHAN; SHI, LIANG-RONG; DING, MEI-QIAN; ZHU, YI-BEI; LI, XIAO-DONG; XU, BIN; JIANG, JING-TING; WU, CHANG-PING
2015-01-01
Radiofrequency ablation (RFA) causes coagulative necrosis of tumor tissue and the production of local tumor protein debris. These fragments of tumor protein debris contain a large number of various antigens, which can stimulate a specific cellular immune response. In the present study, dendritic cells (DCs) were loaded with tumor protein lysate antigens that were produced in situ by RFA, and were used to treat murine colon carcinoma in combination with cytokine-induced killer (CIK) cells. Subsequent to the treatment of murine colon carcinoma by RFA, the in situ supernatant of tumor lysis was collected and the DCs were loaded with the lysate antigen to generate Ag-DCs. CIK cells induced from the spleen cells of mice were co-cultured with Ag-DCs to generate Ag-DC-CIK cells. The results revealed that the Ag-DC-CIK cells exhibited strong antitumor activity in vitro and in vivo. The morphology and immunophenotypes of these cells were determined using microscopy and flow cytometry, respectively. The cytotoxic activity of Ag-DC-CIK cells was determined using a CCK-8 assay. To establish a mouse model, mice were randomized into Ag-DC-CIK, DC-CIK, CIK and PBS control groups and monitored for tumor growth and survival time. ANOVA was used to compare the trends in the three groups for implanted tumor volumes. The log-rank test was used to compare the survival time. The present findings indicated that DCs loaded with the protein lysate antigens of tumors, produced in situ by RFA, combined with CIK cells may be a novel strategy for cancer treatment. PMID:25788999
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Liver natural killer cells: subsets and roles in liver immunity
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
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Mehlomakulu, N N; Prior, K J; Setati, M E; Divol, B
2017-03-01
The control of the wine spoilage yeast Brettanomyces bruxellensis using biological methods such as killer toxins (instead of the traditional chemical methods, e.g. SO 2 ) has been the focus of several studies within the last decade. Our previous research demonstrated that the killer toxins CpKT1 and CpKT2 isolated from the wine yeast Candida pyralidae were active and stable under winemaking conditions. In this study, we report the possible mode of action of CpKT1 on B. bruxellensis cells in red grape juice. Brettanomyces bruxellensis cells were exposed to CpKT1 either directly or through co-inoculation with C. pyralidae. This exposure yielded a temporary or permanent decline of the spoilage yeast population depending on the initial cell concentration. Scanning electron microscopy revealed cell surface abrasion while propidium iodide viability staining showed that CpKT1 caused plasma membrane damage on B. bruxellensis cells. Our data show that the exposure to CpKT1 resulted in increased levels of β-glucan, suggesting a compensatory response of the sensitive cells. The toxin CpKT1 causes cell membrane and cell wall damage in B. bruxellensis. Candida pyralidae shows potential to be used as a biocontrol agent against B. bruxellensis in grape juice/wine. © 2016 The Society for Applied Microbiology.
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Takahashi, Naomi; Sugaya, Makoto; Suga, Hiraku; Oka, Tomonori; Kawaguchi, Makiko; Miyagaki, Tomomitsu; Fujita, Hideki; Inozume, Takashi; Sato, Shinichi
2017-08-01
Immune checkpoint therapy, which targets regulatory pathways in T cells to enhance antitumor immune responses, has led to important clinical advances. CD155 is expressed in various types of cancer, and this surface molecule on tumor cells functions either as a co-stimulatory molecule or a co-inhibitory molecule, depending on its receptor. CD226, a CD155 ligand, is mainly expressed on natural killer cells and CD8 + T cells, playing important roles in natural killer cell-mediated cytotoxicity. In this study, we investigated the expression and function of CD155 and CD226 in cutaneous T-cell lymphoma (CTCL). CD155 was strongly expressed on tumor cells and CD155 mRNA expression levels were increased in CTCL lesional skin. CD226 expression on natural killer cells and CD8 + cells in peripheral blood of CTCL patients was decreased. On the other hand, serum CD226 levels were significantly elevated in CTCL patients, strongly reflecting disease activity, suggesting that soluble CD226 in sera was generated by shedding of its membrane form. Recombinant CD226 itself showed cytotoxic activity against CD155-expressing CTCL cells in vitro. These data suggest that soluble CD226 elevated in sera of CTCL patients would be important for tumor immunity by interacting with CD155 on tumor cells. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
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Ryu, Je Il; Han, Myung Hoon; Cheong, Jin Hwan; Kim, Jae Min; Kim, Choong Hyun
2017-03-01
The therapeutic outcome for those with malignant glioma is poor, even though diverse therapeutic modalities have been developed. Immunotherapy has emerged as a therapeutic approach for malignant gliomas, making it possible to selectively treat tumors while sparing normal tissue. Here, we review clinical trials of adoptive immunotherapy approaches for malignant gliomas. We also describe a clinical trial that examined the efficacy and safety of autologous cytokine-induced killer (CIK) cells along with concomitant chemoradiotherapy for newly diagnosed glioblastoma. These CIK cells identify and kill autologous tumor cells. This review focuses on the use of adoptive immunotherapy for malignant gliomas and reviews the current literature on the concept of antitumor activity mediated by CIK cells.
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Streck, R J; Helinski, E H; Ovak, G M; Pauly, J L
1990-09-01
Lymphokine (i.e., interleukin 2; IL-2)-activated killer (LAK) cells derived from normal human blood are known to destroy human tumor target cells. Accordingly, immunotherapy modalities using IL-2, either alone or in combination with LAK cells, have been evaluated for eradicating metastatic cancer. In studies conducted to characterize receptors on LAK cell membrane ultrastructures, we observed that LAK cells kill autologous human monocyte-derived macrophages (M phi). In these experiments, peripheral blood mononuclear cells of a healthy adult donor were cultured to generate LAK cells and autologous non-adherent M phi. Thereafter, conjugates were prepared by incubating for 3 h autologous populations of LAK cells and M phi. Examination of the conjugates by scanning electron microscopy (SEM) identified LAK cell-mediated killing of M phi. Moreover, SEM analysis of the LAK cell membrane architecture identified microvilli-like ultrastructures that provided a physical bridge that joined together the LAK cell and M phi. The immunological mechanism(s) underling LAK cell killing of autologous M phi is not known; nevertheless, these conjugates will provide a useful model to study membrane receptors on ultrastructures that mediate the initial stages of cytolysis that include target cell recognition and cell-to-cell adhesion. The results of our observations and the findings of other investigators who have also demonstrated LAK cell killing of autologous normal human leukocytes are discussed in the context of the association of IL-2 and IL-2-activated killer cells with side effects observed in ongoing clinical trials and with autoimmune disorders.
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Yang, Ching-Fen; Hsu, Chih-Yi; Ho, Donald M-T
2018-05-01
Aggressive natural killer (NK)-cell leukaemia (ANKCL) and extranodal NK/T-cell lymphoma (ENKTCL) with secondary bone marrow involvement are rare bone marrow NK/T-cell neoplasms and share similar features. This study aimed to distinguish these two entities. We studied bone marrow NK/T-cell neoplasms by classifying them into those with no extramedullary mass (group 1, eight cases) and those with extramedullary mass (group 2, 13 cases). The two groups showed similar clinical presentations and pathological features. Fever and cytopenia were the most common clinical presentations in both groups. The neoplastic cells varied from small and relatively monotonous cells to large pleomorphic cells. In six cases (two in group 1, and four in group 2), the neoplastic infiltrate was inconspicuous, consisting of ≤10% of marrow cells in the interstitium, which were hardly identified by haematoxylin and eosin staining alone. Nearly all patients rapidly died, regardless of the neoplastic infiltrate volume. All of the group 1 patients fulfilled the World Health Organisation 2017 diagnostic criteria of ANKCL, and their survival was significantly worse than that of the group 2 patients (P = 0.035). In addition, there was a significant association between being in group 1 and chromosome 7 abnormalities. Chromosome 6q deletion, which is commonly reported in ENKTCL, was seen in two of our group 2 patients, and was not observed in any of our group 1 patients. ANKCL with no extramedullary mass should be distinguished from ENKTCL with bone marrow involvement, as the former shows distinct outcomes and genetic features. © 2018 John Wiley & Sons Ltd.
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Co-Expansion of Cytokine-Induced Killer Cells and Vγ9Vδ2 T Cells for CAR T-Cell Therapy
Chen, Can; Tan, Wee-Kiat; Chi, Zhixia; Xu, Xue-Hu; Wang, Shu
2016-01-01
Gamma delta (γδ) T cells and cytokine-induced killer (CIK) cells, which are a heterogeneous population of T lymphocytes and natural killer T (NKT) cells, have been separately expanded ex vivo and shown to be capable of targeting and mediating cytotoxicity against various tumor cells in a major histocompatibility complex-unrestricted manner. However, the co-expansion and co-administration of these immune cells have not been explored. In this study we describe an efficient method to expand simultaneously both CIK and Vγ9Vδ2 T cells, termed as CIKZ cells, from human peripheral blood mononuclear cells (PBMCs) using Zometa, interferon-gamma (IFN-γ), interleukin 2 (IL-2), anti-CD3 antibody and engineered K562 feeder cells expressing CD64, CD137L and CD86. A 21-day culture of PBMCs with this method yielded nearly 20,000-fold expansion of CIKZ cells with γδ T cells making up over 20% of the expanded population. The expanded CIKZ cells exhibited antitumor cytotoxicity and could be modified to express anti-CD19 chimeric antigen receptor (CAR), anti-CEA CAR, and anti-HER2 CAR to enhance their specificity and cytotoxicity against CD19-, CEA-, or HER2-positive tumor cells. The tumor inhibitory activity of anti-CD19 CAR-modified CIKZ cells was further demonstrated in vivo in a Raji tumor mouse model. The findings herein substantiate the feasibility of co-expanding CIK and γδ cells for adoptive cellular immunotherapy applications such as CAR T-cell therapy against cancer. PMID:27598655
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Ridgway, Sam H; Hanson, Alicia C
2014-01-01
Among cetaceans, killer whales and sperm whales have the widest distribution in the world's oceans. Both species use echolocation, are long-lived, and have the longest periods of gestation among whales. Sperm whales dive much deeper and much longer than killer whales. It has long been thought that sperm whales have the largest brains of all living things, but our brain mass evidence, from published sources and our own specimens, shows that big males of these two species share this distinction. Despite this, we also find that cerebellum size is very different between killer whales and sperm whales. The sperm whale cerebellum is only about 7% of the total brain mass, while the killer whale cerebellum is almost 14%. These results are significant because they contradict claims that the cerebellum scales proportionally with the rest of the brain in all mammals. They also correct the generalization that all cetaceans have enlarged cerebella. We suggest possible reasons for the existence of such a large cerebellar size difference between these two species. Cerebellar function is not fully understood, and comparing the abilities of animals with differently sized cerebella can help uncover functional roles of the cerebellum in humans and animals. Here we show that the large cerebellar difference likely relates to evolutionary history, diving, sensory capability, and ecology. © 2014 S. Karger AG, Basel.
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Herpesvirus Evasion of Natural Killer Cells.
De Pelsmaeker, Steffi; Romero, Nicolas; Vitale, Massimo; Favoreel, Herman W
2018-06-01
Natural killer (NK) cells play an important role in the host response against viral infections and cancer development. They are able to kill virus-infected and tumor cells, and they produce different important cytokines that stimulate the antiviral and antitumor adaptive immune response, particularly interferon gamma. NK cells are of particular importance in herpesvirus infections, which is illustrated by systemic and life-threatening herpesvirus disease symptoms in patients with deficiencies in NK cell activity and by the myriad of reports describing herpesvirus NK cell evasion strategies. The latter is particularly obvious for cytomegaloviruses, but increasing evidence indicates that most, if not all, members of the herpesvirus family suppress NK cell activity to some extent. This review discusses the different NK cell evasion strategies described for herpesviruses and how this knowledge may translate to clinical applications. Copyright © 2018 American Society for Microbiology.
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Yu, Junli; Venstrom, Jeffrey M; Liu, Xiao-Rong; Pring, James; Hasan, Reenat S; O'Reilly, Richard J; Hsu, Katharine C
2009-04-16
Alloreactive natural killer (NK) cells are an important influence on hematopoietic stem cell transplantation (HSCT) outcome. In HLA-mismatched HSCT, alloreactivity occurs when licensed donor NK cells expressing inhibitory killer Ig-like receptors (KIR) for donor MHC class I ligands recognize the lack of the class I ligands in the mismatched recipient ("missing self"). Studies in HLA-matched HSCT, however, have also demonstrated improved outcome in patients lacking class I ligands for donor inhibitory KIR ("missing ligand"), indicating that classically nonlicensed donor NK cells expressing KIR for non-self MHC class I ligands may exhibit functional competence in HSCT. We examined NK function in 16 recipients of T cell-depleted allografts from HLA-identical or KIR-ligand matched donors after myeloablative therapy. After HSCT, nonlicensed NK cells expressing inhibitory KIR for non-self class I exhibit robust intracellular IFN-gamma and cytotoxic response to target cells lacking cognate ligand, gradually becoming tolerized to self by day 100. These findings could not be correlated with cytokine environment or phenotypic markers of NK development, nor could they be attributed to non-KIR receptors such as CD94/NKG2A. These findings confirm that NK alloreactivity can occur in HLA-matched HSCT, where tolerance to self is either acquired by the stem cell-derived NK cell after exiting the bone marrow or where tolerance to self can be temporarily overcome.
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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.
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NASA Astrophysics Data System (ADS)
Taik Lim, Yong; Cho, Mi Young; Noh, Young-Woock; Chung, Jin Woong; Chung, Bong Hyun
2009-11-01
This study describes the development of near-infrared optical imaging technology for the monitoring of immunotherapeutic cell-based cancer therapy using natural killer (NK) cells labeled with fluorescent nanocrystals. Although NK cell-based immunotherapeutic strategies have drawn interest as potent preclinical or clinical methods of cancer therapy, there are few reports documenting the molecular imaging of NK cell-based cancer therapy, primarily due to the difficulty of labeling of NK cells with imaging probes. Human natural killer cells (NK92MI) were labeled with anti-human CD56 antibody-coated quantum dots (QD705) for fluorescence imaging. FACS analysis showed that the NK92MI cells labeled with anti-human CD56 antibody-coated QD705 have no effect on the cell viability. The effect of anti-human CD56 antibody-coated QD705 labeling on the NK92MI cell function was investigated by measuring interferon gamma (IFN- γ) production and cytolytic activity. Finally, the NK92MI cells labeled with anti-human CD56 antibody-coated QD705 showed a therapeutic effect similar to that of unlabeled NK92MI cells. Images of intratumorally injected NK92MI cells labeled with anti-human CD56 antibody-coated could be acquired using near-infrared optical imaging both in vivo and in vitro. This result demonstrates that the immunotherapeutic cells labeled with fluorescent nanocrystals can be a versatile platform for the effective tracking of injected therapeutic cells using optical imaging technology, which is very important in cell-based cancer therapies.
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Funke, Christina; King, Donald P; McBain, Jim F; Adelung, Dieter; Stott, Jeffrey L
2003-05-30
Interleukin-6 (IL-6) is a cytokine that can reach detectable systemic levels and is a major inducer of the acute phase response. As such, clinical assays to identify this cytokine in mammalian sera are of diagnostic value. A 558 base-pair (bp) fragment of killer whale IL-6 was cloned and expressed as a 21 kDa protein in Escherichia coli. Biological activity of the recombinant killer whale IL-6 (rkwIL-6) was demonstrated using the IL-6-dependent B9 mouse hybridoma cell line; acute phase sera from a killer whale and supernatants from lipopolysaccharide (LPS)-stimulated killer whale peripheral blood mononuclear cells (PBMCs) also supported the proliferation of the B9 hybridoma. Rat anti-mouse IL-6 receptor antibody effectively blocked biological activity of all three sources of IL-6. Polyclonal antisera, specific for the recombinant protein, were obtained by successive immunization of a rabbit with rkwIL-6. The polyclonal antibody was capable of neutralizing the biological activity of both recombinant and native kwIL-6. A competitive enzyme-linked immunosorbent assay (ELISA) was developed using the polyclonal rabbit anti-rkwIL-6 and the recombinant protein; sensitivity of the assay was in the range of 1 ng/ml. The ELISA was subsequently used to identify the presence of native IL-6 in acute phase sera of two species of delphinidae, a killer whale and a bottlenose dolphin. The application of quantitative cytokine assays as diagnostic tools for monitoring cetacean health are becoming feasible as many animals are now being trained for fluke presentation, making blood collection a routine procedure.
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Leveraging natural killer cells for cancer immunotherapy.
Grossenbacher, Steven K; Aguilar, Ethan G; Murphy, William J
2017-05-01
Natural killer (NK) cells are potent antitumor effector cells of the innate immune system. Based on their ability to eradicate tumors in vitro and in animal models, significant enthusiasm surrounds the prospect of leveraging human NK cells as vehicles for cancer immunotherapy. While interest in manipulating the effector functions of NK cells has existed for over 30 years, there is renewed optimism for this approach today. Although T cells receive much of the clinical and preclinical attention when it comes to cancer immunotherapy, new strategies are utilizing adoptive NK-cell immunotherapy and monoclonal antibodies and engineered molecules which have been developed to specifically activate NK cells against tumors. Despite the numerous challenges associated with the preclinical and clinical development of NK cell-based therapies for cancer, NK cells possess many unique immunological properties and hold the potential to provide an effective means for cancer immunotherapy.
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Natural killer cells in host defense against veterinary pathogens.
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. Copyright © 2015 Elsevier B.V. All rights reserved.
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The Broad Spectrum of Human Natural Killer Cell Diversity.
Freud, Aharon G; Mundy-Bosse, Bethany L; Yu, Jianhua; Caligiuri, Michael A
2017-11-21
Natural killer (NK) cells provide protection against infectious pathogens and cancer. For decades it has been appreciated that two major NK cell subsets (CD56 bright and CD56 dim ) exist in humans and have distinct anatomical localization patterns, phenotypes, and functions in immunity. In light of this traditional NK cell dichotomy, it is now clear that the spectrum of human NK cell diversity is much broader than originally appreciated as a result of variegated surface receptor, intracellular signaling molecule, and transcription factor expression; tissue-specific imprinting; and foreign antigen exposure. The recent discoveries of tissue-resident NK cell developmental intermediates, non-NK innate lymphoid cells, and the capacity for NK cells to adapt and differentiate into long-lived memory cells has added further complexity to this field. Here we review our current understanding of the breadth and generation of human NK cell diversity. Copyright © 2017 Elsevier Inc. All rights reserved.
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Guo, Yalin; Maillard, Ivan; Chakraborti, Sankhamala; Rothenberg, Ellen V.
2008-01-01
CBFβ is the non-DNA binding subunit of the core binding factors (CBFs). Mice with reduced CBFβ levels display profound, early defects in T-cell but not B-cell development. Here we show that CBFβ is also required at very early stages of natural killer (NK)–cell development. We also demonstrate that T-cell development aborts during specification, as the expression of Gata3 and Tcf7, which encode key regulators of T lineage specification, is substantially reduced, as are functional thymic progenitors. Constitutively active Notch or IL-7 signaling cannot restore T-cell expansion or differentiation of CBFβ insufficient cells, nor can overexpression of Runx1 or CBFβ overcome a lack of Notch signaling. Therefore, the ability of the prethymic cell to respond appropriately to Notch is dependent on CBFβ, and both signals converge to activate the T-cell developmental program. PMID:18390836
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Uemura, Yu; Isobe, Yasushi; Uchida, Akiko; Asano, Junko; Nishio, Yuji; Sakai, Hirotaka; Hoshikawa, Masahiro; Takagi, Masayuki; Nakamura, Naoya; Miura, Ikuo
2018-04-01
Peripheral T- or natural killer (NK)-cell lymphomas are rare and difficult-to-recognize diseases. It remains arduous to distinguish between NK cell- and cytotoxic T-lymphocyte-derived lymphomas through routine histological evaluation. To clarify the cells of origin, we focused on NK-cell receptors and examined the expression using immunohistochemistry in 22 cases with T- and NK-cell neoplasms comprising angioimmunoblastic T-cell lymphoma, anaplastic lymphoma kinase (ALK)-positive and -negative anaplastic large-cell lymphomas, extranodal NK/T-cell lymphoma, nasal type, monomorphic epitheliotropic intestinal T-cell lymphoma, aggressive NK-cell leukemia, and other peripheral T-cell lymphomas. Inhibitory receptor leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1) was detected in 14 (64%) cases, whereas activating receptors DNAM1, NKp46, and NKG2D were expressed in 7 (32%), 9 (41%), and 5 (23%) cases, respectively. Although LILRB1 was detected regardless of the disease entity, the activating NK-cell receptors were expressed predominantly in TIA-1-positive neoplasms (DNAM1, 49%; NKp46, 69%; and NKG2D, 38%). In addition, NKp46 and NKG2D were detected only in NK-cell neoplasms and cytotoxic T-lymphocyte-derived lymphomas including monomorphic epitheliotropic intestinal T-cell lymphoma. One Epstein-Barr virus-harboring cytotoxic T-lymphocyte-derived lymphoma mimicking extranodal NK/T-cell lymphoma, nasal type lacked these NK-cell receptors, indicating different cell origin from NK and innate-like T cells. Furthermore, NKG2D expression showed a negative impact on survival among the 22 examined cases, which mainly received the standard chemotherapy regimen (log-rank test, P = .024). We propose that the presence of activating NK-cell receptors may provide new insights into understanding peripheral T-cell lymphomas and characterizing them as innate-like T-cell neoplasm. © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
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Hammer, Quirin; Rückert, Timo; Borst, Eva Maria; Dunst, Josefine; Haubner, André; Durek, Pawel; Heinrich, Frederik; Gasparoni, Gilles; Babic, Marina; Tomic, Adriana; Pietra, Gabriella; Nienen, Mikalai; Blau, Igor Wolfgang; Hofmann, Jörg; Na, Il-Kang; Prinz, Immo; Koenecke, Christian; Hemmati, Philipp; Babel, Nina; Arnold, Renate; Walter, Jörn; Thurley, Kevin; Mashreghi, Mir-Farzin; Messerle, Martin; Romagnani, Chiara
2018-05-01
Natural killer (NK) cells are innate lymphocytes that lack antigen-specific rearranged receptors, a hallmark of adaptive lymphocytes. In some people infected with human cytomegalovirus (HCMV), an NK cell subset expressing the activating receptor NKG2C undergoes clonal-like expansion that partially resembles anti-viral adaptive responses. However, the viral ligand that drives the activation and differentiation of adaptive NKG2C + NK cells has remained unclear. Here we found that adaptive NKG2C + NK cells differentially recognized distinct HCMV strains encoding variable UL40 peptides that, in combination with pro-inflammatory signals, controlled the population expansion and differentiation of adaptive NKG2C + NK cells. Thus, we propose that polymorphic HCMV peptides contribute to shaping of the heterogeneity of adaptive NKG2C + NK cell populations among HCMV-seropositive people.
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Shimada, Shigeki; Takeda, Masamitsu; Nishihira, Jun; Kaneuchi, Masanori; Sakuragi, Noriaki; Minakami, Hisanori; Yamada, Hideto
2009-11-01
A high dose of intravenous immunoglobulin (HIVIg) therapy is effective in various diseases such as autoimmune diseases, and also is expected to have efficacy in recurrent spontaneous abortion (RSA). The aim of this study was to understand immunological mechanisms of this therapy. By flowcytometric analyses, we examined phenotypic changes of a variety of immunological cells including natural killer (NK) cells, cytotoxic T cells, regulatory T cells and macrophages in peripheral blood of RSA women with HIVIg therapy (n = 8). Expression percentages of inhibitory CD94 on NK cells significantly (P = 0.01) increased after the therapy (58.8 +/- 21.4% versus 71.0 +/- 17.6%). Mechanisms of possible efficacy of HIVIg therapy for RSA may include enhancement of CD94 expression and subsequent suppression of NK cell cytotoxicity.
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Schmidt, Stanislaw; Tramsen, Lars; Perkhofer, Susanne; Lass-Flörl, Cornelia; Hanisch, Mitra; Röger, Frauke; Klingebiel, Thomas; Koehl, Ulrike; Lehrnbecher, Thomas
2013-07-01
Mucormycosis has a high mortality and is increasingly diagnosed in hematopoietic stem cell transplant (HSCT) recipients. In this setting, there is a growing interest to restore host defense to combat infections by adoptively transferring donor-derived immunocompetent cells. Natural killer (NK) cells exhibit antitumor and antiinfective activity, but the interaction with Mucormycetes is unknown. Our data demonstrate that both unstimulated and IL-2 prestimulated human NK cells damage Rhizopus oryzae hyphae, but do not affect resting conidia. The damage of the fungus is mediated, at least in part, by perforin. R. oryzae hyphae decrease the secretion of immunoregulatory molecules by NK cells, such as IFN-γ and RANTES, indicating an immunosuppressive effect of the fungus. Our data indicate that NK cells exhibit activity against Mucormycetes and future research should evaluate NK cells as a potential tool for adoptive immunotherapy in HSCT. Copyright © 2012 Elsevier GmbH. All rights reserved.
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Therapeutic manipulation of natural killer (NK) T cells in autoimmunity: are we close to reality?
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
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Lemieszek, Marta Kinga; Nunes, Fernando Herminio Ferreira Milheiro; Sawa-Wejksza, Katarzyna; Rzeski, Wojciech
2017-01-01
Numerous studies indicate the crucial role of natural killer (NK) cells in the prevention of tumor growth and inhibition of their metastasis, which suggests the possibility of their use in cancer treatment. This therapeutic strategy required finding a selective NK cell stimulator that, upon administration, did not disturb organism homeostasis, unlike natural activators (interleukin-2 or interleukin-12). Because the majority of anticancer agents derived from Basidiomycetes are able to stimulate lymphocytes, we describe the influence of Boletus edulis RNA on a human NK cell line (NK92). Our studies showed that a B. edulis RNA fraction was not toxic against NK92 cells. Furthermore, the tested fraction significantly stimulated NK92 cell proliferation and their cytotoxicity against tumor cells. We demonstrate here, to our knowledge for the first time, that B. edulis RNA enhances NK cell activity and possesses immunomodulatory potential.
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Confinement of activating receptors at the plasma membrane controls natural killer cell tolerance.
Guia, Sophie; Jaeger, Baptiste N; Piatek, Stefan; Mailfert, Sébastien; Trombik, Tomasz; Fenis, Aurore; Chevrier, Nicolas; Walzer, Thierry; Kerdiles, Yann M; Marguet, Didier; Vivier, Eric; Ugolini, Sophie
2011-04-05
Natural killer (NK) cell tolerance to self is partly ensured by major histocompatibility complex (MHC) class I-specific inhibitory receptors on NK cells, which dampen their reactivity when engaged. However, NK cells that do not detect self MHC class I are not autoreactive. We used dynamic fluorescence correlation spectroscopy to show that MHC class I-independent NK cell tolerance in mice was associated with the presence of hyporesponsive NK cells in which both activating and inhibitory receptors were confined in an actin meshwork at the plasma membrane. In contrast, the recognition of self MHC class I by inhibitory receptors "educated" NK cells to become fully reactive, and activating NK cell receptors became dynamically compartmentalized in membrane nanodomains. We propose that the confinement of activating receptors at the plasma membrane is pivotal to ensuring the self-tolerance of NK cells.
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Faure-Dupuy, Suzanne; Lucifora, Julie; Durantel, David
2017-01-01
The hepatitis B virus (HBV) infects hepatocytes, which are the main cell type composing a human liver. However, the liver is enriched with immune cells, particularly innate cells (e.g., myeloid cells, natural killer and natural killer T-cells (NK/NKT), dendritic cells (DCs)), in resting condition. Hence, the study of the interaction between HBV and innate immune cells is instrumental to: (1) better understand the conditions of establishment and maintenance of HBV infections in this secondary lymphoid organ; (2) define the role of these innate immune cells in treatment failure and pathogenesis; and (3) design novel immune-therapeutic concepts based on the activation/restoration of innate cell functions and/or innate effectors. This review will summarize and discuss the current knowledge we have on this interplay between HBV and liver innate immunity. PMID:28452930
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Sjölin, Hanna; Tomasello, Elena; Mousavi-Jazi, Mehrdad; Bartolazzi, Armando; Kärre, Klas; Vivier, Eric; Cerboni, Cristina
2002-01-01
Natural killer (NK) cells are major contributors to early defense against infections. Their effector functions are controlled by a balance between activating and inhibiting signals. To date, however, the involvement of NK cell activating receptors and signaling pathways in the defense against pathogens has not been extensively investigated. In mice, several NK cell activating receptors are coexpressed with and function through the immunoreceptor tyrosine-based activation motif (ITAM)-bearing molecule KARAP/DAP12. Here, we have analyzed the role of KARAP/DAP12 in the early antiviral response to murine cytomegalovirus (MCMV). In KARAP/DAP12 mutant mice bearing a nonfunctional ITAM, we found a considerable increase in viral titers in the spleen (30–40-fold) and in the liver (2–5-fold). These effects were attributed to NK cells. The formation of hepatic inflammatory foci appeared similar in wild-type and mutant mice, but the latter more frequently developed severe hepatitis with large areas of focal necrosis. Moreover, the percentage of hepatic NK cells producing interferon γ was reduced by 56 ± 22% in the absence of a functional KARAP/DAP12. This is the first study that shows a crucial role for a particular activating signaling pathway, in this case the one induced through KARAP/DAP12, in the NK cell–mediated resistance to an infection. Our results are discussed in relation to recent reports demonstrating that innate resistance to MCMV requires the presence of NK cells expressing the KARAP/DAP12-associated receptor Ly49H. PMID:11927627
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Immunosuppressive Effects of Triclosan, Nonylphenol, and DDT on Human Natural Killer Cells In Vitro
Udoji, Felicia; Martin, Tamara; Etherton, Rachel; Whalen, Margaret M.
2010-01-01
Human natural killer (NK) cells are a first line immune defense against tumor cells and virally infected cells. If their function is impaired, it leaves an individual more susceptible to cancer development or viral infection. The ability of compounds that contaminate the environment to suppress the function of NK cells could contribute to increased risk of cancer development. There are a wide spectrum of compounds that significantly contaminate water and food that is consumed by humans leading to accumulation of some of these compounds in human tissues. In the current study, we examined the ability of three such compounds to diminish the function of human NK cells. Triclosan (TC) is an antimicrobial agent used in a large number of antibacterial soaps. Nonylphenol (NP) is a degradation product of compounds used as surfactants and as stabilizers in plastics. 4, 4′-dichlorodiphenyltrichloroethane (DDT) is a pesticide that is mainly used to control mosquitoes. The compounds were examined for their ability to suppress NK function following exposures of 1 hr, 24 hr, 48 hr, and 6 d. Each agent was able to substantially decrease NK lytic function within 24 hr. At a concentration of 5 μM, both TC and NP inhibited NK lytic function by 87 and 30%, respectively; DDT decreased function by 55% at 2.5 μM. The negative effects of each of these compounds persisted and/or intensified following a brief (1 hr) exposure to the compounds, indicating that the impairment of function cannot be eliminated by removal of the compound under in vitro conditions. PMID:20297919
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Geographic patterns of genetic differentiation among killer whales in the northern North Pacific.
Parsons, Kim M; Durban, John W; Burdin, Alexander M; Burkanov, Vladimir N; Pitman, Robert L; Barlow, Jay; Barrett-Lennard, Lance G; LeDuc, Richard G; Robertson, Kelly M; Matkin, Craig O; Wade, Paul R
2013-01-01
The difficulties associated with detecting population boundaries have long constrained the conservation and management of highly mobile, wide-ranging marine species, such as killer whales (Orcinus orca). In this study, we use data from 26 nuclear microsatellite loci and mitochondrial DNA sequences (988bp) to test a priori hypotheses about population subdivisions generated from a decade of killer whale surveys across the northern North Pacific. A total of 462 remote skin biopsies were collected from wild killer whales primarily between 2001 and 2010 from the northern Gulf of Alaska to the Sea of Okhotsk, representing both the piscivorous "resident" and the mammal-eating "transient" (or Bigg's) killer whales. Divergence of the 2 ecotypes was supported by both mtDNA and microsatellites. Geographic patterns of genetic differentiation were supported by significant regions of genetic discontinuity, providing evidence of population structuring within both ecotypes and corroborating direct observations of restricted movements of individual whales. In the Aleutian Islands (Alaska), subpopulations, or groups with significantly different mtDNA and microsatellite allele frequencies, were largely delimited by major oceanographic boundaries for resident killer whales. Although Amchitka Pass represented a major subdivision for transient killer whales between the central and western Aleutian Islands, several smaller subpopulations were evident throughout the eastern Aleutians and Bering Sea. Support for seasonally sympatric transient subpopulations around Unimak Island suggests isolating mechanisms other than geographic distance within this highly mobile top predator.
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Activation of natural killer cells by hepatitis C virus particles in vitro
Farag, M M S; Weigand, K; Encke, J; Momburg, F
2011-01-01
Little is known about the ability of hepatitis C virus (HCV) to alter early innate immune responses in infected patients. Previous studies have shown that natural killer (NK) cells are functionally impaired after interaction of recombinant HCV glycoprotein E2 with the co-stimulatory CD81 molecule in vitro; however, the functional consequences of a prolonged contact of NK cells with HCV particles have remained unclear. We have examined the phenotypes of purified, interleukin-2-activated NK cells from healthy donors and HCV genotype 1b patients after culture for 5 days with HCV pseudoparticles (HCVpp) and serum samples containing HCV genotype 1b. NK cells from healthy donors and chronic HCV patients were found to up-regulate receptors associated with activation (NKp46, NKp44, NKp30, NKG2D), while NK receptors from the killer cell immunoglobulin-like receptor family (KIR/CD158), predominantly having an inhibitory function, were significantly down-modulated after culture in the presence of HCV particles compared with control cultures of NK cells. HCV-infected sera and HCVpp elicited significantly higher secretion of the NK effector lymphokines interferon-γ and tumour necrosis factor-α. Furthermore, HCV stimulated the cytotoxic potential of NK cells from normal donors and patients. The enhanced activation of NK cells after prolonged culture with HCVpp or HCV-containing sera for 5 days suggests that these innate effector cells may play an important role in viral control during early phases of HCV infection. PMID:21682720
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Transcriptional and post-transcriptional regulation of NK cell development and function
Leong, Jeffrey W.; Wagner, Julia A.; Ireland, Aaron R.; Fehniger, Todd A.
2016-01-01
Natural killer (NK) cells are specialized innate lymphoid cells that survey against viral infections and malignancy. Numerous advances have improved our understanding of the molecular mechanisms that control NK cell development and function over the past decade. These include both studies on the regulatory effects of transcription factors and translational repression via microRNAs. In this review, we summarize our current knowledge of DNA-binding transcription factors that regulate gene expression and thereby orchestrate NK cell development and activation, with an emphasis on recent discoveries. Additionally, we highlight our understanding of how RNA-bindings microRNAs fine tune the NK cell molecular program. We also underscore the large number of open questions in field that are now being addressed using new technological approaches and genetically engineered model organisms. Ultimately, a deeper understanding of the basic molecular biology of NK cells will facilitate new strategies to manipulate NK cells for the treatment of human disease. PMID:26948928
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Wade, P.R.; Burkanov, V.N.; Dahlheim, M.E.; Friday, N.A.; Fritz, L.W.; Loughlin, Thomas R.; Mizroch, S.A.; Muto, M.M.; Rice, D.W.; Barrett-Lennard, L. G.; Black, N.A.; Burdin, A.M.; Calambokidis, J.; Cerchio, S.; Ford, J.K.B.; Jacobsen, J.K.; Matkin, C.O.; Matkin, D.R.; Mehta, A.V.; Small, R.J.; Straley, J.M.; McCluskey, S.M.; VanBlaricom, G.R.; Clapham, P.J.
2007-01-01
Springer et al. (2003) contend that sequential declines occurred in North Pacific populations of harbor and fur seals, Steller sea lions, and sea otters. They hypothesize that these were due to increased predation by killer whales, when industrial whaling's removal of large whales as a supposed primary food source precipitated a prey switch. Using a regional approach, we reexamined whale catch data, killer whale predation observations, and the current biomass and trends of potential prey, and found little support for the prey-switching hypothesis. Large whale biomass in the Bering Sea did not decline as much as suggested by Springer et al., and much of the reduction occurred 50-100 yr ago, well before the declines of pinnipeds and sea otters began; thus, the need to switch prey starting in the 1970s is doubtful. With the sole exception that the sea otter decline followed the decline of pinnipeds, the reported declines were not in fact sequential. Given this, it is unlikely that a sequential megafaunal collapse from whales to sea otters occurred. The spatial and temporal patterns of pinniped and sea otter population trends are more complex than Springer et al. suggest, and are often inconsistent with their hypothesis. Populations remained stable or increased in many areas, despite extensive historical whaling and high killer whale abundance. Furthermore, observed killer whale predation has largely involved pinnipeds and small cetaceans; there is little evidence that large whales were ever a major prey item in high latitudes. Small cetaceans (ignored by Springer et al.) were likely abundant throughout the period. Overall, we suggest that the Springer et al. hypothesis represents a misleading and simplistic view of events and trophic relationships within this complex marine ecosystem. ?? 2007 by the Society for Marine Mammalogy.
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Wagner, Julia A; Berrien-Elliott, Melissa M; Rosario, Maximillian; Leong, Jeffrey W; Jewell, Brea A; Schappe, Timothy; Abdel-Latif, Sara; Fehniger, Todd A
2017-03-01
Cytokine-induced memory-like natural killer (NK) cells differentiate after short-term preactivation with IL-12, IL-15, and IL-18 and display enhanced effector function in response to cytokines or tumor targets for weeks after the initial preactivation. Conventional NK cell function depends on a licensing signal, classically delivered by an inhibitory receptor engaging its cognate MHC class I ligand. How licensing status integrates with cytokine-induced memory-like NK cell responses is unknown. We investigated this interaction using killer cell immunoglobulin-like receptor- and HLA-genotyped primary human NK cells. Memory-like differentiation resulted in enhanced IFN-γ production triggered by leukemia targets or FcγRIIIa ligation within licensed NK cells, which exhibited the highest functionality of the NK cell subsets interrogated. IFN-γ production by unlicensed memory-like NK cells was also enhanced to a level comparable with that of licensed control NK cells. Mechanistically, differences in responses to FcγRIIIa-based triggering were not explained by alterations in key signaling intermediates, indicating that the underlying biology of memory-like NK cells is distinct from that of adaptive NK cells in human cytomegalovirus-positive individuals. Additionally, memory-like NK cells responded robustly to cytokine receptor restimulation with no impact of licensing status. These results demonstrate that both licensed and unlicensed memory-like NK cell populations have enhanced functionality, which may be translated to improve leukemia immunotherapy. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
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López-Karpovitch, Xavier; Graue, Gerardo; Crespo-Solís, Erick; Piedras, Josefa
2008-07-01
High P-glycoprotein-mediated multidrug resistance-1 (P-gp/MDR1) activity in lymphocytes from idiopathic thrombocytopenic purpura (ITP) patients may affect disease outcome. ITP treatment includes glucocorticoids that are substrates of P-gp; hence, P-gp functional activity and antigenic expression were assessed by flow cytometry in T and natural killer (NK) cells from ITP patients before and after prednisone therapy. Herein, patients' T and NK cells did not show increased MDR1 functional activity, whereas P-gp antigenic expression was significantly enhanced in both therapy-free and prednisone-treated patients. Prednisone treatment did not significantly modify the function and expression of MDR1 in T and NK cells of ITP patients.
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DENG, QI; BAI, XUE; LV, HAI-RONG; XIAO, XIA; ZHAO, MING-FENG; LI, YU-MING
2015-01-01
There is a current requirement for novel therapeutic strategies for the treatment of hematopoietic tumors. Residual tumor cells are the main origin of tumor relapse. The aim of this study was to eliminate the residual tumor cells of hematopoietic tumors. Cytokine-induced killer (CIK) cells are used in immunotherapy to deplete the residual cells. However, it is necessary to increase the antitumor activity and clinical applicability of CIK cells. The present study investigated the antitumor activity of CIK cells to the SU-DHL2 human B-cell lymphoma and K562 human chronic myelogenous leukemia cell lines. CD3+CD56+ cells from healthy donors were expanded in culture with cytokines and anti-CD20 monoclonal antibody (mAb; rituximab) to generate CIK cells. A preliminary investigation of their mechanism was then performed. The increase in the cytotoxicity of the CIK cells induced by the anti-CD20 mAb was associated with an increase in the expression of cytotoxic factors. The expression of components of the signal transducer and activator of transcription (STAT) and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathways was found to increase. Upregulation of the expression of STAT1, STAT3 and STAT5 is important as these co-stimulatory molecules enhance T-cell proliferation. Activation of the MAPK signaling pathway is a possible mechanism for the anti-apoptosis effect on the proliferation of CIK cells. In conclusion, anti-CD20 mAb may play an important role in the improvement of CIK-mediated cytotoxicity to tumor cells. These observations may aid in the improvement of the effects of immunotherapy in depleting the residual cells of hematopoietic tumors. Thus, the use of CIK cells cultured with anti-CD20 mAb could be a novel therapeutic strategy for the depletion of chemotherapy-resistant or residual cells in anaplastic large and B-cell lymphoma. PMID:25780412
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Liu, Shu Qin; Kawai, Koji; Shiraiwa, Hiroshi; Hayashi, Hitoshi; Akaza, Hideyuki; Hashizaki, Kazuko; Shiba, Reiko; Saijo, Kaoru
1998-01-01
A high rate of induction (9 of 10 cases) of human autologous cytotoxic T lymphocytes (CTL) was achieved in vitro from peripheral blood mononuclear cells of renal carcinoma patients by applying an interleukin (IL)‐cocktail consisting of IL‐1, ‐2, ‐4, and ‐6. The CTL specifically lysed their own target carcinoma cells within 24 h but did not kill neighboring autologous normal kidney cells or allogeneic renal cancer cell lines. In the case of TUHR4TKB, for which autologous CTL were not induced, no expression of MHC class‐I molecules was observed on the surface of these carcinoma cells, although they were sensitive to autologous natural killer cells. The results imply that adoptive immunotherapy for metastasized renal carcinoma will be feasible with autologous CTL in combination with natural killer cells. PMID:9914789
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Memory-like Responses of Natural Killer Cells
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
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WANG, DONGDONG; SAGA, YASUSHI; MIZUKAMI, HIROAKI; SATO, NAOTO; NONAKA, HIROAKI; FUJIWARA, HIROYUKI; TAKEI, YUJI; MACHIDA, SHIZUO; TAKIKAWA, OSAMU; OZAWA, KEIYA; SUZUKI, MITSUAKI
2012-01-01
This study examined the role of the immunosuppressive enzyme indoleamine-2,3-dioxygenase (IDO) in ovarian cancer progression, and the possible application of this enzyme as a target for ovarian cancer therapy. We transfected a short hairpin RNA vector targeting IDO into the human ovarian cancer cell line SKOV-3, that constitutively expresses IDO and established an IDO downregulated cell line (SKOV-3/shIDO) to determine whether inhibition of IDO mediates the progression of ovarian cancer. IDO downregulation suppressed tumor growth and peritoneal dissemination in vivo, without influencing cancer cell growth. Moreover, IDO downregulation enhanced the sensitivity of cancer cells to natural killer (NK) cells in vitro, and promoted NK cell accumulation in the tumor stroma in vivo. These findings indicate that downregulation of IDO controls ovarian cancer progression by activating NK cells, suggesting IDO targeting as a potential therapy for ovarian cancer. PMID:22179492
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Natural Killer T Cells: An Ecological Evolutionary Developmental Biology Perspective
Kumar, Amrendra; Suryadevara, Naveenchandra; Hill, Timothy M.; Bezbradica, Jelena S.; Van Kaer, Luc; Joyce, Sebastian
2017-01-01
Type I natural killer T (NKT) cells are innate-like T lymphocytes that recognize glycolipid antigens presented by the MHC class I-like protein CD1d. Agonistic activation of NKT cells leads to rapid pro-inflammatory and immune modulatory cytokine and chemokine responses. This property of NKT cells, in conjunction with their interactions with antigen-presenting cells, controls downstream innate and adaptive immune responses against cancers and infectious diseases, as well as in several inflammatory disorders. NKT cell properties are acquired during development in the thymus and by interactions with the host microbial consortium in the gut, the nature of which can be influenced by NKT cells. This latter property, together with the role of the host microbiota in cancer therapy, necessitates a new perspective. Hence, this review provides an initial approach to understanding NKT cells from an ecological evolutionary developmental biology (eco-evo-devo) perspective. PMID:29312339
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Powell, Jeralyn J.; Davis, McLisa V.; Whalen, Margaret M.
2008-01-01
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 intital 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 exposure of NK cells to TBT or DBT diminished the negative effect of the BT on the lytic function of NK cells. This suggests that interaction TBT and DBT with functionally relevant sulfhydryl groups in NK cells may be part of the mechanism by which they decrease NK lytic function. PMID:18821099
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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.
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Natural Killer T Cells: An Ecological Evolutionary Developmental Biology Perspective.
Kumar, Amrendra; Suryadevara, Naveenchandra; Hill, Timothy M; Bezbradica, Jelena S; Van Kaer, Luc; Joyce, Sebastian
2017-01-01
Type I natural killer T (NKT) cells are innate-like T lymphocytes that recognize glycolipid antigens presented by the MHC class I-like protein CD1d. Agonistic activation of NKT cells leads to rapid pro-inflammatory and immune modulatory cytokine and chemokine responses. This property of NKT cells, in conjunction with their interactions with antigen-presenting cells, controls downstream innate and adaptive immune responses against cancers and infectious diseases, as well as in several inflammatory disorders. NKT cell properties are acquired during development in the thymus and by interactions with the host microbial consortium in the gut, the nature of which can be influenced by NKT cells. This latter property, together with the role of the host microbiota in cancer therapy, necessitates a new perspective. Hence, this review provides an initial approach to understanding NKT cells from an ecological evolutionary developmental biology (eco-evo-devo) perspective.
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Zhang, Yong; Zhu, Yu'nan; Zhao, Erjiang; He, Xiaolei; Zhao, Lingdi; Wang, Zibing; Fu, Xiaomin; Qi, Yalong; Ma, Baozhen; Song, Yongping; Gao, Quanli
2017-11-01
Our study was conducted to explore the efficacy of autologous cytokine-induced killer (CIK) cells in patients with advanced malignant melanoma. Materials & Methods: Here we reviewed 113 stage IV malignant melanoma patients among which 68 patients received CIK cell immunotherapy alone, while 45 patients accepted CIK cell therapy combined with chemotherapy. Results: We found that the median survival time in CIK cell group was longer than the combined therapy group (21 vs 15 months, p = 0.07). In addition, serum hemoglobin level as well as monocyte proportion and lymphocyte count were associated with patients' survival time. These indicated that CIK cell immunotherapy might extend survival time in advanced malignant melanoma patients. Furthermore, serum hemoglobin level, monocyte proportion and lymphocyte count could be prognostic indicators for melanoma.
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Matalon, Omri; Ben-Shmuel, Aviad; Kivelevitz, Jessica; Sabag, Batel; Fried, Sophia; Joseph, Noah; Noy, Elad; Biber, Guy; Barda-Saad, Mira
2018-03-01
Natural killer (NK) cells are a powerful weapon against viral infections and tumor growth. Although the actin-myosin (actomyosin) cytoskeleton is crucial for a variety of cellular processes, the role of mechanotransduction, the conversion of actomyosin mechanical forces into signaling cascades, was never explored in NK cells. Here, we demonstrate that actomyosin retrograde flow (ARF) controls the immune response of primary human NK cells through a novel interaction between β-actin and the SH2-domain-containing protein tyrosine phosphatase-1 (SHP-1), converting its conformation state, and thereby regulating NK cell cytotoxicity. Our results identify ARF as a master regulator of the NK cell immune response. Since actin dynamics occur in multiple cellular processes, this mechanism might also regulate the activity of SHP-1 in additional cellular systems. © 2018 The Authors.
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Kim, Yoon Hee; Won, Yeong-Seon; Yang, Xue; Kumazoe, Motofumi; Yamashita, Shuya; Hara, Aya; Takagaki, Akiko; Goto, Keiichi; Nanjo, Fumio; Tachibana, Hirofumi
2016-05-11
Tea catechins, such as (-)-epigallocatechin-3-O-gallate (EGCG), have been shown to effectively enhance immune activity and prevent cancer, although the underlying mechanism is unclear. Green tea catechins are instead converted to catechin metabolites in the intestine. Here, we show that these green tea catechin metabolites enhance CD4(+) T cell activity as well as natural killer (NK) cell activity. Our data suggest that the absence of a 4'-hydroxyl on this phenyl group (B ring) is important for the effect on immune activity. In particular, 5-(3',5'-dihydroxyphenyl)-γ-valerolactone (EGC-M5), a major metabolite of EGCG, not only increased the activity of CD4(+) T cells but also enhanced the cytotoxic activity of NK cells in vivo. These data suggest that EGC-M5 might show immunostimulatory activity.
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Anantha, R V; Mazzuca, D M; Xu, S X; Porcelli, S A; Fraser, D D; Martin, C M; Welch, I; Mele, T; Haeryfar, S M M; McCormick, J K
2014-01-01
Sepsis is characterized by a severe systemic inflammatory response to infection that is associated with high morbidity and mortality despite optimal care. Invariant natural killer T (iNK T) cells are potent regulatory lymphocytes that can produce pro- and/or anti-inflammatory cytokines, thus shaping the course and nature of immune responses; however, little is known about their role in sepsis. We demonstrate here that patients with sepsis/severe sepsis have significantly elevated proportions of iNK T cells in their peripheral blood (as a percentage of their circulating T cells) compared to non-septic patients. We therefore investigated the role of iNK T cells in a mouse model of intra-abdominal sepsis (IAS). Our data show that iNK T cells are pathogenic in IAS, and that T helper type 2 (Th2) polarization of iNK T cells using the synthetic glycolipid OCH significantly reduces mortality from IAS. This reduction in mortality is associated with the systemic elevation of the anti-inflammatory cytokine interleukin (IL)-13 and reduction of several proinflammatory cytokines within the spleen, notably interleukin (IL)-17. Finally, we show that treatment of sepsis with OCH in mice is accompanied by significantly reduced apoptosis of splenic T and B lymphocytes and macrophages, but not natural killer cells. We propose that modulation of iNK T cell responses towards a Th2 phenotype may be an effective therapeutic strategy in early sepsis. PMID:24965554
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Schmied, Laurent; Terszowski, Grzegorz; Gonzalez, Asensio; Schmitter, Karin; Hirsch, Hans H; Garzoni, Christian; van Delden, Christian; Boggian, Katia; Mueller, Nicolas J; Berger, Christoph; Villard, Jean; Manuel, Oriol; Meylan, Pascal; Hess, Christoph; Stern, Martin
2015-12-01
Natural killer cell function is regulated by inhibitory and activating killer cell immunoglobulin-like receptors (KIR). Previous studies have documented associations of KIR genotype with the risk of cytomegalovirus (CMV) replication after solid organ transplantation. In this study of 649 solid organ transplant recipients, followed prospectively for infectious disease events within the Swiss Transplant Cohort Study, we were interested to see if KIR genotype associated with virus infections other than CMV. We found that KIR B haplotypes (which have previously been linked to protection from CMV replication) were associated with protection from varicella zoster virus infection (hazard ratio, 0.43; 95% confidence interval, 0.21-0.91; P = 0.03). No significant associations were detected regarding the risk of herpes simplex, Epstein-Barr virus or BK polyomavirus infections. In conclusion, these data provide evidence that the relative protection of KIR haplotype B from viral replication after solid organ transplantation may extend beyond CMV to other herpes viruses, such as varicella zoster virus and possibly Epstein-Barr virus.
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Testa, U; Care, A; Montesoro, E; Fossati, C; Giannella, G; Masciulli, R; Fagioli, M; Bulgarini, D; Habetswallner, D; Isacchi, G
1990-01-01
We have developed a culture system for "long-term" growth of human lymphokine-activated killer (LAK) cells exhibiting an elevated, wide-spectrum antitumor cytotoxicity. The system allows the exponential growth of monocyte-depleted low-density lymphocytes in the presence of human serum and recombinant human interleukin-2 (10(3) U/ml), alone or in combination with interleukin-1 alpha or beta (both at 10 U/ml). Eighteen cultures were established from 18 normal adult donors. The membrane phenotypes of the final LAK cell population, assessed by a panel of monoclonal antibodies (mAb), consist of three main types: (a) NKH-1+, Ti alpha/beta-, Ti gamma/delta-, and CD3- lymphocytes; (b) NKH-1+, Ti alpha/beta-, Ti gamma/delta+, and CD3+ lymphocytes and (c) NKH-1+, Ti alpha/beta+, Ti gamma/delta- and CD3+ lymphocytes. Northern blot analysis showed that all these cell populations express relatively high levels of perforin RNA, particularly cells exhibiting the first phenotype. This culture system may provide a tool for cellular and molecular studies on the mechanisms of antitumor cytotoxicity, as well as the basis for new adoptive immunotherapy protocols in advanced center.
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Morisaki, Takashi; Umebayashi, Masayo; Kiyota, Akifumi; Koya, Norihiro; Tanaka, Hiroto; Onishi, Hideya; Katano, Mitsuo
2012-06-01
We explored the possibility of combining adoptive immunotherapy with cytokine-activated killer (CAK) cells and the epidermal growth factor receptor monoclonal antibody, cetuximab, as a treatment for cholangiocarcinoma. CAK cells were cultured with a high-dose of interleukin-2 and anti-CD3 monoclonal antibodies. This cell population contained both activated CD16+/CD56+ (NK) cells and CD3+/NKG2D(high+) T-cells. The effect of CAK cells and cetuximab, alone and in combination, on the viability of human cholangiocarcinoma cells was evaluated. Culture of CAK cells alone, but not cetuximab alone, exhibited modest cytotoxicity toward cholangiocarcinoma cells. However, combining CAK cells with cetuximab significantly enhanced cytotoxicity. This enhancement was inhibited by the addition of excess human immunoglobulins, suggesting that antibody-dependent cytotoxicity, mediated by activated NK cells in the CAK cell culture was involved in this mechanism. Cetuximab may be used to enhance CAK cell therapeutic activity in patients with cholangiocarcinoma, by potentiating antibody-dependent cellular cytotoxicity.
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Hu, Lei-Ming; Takata, Katsuyoshi; Miyata-Takata, Tomoko; Asano, Naoko; Takahashi, Emiko; Furukawa, Katsuya; Miyoshi, Hiroaki; Satou, Akira; Kohno, Kei; Kosugi, Hiroshi; Kinoshita, Tomohiro; Hirooka, Yoshiki; Goto, Hidemi; Nakamura, Shigeo; Kato, Seiichi
2017-06-01
Epstein-Barr virus-positive (EBV + ) intestinal T/natural killer (NK) cell lymphoma (ITNKL) is an uncommon tumour with an extremely aggressive clinical behaviour. However, the clinicopathological characteristics of this tumour, including T cell receptor (TCR) phenotype and the patient's background, remain unknown. The aim of this study was to elucidate the detailed clinicopathological profile of EBV + ITNKL. We enrolled 12 patients with EBV + ITNKL without nasal involvement into the study. All patients were characterized by involvement of the small intestine with concurrent lesions of the large intestine in two patients. Seven patients (58%) had Lugano stages IIE/IV disease and eight (67%) were categorized as high-intermediate/high-risk according to the Prognostic Index for PTCL (PIT). Three patients (25%) with an age of onset of less than 50 years had chronic active EBV infection (CAEBV). Five CD56-positive patients (42%) had a poorer prognosis than those without CD56 expression (P = 0.008). NK cell-type lymphoma defined by the absence of any TCR expression or clonal TCR-γ rearrangement was found in six patients (50%). Interestingly, EBV + intra-epithelial lymphocytosis was observed in one case with a background of CAEBV. This study is the first to shed light on the significant heterogeneity of EBV + ITNKL and its relationship with CAEBV, especially in patients younger than 50 years of age. These observations will provide a guide for diagnostic and therapeutic approaches in routine practice. © 2017 John Wiley & Sons Ltd.
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High-frequency modulated signals of killer whales (Orcinus orca) in the North Pacific.
Simonis, Anne E; Baumann-Pickering, Simone; Oleson, Erin; Melcón, Mariana L; Gassmann, Martin; Wiggins, Sean M; Hildebrand, John A
2012-04-01
Killer whales in the North Pacific, similar to Atlantic populations, produce high-frequency modulated signals, based on acoustic recordings from ship-based hydrophone arrays and autonomous recorders at multiple locations. The median peak frequency of these signals ranged from 19.6-36.1 kHz and median duration ranged from 50-163 ms. Source levels were 185-193 dB peak-to-peak re: 1 μPa at 1 m. These uniform, repetitive, down-swept signals are similar to bat echolocation signals and possibly could have echolocation functionality. A large geographic range of occurrence suggests that different killer whale ecotypes may utilize these signals.
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Vaillier, D; Daculsi, R; Gualde, N
1994-04-01
The effects of prostaglandin E2 (PGE2) have been studied on a highly purified population of murine IL-2 activated killer cells obtained by selecting plastic-adherent splenocytes (AK cells) after incubation with high doses of recombinant IL-2. AK cells were highly cytotoxic for YAC-1 target cells. The cytotoxic activity was detectable at one hour after initiation of the cytotoxic assay and then increased with time. Cytotoxic activity of AK cells was inhibited by the addition of PGE2 or forskolin during the cytotoxic assay. When AK cells were generated in the presence of PGE2, the yielding cytotoxic activity was lower than the one expressed by "regular" AK cells but were insensitive to the inhibitory effect of PGE2 even if their lytic capability was still suppressed by forskolin. The presence of PGE2 during the AK cell culture had no effect on the cellular proliferation. Moreover, using tetrazolium-based colorimetric assay which reflects the cellular activation, it was observed that AK cells cultured in presence of PGE2 had an increased capacity to cleave the tetrazolium salt to formazan. Since the cytotoxic activity of killer cells is related to expression of serine esterase enzymes we evaluated the effects of PGE2 on serine esterase (Granzyme A) release after one hour of incubation of AK cells either alone or in presence of PGE2, YAC-1 cells or both. We observed that (i) AK cells spontaneously release granzyme A, (ii) the level of granzyme A was significantly increased when AK cells were incubated either with YAC-1 cells or PGE2 but did not change when YAC-1 cells and PGE2 were both associated with AK cells.
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Nitta, Yukiko; Iwatsuki, Keiji; Kimura, Hiroshi; Kojima, Seiji; Morishima, Tsuneo; Tsuji, Kazuhide; Oono, Takashi
2005-01-01
Natural killer (NK) lymphoma in Asia is frequently associated with latent Epstein-Barr (EBV) infection. Unlike the adult cases, EBV-associated NK/T cell lymphomas in children are often preceded by various EBV-related disorders, including chronic active EBV infection (CAEBV), hypersensitivity to mosquito bites (HMB), virus-associated haemophagocytic syndrome (VAHS), and hydroa vacciniforme (HV)-like eruptions. Here, we report a 14-year-old Japanese girl who sequentially developed all the symptoms related to EBV-associated NK/T cell lymphoproliferative disorders in a 12-year clinical course. Our observations confirm the spectrum of EBV-associated cutaneous disorders and indicate the importance of long-term follow-up.
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First longitudinal study of seal-feeding killer whales (Orcinus orca) in Norwegian coastal waters.
Jourdain, Eve; Vongraven, Dag; Bisther, Anna; Karoliussen, Richard
2017-01-01
Killer whales (Orcinus orca) have been documented preying on either fish or marine mammals in several regions, suggesting that this odontocete species has the ability to specialize on different types of prey. Off Norway, killer whales have been shown to rely on the Atlantic herring (Clupea harengus) as a main prey resource. Infrequent observations have revealed seals as an additional component of their diet, yet the extent of predation on marine mammals has remained largely unknown. Here, we present the findings of 29 years of photographic and observational data on seal-feeding killer whale groups identified in Norwegian coastal waters. Four groups have been observed preying and feeding on seals over several years, taking both harbor (Phoca vitulina) and grey (Halichoerus grypus) seals. These stable groups are shown to adopt small group sizes, were typically observed in near-shore areas and were not encountered on herring wintering grounds. Behavioral and social traits adopted by these groups are similar to those of pinniped-feeding killer whales from other regions. The potential ecological reasons and the extent of such prey specializations are discussed.
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First longitudinal study of seal-feeding killer whales (Orcinus orca) in Norwegian coastal waters
Bisther, Anna; Karoliussen, Richard
2017-01-01
Killer whales (Orcinus orca) have been documented preying on either fish or marine mammals in several regions, suggesting that this odontocete species has the ability to specialize on different types of prey. Off Norway, killer whales have been shown to rely on the Atlantic herring (Clupea harengus) as a main prey resource. Infrequent observations have revealed seals as an additional component of their diet, yet the extent of predation on marine mammals has remained largely unknown. Here, we present the findings of 29 years of photographic and observational data on seal-feeding killer whale groups identified in Norwegian coastal waters. Four groups have been observed preying and feeding on seals over several years, taking both harbor (Phoca vitulina) and grey (Halichoerus grypus) seals. These stable groups are shown to adopt small group sizes, were typically observed in near-shore areas and were not encountered on herring wintering grounds. Behavioral and social traits adopted by these groups are similar to those of pinniped-feeding killer whales from other regions. The potential ecological reasons and the extent of such prey specializations are discussed. PMID:28666015
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Robeck, Todd R; Nollens, Hendrik H
2013-01-01
Gestation and lactation result in metabolic alterations of the dam because of varying demands of the fetus and offspring during the different stages of development. Despite killer whales (Orcinus orca) having one of the longest gestations and highest birth weights of all mammals in human care, these metabolic alterations, and their impact on the physiology of the dam have not been measured. The objectives of this analysis were to determine if physiologic demands on the killer whale during pregnancy and lactation have measurable effects on hematology and biochemical analytes and if detectable, to compare these changes to those which are observed in other mammalian species. Forty hematologic and biochemical analytes from seven female killer whales (22 pregnancies, 1,507 samples) were compared between the following stages: (1) non-pregnant or lactating (control); (2) gestation; and (3) the first 12 months of lactation. Decreased hematocrit, hemoglobin, and red blood cell counts were indicative of plasma volume expansion during mid and late gestation. The killer whales exhibited a progressively increasing physiologic inflammatory state leading up to parturition. Gestation and lactation caused significant shifts in the serum lipid profiles. Gestation and lactation cause significant physiologic changes in the killer whale dam. The last 12 months of gestation had greater physiological impact than lactation, but changes associated with and immediately following parturition were the most dramatic. During this period, killer whales may experience increased susceptibility to illness, and anthropogenic and environmental disturbances. © 2013 Wiley Periodicals, Inc.
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Schmidt, Stanislaw; Tramsen, Lars; Hanisch, Mitra; Latgé, Jean-Paul; Huenecke, Sabine; Koehl, Ulrike
2011-01-01
Because natural killer (NK) cells kill tumor cells and combat infections, there is growing interest in adoptively transferring NK cells to hematopoietic stem cell recipients. Unfortunately, in humans, the activity of NK cells against Aspergillus species, the major cause of invasive fungal infection in stem cell recipients, are poorly characterized. Our results show that unstimulated and interleukin-2 prestimulated human NK cells kill Aspergillus fumigatus hyphae but do not affect resting conidia. Killing is also induced by the supernatant of prestimulated NK cells and human perforin. The high levels of interferon-γ and granulocyte macrophage colony-stimulating factor produced by prestimulated NK cells are significantly reduced by Aspergillus, indicating an immunosuppressive effect of the fungus. Whereas Aspergillus hyphae activate NK cells, resting, and germinating, conidia and conidia of ΔrodA mutants lacking the hydrophobic surface layer do not. Our results suggest that adoptively transferred human NK cells may be a potential antifungal tool in the transplantation context. PMID:21208932
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Pluripotent stem cell-derived natural killer cells for cancer therapy
Knorr, David A.; Kaufman, Dan S.
2010-01-01
Human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) provide an accessible, genetically tractable and homogenous starting cell populations to efficiently study human blood cell development. These cell populations provide platforms to develop new cell-based therapies to treat both malignant and non-malignant hematological diseases. Our group has previously demonstrated the ability of hESC-derived hematopoietic precursors to produce functional natural killer (NK) cells as well as an explanation of the underlying mechanism responsible for inefficient development of T and B cells from hESCs. hESCs and iPSCs, which can be reliably engineered in vitro, provide an important new model system to study human lymphocyte development and produce enhanced cell-based therapies with potential to serve as a “universal” source of anti-tumor lymphocytes for novel clinical therapies. This review will focus on the application of hESC-derived NK cells with currently used and novel therapeutics for clinical trials, current barriers to translation, and future applications through genetic engineering approaches. PMID:20801411
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Vose, Julie; Armitage, James; Weisenburger, Dennis
2008-09-01
Peripheral T-cell lymphoma (PTCL) and natural killer/T-cell lymphoma (NKTCL) are rare and heterogeneous forms of non-Hodgkin's lymphoma (NHL) that, in general, are associated with a poor clinical outcome. A cohort of 1,314 cases of PTCL and NKTCL was organized from 22 centers worldwide, consisting of patients with previously untreated PTCL or NKTCL who were diagnosed between 1990 and 2002. Tissue biopsies, immunophenotypic markers, molecular genetic studies, and clinical information from consecutive patients at each site were reviewed by panels of four expert hematopathologists and classified according to the WHO classification. A diagnosis of PTCL or NKTCL was confirmed in 1,153 (87.8%) of the cases. The most common subtypes were PTCL not otherwise specified (NOS; 25.9%), angioimmunoblastic type (18.5%), NKTCL (10.4%), and adult T-cell leukemia/lymphoma (ATLL; 9.6%). Misclassification occurred in 10.4% of the cases including Hodgkin's lymphoma (3%), B-cell lymphoma (1.4%), unclassifiable lymphoma (2.8%), or a diagnosis other than lymphoma (2.3%). We found marked variation in the frequency of the various subtypes by geographic region. The use of an anthracycline-containing regimen was not associated with an improved outcome in PTCL-NOS or angioimmunoblastic type, but was associated with an improved outcome in anaplastic large-cell lymphoma, ALK positive. The WHO classification is useful for defining subtypes of PTCL and NKTCL. However, expert hematopathology review is important for accurate diagnosis. The clinical outcome for patients with most of these lymphoma subtypes is poor with standard therapies, and novel agents and new modalities are needed to improve survival.
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The natural cytotoxicity in cosmonauts on board space stations
NASA Astrophysics Data System (ADS)
Meshkov, D.; Rykova, M.
The nature of the changes of resistance to infection seems to be very important. Our studies indicate that different functions of natural killers could be depressed after the spaceflight. The decrease of the percentage of the lymphocytes that can bind target cells lead to the lowering of the "active" NK level and this can be resulted in the depression of total NK activity and lowering of resistance to viral and tumor antigens. The investigation of natural killer cells in cosmonauts before and after short and long-term spaceflights also revealed the important role of spaceflight duration, stress and individual immune reactivity.
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Nattermann, Jacob; Nischalke, Hans Dieter; Hofmeister, Valeska; Ahlenstiel, Golo; Zimmermann, Henning; Leifeld, Ludger; Weiss, Elisabeth H.; Sauerbruch, Tilman; Spengler, Ulrich
2005-01-01
Impaired activity of natural killer cells has been proposed as a mechanism contributing to viral persistence in hepatitis C virus (HCV) infection. Natural cytotoxicity is regulated by interactions of HLA-E with inhibitory CD94/NKG2A receptors on natural killer (NK) cells. Here, we studied whether HCV core encodes peptides that bind to HLA-E and inhibit natural cytotoxicity. We analyzed 30 HCV core-derived peptides. Peptide-induced stabilization of HLA-E expression was measured flow cytometrically after incubating HLA-E-transfected cells with peptides. NK cell function was studied with a 51chromium-release-assay. Intrahepatic HLA-E expression was analyzed by an indirect immunoperoxidase technique and flow cytometry of isolated cells using a HLA-E-specific antibody. We identified peptide aa35–44, a well-characterized HLA-A2 restricted T cell epitope, as a peptide stabilizing HLA-E expression and thereby inhibiting NK cell-mediated lysis. Blocking experiments confirmed that this inhibitory effect of peptide aa35–44 on natural cytotoxicity was mediated via interactions between CD94/NKG2A receptors and enhanced HLA-E expression. In line with these in vitro data we found enhanced intrahepatic HLA-E expression on antigen-presenting cells in HCV-infected patients. Our data indicate the existence of T cell epitopes that can be recognized by HLA-A2 and HLA-E. This dual recognition may contribute to viral persistence in hepatitis C. PMID:15681828
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Forest bathing enhances human natural killer activity and expression of anti-cancer proteins.
Li, Q; Morimoto, K; Nakadai, A; Inagaki, H; Katsumata, M; Shimizu, T; Hirata, Y; Hirata, K; Suzuki, H; Miyazaki, Y; Kagawa, T; Koyama, Y; Ohira, T; Takayama, N; Krensky, A M; Kawada, T
2007-01-01
In order to explore the effect of forest bathing on human immune function, we investigated natural killer (NK) activity; the number of NK cells, and perforin, granzymes and granulysin-expression in peripheral blood lymphocytes (PBL) during a visit to forest fields. Twelve healthy male subjects, age 37-55 years, were selected with informed consent from three large companies in Tokyo, Japan. The subjects experienced a three-day/two-night trip in three different forest fields. On the first day, subjects walked for two hours in the afternoon in a forest field; and on the second day, they walked for two hours in the morning and afternoon, respectively, in two different forest fields. Blood was sampled on the second and third days, and NK activity; proportions of NK, T cells, granulysin, perforin, and granzymes A/B-expressing cells in PBL were measured. Similar measurements were made before the trip on a normal working day as the control. Almost all of the subjects (11/12) showed higher NK activity after the trip (about 50 percent increased) compared with before. There are significant differences both before and after the trip and between days 1 and 2 in NK activity. The forest bathing trip also significantly increased the numbers of NK, perforin, granulysin, and granzymes A/B-expressing cells. Taken together, these findings indicate that a forest bathing trip can increase NK activity, and that this effect at least partially mediated by increasing the number of NK cells and by the induction of intracellular anti-cancer proteins.
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NASA Astrophysics Data System (ADS)
Yoshino, R.; Kondoh, T.; Neyatani, Y.; Itami, K.; Kawano, Y.; Isei, N.
1997-02-01
A killer pellet is an impurity pellet that is injected into a tokamak plasma in order to terminate a discharge without causing serious damage to the tokamak machine. In JT-60U neon ice pellets have been injected into OH and NB heated plasmas and fast plasma shutdowns have been demonstrated without large vertical displacement. The heat pulse on the divertor plate has been greatly reduced by killer pellet injection (KPI), but a low-power heat flux tail with a long time duration is observed. The total energy on the divertor plate increases with longer heat flux tail, so it has been reduced by shortening the tail. Runaway electron (RE) generation has been observed just after KPI and/or in the later phase of the plasma current quench. However, RE generation has been avoided when large magnetic perturbations are excited. These experimental results clearly show that KPI is a credible fast shutdown method avoiding large vertical displacement, reducing heat flux on the divertor plate, and avoiding (or minimizing) RE generation.
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Manickam, Cordelia; Nwanze, Chiadika; Ram, Daniel R; Shah, Spandan V; Smith, Scott; Jones, Rhianna; Hueber, Brady; Kroll, Kyle; Varner, Valerie; Goepfert, Paul; Jost, Stephanie; Reeves, R Keith
2018-05-03
Recently, a seemingly novel innate immune cell subset bearing features of natural killer and B cells was identified in mice. So-called NKB cells appear as first responders to infections, but whether this cell population is truly novel or is in fact a subpopulation of B cells and exists in higher primates remains unclear. The objective of this study was to identify NKB cells in primates and study the impact of HIV/SIV infections. NKB cells were quantified in both naïve and lentivirus infected rhesus macaques and humans by excluding lineage markers (CD3, CD127), and positive Boolean gating for CD20, NKG2A/C and/or NKp46. Additional phenotypic measures were conducted by RNA-probe and traditional flow cytometry. Circulating cytotoxic NKB cells were found at similar frequencies in humans and rhesus macaques (range, 0.01-0.2% of total lymphocytes). NKB cells were notably enriched in spleen (median, 0.4% of lymphocytes), but were otherwise systemically distributed in tonsil, lymph nodes, colon, and jejunum. Expression of immunoglobulins was highly variable, but heavily favoured IgM and IgA rather than IgG. Interestingly, NKB cell frequencies expanded in PBMC and colon during SIV infection, as did IgG expression, but were generally unaltered in HIV-infected humans. These results suggest a cell type expressing both natural killer and B-cell features exists in rhesus macaques and humans and are perturbed by HIV/SIV infection. The full functional niche remains unknown, but the unique phenotype and systemic distribution could make NKB cells unique targets for immunotherapeutics or vaccine strategies.
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Role of natural killer cells in antibacterial immunity.
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.
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Type II Natural Killer T (NKT) Cells And Their Emerging Role In Health And Disease
Dhodapkar, Madhav V.; Kumar, Vipin
2016-01-01
Natural killer T (NKT) cells recognize lipid antigens presented by a class I MHC-like molecule CD1d, a member of the CD1 family. While most of the initial studies on NKT cells focused on a subset with semi-invariant T cell receptor (TCR) termed iNKT cells, majority of CD1d-restricted lipid-reactive human T cells express diverse TCRs and are termed as type II NKT cells. These cells constitute a distinct population of circulating and tissue-resident effector T cells with immune-regulatory properties. They react to a growing list of self- as well as non-self lipid ligands, and share some properties with both iNKT as well as conventional T cells. Emerging body of evidence points to their role in the regulation of immunity to pathogens/tumors and in autoimmune/metabolic disorders. Improved understanding of the biology of these cells and the ability to manipulate their function may be of therapeutic benefit in diverse disease conditions. PMID:28115591
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An update on the management of peripheral T-cell lymphoma and emerging treatment options
Phillips, Adrienne A; Owens, Colette; Lee, Sangmin; Bhagat, Govind
2011-01-01
Peripheral T-cell lymphomas (PTCLs) comprise a rare and heterogeneous subset of non-Hodgkin’s lymphomas (NHLs) that arise from post-thymic T-cells or natural killer (NK)-cells at nodal or extranodal sites. Worldwide, PTCLs represent approximately 12% of all NHLs and the 2008 World Health Organization (WHO) classification includes over 20 biologically and clinically distinct T/NK-cell neoplasms that differ significantly in presentation, pathology, and response to therapy. Because of the rarity and heterogeneity of these diseases, large clinical trials have not been conducted and optimal therapy is not well defined. Most subtypes are treated with similar combination chemotherapy regimens as used for aggressive B-cell NHL, but with poorer outcomes. New treatment combinations and novel agents are currently being explored for PTCLs and this review highlights a number of options that appear promising. PMID:22287871
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Sustained disruption of narwhal habitat use and behavior in the presence of Arctic killer whales
Breed, Greg A.; Matthews, Cory J. D.; Marcoux, Marianne; Higdon, Jeff W.; LeBlanc, Bernard; Petersen, Stephen D.; Orr, Jack; Reinhart, Natalie R.; Ferguson, Steven H.
2017-01-01
Although predators influence behavior of prey, analyses of electronic tracking data in marine environments rarely consider how predators affect the behavior of tracked animals. We collected an unprecedented dataset by synchronously tracking predator (killer whales, N = 1; representing a family group) and prey (narwhal, N = 7) via satellite telemetry in Admiralty Inlet, a large fjord in the Eastern Canadian Arctic. Analyzing the movement data with a switching-state space model and a series of mixed effects models, we show that the presence of killer whales strongly alters the behavior and distribution of narwhal. When killer whales were present (within about 100 km), narwhal moved closer to shore, where they were presumably less vulnerable. Under predation threat, narwhal movement patterns were more likely to be transiting, whereas in the absence of threat, more likely resident. Effects extended beyond discrete predatory events and persisted steadily for 10 d, the duration that killer whales remained in Admiralty Inlet. Our findings have two key consequences. First, given current reductions in sea ice and increases in Arctic killer whale sightings, killer whales have the potential to reshape Arctic marine mammal distributions and behavior. Second and of more general importance, predators have the potential to strongly affect movement behavior of tracked marine animals. Understanding predator effects may be as or more important than relating movement behavior to resource distribution or bottom-up drivers traditionally included in analyses of marine animal tracking data. PMID:28223481
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Sustained disruption of narwhal habitat use and behavior in the presence of Arctic killer whales.
Breed, Greg A; Matthews, Cory J D; Marcoux, Marianne; Higdon, Jeff W; LeBlanc, Bernard; Petersen, Stephen D; Orr, Jack; Reinhart, Natalie R; Ferguson, Steven H
2017-03-07
Although predators influence behavior of prey, analyses of electronic tracking data in marine environments rarely consider how predators affect the behavior of tracked animals. We collected an unprecedented dataset by synchronously tracking predator (killer whales, [Formula: see text] = 1; representing a family group) and prey (narwhal, [Formula: see text] = 7) via satellite telemetry in Admiralty Inlet, a large fjord in the Eastern Canadian Arctic. Analyzing the movement data with a switching-state space model and a series of mixed effects models, we show that the presence of killer whales strongly alters the behavior and distribution of narwhal. When killer whales were present (within about 100 km), narwhal moved closer to shore, where they were presumably less vulnerable. Under predation threat, narwhal movement patterns were more likely to be transiting, whereas in the absence of threat, more likely resident. Effects extended beyond discrete predatory events and persisted steadily for 10 d, the duration that killer whales remained in Admiralty Inlet. Our findings have two key consequences. First, given current reductions in sea ice and increases in Arctic killer whale sightings, killer whales have the potential to reshape Arctic marine mammal distributions and behavior. Second and of more general importance, predators have the potential to strongly affect movement behavior of tracked marine animals. Understanding predator effects may be as or more important than relating movement behavior to resource distribution or bottom-up drivers traditionally included in analyses of marine animal tracking data.
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Ebbo, Mikael; Gérard, Laurence; Carpentier, Sabrina; Vély, Frédéric; Cypowyj, Sophie; Farnarier, Catherine; Vince, Nicolas; Malphettes, Marion; Fieschi, Claire; Oksenhendler, Eric; Schleinitz, Nicolas; Vivier, Eric
2016-04-01
Natural Killer (NK) cells have been shown to exert antiviral and antitumoural activities. Nevertheless most available data are derived from mouse models and functions of these cells in human remain unclear. To evaluate the impact of low circulating NK cell counts and to provide some clues to the role of NK cells in natural conditions, we studied a large cohort of patients with common variable immunodeficiency (CVID) included in a multicenter cohort of patients with primary hypogammaglobulinaemia. Patients were classified into three groups on the basis of their NK cell counts: severe and mild NK cell lymphopenia (<50 and 50-99×10(6)/L respectively), and normal NK cell counts (>100×10(6)/L). Clinical events were analyzed and compared between these three groups of patients. During study period, 457 CVID patients were included: 99 (21.7%) with severe NK cell lymphopenia, 118 (25.8%) with mild NK cell lymphopenia and 240 (52.5%) with normal NK cell counts. Non-infectious complications (57% vs. 36% and 35%), and, particularly, granulomatous complications (25.3% vs. 13.6% and 8.8%), were more frequent in patients with severe NK cell lymphopenia than in other groups. Invasive infections (68.7% vs. 60.2% and 48.8%), including bacteraemia (22.2% vs. 5.9% and 8.3%) and infectious pneumonia (63.6% vs. 59.3% and 44.2%), were also more frequent in this population. However, no difference was observed for viral infections and neoplasms. Low circulating NK cell counts are associated with more severe phenotypes of CVID, which may indicate a protective role of these immune cells against severe bacterial infections and other complications and non-redundant immune functions when the adaptive immune response is not optimal. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.
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Wingender, Gerhard; Schumak, Beatrix; Schurich, Anna; Gessner, J Engelbert; Endl, Elmar; Limmer, Andreas; Knolle, Percy A
2006-01-01
Dissemination of soluble molecules or antigens via the blood stream is considered to lead to a uniform distribution in the various organs of the body, but organ-specific microarchitecture and vascularization may influence this. Following intravenous injection of αCD3ε antibody (αCD3εAb) we observed clear differences in antibody binding to Fcγ receptor (FcγR)+ antigen-presenting cells (APCs) or T lymphocytes in different organs. Significant binding of blood-borne αCD3εAb was only detected in the spleen and liver and not in the thymus or lymph node. In the spleen, only 10% of dendritic cells/macrophages and 40% of T-cell receptor (TCR)-β+ cells were positive for αCD3εAb, and, dependent on FcγR-mediated cross-linking of αCD3εAb, a similar percentage of splenic TCR-β+ cells were stimulated and became CD69+. Stimulation of TCR-β+ cells in the liver was at least as efficient as in the spleen, but almost all T cells and all scavenger liver sinusoidal endothelial cells bound αCD3εAb. In contrast to CD69 up-regulation, only CD4+ natural killer T (NKT) cells and CD11ahigh CD8+ T cells were activated by αCD3εAb and expressed interferon (IFN)-γ. Again, IFN-γ release from NKT/T cells was at least as efficient in the liver as in the spleen. Taken together, our results support the notion that the combination of extensive hepatic vascularization and very high scavenger activity allows the liver to fulfill its metabolic tasks and to promote stimulation of the large but widely distributed hepatic population of NKT/T cells. PMID:16423047
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Nitric oxide inhibits exocytosis of cytolytic granules from lymphokine-activated killer cells
Ferlito, Marcella; Irani, Kaikobad; Faraday, Nauder; Lowenstein, Charles J.
2006-01-01
NO inhibits cytotoxic T lymphocyte killing of target cells, although the precise mechanism is unknown. We hypothesized that NO decreases exocytosis of cytotoxic granules from activated lymphocytes. We now show that NO inhibits lymphokine-activated killer cell killing of K562 target cells. Exogenous and endogenous NO decreases the release of granzyme B, granzyme A, and perforin: all contents of cytotoxic granules. NO inhibits the signal transduction cascade initiated by cross-linking of the T cell receptor that leads to granule exocytosis. In particular, we found that NO decreases the expression of Ras, a critical signaling component within the exocytic pathway. Ectopic expression of Ras prevents NO inhibition of exocytosis. Our data suggest that Ras mediates NO inhibition of lymphocyte cytotoxicity and emphasize that alterations in the cellular redox state may regulate the exocytic signaling pathway. PMID:16857739
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Primary pulmonary NK/T-cell lymphoma: A case report and literature review.
Qiu, Yajuan; Hou, Junna; Hao, Dexun; Zhang, Dandan
2018-06-01
Extranodal natural killer (NK)/T-cell lymphoma (ENKTL) is an aggressive disease with poor prognosis. The lung is a relatively rare site of involvement. The current study presents a case of primary pulmonary ENKTL with fever and dyspnea, mimicking pneumonia and initially treated with empirical antibiotics. The patient demonstrated rapid deterioration and died shortly following diagnosis. To the best of our knowledge, large-scale investigations referring to primary pulmonary ENKTL are not available. As a result, the exact incidence and clinical features of primary pulmonary ENKTL are unknown. In the current report, a literature review is presented to discuss the clinical characteristics, diagnosis, treatment, and prognosis factors of this malignant disease.
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Faridi, R M; Agrawal, S
2011-02-01
Decidual natural killer (NK) cells play key developmental roles at the feto-maternal interface. Individual differences in NK-cell interactions are dependent on the combinations of variable killer immunoglobulin-like receptor (KIR) and HLA class-I gene products. As different receptor-ligand interactions may result in altered NK-cell-mediated immunity against pathogens, it is proposed that the relationship between these genes may be important in a state such as recurrent miscarriage (RM). We had earlier reported that the predisposition to RM is influenced by the maternal KIR gene content. In the present study, we have attempted to extend our findings in the light of contribution from the paternal antigens on the outcome of pregnancy, since maternal NK cells may potentially encounter non-self-paternal HLA-C alleles on trophoblasts. All HLA-C allotypes fall into two major KIR epitopes--C1 (HLA-C*01/*03/*07/*08/*12/*14/*16) and C2 (HLA-C*02/*04/*05/*06/*15/*17/*18)--on the basis of a dimorphism at position 80 of the α1 domain. PCR-sequence specific primer-based genotyping was used to determine the maternal KIR gene content and HLA-C genotypes down to allele level in couples experiencing RM and controls. KIR2DL1 with both partners homozygous for HLA C2 was significantly higher in control couples when compared with the patients [P = 0.0004, odds ratio (OR) = 0.28, 95% confidence interval (CI) = 0.13-0.58]. The activating KIR2DS2 with both partners homozygous for HLA C1 was significantly higher in patients when compared with the controls (P = 0.002, OR = 2.83, 95% CI = 1.47-5.40). Our results represented the 'top-end' of the activation spectrum of KIR-HLA-C compound genotype for NK cells and this may contribute to the immunological etiology of RM.
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Nakata, Shinsuke; Imagawa, Akihisa; Miyata, Yugo; Yoshikawa, Atsushi; Kozawa, Junji; Okita, Kohei; Funahashi, Tohru; Nakamura, Seiji; Matsubara, Kenichi; Iwahashi, Hiromi; Shimomura, Iichiro
2013-01-01
Fulminant type 1 diabetes is an independent subtype of type 1 diabetes characterized by extremely rapid onset and absence of islet-related autoantibodies. However, detailed pathophysiology of this subtype is poorly understood. In this study, a comprehensive approach was applied to understand the pathogenesis of fulminant type 1 diabetes. We determined the genes that were differentially expressed in fulminant type 1 diabetes compared with type 1A diabetes and healthy control, using gene expression microarray in peripheral blood cells. Using volcano plot analysis, we found reduced expression of killer cell lectin-like receptor subfamily C, member 3 (KLRC3) which encodes NKG2E, a natural killer (NK) cell activating receptor, in fulminant type 1 diabetes, compared with healthy controls. This difference was confirmed by real-time RT-PCR among NK-enriched cells. The expression of KLRD1 (CD94), which forms heterodimer with NKG2E (KLRC3), was also reduced in NK-enriched cells in fulminant type 1 diabetes. Furthermore, flow cytometry showed significantly lower proportion of NK cells among peripheral blood mononuclear cells (PBMCs) in fulminant type 1 diabetes than in healthy controls. In patients with fulminant type 1 diabetes, the relative proportion of NK cells correlated significantly with the time period between onset of fever to the appearance of hyperglycemic-related symptoms. We conclude the presence of reduced NK activating receptor gene expression and low proportion of NK cells in fulminant type 1 diabetes. Copyright © 2013 Elsevier B.V. All rights reserved.
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Activation of natural killer cells by hepatitis C virus particles in vitro.
Farag, M M S; Weigand, K; Encke, J; Momburg, F
2011-09-01
Little is known about the ability of hepatitis C virus (HCV) to alter early innate immune responses in infected patients. Previous studies have shown that natural killer (NK) cells are functionally impaired after interaction of recombinant HCV glycoprotein E2 with the co-stimulatory CD81 molecule in vitro; however, the functional consequences of a prolonged contact of NK cells with HCV particles have remained unclear. We have examined the phenotypes of purified, interleukin-2-activated NK cells from healthy donors and HCV genotype 1b patients after culture for 5 days with HCV pseudoparticles (HCVpp) and serum samples containing HCV genotype 1b. NK cells from healthy donors and chronic HCV patients were found to up-regulate receptors associated with activation (NKp46, NKp44, NKp30, NKG2D), while NK receptors from the killer cell immunoglobulin-like receptor family (KIR/CD158), predominantly having an inhibitory function, were significantly down-modulated after culture in the presence of HCV particles compared with control cultures of NK cells. HCV-infected sera and HCVpp elicited significantly higher secretion of the NK effector lymphokines interferon-γ and tumour necrosis factor-α. Furthermore, HCV stimulated the cytotoxic potential of NK cells from normal donors and patients. The enhanced activation of NK cells after prolonged culture with HCVpp or HCV-containing sera for 5 days suggests that these innate effector cells may play an important role in viral control during early phases of HCV infection. © 2011 The Authors. Clinical and Experimental Immunology © 2011 British Society for Immunology.
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Age-related alteration of expression and function of TLRs and NK activity in oral candidiasis.
Oouchi, M; Hasebe, A; Hata, H; Segawa, T; Yamazaki, Y; Yoshida, Y; Kitagawa, Y; Shibata, K-I
2015-07-01
Roles of aging or immune responses mediated by Toll-like receptors and natural killer cell in the onset or progression of human candidiasis remain unclear. This study was designed to elucidate the roles using peripheral blood mononuclear cells from healthy donors and patients with oral candidiasis. Subjects tested were healthy volunteers and patients who visited Dental Clinical Division of Hokkaido University Hospital. The patients with oral candidiasis included 39 individuals (25-89 years of age) with major complaints on pain in oral mucosa and/or dysgeusia. Healthy volunteers include students (25-35 years of age) and teaching staffs (50-65 years of age) of Hokkaido University Graduate School of Dental Medicine. Functions of Toll-like receptors 2 and 4 were downregulated significantly and the natural killer activity was slightly, but not significantly downregulated in aged healthy volunteers compared with healthy young volunteers. Functions of Toll-like receptors 2 and 4 and the natural killer activity were significantly downregulated in patients with oral candidiasis compared with healthy volunteers. Downregulation of functions of Toll-like receptors 2 and 4 as well as natural killer activity is suggested to be associated with the onset or progression of oral candidiasis in human. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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2013-02-18
Brain and Central Nervous System Tumors; Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Lymphoproliferative Disorder; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms; Unspecified Adult Solid Tumor, Protocol Specific
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Desforges, Jean-Pierre; Jasperse, Lindsay; Jensen, Trine Hammer; Grøndahl, Carsten; Bertelsen, Mads F; Guise, Sylvain De; Sonne, Christian; Dietz, Rune; Levin, Milton
2018-01-01
Natural killer (NK) cells are a vital part of the rapid and non-specific immune defense against invading pathogens and tumor cells. This study evaluated NK cell-like activity by flow cytometry for the first time in three ecologically and culturally important Arctic mammal species: polar bear (Ursus maritimus), muskox (Ovibos moschatus) and reindeer (Rangifer tarandus). NK cell-like activity for all three species was most effective against the mouse lymphoma cell line YAC-1, compared to the human leukemia cell line K562; NK cell response displayed the characteristic increase in cytotoxic activity when the effector:target cell ratio increased. Comparing NK activity between fresh and cryopreserved mouse lymphocytes revealed little to no difference in function, highlighting the applicability of cryopreserving cells in field studies. The evaluation of this important innate immune function in Arctic mammals can contribute to future population health assessments, especially as pollution-induced suppression of immune function may increase infectious disease susceptibility. Copyright © 2017 Elsevier B.V. All rights reserved.
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The Role of TOX in the Development of Innate Lymphoid Cells.
Seehus, Corey R; Kaye, Jonathan
2015-01-01
TOX, an evolutionarily conserved member of the HMG-box family of proteins, is essential for the development of various cells of both the innate and adaptive immune system. TOX is required for the development of CD4(+) T lineage cells in the thymus, including natural killer T and T regulatory cells, as well as development of natural killer cells and fetal lymphoid tissue inducer cells, the latter required for lymph node organogenesis. Recently, we have identified a broader role for TOX in the innate immune system, demonstrating that this nuclear protein is required for generation of bone marrow progenitors that have potential to give rise to all innate lymphoid cells. Innate lymphoid cells, classified according to transcription factor expression and cytokine secretion profiles, derive from common lymphoid progenitors in the bone marrow and require Notch signals for their development. We discuss here the role of TOX in specifying CLP toward an innate lymphoid cell fate and hypothesize a possible role for TOX in regulating Notch gene targets during innate lymphoid cell development.
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Isobe, Yasushi; Hamano, Yasuharu; Ito, Yoshinori; Kimura, Hiroshi; Tsukada, Nobuhiro; Sugimoto, Koichi; Komatsu, Norio
2013-02-01
Here, we describe a Japanese woman showing a monoclonal expansion of EBV-infected natural killer (NK) cells after receiving allogeneic peripheral blood stem cell transplantation (PBSCT). The patient initially had T-cell-type chronic active EBV disease (CAEBV) and subsequently developed liver T-cell lymphoma. L-Asparaginase-containing chemotherapy led to a favorable lymphoma response. To eradicate CAEBV and the lymphoma, she further received allogeneic PBSCT from a human leukocyte antigen-matched sibling donor. After the PBSCT, the patient presented with transient lymphocytosis of NK cells, which were infected with a monoclonal EBV strain other than previously detected ones. These NK cells seemed to have been transmitted from the healthy donor to the recipient. The patient and donor remain well in spite of carrying these NK cells. This is the first report of an asymptomatic Japanese carrier harboring monoclonal EBV-infected NK cells. Copyright © 2012 Elsevier B.V. All rights reserved.
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Sivori, Simona; Falco, Michela; Marcenaro, Emanuela; Parolini, Silvia; Biassoni, Roberto; Bottino, Cristina; Moretta, Lorenzo; Moretta, Alessandro
2002-01-01
In this study we analyzed the progression of cell surface receptor expression during the in vitro-induced human natural killer (NK) cell maturation from CD34+ Lin− cell precursors. NKp46 and NKp30, two major triggering receptors that play a central role in natural cytotoxicity, were expressed before the HLA class I-specific inhibitory receptors. Moreover, their appearance at the cell surface correlated with the acquisition of cytolytic activity by developing NK cells. Although the early expression of triggering receptors may provide activating signals required for inducing further cell differentiation, it may also affect the self-tolerance of developing NK cells. Our data show that a fail-safe mechanism preventing killing of normal autologous cells may be provided by the 2B4 surface molecule, which, at early stages of NK cell differentiation, functions as an inhibitory rather than as an activating receptor. PMID:11917118
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Ripa, M; Pogliaghi, M; Chiappetta, S; Galli, L; Pensieroso, S; Cavarelli, M; Scarlatti, G; De Biasi, S; Cossarizza, A; De Battista, D; Malnati, M; Lazzarin, A; Nozza, S; Tambussi, G
2015-09-01
We evaluated the dynamics of innate and adaptive immunity in patients treated with combined antiretroviral therapy (cART) during primary human immunodeficiency virus infection (PHI), enrolled in a prospective randomized trial (MAIN, EUDRACT 2008-007004-29). After 48 weeks of cART, we documented a reduction in activated B cells and CD8(+) T cells. Natural killer cell and dendritic cell frequencies were measured and a decrease in CD16(+) CD56(dim) with a reciprocal rise in CD56(high) natural killer cells and an increase in myeloid and plasmacytoid dendritic cells were recorded. In conclusion, 48 weeks of cART during PHI showed significant benefits for both innate and adaptive immunity. Copyright © 2015 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
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Kubo, Takahiko; Yoshimura, Atsushi; Kurata, Nori
2016-05-03
Pollen killer genes disable noncarrier pollens, and are responsible for male sterility and segregation distortion in hybrid populations of distantly related plant species. The genetic networks and the molecular mechanisms underlying the pollen killer system remain largely unknown. Two pollen killer genes, S24 and S35, have been found in an intersubspecific cross of Oryza sativa ssp. indica and japonica The effect of S24 is counteracted by an unlinked locus EFS Additionally, S35 has been proposed to interact with S24 to induce pollen sterility. These genetic interactions are suggestive of a single S24-centric genetic pathway (EFS-S24-S35) for the pollen killer system. To examine this hypothetical genetic pathway, the S35 and the S24 regions were further characterized and genetically dissected in this study. Our results indicated that S35 causes pollen sterility independently of both the EFS and S24 genes, but is dependent on a novel gene close to the S24 locus, named incentive for killing pollen (INK). We confirmed the phenotypic effect of the INK gene separately from the S24 gene, and identified the INK locus within an interval of less than 0.6 Mb on rice chromosome 5. This study characterized the genetic effect of the two independent genetic pathways of INK-S35 and EFS-S24 in indica-japonica hybrid progeny. Our results provide clear evidence that hybrid male sterility in rice is caused by several pollen killer networks with multiple factors positively and negatively regulating pollen killer genes. Copyright © 2016 Kubo et al.
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Kubo, Takahiko; Yoshimura, Atsushi; Kurata, Nori
2016-01-01
Pollen killer genes disable noncarrier pollens, and are responsible for male sterility and segregation distortion in hybrid populations of distantly related plant species. The genetic networks and the molecular mechanisms underlying the pollen killer system remain largely unknown. Two pollen killer genes, S24 and S35, have been found in an intersubspecific cross of Oryza sativa ssp. indica and japonica. The effect of S24 is counteracted by an unlinked locus EFS. Additionally, S35 has been proposed to interact with S24 to induce pollen sterility. These genetic interactions are suggestive of a single S24-centric genetic pathway (EFS–S24–S35) for the pollen killer system. To examine this hypothetical genetic pathway, the S35 and the S24 regions were further characterized and genetically dissected in this study. Our results indicated that S35 causes pollen sterility independently of both the EFS and S24 genes, but is dependent on a novel gene close to the S24 locus, named incentive for killing pollen (INK). We confirmed the phenotypic effect of the INK gene separately from the S24 gene, and identified the INK locus within an interval of less than 0.6 Mb on rice chromosome 5. This study characterized the genetic effect of the two independent genetic pathways of INK–S35 and EFS–S24 in indica–japonica hybrid progeny. Our results provide clear evidence that hybrid male sterility in rice is caused by several pollen killer networks with multiple factors positively and negatively regulating pollen killer genes. PMID:27172610
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CXCR6 marks a novel subset of T-betloEomeshi natural killer cells residing in human liver
Stegmann, Kerstin A.; Robertson, Francis; Hansi, Navjyot; Gill, Upkar; Pallant, Celeste; Christophides, Theodoros; Pallett, Laura J.; Peppa, Dimitra; Dunn, Claire; Fusai, Giuseppe; Male, Victoria; Davidson, Brian R.; Kennedy, Patrick; Maini, Mala K.
2016-01-01
Natural killer cells (NK) are highly enriched in the human liver, where they can regulate immunity and immunopathology. We probed them for a liver-resident subset, distinct from conventional bone-marrow-derived NK. CXCR6+ NK were strikingly enriched in healthy and diseased liver compared to blood (p < 0.0001). Human hepatic CXCR6+ NK had an immature phenotype (predominantly CD56brightCD16−CD57−), and expressed the tissue-residency marker CD69. CXCR6+ NK produced fewer cytotoxic mediators and pro-inflammatory cytokines than the non-liver-specific CXCR6− fraction. Instead CXCR6+ NK could upregulate TRAIL, a key death ligand in hepatitis pathogenesis. CXCR6 demarcated liver NK into two transcriptionally distinct populations: T-bethiEomeslo(CXCR6−) and T-betloEomeshi(CXCR6+); the latter was virtually absent in the periphery. The small circulating CXCR6+ subset was predominantly T-bethiEomeslo, suggesting its lineage was closer to CXCR6− peripheral than CXCR6+ liver NK. These data reveal a large subset of human liver-resident T-betloEomeshi NK, distinguished by their surface expression of CXCR6, adapted for hepatic tolerance and inducible anti-viral immunity. PMID:27210614
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CXCR6 marks a novel subset of T-bet(lo)Eomes(hi) natural killer cells residing in human liver.
Stegmann, Kerstin A; Robertson, Francis; Hansi, Navjyot; Gill, Upkar; Pallant, Celeste; Christophides, Theodoros; Pallett, Laura J; Peppa, Dimitra; Dunn, Claire; Fusai, Giuseppe; Male, Victoria; Davidson, Brian R; Kennedy, Patrick; Maini, Mala K
2016-05-23
Natural killer cells (NK) are highly enriched in the human liver, where they can regulate immunity and immunopathology. We probed them for a liver-resident subset, distinct from conventional bone-marrow-derived NK. CXCR6+ NK were strikingly enriched in healthy and diseased liver compared to blood (p < 0.0001). Human hepatic CXCR6+ NK had an immature phenotype (predominantly CD56(bright)CD16-CD57-), and expressed the tissue-residency marker CD69. CXCR6+ NK produced fewer cytotoxic mediators and pro-inflammatory cytokines than the non-liver-specific CXCR6- fraction. Instead CXCR6+ NK could upregulate TRAIL, a key death ligand in hepatitis pathogenesis. CXCR6 demarcated liver NK into two transcriptionally distinct populations: T-bet(hi)Eomes(lo)(CXCR6-) and T-bet(lo)Eomes(hi)(CXCR6+); the latter was virtually absent in the periphery. The small circulating CXCR6+ subset was predominantly T-bet(hi)Eomes(lo), suggesting its lineage was closer to CXCR6- peripheral than CXCR6+ liver NK. These data reveal a large subset of human liver-resident T-bet(lo)Eomes(hi) NK, distinguished by their surface expression of CXCR6, adapted for hepatic tolerance and inducible anti-viral immunity.
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Sojka, Dorothy K; Plougastel-Douglas, Beatrice; Yang, Liping; Pak-Wittel, Melissa A; Artyomov, Maxim N; Ivanova, Yulia; Zhong, Chao; Chase, Julie M; Rothman, Paul B; Yu, Jenny; Riley, Joan K; Zhu, Jinfang; Tian, Zhigang; Yokoyama, Wayne M
2014-01-01
Natural killer (NK) cells belong to the innate immune system; they can control virus infections and developing tumors by cytotoxicity and producing inflammatory cytokines. Most studies of mouse NK cells, however, have focused on conventional NK (cNK) cells in the spleen. Recently, we described two populations of liver NK cells, tissue-resident NK (trNK) cells and those resembling splenic cNK cells. However, their lineage relationship was unclear; trNK cells could be developing cNK cells, related to thymic NK cells, or a lineage distinct from both cNK and thymic NK cells. Herein we used detailed transcriptomic, flow cytometric, and functional analysis and transcription factor-deficient mice to determine that liver trNK cells form a distinct lineage from cNK and thymic NK cells. Taken together with analysis of trNK cells in other tissues, there are at least four distinct lineages of NK cells: cNK, thymic, liver (and skin) trNK, and uterine trNK cells. DOI: http://dx.doi.org/10.7554/eLife.01659.001 PMID:24714492
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Tang, Qin; Iyer, Sowmya; Lobbardi, Riadh; Moore, John C; Chen, Huidong; Lareau, Caleb; Hebert, Christine; Shaw, McKenzie L; Neftel, Cyril; Suva, Mario L; Ceol, Craig J; Bernards, Andre; Aryee, Martin; Pinello, Luca; Drummond, Iain A; Langenau, David M
2017-10-02
Recent advances in single-cell, transcriptomic profiling have provided unprecedented access to investigate cell heterogeneity during tissue and organ development. In this study, we used massively parallel, single-cell RNA sequencing to define cell heterogeneity within the zebrafish kidney marrow, constructing a comprehensive molecular atlas of definitive hematopoiesis and functionally distinct renal cells found in adult zebrafish. Because our method analyzed blood and kidney cells in an unbiased manner, our approach was useful in characterizing immune-cell deficiencies within DNA-protein kinase catalytic subunit ( prkdc ), interleukin-2 receptor γ a ( il2rga ), and double-homozygous-mutant fish, identifying blood cell losses in T, B, and natural killer cells within specific genetic mutants. Our analysis also uncovered novel cell types, including two classes of natural killer immune cells, classically defined and erythroid-primed hematopoietic stem and progenitor cells, mucin-secreting kidney cells, and kidney stem/progenitor cells. In total, our work provides the first, comprehensive, single-cell, transcriptomic analysis of kidney and marrow cells in the adult zebrafish. © 2017 Tang et al.
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Iyer, Sowmya; Lobbardi, Riadh; Chen, Huidong; Hebert, Christine; Shaw, McKenzie L.; Neftel, Cyril; Suva, Mario L.; Bernards, Andre; Aryee, Martin; Drummond, Iain A.
2017-01-01
Recent advances in single-cell, transcriptomic profiling have provided unprecedented access to investigate cell heterogeneity during tissue and organ development. In this study, we used massively parallel, single-cell RNA sequencing to define cell heterogeneity within the zebrafish kidney marrow, constructing a comprehensive molecular atlas of definitive hematopoiesis and functionally distinct renal cells found in adult zebrafish. Because our method analyzed blood and kidney cells in an unbiased manner, our approach was useful in characterizing immune-cell deficiencies within DNA–protein kinase catalytic subunit (prkdc), interleukin-2 receptor γ a (il2rga), and double-homozygous–mutant fish, identifying blood cell losses in T, B, and natural killer cells within specific genetic mutants. Our analysis also uncovered novel cell types, including two classes of natural killer immune cells, classically defined and erythroid-primed hematopoietic stem and progenitor cells, mucin-secreting kidney cells, and kidney stem/progenitor cells. In total, our work provides the first, comprehensive, single-cell, transcriptomic analysis of kidney and marrow cells in the adult zebrafish. PMID:28878000
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Tsai, Jy-Ping; Chen, Hsin-Wei; Cheng, Mei-Lien; Liu, Hsiung-Kun; Lee, Yi-Ping; Hsieh, Chia Ling; Luh, Kwen-Tay; Wu, Chew-Wun; Hsu, Li-Han; Chao, Tsu-Yi; Wang, Wen-Hua; Chang, Chung-Ming; Ting, Chou-Chik
2005-01-01
A different degree of immunodeficiency is often found at tumor sites in cancer patients. At the late stage many patients develop malignant effusion that contains large numbers of tumor cells and host immune cells that constantly interact with each other. These sites may provide an ideal model to examine in situ anti-tumor immunity. The T cells in effusion were found to be immunodeficient, which suggested a defective anti-tumor cytotoxic T lymphocytes response. To pursue the mechanism for the T cell deficiency, we determined the production of immunomodulating cytokines in the effusion and detected the presence of transforming growth factor-beta1 (TGFbeta), prostaglandin E2, IL-6, IL-10, and IFNgamma. There was no detectable IL-2, IL-4, IL-12, or TNFalpha. The most prominent feature was the presence of TGFbeta and IL-6 at a very high level. Thus, the possible role of these two cytokines on T cell competence was further determined. TGFbeta was found to induce T cell anergy and reduced the production of perforin in T killer cells and their lytic activity. These events lead to the induction of peripheral T cell tolerance with profound T cell deficiency. IL-6 did not affect perforin production or cytolytic activity of the T killer cells. But the CD4+ CD25+ regulatory T cells (TR) that were often employed by TGFbeta to suppress T cell response were reduced in the malignant effusion, consistent with the fact that IL-6 down-regulates TR and this may represent the host's vigorous response to the tumor's subversion. These results show that TGFbeta and IL-6 might play pivotal but opposing roles in the host tumor interaction that, together with other immunomodulating components, determines the outcome for the development of local tumor immunity.
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Kaltenmeier, Christof T.; Vollmer, Laura L.; Vernetti, Lawrence A.; Caprio, Lindsay; Davis, Keanu; Korotchenko, Vasiliy N.; Day, Billy W.; Tsang, Michael; Hulkower, Keren I.; Lotze, Michael T.
2017-01-01
Dual specificity mitogen-activated protein kinase (MAPK) phosphatases [dual specificity phosphatase/MAP kinase phosphatase (DUSP-MKP)] have been hypothesized to maintain cancer cell survival by buffering excessive MAPK signaling caused by upstream activating oncogenic products. A large and diverse body of literature suggests that genetic depletion of DUSP-MKPs can reduce tumorigenicity, suggesting that hyperactivating MAPK signaling by DUSP-MKP inhibitors could be a novel strategy to selectively affect the transformed phenotype. Through in vivo structure-activity relationship studies in transgenic zebrafish we recently identified a hyperactivator of fibroblast growth factor signaling [(E)-2-benzylidene-5-bromo-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one (BCI-215)] that is devoid of developmental toxicity and restores defective MAPK activity caused by overexpression of DUSP1 and DUSP6 in mammalian cells. Here, we hypothesized that BCI-215 could selectively affect survival of transformed cells. In MDA-MB-231 human breast cancer cells, BCI-215 inhibited cell motility, caused apoptosis but not primary necrosis, and sensitized cells to lymphokine-activated killer cell activity. Mechanistically, BCI-215 induced rapid and sustained phosphorylation of extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK) in the absence of reactive oxygen species, and its toxicity was partially rescued by inhibition of p38 but not JNK or ERK. BCI-215 also hyperactivated MKK4/SEK1, suggesting activation of stress responses. Kinase phosphorylation profiling documented BCI-215 selectively activated MAPKs and their downstream substrates, but not receptor tyrosine kinases, SRC family kinases, AKT, mTOR, or DNA damage pathways. Our findings support the hypothesis that BCI-215 causes selective cancer cell cytotoxicity in part through non-redox-mediated activation of MAPK signaling, and the findings also identify an intersection with immune cell killing that is worthy of further exploration. PMID:28154014
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Mancusi, Antonella; Ruggeri, Loredana; Urbani, Elena; Pierini, Antonio; Massei, Maria Speranza; Carotti, Alessandra; Terenzi, Adelmo; Falzetti, Franca; Tosti, Antonella; Topini, Fabiana; Bozza, Silvia; Romani, Luigina; Tognellini, Rita; Stern, Martin; Aversa, Franco; Martelli, Massimo F; Velardi, Andrea
2015-05-14
Because activating killer cell immunoglobulinlike receptors (KIRs) are heterogeneously expressed in the population, we investigated the role of donor activating KIRs in haploidentical hematopoietic transplants for acute leukemia. Transplants were grouped according to presence vs absence of KIR-ligand mismatches in the graft-vs-host direction (ie, of donor-vs-recipient natural killer [NK]-cell alloreactivity). In the absence of donor-vs-recipient NK-cell alloreactivity, donor activating KIRs had no effects on outcomes. In the 69 transplant pairs with donor-vs-recipient NK-cell alloreactivity, transplantation from donors with KIR2DS1 and/or KIR3DS1 was associated with reduced risk of nonrelapse mortality, largely infection related (KIR2DS1 present vs absent: hazard ratio [HR], 0.25; P = .01; KIR3DS1 present vs absent: HR, 0.18; P = .006), and better event-free survival (KIR2DS1 present vs absent: HR, 0.31; P = .011; KIR3DS1 present vs absent: HR, 0.30; P = .008). Transplantation from donors with KIR2DS1 and/or KIR3DS1 was also associated with a 50% reduction in infection rate (P = .003). In vitro analyses showed that KIR2DS1 binding to its HLA-C2 ligand upregulated inflammatory cytokine production by alloreactive NK cells in response to infectious challenges. Because ∼40% of donors able to exert donor-vs-recipient NK-cell alloreactivity carry KIR2DS1 and/or KIR3DS1, searching for them may become a feasible, additional criterion in donor selection. © 2015 by The American Society of Hematology.
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Ito, A; Kataoka, T R; Kim, D K; Koma , Y; Lee, Y M; Kitamura, Y
2001-04-01
The mouse mi locus encodes a basic-helix-loop-helix-leucine zipper-type transcription factor, microphthalmia transcription factor (MITF). Mice of mi/mi genotype express a mutant form of MITF (mi-MITF), whereas mice of tg/tg genotype have a transgene in the 5' flanking region of the mi gene and do not express MITF. Although the mi/mi mouse is deficient in natural killer (NK) activity, it was found that the tg/tg mouse was normal in this respect. To know the cause, spleen cells of both genotypes were compared. Although the proportion of spleen cells expressing an NK cell marker, NK1.1, was comparable in both mice, the proportion of large granular lymphocytes decreased only in mi/mi mice. The difference between mi/mi and tg/tg mice was reproducible in the culture supplemented with interleukin-2. Moreover, the perforin gene expression was reduced in mi/mi-cultured spleen cells. Wild-type (+) MITF transactivated, but mi-MITF suppressed, the perforin gene promoter through the NF-P motif, a strong cis-acting element. However, neither +-MITF nor mi-MITF bound the NF-P motif. Instead, 2 nuclear factors that bound the NF-P motif were retained in the cytoplasm of mi/mi-cultured spleen cells. In addition, overexpression of mi-MITF resulted in cytoplasmic retention of the 2 NF-P motif-binding factors in cytotoxic T lymphocytes. The presence of mi-MITF rather than the absence of +-MITF appeared to lead to poor transactivation of the NF-P motif by intercepting NF-P motif-binding factors. This inhibitory effect of mi-MITF may cause the deficient cytotoxicity of NK cells in mi/mi mice. (Blood. 2001;97:2075-2083)
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Generation of cellular immune memory and B-cell immunity is impaired by natural killer cells.
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.
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Killer artificial antigen-presenting cells: the synthetic embodiment of a ‘guided missile’
Schütz, Christian; Oelke, Mathias; Schneck, Jonathan P; Mackensen, Andreas; Fleck, Martin
2010-01-01
At present, the treatment of T-cell-dependent autoimmune diseases relies exclusively on strategies leading to nonspecific suppression of the immune systems causing a substantial reduced ability to control concomitant infections or malignancies. Furthermore, long-term treatment with most drugs is accompanied by several serious adverse effects and does not consequently result in cure of the primary immunological malfunction. By contrast, antigen-specific immunotherapy offers the potential to achieve the highest therapeutic efficiency in accordance with minimal adverse effects. Therefore, several studies have been performed utilizing antigen-presenting cells specifically engineered to deplete allo- or antigen-specific T cells (‘guided missiles’). Many of these strategies take advantage of the Fas/Fas ligand signaling pathway to efficiently induce antigen-presenting cell-mediated apoptosis in targeted T cells. In this article, we discuss the advantages and shortcomings of a novel non-cell-based ‘killer artificial antigen-presenting cell’ strategy, developed to overcome obstacles related to current cell-based approaches for the treatment of T-cell-mediated autoimmunity. PMID:20636007
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CD161 Defines a Functionally Distinct Subset of Pro-Inflammatory Natural Killer Cells
Kurioka, Ayako; Cosgrove, Cormac; Simoni, Yannick; van Wilgenburg, Bonnie; Geremia, Alessandra; Björkander, Sophia; Sverremark-Ekström, Eva; Thurnheer, Christine; Günthard, Huldrych F.; Khanna, Nina; Aubert, V; Arancibia-Cárcamo, CV; Walker, Lucy Jane; Arancibia-Cárcamo, Carolina V.; Newell, Evan W.; Willberg, Christian B.; Klenerman, Paul
2018-01-01
CD161 is a C-type lectin-like receptor expressed on the majority of natural killer (NK) cells; however, the significance of CD161 expression on NK cells has not been comprehensively investigated. Recently, we found that CD161 expression identifies a transcriptional and innate functional phenotype that is shared across various T cell populations. Using mass cytometry and microarray experiments, we demonstrate that this functional phenotype extends to NK cells. CD161 marks NK cells that have retained the ability to respond to innate cytokines during their differentiation, and is lost upon cytomegalovirus-induced maturation in both healthy and human immunodeficiency virus (HIV)-infected patients. These pro-inflammatory NK cells are present in the inflamed lamina propria where they are enriched for integrin CD103 expression. Thus, CD161 expression identifies NK cells that may contribute to inflammatory disease pathogenesis and correlates with an innate responsiveness to cytokines in both T and NK cells. PMID:29686665
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McGrath, Emma; Ryan, Elizabeth J; Lynch, Lydia; Golden-Mason, Lucy; Mooney, Eoghan; Eogan, Maeve; O'Herlihy, Colm; O'Farrelly, Cliona
2009-04-01
Cycle-dependent fluctuations in natural killer (NK) cell populations in endometrium and circulation may differ, contributing to unexplained infertility. NK cell phenotypes were determined by flow cytometry in endometrial biopsies and matched blood samples. While circulating and endometrial T cell populations remained constant throughout the menstrual cycle in fertile and infertile women, circulating NK cells in infertile women increased during the secretory phase. However, increased expression of CD94, CD158b (secretory phase), and CD158a (proliferative phase) by endometrial NK cells from infertile women was observed. These changes were not reflected in the circulation. In infertile women, changes in circulating NK cell percentages are found exclusively during the secretory phase and not in endometrium; cycle-related changes in NK receptor expression are observed only in infertile endometrium. While having exciting implications for understanding NK cell function in fertility, our data emphasize the difficulty in attaching diagnostic or prognostic significance to NK cell analyses in individual patients.
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Manufacturing Natural Killer Cells as Medicinal Products
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
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Kumai, Takumi; Kobayashi, Hiroya; Komabayashi, Yuki; Ueda, Seigo; Kishibe, Kan; Ohkuri, Takayuki; Takahara, Miki; Celis, Esteban; Harabuchi, Yasuaki
2015-01-01
Nasal natural killer/T-cell lymphoma (NNKTL) is associated with Epstein–Barr virus and has a poor prognosis because of local invasion and/or multiple dissemination. Various chemokines play a role in tumor proliferation and invasion, and chemokine receptors including the C-C chemokine receptor 4 (CCR4) are recognized as potential targets for treating hematologic malignancies. The aim of the present study was to determine whether specific chemokines are produced by NNKTL. We compared chemokine expression patterns in culture supernatants of NNKTL cell lines with those of other lymphoma or leukemia cell lines using chemokine protein array and ELISA. Chemokine (C-C motif) ligand (CCL) 17 and CCL22 were highly produced by NNKTL cell lines as compared to the other cell lines. In addition, CCL17 and CCL22 were readily observed in the sera of NNKTL patients. The levels of these chemokines were significantly higher in patients than in healthy controls. Furthermore, we detected the expression of CCR4 (the receptor for CCL17 and CCL22) on the surface of NNKTL cell lines and in tissues of NNKTL patients. Anti-CCR4 monoclonal antibody (mAb) efficiently induced antibody-dependent cellular cytotoxicity mediated by natural killer cells against NNKTL cell lines. Our results suggest that CCL17 and CCL22 may be important factors in the development of NNKTL and open up the possibility of immunotherapy of this lymphoma using anti-CCR4 mAb. PMID:25754123
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Chen, Chi-Fang; Chu, Che-Yu; Chen, Te-Hao; Lee, Shyh-Jye; Shen, Chia-Ning; Hsiao, Chung-Der
2011-01-01
Background Zebrafish skin is composed of enveloping and basal layers which form a first-line defense system against pathogens. Zebrafish epidermis contains ionocytes and mucous cells that aid secretion of acid/ions or mucous through skin. Previous studies demonstrated that fish skin is extremely sensitive to external stimuli. However, little is known about the molecular mechanisms that modulate skin cell apoptosis in zebrafish. Methodology/Principal Findings This study aimed to create a platform to conduct conditional skin ablation and determine if it is possible to attenuate apoptotic stimuli by overexpressing potential apoptosis modulating genes in the skin of live animals. A transgenic zebrafish line of Tg(krt4:NTR-hKikGR)cy17 (killer line), which can conditionally trigger apoptosis in superficial skin cells, was first established. When the killer line was incubated with the prodrug metrodinazole, the superficial skin displayed extensive apoptosis as judged by detection of massive TUNEL- and active caspase 3-positive signals. Great reductions in NTR-hKikGR+ fluorescent signals accompanied epidermal cell apoptosis. This indicated that NTR-hKikGR+ signal fluorescence can be utilized to evaluate apoptotic events in vivo. After removal of metrodinazole, the skin integrity progressively recovered and NTR-hKikGR+ fluorescent signals gradually restored. In contrast, either crossing the killer line with testing lines or transiently injecting the killer line with testing vectors that expressed human constitutive active Akt1, mouse constitutive active Stat3, or HPV16 E6 element displayed apoptosis-resistant phenotypes to cytotoxic metrodinazole as judged by the loss of reduction in NTR-hKikGR+ fluorescent signaling. Conclusion/Significance The killer/testing line binary system established in the current study demonstrates a nitroreductase/metrodinazole system that can be utilized to conditionally perform skin ablation in a real-time manner, and provides a valuable tool to visualize and quantify the anti-apoptotic potential of interesting target genes in vivo. The current work identifies a potential use for transgenic zebrafish as a high-throughput platform to validate potential apoptosis modulators in vivo. PMID:21655190
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Williams, Rob; Krkošek, Martin; Ashe, Erin; Branch, Trevor A; Clark, Steve; Hammond, Philip S; Hoyt, Erich; Noren, Dawn P; Rosen, David; Winship, Arliss
2011-01-01
Ecosystem-based management (EBM) of marine resources attempts to conserve interacting species. In contrast to single-species fisheries management, EBM aims to identify and resolve conflicting objectives for different species. Such a conflict may be emerging in the northeastern Pacific for southern resident killer whales (Orcinus orca) and their primary prey, Chinook salmon (Oncorhynchus tshawytscha). Both species have at-risk conservation status and transboundary (Canada-US) ranges. We modeled individual killer whale prey requirements from feeding and growth records of captive killer whales and morphometric data from historic live-capture fishery and whaling records worldwide. The models, combined with caloric value of salmon, and demographic and diet data for wild killer whales, allow us to predict salmon quantities needed to maintain and recover this killer whale population, which numbered 87 individuals in 2009. Our analyses provide new information on cost of lactation and new parameter estimates for other killer whale populations globally. Prey requirements of southern resident killer whales are difficult to reconcile with fisheries and conservation objectives for Chinook salmon, because the number of fish required is large relative to annual returns and fishery catches. For instance, a U.S. recovery goal (2.3% annual population growth of killer whales over 28 years) implies a 75% increase in energetic requirements. Reducing salmon fisheries may serve as a temporary mitigation measure to allow time for management actions to improve salmon productivity to take effect. As ecosystem-based fishery management becomes more prevalent, trade-offs between conservation objectives for predators and prey will become increasingly necessary. Our approach offers scenarios to compare relative influence of various sources of uncertainty on the resulting consumption estimates to prioritise future research efforts, and a general approach for assessing the extent of conflict between conservation objectives for threatened or protected wildlife where the interaction between affected species can be quantified.
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Williams, Rob; Krkošek, Martin; Ashe, Erin; Branch, Trevor A.; Clark, Steve; Hammond, Philip S.; Hoyt, Erich; Noren, Dawn P.; Rosen, David; Winship, Arliss
2011-01-01
Ecosystem-based management (EBM) of marine resources attempts to conserve interacting species. In contrast to single-species fisheries management, EBM aims to identify and resolve conflicting objectives for different species. Such a conflict may be emerging in the northeastern Pacific for southern resident killer whales (Orcinus orca) and their primary prey, Chinook salmon (Oncorhynchus tshawytscha). Both species have at-risk conservation status and transboundary (Canada–US) ranges. We modeled individual killer whale prey requirements from feeding and growth records of captive killer whales and morphometric data from historic live-capture fishery and whaling records worldwide. The models, combined with caloric value of salmon, and demographic and diet data for wild killer whales, allow us to predict salmon quantities needed to maintain and recover this killer whale population, which numbered 87 individuals in 2009. Our analyses provide new information on cost of lactation and new parameter estimates for other killer whale populations globally. Prey requirements of southern resident killer whales are difficult to reconcile with fisheries and conservation objectives for Chinook salmon, because the number of fish required is large relative to annual returns and fishery catches. For instance, a U.S. recovery goal (2.3% annual population growth of killer whales over 28 years) implies a 75% increase in energetic requirements. Reducing salmon fisheries may serve as a temporary mitigation measure to allow time for management actions to improve salmon productivity to take effect. As ecosystem-based fishery management becomes more prevalent, trade-offs between conservation objectives for predators and prey will become increasingly necessary. Our approach offers scenarios to compare relative influence of various sources of uncertainty on the resulting consumption estimates to prioritise future research efforts, and a general approach for assessing the extent of conflict between conservation objectives for threatened or protected wildlife where the interaction between affected species can be quantified. PMID:22096495
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Li, Jian-Ting; Guo, Cheng; Li, Ming-Long; Wei, Yong-Qing; Hou, Yan-Feng; Jiao, Yu-Lian; Zhao, Yue-Ran; Sun, Hui; Xu, Jin; Cao, Ming-Feng; Feng, Li; Yu, Gui-Na; Gao, Ling; Liu, Yi-Qing; Zhang, Bing-Chang; Zhao, Jia-Jun; Zhang, Hai-Qing
2016-08-01
Natural killer (NK) cells serve as primary immune surveillance and are partially regulated by combinations of killer immunoglobulin-like receptors (KIR) and their human leukocyte antigen-C (HLA-C) ligands. Alterations in NK cell activity have been associated with Hashimoto thyroiditis (HT). The aim of this study was to determine whether certain KIR/HLA-C genotype combinations play a role in HT pathogenesis. The present study enrolled 107 unrelated HT patients and 108 random healthy individuals in a case-control study. Blood was collected for DNA extraction; typing of KIR genes and HLA-C alleles was performed by polymerase chain reaction with sequence specific primers (PCR-SSP), followed by electrophoresis on agarose gels. Among a panel of KIR2D/HLA-C genotype combinations, the frequency of KIR2DS2/HLA-C1 was significantly increased in HT patients compared to controls (33.64% vs. 12.96%, P<.001). To further analyze the precise genotype, we investigated inhibitory or activating KIR/HLA-C gene pairs when their corresponding activating or inhibitory KIR genes were absent in the 2 groups. Only the frequency of KIR2DS2(-)2DL2/3(+)HLA-C1(+) was significantly decreased in HT patients compared to controls (48.60% vs. 70.37%, P = .001). Our data suggest that KIR2DS2/HLA-C1 may correlate with HT pathogenesis. On the contrary, the predominance of KIR2DL2/3/HLA-C1 in the absence of KIR2DS2 suggests a potential inhibitory role in HT pathogenesis. In conclusion, our findings may further elucidate the mechanisms underlying the pathogenesis of HT and other autoimmune diseases. HLA-C = human leukocyte antigen-C HT = Hashimoto thyroiditis KIR = killer immunoglobulin-like receptor NK = natural killer PCR = polymerase chain reaction.
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Sarkar, Saheli; Sabhachandani, Pooja; Ravi, Dashnamoorthy; Potdar, Sayalee; Purvey, Sneha; Beheshti, Afshin; Evens, Andrew M; Konry, Tania
2017-01-01
Natural killer (NK) cells are phenotypically and functionally diverse lymphocytes that recognize and kill cancer cells. The susceptibility of target cancer cells to NK cell-mediated cytotoxicity depends on the strength and balance of regulatory (activating/inhibitory) ligands expressed on target cell surface. We performed gene expression arrays to determine patterns of NK cell ligands associated with B-cell non-Hodgkin lymphoma (b-NHL). Microarray analyses revealed significant upregulation of a multitude of NK-activating and costimulatory ligands across varied b-NHL cell lines and primary lymphoma cells, including ULBP1, CD72, CD48, and SLAMF6. To correlate genetic signatures with functional anti-lymphoma activity, we developed a dynamic and quantitative cytotoxicity assay in an integrated microfluidic droplet generation and docking array. Individual NK cells and target lymphoma cells were co-encapsulated in picoliter-volume droplets to facilitate monitoring of transient cellular interactions and NK cell effector outcomes at single-cell level. We identified significant variability in NK-lymphoma cell contact duration, frequency, and subsequent cytolysis. Death of lymphoma cells undergoing single contact with NK cells occurred faster than cells that made multiple short contacts. NK cells also killed target cells in droplets via contact-independent mechanisms that partially relied on calcium-dependent processes and perforin secretion, but not on cytokines (interferon-γ or tumor necrosis factor-α). We extended this technique to characterize functional heterogeneity in cytolysis of primary cells from b-NHL patients. Tumor cells from two diffuse large B-cell lymphoma patients showed similar contact durations with NK cells; primary Burkitt lymphoma cells made longer contacts and were lysed at later times. We also tested the cytotoxic efficacy of NK-92, a continuously growing NK cell line being investigated as an antitumor therapy, using our droplet-based bioassay. NK-92 cells were found to be more efficient in killing b-NHL cells compared with primary NK cells, requiring shorter contacts for faster killing activity. Taken together, our combined genetic and microfluidic analysis demonstrate b-NHL cell sensitivity to NK cell-based cytotoxicity, which was associated with significant heterogeneity in the dynamic interaction at single-cell level.
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Development and Validation of a Technique for Detection of Stress and Pregnancy in Large Whales
2015-09-30
humpback whales, blue whales, and possibly insular false killer whales). 2 2) The second objective is to complete the biological validation using...identification using high-pressure liquid chromatography (HPLC). Briefly, pooled blubber extract from animals of known gender will be serially diluted 1...progesterone in captive female false killer whales, pseudorca crassidens. Gen. Comp. Endocrinol. 115:323-332. Atkinson, S., Crocker, D., Houser, D
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Amino acid and vitamin supplementation improved health conditions in elderly participants
Ohtani, Masaru; Kawada, Shigeo; Seki, Taizo; Okamoto, Yasuyuki
2012-01-01
The purpose of this study was to investigate the effects of supplementation with amino acids and vitamins on health conditions in unhealthy older people. One bedridden inpatient group (n = 10; mean age, 79.8 ± 8.5 y) and one outpatient group (n = 9; mean age, 72.9 ± 12.2 y) participated in this study. A mixture supplementation with amino acids containing arginine (500 mg/day), glutamine (600 mg/day), and leucine (1200 mg/day), and 11 kinds of vitamins was daily administrated for 8 weeks. In both groups, general blood biomarkers such as white blood cell count, natural killer cell activity, and C-reactive protein levels were measured. All measurements were taken before (baseline), at 4 weeks (mid-point), and after each trial (post-point). At mid-point, natural killer cell activity in the outpatient group increased significantly compared to baseline. At post-point, natural killer cell activity in the outpatient and inpatient groups increased significantly compared to baseline. The other blood biomarkers did not show any significant change throughout the trial. This pilot study suggested that a mixture of arginine, glutamine, leucine, and vitamins is useful to support innate immunity in unhealthy older people, even if their diseases, symptoms, and prescribed medicines are different. PMID:22448099
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Seidel, Ursula J. E.; Schlegel, Patrick; Lang, Peter
2013-01-01
In the last decade several therapeutic antibodies have been Federal Drug Administration (FDA) and European Medicines Agency (EMEA) approved. Although their mechanisms of action in vivo is not fully elucidated, antibody-dependent cellular cytotoxicity (ADCC) mediated by natural killer (NK) cells is presumed to be a key effector function. A substantial role of ADCC has been demonstrated in vitro and in mouse tumor models. However, a direct in vivo effect of ADCC in tumor reactivity in humans remains to be shown. Several studies revealed a predictive value of FcγRIIIa-V158F polymorphism in monoclonal antibody treatment, indicating a potential effect of ADCC on outcome for certain indications. Furthermore, the use of therapeutic antibodies after allogeneic hematopoietic stem cell transplantation is an interesting option. Studying the role of the FcγRIIIa-V158F polymorphism and the influence of Killer-cell Immunoglobuline-like Receptor (KIR) receptor ligand incompatibility on ADCC in this approach may contribute to future transplantation strategies. Despite the success of approved second-generation antibodies in the treatment of several malignancies, efforts are made to further augment ADCC in vivo by antibody engineering. Here, we review currently used therapeutic antibodies for which ADCC has been suggested as effector function. PMID:23543707
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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.
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ACCUMULATION OF DIBUTYLTIN IN HUMAN NATURAL KILLER CELLS
NK cells are a subset of lymphocytes capable of killing tumor cells, virally infected cells and antibody coated cells. Dibutyltin dichloride (DBT) is a butyltin that has been used as a stabilizer in polyvinyl chloride (PVC) plastics and also as a deworming product in poultry. DBT...
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Regulation of NKT Cell Localization in Homeostasis and Infection
Slauenwhite, Drew; Johnston, Brent
2015-01-01
Natural killer T (NKT) cells are a specialized subset of T lymphocytes that regulate immune responses in the context of autoimmunity, cancer, and microbial infection. Lipid antigens derived from bacteria, parasites, and fungi can be presented by CD1d molecules and recognized by the canonical T cell receptors on NKT cells. Alternatively, NKT cells can be activated through recognition of self-lipids and/or pro-inflammatory cytokines generated during infection. Unlike conventional T cells, only a small subset of NKT cells traffic through the lymph nodes under homeostatic conditions, with the largest NKT cell populations localizing to the liver, lungs, spleen, and bone marrow. This is thought to be mediated by differences in chemokine receptor expression profiles. However, the impact of infection on the tissue localization and function of NKT remains largely unstudied. This review focuses on the mechanisms mediating the establishment of peripheral NKT cell populations during homeostasis and how tissue localization of NKT cells is affected during infection. PMID:26074921
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Molecular characterization of a novel gammaretrovirus in killer whales (Orcinus orca).
Lamere, Sarah A; St Leger, Judy A; Schrenzel, Mark D; Anthony, Simon J; Rideout, Bruce A; Salomon, Daniel R
2009-12-01
There are currently no published data documenting the presence of retroviruses in cetaceans, though the occurrences of cancers and immunodeficiency states suggest the potential. We examined tissues from adult killer whales and detected a novel gammaretrovirus by degenerate PCR. Reverse transcription-PCR also demonstrated tissue and serum expression of retroviral mRNA. The full-length sequence of the provirus was obtained by PCR, and a TaqMan-based copy number assay did not demonstrate evidence of productive infection. PCR on blood samples from 11 healthy captive killer whales and tissues from 3 free-ranging animals detected the proviral DNA in all tissues examined from all animals. A survey of multiple cetacean species by PCR for gag, pol, and env sequences showed homologs of this virus in the DNA of eight species of delphinids, pygmy and dwarf sperm whales, and harbor porpoises, but not in beluga or fin whales. Analysis of the bottlenose dolphin genome revealed two full-length proviral sequences with 97.4% and 96.9% nucleotide identity to the killer whale gammaretrovirus. The results of single-cell PCR on killer whale sperm and Southern blotting are also consistent with the conclusion that the provirus is endogenous. We suggest that this gammaretrovirus entered the delphinoid ancestor's genome before the divergence of modern dolphins or that an exogenous variant existed following divergence that was ultimately endogenized. However, the transcriptional activity demonstrated in tissues and the nearly intact viral genome suggest a more recent integration into the killer whale genome, favoring the latter hypothesis. The proposed name for this retrovirus is killer whale endogenous retrovirus.
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Bosma, Anneleen; Abdel-Gadir, Azza; Isenberg, David A.; Jury, Elizabeth C.; Mauri, Claudia
2012-01-01
Summary B cells perform many immunological functions, including presenting lipid antigen to CD1d-restricted invariant natural killer T (iNKT) cells, known to contribute to maintaining tolerance in autoimmunity. Patients with systemic lupus erythematous (SLE) display dysregulated B cell responses and reduced peripheral iNKT cell frequencies. The significance of these defects and how they relate to SLE pathogenesis remain elusive. We report that B cells are essential for iNKT cell expansion and activation in healthy donors but fail to exert a similar effect in SLE patients. Defective B cell-mediated stimulation of iNKT cells in SLE patients was associated with altered CD1d recycling, a defect recapitulated in B cells from healthy donors after stimulation with interferon-α (IFN-α) and anti-immunoglobulin (Ig). iNKT cell number and function were restored in SLE patients responding to anti-CD20 treatment upon normalization of CD1d expression exclusively in repopulated immature B cells. We propose that healthy B cells are pivotal for iNKT cell homeostasis. PMID:22406267
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Raju, N. B.; Perkins, D. D.
1991-01-01
It was shown previously that when a chromosomal Spore killer factor is heterozygous in Neurospora species with eight-spored asci, the four sensitive ascospores in each ascus die and the four survivors are all killers. Sk-2(K) and Sk-3(K) are nonrecombining haplotypes that segregate with the centromere of linkage group III. No killing occurs when either one of these killers is homozygous, but each is sensitive to killing by the other in crosses of Sk-2(K) X Sk-3(K). In the present study, Sk-2(K) and Sk-3(K) were transferred by recurrent backcrosses from the eight-spored species Neurospora crassa into Neurospora tetrasperma, a pseudohomothallic species which normally makes asci with four large spores, each heterokaryotic for mating type and for any other centromere-linked genes that are heterozygous in the cross. The action of Sk-2(K) and Sk-3(K) in N. tetrasperma is that predicted from their behavior in eight-spored species. A sensitive nucleus is protected from killing if it is enclosed in the same ascospore with a killer nucleus. Crosses of Sk-2(K) X Sk-2(S), Sk-3(K) X Sk-3(S), and Sk-2(K) X Sk-3(K) all produce four-spored asci that are wild type in appearance, with the ascospores heterokaryotic and viable. The Eight-spore gene E, which shows variable penetrance, was used to obtain N. tetrasperma asci in which two to eight spores are small and homokaryotic. When killer and sensitive alleles are segregating in the presence of E, only those ascospores that contain a killer allele survive. Half of the small ascospores are killed. In crosses of Sk-2(K) X Sk-3(K) (with E heterozygous), effectively all small ascospores are killed. The ability of N. tetrasperma to carry killer elements in cryptic condition suggests a possible role for Spore killers in the origin of pseudohomothallism, with adoption of the four-spored mode restoring ascospore viability of crosses in which killing would otherwise occur. PMID:1834522
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Dufva, Olli; Kankainen, Matti; Kelkka, Tiina; Sekiguchi, Nodoka; Awad, Shady Adnan; Eldfors, Samuli; Yadav, Bhagwan; Kuusanmäki, Heikki; Malani, Disha; Andersson, Emma I; Pietarinen, Paavo; Saikko, Leena; Kovanen, Panu E; Ojala, Teija; Lee, Dean A; Loughran, Thomas P; Nakazawa, Hideyuki; Suzumiya, Junji; Suzuki, Ritsuro; Ko, Young Hyeh; Kim, Won Seog; Chuang, Shih-Sung; Aittokallio, Tero; Chan, Wing C; Ohshima, Koichi; Ishida, Fumihiro; Mustjoki, Satu
2018-04-19
Aggressive natural killer-cell (NK-cell) leukemia (ANKL) is an extremely aggressive malignancy with dismal prognosis and lack of targeted therapies. Here, we elucidate the molecular pathogenesis of ANKL using a combination of genomic and drug sensitivity profiling. We study 14 ANKL patients using whole-exome sequencing (WES) and identify mutations in STAT3 (21%) and RAS-MAPK pathway genes (21%) as well as in DDX3X (29%) and epigenetic modifiers (50%). Additional alterations include JAK-STAT copy gains and tyrosine phosphatase mutations, which we show recurrent also in extranodal NK/T-cell lymphoma, nasal type (NKTCL) through integration of public genomic data. Drug sensitivity profiling further demonstrates the role of the JAK-STAT pathway in the pathogenesis of NK-cell malignancies, identifying NK cells to be highly sensitive to JAK and BCL2 inhibition compared to other hematopoietic cell lineages. Our results provide insight into ANKL genetics and a framework for application of targeted therapies in NK-cell malignancies.
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Liang, Shuzhen; Xu, Kecheng; Niu, Lizhi; Wang, Xiaohua; Liang, Yingqing; Zhang, Mingjie; Chen, Jibing; Lin, Mao
2017-01-01
In the present study, we aimed to compare the clinical outcome of autogeneic and allogeneic natural killer (NK) cells immunotherapy for the treatment of recurrent breast cancer. Between July 2016 and February 2017, 36 patients who met the enrollment criteria were randomly assigned to two groups: autogeneic NK cells immunotherapy group (group I, n=18) and allogeneic NK cells immunotherapy group (group II, n=18). The clinical efficacy, quality of life, immune function, circulating tumor cell (CTC) level, and other related indicators were evaluated. We found that allogeneic NK cells immunotherapy has better clinical efficacy than autogeneic therapy. Moreover, allogeneic NK cells therapy improves the quality of life, reduces the number of CTCs, reduces carcinoembryonic antigen and cancer antigen 15-3 (CA15-3) expression, and significantly enhances immune function. To our knowledge, this is the first clinical trial to compare the clinical outcome of autogeneic and allogeneic NK cells immunotherapy for recurrent breast cancer. PMID:28894383
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Inflammatory bowel disease: cause and immunobiology.
Baumgart, Daniel C; Carding, Simon R
2007-05-12
Crohn's disease and ulcerative colitis are idiopathic inflammatory bowel disorders. In this paper, we discuss how environmental factors (eg, geography, cigarette smoking, sanitation and hygiene), infectious microbes, ethnic origin, genetic susceptibility, and a dysregulated immune system can result in mucosal inflammation. After describing the symbiotic interaction of the commensal microbiota with the host, oral tolerance, epithelial barrier function, antigen recognition, and immunoregulation by the innate and adaptive immune system, we examine the initiating and perpetuating events of mucosal inflammation. We pay special attention to pattern-recognition receptors, such as toll-like receptors and nucleotide-binding-oligomerisation-domains (NOD), NOD-like receptors and their mutual interaction on epithelial cells and antigen-presenting cells. We also discuss the important role of dendritic cells in directing tolerance and immunity by modulation of subpopulations of effector T cells, regulatory T cells, Th17 cells, natural killer T cells, natural killer cells, and monocyte-macrophages in mucosal inflammation. Implications for novel therapies, which are discussed in detail in the second paper in this Series, are covered briefly.
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Taglia, Lauren; Matusiak, Damien; Benya, Richard V
2008-01-01
Gastrin-releasing peptide (GRP) and its receptor (GRPR) are not normally expressed by epithelial cells lining the adult human colon. However post malignant transformation both GRP and its receptor are aberrantly expressed in the colon where we have previously shown they act to retard metastasis by enhancing tumor cell attachment to the extracellular matrix. In the present study, we show that GRP signaling via its cognate receptor when both are aberrantly expressed in human colon cancer cells causes heat shock protein 72 (Hsp72) to be expressed. We show that GRP/GRPR induces expression of Hsp72 by signaling via focal adhesion kinase. When expressed, Hsp72 promotes the binding of CD16+ and CD94+ natural killer cells, resulting in tumor cell cytolysis. These findings demonstrate the presence of a novel mechanism whereby aberrantly expressed GRP/GRPR in human colorectal cancer attenuates tumor progression and may promote a favorable outcome.
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Szabo, Peter A; Rudak, Patrick T; Choi, Joshua; Xu, Stacey X; Schaub, Robert; Singh, Bhagirath; McCormick, John K; Haeryfar, S M Mansour
2017-03-01
During toxic shock syndrome (TSS), bacterial superantigens trigger a polyclonal T -cell response leading to a potentially catastrophic "cytokine storm". Whether innate-like invariant natural killer T (iNKT) cells, with remarkable immunomodulatory properties, participate in TSS is unclear. Using genetic and cell depletion approaches, we generated iNKT cell-deficient, superantigen-sensitive HLA-DR4-transgenic (DR4tg) mice, which were compared with their iNKT-sufficient counterparts for responsiveness to staphylococcal enterotoxin B (SEB). Both approaches indicate that iNKT cells are pathogenic in TSS. Importantly, treating DR4tg mice with a TH2-polarizing glycolipid agonist of iNKT cells reduced SEB-inflicted morbidity/mortality. Therefore, iNKT cells may constitute an attractive therapeutic target in superantigen-mediated illnesses. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.
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The mitochondrial death squad: hardened killers or innocent bystanders?
Ekert, Paul G; Vaux, David L
2005-12-01
Since the discovery that formation of the apoptosome in mammalian cells is triggered by cytochrome c released from the mitochondria, many other mitochondrial proteins have been suspected to be part of a conspiracy to cause cell death. AIF, EndoG, ANT, cyclophilin D, Bit1, p53AIP, GRIM-19, DAP3, Nur77/TR3/NGFB-1, HtrA2/Omi and Smac/Diablo have all been convicted as killers, but new genetic technology is raising questions about their guilt. Gene knockout experiments suggest that many were wrongly convicted on circumstantial evidence, and just happened to be in the wrong place at the wrong time.
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Koehler, Rebecca N; Alter, Galit; Tovanabutra, Sodsai; Saathoff, Elmar; Arroyo, Miguel A; Walsh, Anne M; Sanders-Buell, Eric E; Maboko, Leonard; Hoelscher, Michael; Robb, Merlin L; Michael, Nelson L; McCutchan, Francine E; Kim, Jerome H; Kijak, Gustavo H
2013-10-15
Here we explore the association between killer cell immunoglobulin-like receptor (KIR)/HLA and human immunodeficiency virus type 1 (HIV-1) acquisition with different viral subtypes circulating in East Africa. In the prospective Cohort Development (CODE) cohort (Mbeya, Tanzania), carriers of KIR3DS1 and its putative ligand (HLA-A or HLA-B Bw4-80Ile alleles) showed increased HIV-1 acquisition risk (odds ratio [OR] = 3.46; 95% confidence interval [CI], 1.12-10.63; P = .04) and a trend for enrichment for subtype A and A-containing recombinants (78% vs. 46%; OR = 4.05; 95% CI, .91-28.30; P = .09) at the expense of subtype C (11% vs. 43%; OR = 0.17; 95% CI, .01-.97; P = .08). In vitro, only natural killer cells from KIR3DS1(+)/HLA-Bw4-80Ile(+) healthy donors showed a 2-fold increased capacity to inhibit replication of subtype C vs subtype A viruses (P = .01). These findings suggest the presence of an innate sieve effect and may inform HIV-1 vaccine development.
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Role of interleukin (IL)-17 and T-helper (Th)17 cells in cancer.
Song, Yang; Yang, Jian Ming
2017-11-04
Interleukin-17 (IL-17), a pleiotropic proinflammatory cytokine, is reported to be significantly generated by a distinct subset of CD4 + T-cells, upgrading cancer-elicited inflammation and preventing cancer cells from immune surveillance. T-helper (Th)17 cells produced from naive CD4 + T cells have recently been renowned and generally accepted, gaining eminence in cancer studies and playing the effective role in context of cancer. Th17 cells are the main source of IL-17-secreting cells, It was found that other cell types produced this cytokine as well, including Group 3 innate lymphoid cells (ILC3), δγT cells, invariant natural killer T (iNKT) cells, lymphoid-tissue inducer (LTi)-like cells and Natural killer (NK) cells. Th17-associated cytokines give impetus to tumor progression, or inducing angiogenesis and metastasis. This review demonstrates an understanding on how the pro- or antitumor function of Th17 cells and IL-17 may change cancer progression, leading to the appearance of complex and pivotal biologic activities in tumor. Copyright © 2017 Elsevier Inc. All rights reserved.
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Shamir, Lior; Yerby, Carol; Simpson, Robert; von Benda-Beckmann, Alexander M; Tyack, Peter; Samarra, Filipa; Miller, Patrick; Wallin, John
2014-02-01
Vocal communication is a primary communication method of killer and pilot whales, and is used for transmitting a broad range of messages and information for short and long distance. The large variation in call types of these species makes it challenging to categorize them. In this study, sounds recorded by audio sensors carried by ten killer whales and eight pilot whales close to the coasts of Norway, Iceland, and the Bahamas were analyzed using computer methods and citizen scientists as part of the Whale FM project. Results show that the computer analysis automatically separated the killer whales into Icelandic and Norwegian whales, and the pilot whales were separated into Norwegian long-finned and Bahamas short-finned pilot whales, showing that at least some whales from these two locations have different acoustic repertoires that can be sensed by the computer analysis. The citizen science analysis was also able to separate the whales to locations by their sounds, but the separation was somewhat less accurate compared to the computer method.
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Serum supplementation modulates the effects of dibutyltin on human natural killer cell function
NK cells are a subset of lymphocytes capable of killing tumor cells, virally infected cells and antibody coated cells. Dibutyltin dichloride (DBT) is an organotin used as a stabilizer in polyvinyl chloride (PVC) plastics and as a deworming product in poultry. DBT may leach from P...
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Genetics Home Reference: familial glucocorticoid deficiency
... familial glucocorticoid deficiency type 1 lead to defective trafficking of the receptor to the cell surface. J ... short stature, and natural killer cell deficiency in humans. J Clin Invest. 2012 Mar;122(3):814- ...
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Natural killer cell biology illuminated by primary immunodeficiency syndromes in humans.
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.
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Tian, Xiao; Wei, Feng; Wang, Limei; Yu, Wenwen; Zhang, Naining; Zhang, Xinwei; Han, Ying; Yu, Jinpu; Ren, Xiubao
2017-01-01
Optimal adoptive cell therapy (ACT) should contribute to effective cancer treatment. The unique ability of natural killer (NK) cells to kill cancer cells independent of major histocompatibility requirement makes them suitable as ACT tools. Herceptin, an antihuman epidermal growth factor receptor-2 (anti-HER2) monoclonal antibody, is used to treat HER2 + breast cancer. However, it has limited effectiveness and possible severe cardiotoxicity. Given that Herceptin may increase the cytotoxicity of lymphocytes, we explored the possible augmentation of NK cell cytotoxicity against HER2 + breast cancer cells by Herceptin. We demonstrated that Herceptin could interact with CD16 on NK cells to expand the cytotoxic NK (specifically, CD56 dim ) cell population. Additionally, Herceptin increased NK cell migration and cytotoxicity against HER2 + breast cancer cells. In a pilot study, Herceptin-treated NK cells shrunk lung nodular metastasis in a woman with HER2 + breast cancer who could not tolerate the cardiotoxic side effects of Herceptin. Our findings support the therapeutic potential of Herceptin-treated NK cells in patients with HER2 + and Herceptin-intolerant breast cancer.
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Natural killer cell receptor genes in the family Equidae: not only Ly49.
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 NKR genes.
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Natural Killer Cell Receptor Genes in the Family Equidae: Not only Ly49
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 NKR genes. PMID:23724088
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Human cytomegalovirus infection elicits new decidual natural killer cell effector functions.
Siewiera, Johan; El Costa, Hicham; Tabiasco, Julie; Berrebi, Alain; Cartron, Géraldine; Le Bouteiller, Philippe; Bouteiller, Philippe; Jabrane-Ferrat, Nabila
2013-01-01
During the first trimester of pregnancy the uterus is massively infiltrated by decidual natural killer cells (dNK). These cells are not killers, but they rather provide a microenvironment that is propitious to healthy placentation. Human cytomegalovirus (HCMV) is the most common cause of intrauterine viral infections and a known cause of severe birth defects or fetal death. The rate of HCMV congenital infection is often low in the first trimester of pregnancy. The mechanisms controlling HCMV spreading during pregnancy are not yet fully revealed, but evidence indicating that the innate immune system plays a role in controlling HCMV infection in healthy adults exists. In this study, we investigated whether dNK cells could be involved in controlling viral spreading and in protecting the fetus against congenital HCMV infection. We found that freshly isolated dNK cells acquire major functional and phenotypic changes when they are exposed to HCMV-infected decidual autologous fibroblasts. Functional studies revealed that dNK cells, which are mainly cytokines and chemokines producers during normal pregnancy, become cytotoxic effectors upon their exposure to HCMV-infected autologous decidual fibroblasts. Both the NKG2D and the CD94/NKG2C or 2E activating receptors are involved in the acquired cytotoxic function. Moreover, we demonstrate that CD56(pos) dNK cells are able to infiltrate HCMV-infected trophoblast organ culture ex-vivo and to co-localize with infected cells in situ in HCMV-infected placenta. Taken together, our results present the first evidence suggesting the involvement of dNK cells in controlling HCMV intrauterine infection and provide insights into the mechanisms through which these cells may operate to limit the spreading of viral infection to fetal tissues.
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Modeling Human Natural Killer Cell Development in the Era of Innate Lymphoid Cells
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
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Kobayashi, Eiji; Motoi, Sotaro; Sugiura, Masahito; Kajikawa, Masunori; Kojima, Shuji; Kohroki, Junya; Masuho, Yasuhiko
2014-09-01
Antibody-dependent cellular cytotoxicity (ADCC) mediated by natural killer (NK) cells is a major mechanism of tumor therapy with antibodies. NK cells not only manifest cytotoxicity but also secrete a variety of cytokines/chemokines that regulate immune responses. Using a retroviral vector, in this study we established a KHYG-1 cell line that stably expresses FcγRIIIA (CD16A). The KHYG-1/FcγRIIIA cells exerted potent antibody concentration-dependent ADCC, whereas parental KHYG-1 cells did not. In contrast, without antibody, the natural killer activity of KHYG-1/FcγRIIIA cells was less potent than that of parental KHYG-1 cells. During the course of ADCC, KHYG-1/FcγRIIIA cells secreted IFN-γ and MIP-1α dependent upon antibody concentration, but parental KHYG-1 cells did not. These results suggest that KHYG-1/FcγRIIIA cells would be useful in studies to elucidate the function of NK cells and the mechanism of ADCC. Copyright © 2014 Elsevier B.V. All rights reserved.
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Natural killer cells facilitate PRAME-specific T-cell reactivity against neuroblastoma
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.
2015-01-01
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. PMID:26452036
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Modeling Human Natural Killer Cell Development in the Era of Innate Lymphoid Cells.
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.
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Petri, Robert Michael; Hackel, Alexander; Hahnel, Katrin; Dumitru, Claudia Alexandra; Bruderek, Kirsten; Flohe, Stefanie B; Paschen, Annette; Lang, Stephan; Brandau, Sven
2017-09-12
The interaction of mesenchymal stromal cells (MSCs) with natural killer (NK) cells is traditionally thought of as a static inhibitory model, whereby resting MSCs inhibit NK cell effector function. Here, we use a dynamic in vitro system of poly(I:C) stimulation to model the interaction of NK cells and tissue-resident MSCs in the context of infection or tissue injury. The experiments suggest a time-dependent system of regulation and feedback, where, at early time points, activated MSCs secrete type I interferon to enhance NK cell effector function, while at later time points TGF-β and IL-6 limit NK cell effector function and terminate inflammatory responses by induction of a regulatory senescent-like NK cell phenotype. Importantly, feedback of these regulatory NK cells to MSCs promotes survival, proliferation, and pro-angiogenic properties. Our data provide additional insight into the interaction of stromal cells and innate immune cells and suggest a model of time-dependent MSC polarization and licensing. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
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Influenza Virus Directly Infects Human Natural Killer Cells and Induces Cell Apoptosis▿
Mao, Huawei; Tu, Wenwei; Qin, Gang; Law, Helen Ka Wai; Sia, Sin Fun; Chan, Ping-Lung; Liu, Yinping; Lam, Kwok-Tai; Zheng, Jian; Peiris, Malik; Lau, Yu-Lung
2009-01-01
Influenza is an acute respiratory viral disease that is transmitted in the first few days of infection. Evasion of host innate immune defenses, including natural killer (NK) cells, is important for the virus's success as a pathogen of humans and other animals. NK cells encounter influenza viruses within the microenvironment of infected cells and are important for host innate immunity during influenza virus infection. It is therefore important to investigate the direct effects of influenza virus on NK cells. In this study, we demonstrated for the first time that influenza virus directly infects and replicates in primary human NK cells. Viral entry into NK cells was mediated by both clathrin- and caveolin-dependent endocytosis rather than through macropinocytosis and was dependent on the sialic acids on cell surfaces. In addition, influenza virus infection induced a marked apoptosis of NK cells. Our findings suggest that influenza virus can directly target and kill NK cells, a potential novel strategy of influenza virus to evade the NK cell innate immune defense that is likely to facilitate viral transmission and may also contribute to virus pathogenesis. PMID:19587043
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Ueshima, Chiyuki; Kataoka, Tatsuki R; Hirata, Masahiro; Sugimoto, Akihiko; Iemura, Yoshiki; Minamiguchi, Sachiko; Nomura, Takashi; Haga, Hironori
2018-06-01
The involvement of mast cells in the establishment of pregnancy is unclear. Herein, we found that human mast cells are present in the decidual tissues of parous women and expressed a human-specific protein killer cell Ig-like receptor (KIR) 2DL4, a receptor for human leukocyte antigen G expressed on human trophoblasts. In contrast, decreased numbers of decidual mast cells and reduced KIR2DL4 expression were observed in these cells of infertile women who had undergone long-term corticosteroid treatment. Co-culture of the human mast cell line, LAD2, and human trophoblast cell line, HTR-8/SVneo, accelerated the migration and tube formation of HTR-8/SVneo cells in a KIR2DL4-dependent manner. These observations suggest the possible involvement of human mast cells in the establishment of pregnancy via KIR2DL4 and that long-term corticosteroid treatment may cause infertility by influencing the phenotypes of decidual mast cells. Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
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Zaitseva, O O; PoleZhaeva, T V; Khudvakov, A N; Solomina, O N; Golovchenko, V V
BACKGROUND: Due to their valuable medicinal properties and high physiological activity, plant polysaccharides are currently being extensively studied. The present study aims to investigate rauwolfian (pectin for Rauvolfia serpentina) supplementation on human leukocytes cryopreservation. We determined the сharacteristics of leukocytes undergoing freezing with pectin at different temperatures. Donor leukocytes were frozen under the protection of comprehensive cryoprotectant solution and stored in electrical freezers (-20C, -40C, -80C). A regular decrease of all values starting from a higher temperature (-20С) through to the lower temperature (-80С) was identified. The study showed that pectin rauwolfian stimulated both the oxygen-independent and the oxygen-dependent killer response. We also found that the oxygen-dependent neutrophil killer effect was reduced as the storage temperature was lowered. It was determined that the LPO levels in the cells with added pectin-containing solutions remained the same before freezing, while their antioxidant activity positively increased, which is beneficial for neutrophils for their further freezing to -20C, -40C and -80C. The results of the study make it possible to assume that rauwolfian, a pectin extracted from Rauvolfia serpentina, has an exocellular protectant effect as part of cryopreservative solution on human white blood cells stored at different low temperatures. The versatility of the substance is probably due to the degree of the macromolecule branching, in particular, the structure of carbohydrate side chains, which contain a large number of hydroxyl groups.
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Effect of L-arginine supplementation on immune responsiveness in patients with sickle cell disease.
Scavella, Arnette; Leiva, Lily; Monjure, Hanh; Zea, Arnold H; Gardner, Renee V
2010-08-01
L-arginine (L-Arg) is deficient in sickle cell disease (SSD) during vasoocclusion. We investigated possible causal relationship between L-Arg deficiency and immune dysfunction in SSD in steady-state. Fifteen patients with SSD in steady-state and 13 controls were studied. Plasma L-Arg levels were measured using liquid chromatography. T cell subsets and CD3zeta (CD3zeta) chain expression were analyzed using flow cytometry. Lymphocyte proliferative response to phytohemagglutinin (PHA) and production of IL-6 and interferon-gamma (IFN-gamma) were evaluated with and without L-Arg. SSD patients had significantly lower L-Arg levels than controls. CD3 and CD19 cell populations were comparable for both groups, but SSD patients had above normal numbers of natural killer cells (P = 0.06). Patients and controls exhibited significantly increased lymphocyte blastogenesis to PHA after introduction of L-Arg to cultures; response of patients was significantly greater than values for control individuals. Proliferative response to candida in SSD patients was significantly lower than in controls; L-Arg supplementation did not increase this response. L-Arg had no effect on blastogenic response to PPD and candida albicans. No effect was likewise seen in production of IL-6 and IFN-gamma after addition of L-Arg. CD3zeta chain expression increased after addition of L-Arg in both groups; differences were insignificant. L-Arg levels in steady-state SSD are significantly lower than in controls. L-Arg supplementation enhanced lymphocyte blastogenesis to PHA for both controls and patients, but not in response to antigen. There were no significant differences in CD3zeta chain expression although upregulation of expression occurred after L-Arg supplementation for both groups. (c) 2010 Wiley-Liss, Inc.
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Nagahama, Kiyoko; Eto, Nozomu; Shimojo, Tomofumi; Kondoh, Tomomi; Nakahara, Keiko; Sakakibara, Yoichi; Fukui, Keiichi; Suiko, Masahito
2015-01-01
Natural killer (NK) cells play a key role in innate immune defense against infectious disease and cancer. A reduction of NK activity is likely to be associated with increased risk of these types of disease. In this study, we investigate the activation potential of kumquat pericarp acetone fraction (KP-AF) on NK cells. It is shown to significantly increase IFN-γ production and NK cytotoxic activity in human KHYG-1 NK cells. Moreover, oral administration of KP-AF significantly improves both suppressed plasma IFN-γ levels and NK cytotoxic activity per splenocyte in restraint-stressed mice. These results indicate that raw kumquat pericarp activates NK cells in vitro and in vivo. To identify the active constituents, we also examined IFN-γ production on KHYG-1 cells by the predicted active components. Only β-cryptoxanthin increased IFN-γ production, suggesting that NK cell activation effects of KP-AF may be caused by carotenoids such as β-cryptoxanthin.
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Bassoy, Esen Yonca; Kasahara, Atsuko; Chiusolo, Valentina; Jacquemin, Guillaume; Boydell, Emma; Zamorano, Sebastian; Riccadonna, Cristina; Pellegatta, Serena; Hulo, Nicolas; Dutoit, Valérie; Derouazi, Madiha; Dietrich, Pierre Yves; Walker, Paul R; Martinvalet, Denis
2017-06-01
Glioblastoma is a highly heterogeneous aggressive primary brain tumor, with the glioma stem-like cells (GSC) being more sensitive to cytotoxic lymphocyte-mediated killing than glioma differentiated cells (GDC). However, the mechanism behind this higher sensitivity is unclear. Here, we found that the mitochondrial morphology of GSCs modulates the ER-mitochondria contacts that regulate the surface expression of sialylated glycans and their recognition by cytotoxic T lymphocytes and natural killer cells. GSCs displayed diminished ER-mitochondria contacts compared to GDCs. Forced ER-mitochondria contacts in GSCs increased their cell surface expression of sialylated glycans and reduced their susceptibility to cytotoxic lymphocytes. Therefore, mitochondrial morphology and dynamism dictate the ER-mitochondria contacts in order to regulate the surface expression of certain glycans and thus play a role in GSC recognition and elimination by immune effector cells. Targeting the mitochondrial morphology, dynamism, and contacts with the ER could be an innovative strategy to deplete the cancer stem cell compartment to successfully treat glioblastoma. © 2017 The Authors.
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Suck, G; Branch, D R; Keating, A
2006-05-01
To evaluate gamma-irradiation on KHYG-1, a highly cytotoxic natural killer (NK) cell line and potential candidate for cancer immunotherapy. The NK cell line KHYG-1 was irradiated at 1 gray (Gy) to 50 Gy with gamma-irradiation, and evaluated for cell proliferation, cell survival, and cytotoxicity against tumor targets. We showed that a dose of at least 10 Gy was sufficient to inhibit proliferation of KHYG-1 within the first day but not its cytolytic activity. While 50 Gy had an apoptotic effect in the first hours after irradiation, the killing of K562 and HL60 targets was not different from non-irradiated cells but was reduced for the Ph + myeloid leukemia lines, EM-2 and EM-3. gamma-irradiation (at least 10 Gy) of KHYG-1 inhibits cell proliferation but does not diminish its enhanced cytolytic activity against several tumor targets. This study suggests that KHYG-1 may be a feasible immunotherapeutic agent in the treatment of cancers.
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Dobashi, H; Seki, S; Habu, Y; Ohkawa, T; Takeshita, S; Hiraide, H; Sekine, I
1999-08-01
Although bacterial superantigens have been well characterized as potent stimulators of T cells, their role in natural killer (NK)-type cells remains largely unknown. In the present study, we examined the effect of bacterial superantigens on mouse liver NK cells and NK1.1 Ag(+) (NK1(+)) T cells. C57BL/6 mice were intravenously injected with staphylococcal enterotoxin B (SEB) or streptococcal pyrogenic exotoxin A (SPE-A), and mononuclear cells (MNC) of various organs were obtained from mice 4 hours after being injected with superantigen. MNC were cultured for 48 hours, and interferon gamma (IFN-gamma) levels of supernatants were measured. The antitumor cytotoxicities of the liver and spleen MNC were also evaluated 24 hours after the mice were injected with superantigen. Liver MNC produced more IFN-gamma than did splenocytes, and peripheral blood and lung MNC did not produce any detectable IFN-gamma. In addition, liver MNC acquired a potent antitumor cytotoxicity by the SEB injection, and both NK cells and NK1(+)T cells but not cluster of differentiation (CD)8(+) T cells were responsible for the cytotoxicity as demonstrated by either in vivo or in vitro cell depletion experiments, and the NK-type cells were partly responsible for the increased serum IFN-gamma. Activation of liver NK-type cells was also supported by the fact that liver NK cells proportionally increased and NK1(+) T cells augmented their CD11a expressions after SEB injection. The pretreatment of mice with anti-IFN-gamma Ab and/or with anti-interleukin-12 (IL-12) Ab diminished the SEB-induced cytotoxicity of liver MNC. Furthermore, the in vivo depletion of Kupffer cells decreased the SEB-induced cytotoxicity of liver MNC. Consistent with these results, liver MNC stimulated with superantigens in the presence of Kupffer cells in vitro produced a greater amount of IFN-gamma than did the liver MNC without Kupffer cells or splenocytes. Our results suggest that bacterial superantigen-primed Kupffer cells produce IL-12 and other monokines, while also nonspecifically activating both NK cells and NK1(+) T cells to produce IFN-gamma.
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Curé, Charlotte; Antunes, Ricardo; Alves, Ana Catarina; Visser, Fleur; Kvadsheim, Petter H.; Miller, Patrick J. O.
2013-01-01
Interactions between individuals of different cetacean species are often observed in the wild. Killer whales (Orcinus orca) can be potential predators of many other cetaceans, and the interception of their vocalizations by unintended cetacean receivers may trigger anti-predator behavior that could mediate predator-prey interactions. We explored the anti-predator behaviour of five typically-solitary male sperm whales (Physeter macrocephalus) in the Norwegian Sea by playing sounds of mammal-feeding killer whales and monitoring behavioural responses using multi-sensor tags. Our results suggest that, rather than taking advantage of their large aerobic capacities to dive away from the perceived predator, sperm whales responded to killer whale playbacks by interrupting their foraging or resting dives and returning to the surface, changing their vocal production, and initiating a surprising degree of social behaviour in these mostly solitary animals. Thus, the interception of predator vocalizations by male sperm whales disrupted functional behaviours and mediated previously unrecognized anti-predator responses. PMID:23545484
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Curé, Charlotte; Antunes, Ricardo; Alves, Ana Catarina; Visser, Fleur; Kvadsheim, Petter H; Miller, Patrick J O
2013-01-01
Interactions between individuals of different cetacean species are often observed in the wild. Killer whales (Orcinus orca) can be potential predators of many other cetaceans, and the interception of their vocalizations by unintended cetacean receivers may trigger anti-predator behavior that could mediate predator-prey interactions. We explored the anti-predator behaviour of five typically-solitary male sperm whales (Physeter macrocephalus) in the Norwegian Sea by playing sounds of mammal-feeding killer whales and monitoring behavioural responses using multi-sensor tags. Our results suggest that, rather than taking advantage of their large aerobic capacities to dive away from the perceived predator, sperm whales responded to killer whale playbacks by interrupting their foraging or resting dives and returning to the surface, changing their vocal production, and initiating a surprising degree of social behaviour in these mostly solitary animals. Thus, the interception of predator vocalizations by male sperm whales disrupted functional behaviours and mediated previously unrecognized anti-predator responses.
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Arora, Pooja; Baena, Andres; Yu, Karl O.A.; Saini, Neeraj K.; Kharkwal, Shalu S.; Goldberg, Michael F.; Kunnath-Velayudhan, Shajo; Carreño, Leandro J.; Venkataswamy, Manjunatha M.; Kim, John; Lazar-Molnar, Eszter; Lauvau, Gregoire; Chang, Young-tae; Liu, Zheng; Bittman, Robert; Al-Shamkhani, Aymen; Cox, Liam R.; Jervis, Peter J.; Veerapen, Natacha; Besra, Gurdyal S.; Porcelli, Steven A.
2014-01-01
Summary Many hematopoietic cell types express CD1d and are capable of presenting glycolipid antigens to invariant natural killer T cells (iNKT cells). However, the question of which cells are the principal presenters of glycolipid antigens in vivo remains controversial, and it has been suggested that this might vary depending on the structure of a particular glycolipid antigen. Here we have shown that a single type of cell, the CD8α+ DEC-205+ dendritic cell, was mainly responsible for capturing and presenting a variety of different glycolipid antigens, including multiple forms of α-galactosylceramide that stimulate widely divergent cytokine responses. After glycolipid presentation, these dendritic cells rapidly altered their expression of various costimulatory and coinhibitory molecules in a manner that was dependent on the structure of the antigen. These findings show flexibility in the outcome of two-way communication between CD8α+ dendritic cells and iNKT cells, providing a mechanism for biasing toward either proinflammatory or anti-inflammatory responses. PMID:24412610
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Coombes, Janine L; Han, Seong-Ji; van Rooijen, Nico; Raulet, David H; Robey, Ellen A
2012-07-26
Infection leads to heightened activation of natural killer (NK) cells, a process that likely involves direct cell-to-cell contact, but how this occurs in vivo is poorly understood. We have used two-photon laser-scanning microscopy in conjunction with Toxoplasma gondii mouse infection models to address this question. We found that after infection, NK cells accumulated in the subcapsular region of the lymph node, where they formed low-motility contacts with collagen fibers and CD169(+) macrophages. We provide evidence that interactions with collagen regulate NK cell migration, whereas CD169(+) macrophages increase the activation state of NK cells. Interestingly, a subset of CD169(+) macrophages that coexpress the inflammatory monocyte marker Ly6C had the most potent ability to activate NK cells. Our data reveal pathways through which NK cell migration and function are regulated after infection and identify an important accessory cell population for activation of NK cell responses in lymph nodes. Copyright © 2012 The Authors. Published by Elsevier Inc. All rights reserved.
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SATO, NAOTO; SAGA, YASUSHI; MIZUKAMI, HIROAKI; WANG, DONGDONG; TAKAHASHI, SUZUYO; NONAKA, HIROAKI; FUJIWARA, HIROYUKI; TAKEI, YUJI; MACHIDA, SHIZUO; TAKIKAWA, OSAMU; OZAWA, KEIYA; SUZUKI, MITSUAKI
2012-01-01
This study examined the role of the immunosuppressive enzyme indoleamine-2,3-dioxygenase (IDO) in cervical cancer progression and the possible use of this enzyme for cervical cancer therapy. We analyzed IDO protein expression in 9 cervical cancer cell lines (SKG-I, -II, -IIIa, -IIIb, SiHa, CaSki, BOKU, HCS-2 and ME-180) stimulated with interferon-γ. IDO expression was observed in all cell lines except for SKG-IIIb. We transfected the human cervical cancer cell line CaSki that constitutively expresses IDO with a short hairpin RNA vector targeting IDO, and established an IDO-downregulated cell line to determine whether inhibition of IDO mediates cervical cancer progression. IDO downregulation suppressed tumor growth in vivo, without influencing cancer cell growth in vitro. Moreover, IDO downregulation enhanced the sensitivity of cervical cancer cells to natural killer (NK) cells in vitro and promoted NK cell accumulation in the tumor stroma in vivo. These findings indicate that downregulation of IDO controls cervical cancer progression by activating NK cells, suggesting IDO as a potential therapy for cervical cancer. PMID:22923135
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Kimura, Hiroshi; Hoshino, Yo; Hara, Shinya; Sugaya, Naomi; Kawada, Jun-Ichi; Shibata, Yukiko; Kojima, Seiji; Nagasaka, Tetsuro; Kuzushima, Kiyotaka; Morishima, Tsuneo
2005-02-15
Infections of T cells and natural killer (NK) cells play a central role in the pathogenesis of chronic active Epstein-Barr virus (CAEBV) infection. To characterize the virologic and cytokine profiles of T cell-type and NK cell-type infection, 39 patients with CAEBV infection were analyzed. Patients with T cell-type infection had higher titers of immunoglobulin G against early and late EBV antigens, suggesting lytic cycle infection. However, the pattern of EBV gene expression was latency type II; BZLF1, which is a hallmark of lytic cycle infection, could not be detected in any patients, regardless of infection type. Patients with CAEBV infection had high concentrations of proinflammatory, T helper cell type 1, and anti-inflammatory cytokines. The cytokine profile in patients with NK cell-type infection was similar to that in patients with T cell-type infection, but the concentration of IL-13 was high in patients with NK cell-type infection. These findings should help to clarify the pathogenesis of CAEBV infection and facilitate the development of more-effective treatments.
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Biology and function of adipose tissue macrophages, dendritic cells and B cells.
Ivanov, Stoyan; Merlin, Johanna; Lee, Man Kit Sam; Murphy, Andrew J; Guinamard, Rodolphe R
2018-04-01
The increasing incidence of obesity and its socio-economical impact is a global health issue due to its associated co-morbidities, namely diabetes and cardiovascular disease [1-5]. Obesity is characterized by an increase in adipose tissue, which promotes the recruitment of immune cells resulting in low-grade inflammation and dysfunctional metabolism. Macrophages are the most abundant immune cells in the adipose tissue of mice and humans. The adipose tissue also contains other myeloid cells (dendritic cells (DC) and neutrophils) and to a lesser extent lymphocyte populations, including T cells, B cells, Natural Killer (NK) and Natural Killer T (NKT) cells. While the majority of studies have linked adipose tissue macrophages (ATM) to the development of low-grade inflammation and co-morbidities associated with obesity, emerging evidence suggests for a role of other immune cells within the adipose tissue that may act in part by supporting macrophage homeostasis. In this review, we summarize the current knowledge of the functions ATMs, DCs and B cells possess during steady-state and obesity. Copyright © 2018 Elsevier B.V. All rights reserved.
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Thiopurine use associated with reduced B and natural killer cells in inflammatory bowel disease
Lord, James D; Shows, Donna M
2017-01-01
AIM To identify which blood and mucosal lymphocyte populations are specifically depleted by thiopurine use in vivo. METHODS The thiopurines azathioprine and 6-mercaptopurine have been a mainstay of inflammatory bowel disease (IBD) therapy for decades, but their mechanism of action in vivo remains obscure. Although thiopurines are lymphotoxic at high doses, and have been reported to cause T cell apoptosis in vitro, their ability to control IBD at lower doses suggests that they may selectively deplete particular lymphocyte populations. Blood cells from 19 IBD patients on a thiopurine, 19 IBD patients not on a thiopurine, and 38 matched healthy control subjects were analyzed by multiple multi-color flow cytometry panels to quantify the immune cell subsets contained therein, both as a percent of cells, and as an absolute cell count. Similar analyses were performed on colon biopsies from 17 IBD patients on a thiopurine, 17 IBD patients not on a thiopurine, and 49 healthy screening colonoscopy recipients. RESULTS Complete blood counts revealed lower lymphocyte, but not monocyte or granulocyte, counts in IBD patients who were taking thiopurines at the time of sampling. This reduction was restricted to CD3-negative lymphocytes, wherein both natural killer (NK) and B cells were significantly reduced among thiopurine recipients. Among CD19+ B cells, the transitional B cells were particularly depleted, being nearly absent in both blood and colon biopsies of thiopurine recipients. No differences were associated with thiopurine use in CD8+ T cells, mucosa-associated invariant T (MAIT) cells, invariant natural killer T (iNKT) cells, gamma/delta T cells, Th1, Th17, regulatory T cells (Tregs) or naïve CD4+ T cells. However, patients with IBD had significantly more circulating FOXP3+, Helios+ Tregs and fewer iNKT and MAIT cells than healthy controls. CONCLUSION Thiopurine use is associated with reduced B and NK cell, but not T cell, subpopulations in the blood of IBD patients. PMID:28566883
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Vaillier, D; Daculsi, R; Gualde, N
1995-01-01
We have studied the relationship between cytotoxic activity, size and granularity of murine interleukin-2-activated adherent killer cells issued from spleen cells cultured with high levels of IL-2. The effects of prostaglandin E2 (PGE2) and forskolin upon these cells were assessed. All adherent spleen cells obtained after 5 days of culture were large granular lymphocytes but presented a heterogeneity in size and granularity. After fractionation on a discontinuous-density Percoll gradient, four cellular subpopulations were isolated. Fluorescence-activated cell sorting analysis showed that cells of the lightest fraction (F1) were the largest, while the cells found in the heaviest fraction (F4) were much more granular than the cells collected in the two intermediate fractions (F2 and F3). The serine esterases level was higher in F4 than in unfractionated cells and diminished to about 40% in cells of fractions F2 and F3, which expressed a cytotoxic activity against YAC-1 cells higher than that in unfractionated cells or in F1 or F4, which presented the lowest cytotoxic activity. When AK cells were cultured for 48 h in the presence of either PGE2 or forskolin, which induce an intracellular increase of cAMP, we observed that PGE2 (1 microM) inhibited the cytotoxic activity, but surprisingly forskolin (2 microM) exerted a stimulating effect on the induction of cytotoxic activity. After fractionation on a discontinuous Percoll gradient we observed the same cellular distribution among PGE2 or forskolin-treated or -untreated cells, but PGE2 induced an increase of size and granularity. This effect of PGE2 was more potent on the cells collected in F4. However this variation of granularity was not associated with any variation in the serine esterase level. The cytotoxic activity of PGE2- or forskolin-treated cells did not present any significant variation relative to the control for cells collected in F2 and F3; on the other hand, forskolin-treated cells collected in F4 showed a significantly higher cytotoxicity than did the corresponding untreated or PGE2-treated cells.
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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
2014-01-01
SUMMARY 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, which predisposes for the development of distinct EBV-associated lymphomas. It remains unclear why some individuals experience this symptomatic primary EBV infection, while the majority acquires the virus asymptomatically. Using a mouse model with reconstituted human immune system components, we show here that depletion of human natural killer (NK) cells enhances IM symptoms and promotes EBV-associated tumorigenesis, mainly due to 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. PMID:24360958
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2018-04-20
Adult Nasal Type Extranodal NK/T-Cell Lymphoma; Recurrent Nasopharyngeal Keratinizing Squamous Cell Carcinoma; Recurrent Nasopharyngeal Undifferentiated Carcinoma; Stage IV Nasopharyngeal Keratinizing Squamous Cell Carcinoma AJCC v7; Stage IV Nasopharyngeal Undifferentiated Carcinoma AJCC v7
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Chang, Heng-Kwei
2015-01-01
Retinoic acid (RA), an active metabolite converted from vitamin A, plays an active role in immune function, such as defending against infections and immune regulation. Although RA affects various types of immune cells, including antigen-presenting cells, B lymphocytes, and T lymphocytes, whether it affects natural killer T (NKT) cells remain unknown. In this study, we found that RA decreased interferon (IFN)-γ production by activated NKT cells through T-cell receptor (TCR) and CD28. We also found that RA reduced extracellular signal-regulated kinase (ERK) phosphorylation, but increased phosphatase 2A (PP2A) activity in TCR/CD28-stimulated NKT cells. The increased PP2A activity, at least partly, contributed to the reduction of ERK phosphorylation. Since inhibition of ERK activation decreases IFN-γ production by TCR/CD28-stimulated NKT cells, RA may downregulate IFN-γ production by TCR/CD28-stimulated NKT cells through the PP2A-ERK pathway. Our results demonstrated a novel function of RA in modulating the IFN-γ expression by activated NKT cells. PMID:25343668
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Developmental and Functional Control of Natural Killer Cells by Cytokines
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
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Tumor necrosis factor-{alpha} enhances IL-15-induced natural killer cell differentiation
DOE Office of Scientific and Technical Information (OSTI.GOV)
Lee, Jiwon; Lee, Suk Hyung; Korea University of Science and Technology, Yusong, Daejeon 305-333
2009-09-04
The differentiation of natural killer (NK) cells is regulated by various factors including soluble growth factors and transcription factors. Here, we have demonstrated that tumor necrosis factor-{alpha} (TNF-{alpha}) is a positive regulator of NK cell differentiation. TNF-{alpha} augmented the IL-15-induced expression of NK1.1 and CD122 in mature NK cells, and TNF-{alpha} alone also induced NK cell maturation as well as IL-15. TNF-{alpha} also increased IFN-{gamma} production in NK cells in the presence of IL-15. Meanwhile, mRNA expression of several transcription factors, including T-bet and GATA-3, was increased by the addition of TNF-{alpha} and IL-15. In addition, TNF-{alpha} increased nuclear factor-kappamore » B (NF-{kappa}B) activity in NK cells and inhibition of NF-{kappa}B impeded TNF-{alpha}-enhanced NK cell maturation. Overall, these data suggest that TNF-{alpha} significantly increased IL-15-driven NK cell differentiation by increasing the expression of transcription factors that play crucial roles in NK cell maturation and inducing the NF-{kappa}B activity.« less
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Soluble NKG2D ligands: prevalence, release, and functional impact.
Salih, Helmut Rainer; Holdenrieder, Stefan; Steinle, Alexander
2008-05-01
Natural Killer (NK) cells are capable to recognize and eliminate malignant cells. Anti-tumor responses of NK cells are promoted by the tumor-associated expression of cell stress-inducible ligands of the activating NK receptor NKG2D. Current evidence suggests that established tumors subvert NKG2D-mediated tumor immunosurveillance by releasing NKG2D ligands (NKG2DL). Release of NKG2DL has been observed in a broad variety of human tumor entities and is thought to interfere with NKG2D-mediated tumor immunity in several ways. Further, levels of soluble NKG2DL (sNKG2DL) were also found to be elevated under various non-malignant conditions, although the functional implications remain largely unclear. Here we review and discuss the available data on the prevalence, release, functional impact, and potential clinical value of sNKG2DL.
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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
2007-09-01
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 Valpha24Jalpha18 TCR alpha 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-gamma and tumour necrosis factor-alpha 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.
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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
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Ferreira-Teixeira, Margarida; Paiva-Oliveira, Daniela; Parada, Belmiro; Alves, Vera; Sousa, Vitor; Chijioke, Obinna; Münz, Christian; Reis, Flávio; Rodrigues-Santos, Paulo; Gomes, Célia
2016-10-21
High-grade non-muscle invasive bladder cancer (NMIBC) has a high risk of recurrence and progression to muscle-invasive forms, which seems to be largely related to the presence of tumorigenic stem-like cell populations that are refractory to conventional therapies. Here, we evaluated the therapeutic potential of Natural Killer (NK) cell-based adoptive immunotherapy against chemoresistant bladder cancer stem-like cells (CSCs) in a pre-clinical relevant model, using NK cells from healthy donors and NMIBC patients. Cytokine-activated NK cells from healthy donors and from high-grade NMIBC patients were phenotypically characterized and assayed in vitro against stem-like and bulk differentiated bladder cancer cells. Stem-like cells were isolated from two bladder cancer cell lines using the sphere-forming assay. The in vivo therapeutic efficacy was evaluated in mice bearing a CSC-induced orthotopic bladder cancer. Animals were treated by intravesical instillation of interleukin-activated NK cells. Tumor response was evaluated longitudinally by non-invasive bioluminescence imaging. NK cells from healthy donors upon activation with IL-2 and IL-15 kills indiscriminately both stem-like and differentiated tumor cells via stress ligand recognition. In addition to cell killing, NK cells shifted CSCs towards a more differentiated phenotype, rendering them more susceptible to cisplatin, highlighting the benefits of a possible combined therapy. On the contrary, NK cells from NMIBC patients displayed a low density on NK cytotoxicity receptors, adhesion molecules and a more immature phenotype, losing their ability to kill and drive differentiation of CSCs. The local administration, via the transurethral route, of activated NK cells from healthy donors provides an efficient tumor infiltration and a subsequent robust tumoricidal activity against bladder cancer with high selective cytolytic activity against CSCs, leading to a dramatic reduction in tumor burden from 80 % to complete remission. Although pre-clinical, our results strongly suggest that an immunotherapeutic strategy using allogeneic activated NK cells from healthy donors is effective and should be exploited as a complementary therapeutic strategy in high-risk NMIBC patients to prevent tumor recurrence and progression.
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Killer whales (Orcinus orca) face protracted health risks associated with lifetime exposure to PCBs.
Hickie, Brendan E; Ross, Peter S; Macdonald, Robie W; Ford, John K B
2007-09-15
Polychlorinated biphenyl (PCB) concentrations declined rapidly in environmental compartments and most biota following implementation of regulations in the 1970s. However, the metabolic recalcitrance of PCBs may delay responses to such declines in large, long-lived species, such as the endangered and highly PCB-contaminated resident killer whales (Orcinus orca) of the Northeastern Pacific Ocean. To investigate the influence of life history on PCB-related health risks, we developed models to estimate PCB concentrations in killer whales during the period from 1930 forward to 2030, both within a lifetime (approximately 50 years) and across generations, and then evaluated these in the context of health effects thresholds established for marine mammals. Modeled PCB concentrations in killer whales responded slowly to changes in loadings to the environment as evidenced by slower accumulation and lower magnitude increases in PCB concentrations relative to prey, and a delayed decline that was particularly evident in adult males. Since PCBs attained peak levels well above the effects threshold (17 mg/kg lipid) in approximately 1969, estimated concentrations in both the northern and the more contaminated southern resident populations have declined gradually. Projections suggest that the northern resident population could largely fall below the threshold concentration by 2030 while the endangered southern residents may not do so until at least 2063. Long-lived aquatic mammals are therefore not protected from PCBs by current dietary residue guidelines.
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Saroha, Ashish; Pewzner-Jung, Yael; Ferreira, Natalia S; Sharma, Piyush; Jouan, Youenn; Kelly, Samuel L; Feldmesser, Ester; Merrill, Alfred H; Trottein, François; Paget, Christophe; Lang, Karl S; Futerman, Anthony H
2017-01-01
The role of sphingolipids (SLs) in the immune system has come under increasing scrutiny recently due to the emerging contributions that these important membrane components play in regulating a variety of immunological processes. The acyl chain length of SLs appears particularly critical in determining SL function. Here, we show a role for very-long acyl chain SLs (VLC-SLs) in invariant natural killer T ( i NKT) cell maturation in the thymus and homeostasis in the liver. Ceramide synthase 2-null mice, which lack VLC-SLs, were susceptible to a hepatotropic strain of lymphocytic choriomeningitis virus, which is due to a reduction in the number of i NKT cells. Bone marrow chimera experiments indicated that hematopoietic-derived VLC-SLs are essential for maturation of i NKT cells in the thymus, whereas parenchymal-derived VLC-SLs are crucial for i NKT cell survival and maintenance in the liver. Our findings suggest a critical role for VLC-SL in i NKT cell physiology.
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Adoptive Cell Therapy of Melanoma with Cytokine-induced Killer Cells.
Kim, Ji Sung; Kim, Yong Guk; Pyo, Minji; Lee, Hong Kyung; Hong, Jin Tae; Kim, Youngsoo; Han, Sang-Bae
2015-04-01
Melanoma is the most aggressive skin cancer and its incidence is gradually increasing worldwide. Patients with metastatic melanoma have a very poor prognosis (estimated 5-year survival rate of <16%). In the last few years, several drugs have been approved for malignant melanoma, such as tyrosine kinase inhibitors and immune checkpoint blockades. Although new therapeutic agents have improved progression-free and overall survival, their use is limited by drug resistance and drug-related toxicity. At the same time, adoptive cell therapy of metastatic melanoma with tumor-infiltrating lymphocytes has shown promising results in preclinical and clinical studies. In this review, we summarize the currently available drugs for treatment of malignant melanoma. In addition, we suggest cytokine-induced killer (CIK) cells as another candidate approach for adoptive cell therapy of melanoma. Our preclinical study and several previous studies have shown that CIK cells have potent anti-tumor activity against melanomas in vitro and in an in vivo human tumor xenograft model without any toxicity.
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Adoptive Cell Therapy of Melanoma with Cytokine-induced Killer Cells
Kim, Ji Sung; Kim, Yong Guk; Pyo, Minji; Lee, Hong Kyung; Hong, Jin Tae; Kim, Youngsoo
2015-01-01
Melanoma is the most aggressive skin cancer and its incidence is gradually increasing worldwide. Patients with metastatic melanoma have a very poor prognosis (estimated 5-year survival rate of <16%). In the last few years, several drugs have been approved for malignant melanoma, such as tyrosine kinase inhibitors and immune checkpoint blockades. Although new therapeutic agents have improved progression-free and overall survival, their use is limited by drug resistance and drug-related toxicity. At the same time, adoptive cell therapy of metastatic melanoma with tumor-infiltrating lymphocytes has shown promising results in preclinical and clinical studies. In this review, we summarize the currently available drugs for treatment of malignant melanoma. In addition, we suggest cytokine-induced killer (CIK) cells as another candidate approach for adoptive cell therapy of melanoma. Our preclinical study and several previous studies have shown that CIK cells have potent anti-tumor activity against melanomas in vitro and in an in vivo human tumor xenograft model without any toxicity. PMID:25922594
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The Yin and Yang of Innate Lymphoid Cells in Cancer.
Carrega, Paolo; Campana, Stefania; Bonaccorsi, Irene; Ferlazzo, Guido
2016-11-01
The recent appreciation of novel subsets of innate lymphoid cells (ILCs) as important regulators of tissue homeostasis, inflammation and repair, raise questions regarding the presence and role of these cells in cancer tissues. In addition to natural killer and fetal lymphoid tissue inducer (LTi) cells, the ILC family comprises non-cytolytic, cytokine-producing cells that are classified into ILC1, ILC2 and ILC3 based on phenotypic and functional characteristics. Differently from natural killer cells, which are the prototypical members of ILC1 and whose role in tumors is better established, the involvement of other ILC subsets in cancer progression or resistance is still fuzzy and in several instances controversial, since current studies indicate both context-dependent beneficial or pathogenic effects. Here, we review the current knowledge regarding the involvement of these novel ILC subsets in the context of tumor immunology, highlighting how ILC subsets might behave either as friends or foes. Copyright © 2016 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.
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Characterization of tumor infiltrating Natural Killer cell subset
Nissan, Aviram; Darash-Yahana, Merav; Peretz, Tamar; Mandelboim, Ofer; Rachmilewitz, Jacob
2015-01-01
The presence of tumor-infiltrating Natural Killer (NK) within a tumor bed may be indicative of an ongoing immune response toward the tumor. However, many studies have shown that an intense NK infiltration, is associated with advanced disease and may even facilitate cancer development. The exact role of the tumor infiltrating NK cells and the correlation between their presence and poor prognosis remains unclear. Interestingly, during pregnancy high numbers of a specific NK subset, CD56brightCD16dim, are accumulated within first trimester deciduas. These decidual NK (dNK) cells are unique in their gene expression pattern secret angiogenic factors that induce vascular growth. In the present study we demonstrate a significant enrichment of a CD56brighCD16dim NK cells within tumors. These NK cells express several dNK markers including VEGF. Hence, this study adds new insights into the identity of tumor residual NK cells, which has clear implications for the treatment of human cancer. PMID:26079948
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Back, J.; Malchiodi, E; Cho, S
2009-01-01
Certain cell-surface receptors engage ligands expressed on juxtaposed cells and ligands on the same cell. The structural basis for trans versus cis binding is not known. Here, we showed that Ly49 natural killer (NK) cell receptors bound two MHC class I (MHC-I) molecules in trans when the two ligand-binding domains were backfolded onto the long stalk region. In contrast, dissociation of the ligand-binding domains from the stalk and their reorientation relative to the NK cell membrane allowed monovalent binding of MHC-I in cis. The distinct conformations (backfolded and extended) define the structural basis for cis-trans binding by Ly49 receptors andmore » explain the divergent functional consequences of cis versus trans interactions. Further analyses identified specific stalk segments that were not required for MHC-I binding in trans but were essential for inhibitory receptor function. These data identify multiple distinct roles of stalk regions for receptor function.« less
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Hardy, Andrew W; Graham, David R; Shearer, Gene M; Herbeuval, Jean-Philippe
2007-10-30
Plasmacytoid dendritic cells (pDC) are key players in viral immunity and produce IFN-alpha after HIV-1 exposure, which in turn regulates TNF-related apoptosis-inducing ligand (TRAIL) expression by CD4(+) T cells. We show here that infectious and noninfectious HIV-1 virions induce activation of pDC into TRAIL-expressing IFN-producing killer pDC (IKpDC). IKpDC expressed high levels of activation markers (HLA-DR, CD80, CD83, and CD86) and the migration marker CCR7. Surprisingly, CXCR4 and CCR5 were down-regulated on IKpDC. We also show that HIV-1-induced IKpDC depended on Toll-like receptor 7 (TLR7) activation. HIV-1 or TLR7 agonistexposed IKpDC induced apoptosis of the CD4(+) T cell line SupT1 via the TRAIL pathway. Furthermore, IFN-alpha produced after HIV-induced TLR7 stimulation was responsible for TRAIL expression and the down-regulation of both CXCR4 and CCR5 by IKpDC. In contrast, activation and migration markers were not regulated by IFN-alpha. Finally, IFN-alpha increased the survival of IKpDC. We characterized a subset of pDC with a killer activity that is activated by endosomal-associated viral RNA and not by infection.
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Multi-Agent Simulations of the Immune Response to Hiv during the Acute Stage of Infection
NASA Astrophysics Data System (ADS)
Walshe, R.; Ruskin, H. J.; Callaghan, A.
Results of multi-agent based simulations of the immune response to HIV during the acute phase of infection are presented here. The model successfully recreates the viral dynamics associated with the acute phase of infection, i.e., a rapid rise in viral load followed by a sharp decline to what is often referred to as a "set point", a result of T-cell response and emergence of HIV neutralizing antibodies. The results indicate that sufficient T Killer cell response is the key factor in controlling viral growth during this phase with antibody levels of critical importance only in the absence of a sufficient T Killer response.
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Immunomodulatory effects of aged garlic extract.
Kyo, E; Uda, N; Kasuga, S; Itakura, Y
2001-03-01
Using various kinds of models, we examined the effects of aged garlic extract (AGE) on immune functions. In the immunoglobulin (Ig)E-mediated allergic mouse model, AGE significantly decreased the antigen-specific ear swelling induced by picryl chloride ointment to the ear and intravenous administration of antitrinitrophenyl antibody. In the transplanted carcinoma cell model, AGE significantly inhibited the growth of Sarcoma-180 (allogenic) and LL/2 lung carcinoma (syngenic) cells transplanted into mice. Concomitantly, increases in natural killer (NK) and killer activities of spleen cells were observed in Sarcoma-180--bearing mice administered AGE. In the psychological stress model, AGE significantly prevented the decrease in spleen weight and restored the reduction of anti-SRBC hemolytic plaque-forming cells caused by the electrical stress. These studies strongly suggest that AGE could be a promising candidate as an immune modifier, which maintains the homeostasis of immune functions; further studies are warranted to determine when it is most beneficial.
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Jia, Wei; Feng, Jie; Zhang, Jing-Song; Lin, Chi-Chung; Wang, Wen-Han; Chen, Hong-Ge
2017-01-01
FVPA1, a novel polysaccharide, has been isolated from fruiting bodies of the culinary-medicinal mushroom Flammulina velutipes, a historically popular, widely cultivated and consumed functional food with an attractive taste, beneficial nutraceutical properties such as antitumor and immunomodulatory effects, and a number of essential biological activities. The average molecular weight was estimated to be ~1.8 × 104 Da based on high-performance size exclusion chromatography. Sugar analyses, methylation analyses, and 1H, 13C, and 2-dimensional nuclear magnetic resonance spectroscopy revealed the following structure of the repeating units of the FVPA1 polysaccharide Identification of this structure would conceivably lead to better understanding of the nutraceutical functions of this very important edible fungus. Bioactivity tests in vitro indicated that FVPA1 could significantly enhance natural killer cell activity against K562 tumor cells.
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Veinotte, Linnea; Gebremeskel, Simon; Johnston, Brent
2016-01-01
ABSTRACT Crosstalk interactions between dendritic cells (DCs) and invariant natural killer T (iNKT) cells are important in regulating antitumor responses elicited by glycolipid antigens. iNKT cells constitutively express the chemokine receptor CXCR6, while cytokine-activated DCs upregulate the transmembrane chemokine ligand, CXCL16. This study examined the co-stimulatory role of CXCR6/CXCL16 interactions in glycolipid-dependent iNKT cell activation and tumor control. Spleen and liver DCs in wild-type mice, but not iNKT cell deficient (Jα18−/−) mice, transiently upregulated surface CXCL16 following in vivo administration of the glycolipid antigen α-galactosylceramide. Recombinant CXCL16 did not directly induce iNKT cell activation in vitro but enhanced interferon (IFN)-γ production when mouse or human iNKT cells were stimulated with plate-bound anti-CD3. Compared with glycolipid-loaded CXCL16neg DCs, CXCL16hi DCs induced higher levels of IFNγ production in iNKT cell cultures and following adoptive transfer in vivo. The number of IFNγ+ iNKT cells and expansion of T-bet+ iNKT cells were reduced in vivo when CXCL16−/− DCs were used to activate iNKT cells. Enhanced IFNγ production in vivo was not dependent on CXCR6 expression on natural killer (NK) cells. Adoptive transfer of glycolipid-loaded CXCL16hi DCs provided superior protection against tumor metastasis compared to CXCL16neg DC transfers. Similarly, wild-type DCs provided superior protection against metastasis compared with CXCL16−/− DCs. These experiments implicate an important role for CXCR6/CXCL16 interactions in regulating iNKT cell IFNγ production and tumor control. The selective use of CXCL16hi DCs in adoptive transfer immunotherapies may prove useful for enhancing T helper (Th) type 1 responses and clinical outcomes in cancer patients. PMID:27471636
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Suppression of a Natural Killer Cell Response by Simian Immunodeficiency Virus Peptides
Schafer, Jamie L.; Ries, Moritz; Guha, Natasha; Connole, Michelle; Colantonio, Arnaud D.; Wiertz, Emmanuel J.; Wilson, Nancy A.; Kaur, Amitinder; Evans, David T.
2015-01-01
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. PMID:26333068
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NKT Cells as an Ideal Anti-Tumor Immunotherapeutic
Fujii, Shin-ichiro; Shimizu, Kanako; Okamoto, Yoshitaka; Kunii, Naoki; Nakayama, Toshinori; Motohashi, Shinichiro; Taniguchi, Masaru
2013-01-01
Human natural killer T (NKT) cells are characterized by their expression of an invariant T cell antigen receptor α chain variable region encoded by a Vα24Jα18 rearrangement. These NKT cells recognize α-galactosylceramide (α-GalCer) in conjunction with the MHC class I-like CD1d molecule and bridge the innate and acquired immune systems to mediate efficient and augmented immune responses. A prime example of one such function is adjuvant activity: NKT cells augment anti-tumor responses because they can rapidly produce large amounts of IFN-γ, which acts on NK cells to eliminate MHC negative tumors and also on CD8 cytotoxic T cells to kill MHC positive tumors. Thus, upon administration of α-GalCer-pulsed DCs, both MHC negative and positive tumor cells can be effectively eliminated, resulting in complete tumor eradication without tumor recurrence. Clinical trials have been completed in a cohort of 17 patients with advanced non-small cell lung cancers and 10 cases of head and neck tumors. Sixty percent of advanced lung cancer patients with high IFN-γ production had significantly prolonged median survival times of 29.3 months with only the primary treatment. In the case of head and neck tumors, 10 patients who completed the trial all had stable disease or partial responses 5 weeks after the combination therapy of α-GalCer-DCs and activated NKT cells. We now focus on two potential powerful treatment options for the future. One is to establish artificial adjuvant vector cells containing tumor mRNA and α-GalCer/CD1d. This stimulates host NKT cells followed by DC maturation and NK cell activation but also induces tumor-specific long-term memory CD8 killer T cell responses, suppressing tumor metastasis even 1 year after the initial single injection. The other approach is to establish induced pluripotent stem (iPS) cells that can generate unlimited numbers of NKT cells with adjuvant activity. Such iPS-derived NKT cells produce IFN-γ in vitro and in vivo upon stimulation with α-GalCer/DCs, and mediated adjuvant effects, suppressing tumor growth in vivo. PMID:24348476
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Riedel, Jan-Hendrik; Paust, Hans-Joachim; Turner, Jan-Eric; Tittel, André P.; Krebs, Christian; Disteldorf, Erik; Wegscheid, Claudia; Tiegs, Gisa; Velden, Joachim; Mittrücker, Hans-Willi; Garbi, Natalio; Stahl, Rolf A.K.; Steinmetz, Oliver M.; Kurts, Christian
2012-01-01
Immature renal dendritic cells (DCs) are protective early in murine crescentic GN, but the mechanisms underlying this protection are unknown. Here, depletion of DCs reduced the recruitment of invariant natural killer T (iNKT) cells, which attenuate GN, into the kidney in the early stage of experimental crescentic GN. More than 90% of renal iNKT cells expressed the chemokine receptor CXCR6, and renal DCs produced high amounts of the cognate ligand CXCL16 early after induction of nephritis, suggesting that renal DC-derived CXCL16 might attract protective CXCR6+ iNKT cells. Consistent with this finding, CXCR6-deficient mice exhibited less iNKT cell recruitment and developed nephritis that was more severe, similar to the aggravated nephritis observed in mice depleted of immature DCs. Finally, adoptive transfer of CXCR6-competent NKT cells ameliorated nephritis. Taken together, these results suggest an immunoprotective mechanism involving immature DCs, CXCL16, CXCR6, and regulatory iNKT cells, which might stimulate the development of new therapeutic strategies for GN. PMID:23138484
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Riedel, Jan-Hendrik; Paust, Hans-Joachim; Turner, Jan-Eric; Tittel, André P; Krebs, Christian; Disteldorf, Erik; Wegscheid, Claudia; Tiegs, Gisa; Velden, Joachim; Mittrücker, Hans-Willi; Garbi, Natalio; Stahl, Rolf A K; Steinmetz, Oliver M; Kurts, Christian; Panzer, Ulf
2012-12-01
Immature renal dendritic cells (DCs) are protective early in murine crescentic GN, but the mechanisms underlying this protection are unknown. Here, depletion of DCs reduced the recruitment of invariant natural killer T (iNKT) cells, which attenuate GN, into the kidney in the early stage of experimental crescentic GN. More than 90% of renal iNKT cells expressed the chemokine receptor CXCR6, and renal DCs produced high amounts of the cognate ligand CXCL16 early after induction of nephritis, suggesting that renal DC-derived CXCL16 might attract protective CXCR6(+) iNKT cells. Consistent with this finding, CXCR6-deficient mice exhibited less iNKT cell recruitment and developed nephritis that was more severe, similar to the aggravated nephritis observed in mice depleted of immature DCs. Finally, adoptive transfer of CXCR6-competent NKT cells ameliorated nephritis. Taken together, these results suggest an immunoprotective mechanism involving immature DCs, CXCL16, CXCR6, and regulatory iNKT cells, which might stimulate the development of new therapeutic strategies for GN.
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Peruzzi, Giovanna; Masilamani, Madhan; Borrego, Francisco; Coligan, John E
2009-01-01
Natural killer (NK) cells are lymphocytes generally recognized as sentinels of the innate immune system due to their inherent capacity to deal with diseased (stressed) cells, including malignant and infected. This ability to recognize many potentially pathogenic situations is due to the expression of a diverse panel of activation receptors. Because NK cell activation triggers an aggressive inflammatory response, it is important to have a means of throttling this response. Hence, NK cells also express a panel of inhibitory receptors that recognize ligands expressed by "normal" cells. Little or nothing is known about the endocytosis and trafficking of NK cell receptors, which are of great relevance to understanding how NK cells maintain the appropriate balance of activating and inhibitory receptors on their cell surface. In this review, we focus on the ITIM-containing inhibitory receptor CD94/NKG2A showing that it is endocytosed by a previously undescribed macropinocytic-like process that may be related to the maintenance of its surface expression.
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Welsh, R M; O'Donnell, C L; Shultz, L D
1994-01-01
The activation, proliferation, and antiviral effects of natural killer (NK) cells were examined in a newly developed stock of mice, C57BL/6JSz mice homozygous for the severe combined immunodeficiency (scid) mutation. These mice lack functional T and B cells and express the NK 1.1 alloantigen. Such NK 1.1 expression facilitates the analysis of NK cells and their depletion in vivo with a monoclonal anti-NK 1.1 antibody. These mice, therefore, provide an excellent model to examine unambiguously the interactions between viral infections and NK cells in a system devoid of adaptive immune response mechanisms. Here we show that murine cytomegalovirus (MCMV) and lymphocytic choriomeningitis virus (LCMV) infections resulted in profound levels of NK cell activation. NK cells also proliferated greatly in response to LCMV but generally to a lesser degree in response to MCMV. Depletion of the NK cell activity in vivo caused substantial increases in MCMV synthesis and MCMV-induced pathology. These results further support the concept that NK cells are major regulators of MCMV pathogenesis.
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Barreira da Silva, Rosa; Graf, Claudine
2011-01-01
Human mature dendritic cells (DCs) can efficiently stimulate natural killer (NK)–cell responses without being targeted by their cytotoxicity. To understand this important regulatory crosstalk, we characterized the development of the immunologic synapse between mature DCs and resting NK cells. Conjugates between these 2 innate leukocyte populations formed rapidly, persisted for prolonged time periods and matured with DC-derived f-actin polymerization at the synapse. Polarization of IL-12 and IL-12R to the synapse coincided with f-actin polymerization, while other activating and inhibitory molecules were enriched at the interface between DCs and NK cells earlier. Functional assays revealed that inhibition of f-actin polymerization in mature synapses led to an increase of IFN-γ secretion and cytotoxicity by NK cells. This elevated NK-cell reactivity resulted from decreased inhibitory signaling in the absence of MHC class I polarization at the interface, which was observed on inhibition of f-actin polymerization in DCs. Thus, inhibitory signaling is stabilized by f-actin at the synapse between mature DCs and resting NK cells. PMID:21917751
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Louagie, H; Philippé, J; Vral, A; Cornelissen, M; Thierens, H; De Ridder, L
1998-02-01
To investigate the chromosomal damage caused by gamma-irradiation in T lymphocytes and natural killer (NK) cells and compare this with apoptosis induction in both lymphocyte subsets. Apoptosis induction by gamma-irradiation in T lymphocytes and NK cells was quantified using the annexin V flow cytometric assay. The cytokinesis-block micronucleus (MN) assay was used to evaluate the induced cytogenetic damage. For the MN assays on NK cells, gamma-irradiated peripheral blood mononuclear cells were cultured and stimulated with interleukin 15 (IL-15). Afterwards the NK cells (characterized by the CD3-/CD56+ phenotype) were separated with the FACSort flow cytometer and the number of MN in the sorted binuclear cells was scored. Doses of 1 and 2 Gy gamma-irradiation were applied. Higher numbers of MN in NK cells were found compared with the MN yield in T lymphocytes. In contrast, NK cells were less than T lymphocytes prone to apoptosis after gamma-irradiation. The results support the view that cytogenetic damage and apoptosis after gamma-irradiation are not necessarily correlated.
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Advantages and applications of CAR-expressing natural killer cells
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
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Interactions between human mesenchymal stem cells and natural killer cells.
Sotiropoulou, Panagiota A; Perez, Sonia A; Gritzapis, Angelos D; Baxevanis, Constantin N; Papamichail, Michael
2006-01-01
Mesenchymal stem cells (MSCs) are multipotent progenitor cells representing an attractive therapeutic tool for regenerative medicine. They possess unique immunomodulatory properties, being capable of suppressing T-cell responses and modifying dendritic cell differentiation, maturation, and function, whereas they are not inherently immunogenic, failing to induce alloreactivity to T cells and freshly isolated natural killer (NK) cells. To clarify the generation of host immune responses to implanted MSCs in tissue engineering and their potential use as immunosuppressive elements, the effect of MSCs on NK cells was investigated. We demonstrate that at low NK-to-MSC ratios, MSCs alter the phenotype of NK cells and suppress proliferation, cytokine secretion, and cyto-toxicity against HLA-class I- expressing targets. Some of these effects require cell-to-cell contact, whereas others are mediated by soluble factors, including transforming growth factor-beta1 and prostaglandin E2, suggesting the existence of diverse mechanisms for MSC-mediated NK-cell suppression. On the other hand, MSCs are susceptible to lysis by activated NK cells. Overall, these data improve our knowledge of interactions between MSCs and NK cells and consequently of their effect on innate immune responses and their contribution to the regulation of adaptive immunity, graft rejection, and cancer immunotherapy.
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Natural killer cells and regulatory T cells in early pregnancy loss
SHARMA, SURENDRA
2015-01-01
Survival of the allogeneic embryo in the uterus depends on the maintenance of immune tolerance at the maternal-fetal interface. The pregnant uterus is replete with activated maternal immune cells. How this immune tolerance is acquired and maintained has been a topic of intense investigation. The key immune cells that predominantly populate the pregnant uterus are natural killer (NK) cells. In normal pregnancy, these cells are not killers, but rather provide a microenvironment that is pregnancy compatible and supports healthy placentation. In placental mammals, an array of highly orchestrated immune elements to support successful pregnancy outcome has been incorporated. This includes active cooperation between maternal immune cells, particularly NK cells, and trophoblast cells. This intricate process is required for placentation, immune regulation and to remodel the blood supply to the fetus. During the past decade, various types of maternal immune cells have been thought to be involved in cross-talk with trophoblasts and in programming immune tolerance. RegulatoryT cells (Tregs) have attracted a great deal of attention in promoting implantation and immune tolerance beyond implantation. However, what has not been fully addressed is how this immune-trophoblast axis breaks down during adverse pregnancy outcomes, particularly early pregnancy loss, and in response to unscheduled inflammation. Intense research efforts have begun to shed light on the roles of NK cells and Tregs in early pregnancy loss, although much remains to be unraveled in order to fully characterize the mechanisms underlying their detrimental activity. An increased understanding of host-environment interactions that lead to the cytotoxic phenotype of these otherwise pregnancy compatible maternal immune cells is important for prediction, prevention and treatment of pregnancy maladies, particularly recurrent pregnancy loss. In this review, we discuss relevant information from experimental and human models that may explain the pregnancy disrupting roles of these pivotal sentinel cells at the maternal-fetal interface. PMID:25023688
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Xing, Yawei; Yang, Junwen; Lian, Guanghui; Chen, Shuijiao; Chen, Linlin; Li, Fujun
2017-05-01
Chronic active Epstein-Barr virus infection (CAEBV) associated with hemophagocytic syndrome (HPS) and extra-nodal natural killer (NK)/T-cell lymphoma (ENKL) is a rare life-threatening disorder. This disease is easily misdiagnosed because of its varied presentations. An 18-year-old girl was admitted to our hospital with a history of edema in the lower limbs and intermittent fever lasting for more than 1 month. At admission, she had severe liver injury of unknown etiology. Laboratory test results revealed pancytopenia, hyperferritinemia, hypertriglyceridemia, and hypofibrinogenemia. Results of serologic tests for EBV were positive. Results of a skin biopsy indicated EBV-positive NK/T-cell lymphoma, and bone marrow aspiration revealed focal hemophagocytosis and atypical lymphoid cells. On the basis of these findings, we diagnosed the case as extra-nodal NK/T-cell lymphoma-associated HPS (natural killer/T-cell lymphoma-associated hemophagocytic syndrome), which is commonly induced by CAEBV. Treatment consisted of general management of hepatitis, supplemented with albumin and empirical antibiotic therapy. The patient died from massive gastrointestinal hemorrhage a week after she was discharged from the hospital. ENKL and HPS present with varied features and are generally fatal; therefore, clinicians should proceed with caution in suspected cases. HPS should be considered when the patient presents with fever, hepatosplenomegaly, pancytopenia, and liver failure. When HPS is suspected, clinicians should determine the underlying cause, such as severe infection, including infection with viruses such as EBV; genetic predisposition; or underlying malignancies, especially lymphoma because of its strong association with HPS.
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Li, Xiaofeng; Dai, Dong; Song, Xiuyu; Liu, Jianjing; Zhu, Lei; Xu, Wengui
2014-10-01
There was a continuing controversy on whether the adoptive transfusion of cytokine-induced killer cells (CIK) therapy should have been recommended to reduce the recurrence and metastasis of hepatocellular carcinoma (HCC) after minimally invasive therapy such as TACE (transarterial chemoembolization) or TACE plus RFA (radiofrequency ablation) treatment. The meta-analysis was conducted to compare the effectiveness of CIK cells transfusion therapy combined with TACE or TACE plus RFA treatment with that of minimally invasive therapy alone. Relevant studies were identified by electronic search using a combination of "hepatocellular carcinoma" and "cytokine-induced killer cells". Overall survival (OS) rates and recurrence-free survival (RFS) rates were compared as the major outcome measures. The meta-analysis was divided into two sub-studies (sub-study 1: CIK+TACE+RFA versus TACE+RFA; sub-study 2: CIK+TACE versus TACE) to avoid the risk of bias as we could. Meta-analysis data suggested that CIK cells transfusion therapy combined with TACE plus RFA treatment was associated with higher 1-year RFS rate (odds ratio [OR]=2.46) and 1-year, 2-year OS rates (OR: 1-year=2.09; 3-year=2.16) than TACE plus RFA treatment alone in sub-study 1. For sub-study 2, there were significant differences between CIK+TACE group and TACE group for OS rates (OR: half-year=3.29; 1-year=3.71; 2-year=7.37). CIK cells transfusion therapy truly showed a synergistic effect for HCC patients after minimally invasive treatment especially for a long-term survival. Copyright © 2014 Elsevier Masson SAS. All rights reserved.
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New Directions for Natural Killer T Cells in the Immunotherapy of Cancer
Teyton, Luc
2017-01-01
Natural killer T (NKT) cells have been placed at the interface between innate and adaptive immunity by a long series of experiments that convincingly showed that beyond cytokine secretion and NK cell recruitment, NKT cells were coordinating dendritic cell and B cell maturation through direct membrane contacts and initiate productive responses. As such, NKT cells are the cellular adjuvant of many immune reactions and have functions that go much beyond what their name encapsulates. In addition, the initial discovery of the ligands of NKT cells is deeply linked to cancer biology and therapy. However, for a host of reasons, animal models in which agonists of NKT cells were used did not translate well to human cancers. A systematic reassessment of NKT cells role in tumorigenesis, especially spontaneous one, is now accessible using single cell analysis technologies both in mouse and man, and should be taken advantage of. Similarly, the migration, localization, phenotype of NKT cells following induced expansion after injection of an agonist can be examined at the single cell level. This technological revolution will help evaluate where and how NKT cells can be used in cancer. PMID:29209309
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Chimeric Antigen Receptors in Different Cell Types: New Vehicles Join the Race.
Harrer, Dennis C; Dörrie, Jan; Schaft, Niels
2018-05-01
Adoptive cellular therapy has evolved into a powerful force in the battle against cancer, holding promise for curative responses in patients with advanced and refractory tumors. Autologous T cells, reprogrammed to target malignant cells via the expression of a chimeric antigen receptor (CAR) represent the frontrunner in this approach. Tremendous clinical regressions have been achieved using CAR-T cells against a variety of cancers both in numerous preclinical studies and in several clinical trials, most notably against acute lymphoblastic leukemia, and resulted in a very recent United States Food and Drug Administration approval of the first CAR-T-cell therapy. In most studies CARs are transferred to conventional αβT cells. Nevertheless, transferring a CAR into different cell types, such as γδT cells, natural killer cells, natural killer T cells, and myeloid cells has yet received relatively little attention, although these cell types possess unique features that may aid in surmounting some of the hurdles CAR-T-cell therapy currently faces. This review focuses on CAR therapy using effectors beyond conventional αβT cells and discusses those strategies against the backdrop of developing a safe, powerful, and durable cancer therapy.
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Role of natural killer cells in lung cancer.
Aktaş, Ozge Nur; Öztürk, Ayşe Bilge; Erman, Baran; Erus, Suat; Tanju, Serhan; Dilege, Şükrü
2018-06-01
One of the key immune cells involved in the pathogenesis of lung cancer is natural killer (NK) cells and these cells are novel targets for therapeutic applications in lung cancer. The purpose of this review is to summarize the current literature on lung cancer pathogenesis with a focus on the interaction between NK cells and smoking, how these factors are related to the pathogenesis of lung cancer and how NK cell-based immunotherapy effect lung cancer survival. The relevant literature from PubMed and Medline databases is reviewed in this article. The cytolytic potential of NK cells are reduced in lung cancer and increasing evidence suggests that improving NK cell functioning may induce tumor regression. Recent clinical trials on NK cell-based novel therapies such as cytokines including interleukin (IL)-15, IL-12 and IL-2, NK-92 cell lines and allogenic NK cell immunotherapy showed promising results with less adverse effects on the lung cancer survival. The NK cell targeting strategy has not yet been approved for lung cancer treatment. More clinical studies focusing on the role of NK cells in lung cancer pathogenesis are warranted to develop novel NK cell-based therapeutic approaches for the treatment of lung cancer.
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Immunology: Is Actin at the Lytic Synapse a Friend or a Foe?
Hammer, John A
2018-02-19
Cytotoxic T cells and natural killer cells defend us against disease by secreting lytic granules. Whether actin facilitates or thwarts lytic granule secretion has been an open question. Recent results now indicate that the answer depends on the maturation stage of the immune cell-target cell contact. Published by Elsevier Ltd.
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Carlin, Lindsey E.; Hemann, Emily A.; Zacharias, Zeb R.; Heusel, Jonathan W.; Legge, Kevin L.
2018-01-01
Natural killer (NK) cells are vital components of the antiviral immune response, but their contributions in defense against influenza A virus (IAV) are not well understood. To better understand NK cell responses during IAV infections, we examined the magnitude, kinetics, and contribution of NK cells to immunity and protection during high- and low-dose IAV infections. Herein, we demonstrate an increased accumulation of NK cells in the lung in high-dose vs. low-dose infections. In part, this increase is due to the local proliferation of pulmonary NK cells. However, the majority of NK cell accumulation within the lungs and airways during an IAV infection is due to recruitment that is partially dependent upon CXCR3 and CCR5, respectively. Therefore, altogether, our results demonstrate that NK cells are actively recruited to the lungs and airways during IAV infection and that the magnitude of the recruitment may relate to the inflammatory environment found within the tissues during high- and low-dose IAV infections. PMID:29719539
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Imaging burst kinetics and spatial coordination during serial killing by single natural killer cells
Choi, Paul J.; Mitchison, Timothy J.
2013-01-01
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. PMID:23576740
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Schmidt, Stanislaw; Tramsen, Lars; Rais, Bushra; Ullrich, Evelyn; Lehrnbecher, Thomas
2018-01-01
Natural Killer (NK) cells are involved in the host immune response against infections due to viral, bacterial and fungal pathogens, all of which are a significant cause of morbidity and mortality in immunocompromised patients. Since the recovery of the immune system has a major impact on the outcome of an infectious complication, there is major interest in strengthening the host response in immunocompromised patients, either by using cytokines or growth factors or by adoptive cellular therapies transfusing immune cells such as granulocytes or pathogen-specific T-cells. To date, relatively little is known about the potential of adoptively transferring NK cells in immunocompromised patients with infectious complications, although the anti-cancer property of NK cells is already being investigated in the clinical setting. This review will focus on the antimicrobial properties of NK cells and the current standing and future perspectives of generating and using NK cells as immunotherapy in patients with infectious complications, an approach which is promising and might have an important clinical impact in the future. PMID:29755697
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Natural Killer Cells Control Tumor Growth by Sensing a Growth Factor.
Barrow, Alexander D; Edeling, Melissa A; Trifonov, Vladimir; Luo, Jingqin; Goyal, Piyush; Bohl, Benjamin; Bando, Jennifer K; Kim, Albert H; Walker, John; Andahazy, Mary; Bugatti, Mattia; Melocchi, Laura; Vermi, William; Fremont, Daved H; Cox, Sarah; Cella, Marina; Schmedt, Christian; Colonna, Marco
2018-01-25
Many tumors produce platelet-derived growth factor (PDGF)-DD, which promotes cellular proliferation, epithelial-mesenchymal transition, stromal reaction, and angiogenesis through autocrine and paracrine PDGFRβ signaling. By screening a secretome library, we found that the human immunoreceptor NKp44, encoded by NCR2 and expressed on natural killer (NK) cells and innate lymphoid cells, recognizes PDGF-DD. PDGF-DD engagement of NKp44 triggered NK cell secretion of interferon gamma (IFN)-γ and tumor necrosis factor alpha (TNF-α) that induced tumor cell growth arrest. A distinctive transcriptional signature of PDGF-DD-induced cytokines and the downregulation of tumor cell-cycle genes correlated with NCR2 expression and greater survival in glioblastoma. NKp44 expression in mouse NK cells controlled the dissemination of tumors expressing PDGF-DD more effectively than control mice, an effect enhanced by blockade of the inhibitory receptor CD96 or CpG-oligonucleotide treatment. Thus, while cancer cell production of PDGF-DD supports tumor growth and stromal reaction, it concomitantly activates innate immune responses to tumor expansion. Copyright © 2017 Elsevier Inc. All rights reserved.
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CD20-Positive nodal natural killer/T-cell lymphoma with cutaneous involvement.
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. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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Natural Killer Cell Function and Dysfunction in Hepatitis C Virus Infection
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
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Immunotherapeutic strategies targeting Natural killer T cell responses in cancer
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
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Crystal structure of phototoxic orange fluorescent proteins with α tryptophan-based chromophore
Pletneva, Nadya V.; Pletnev, Vladimir Z.; Sarkisyan, Karen S.; ...
2015-12-23
Phototoxic fluorescent proteins represent a sparse group of genetically encoded photosensitizers that could be used for precise light-induced inactivation of target proteins, DNA damage, and cell killing. Only two such GFP-based fluorescent proteins (FPs), KillerRed and its monomeric variant SuperNova, were described up to date. We present a crystallographic study of their two orange successors, dimeric KillerOrange and monomeric mKiller-Orange, at 1.81 and 1.57 Å resolution, respectively. They are the first orange-emitting protein photosensitizers with a tryptophan-based chromophore (Gln65-Trp66-Gly67). Same as their red progenitors, both orange photosensitizers have a water-filled channel connecting the chromophore to the β-barrel exterior and enablingmore » transport of ROS. In both proteins, Trp66 of the chromophore adopts an unusual trans-cis conformation stabilized by H-bond with the nearby Gln159. This trans-cis conformation along with the water channel was shown to be a key structural feature providing bright orange emission and phototoxicity of both examined orange photosensitizers.« less
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Crystal Structure of Phototoxic Orange Fluorescent Proteins with a Tryptophan-Based Chromophore
Pletneva, Nadya V.; Pletnev, Vladimir Z.; Sarkisyan, Karen S.; Gorbachev, Dmitry A.; Egorov, Evgeny S.; Mishin, Alexander S.; Lukyanov, Konstantin A.; Dauter, Zbigniew; Pletnev, Sergei
2015-01-01
Phototoxic fluorescent proteins represent a sparse group of genetically encoded photosensitizers that could be used for precise light-induced inactivation of target proteins, DNA damage, and cell killing. Only two such GFP-based fluorescent proteins (FPs), KillerRed and its monomeric variant SuperNova, were described up to date. Here, we present a crystallographic study of their two orange successors, dimeric KillerOrange and monomeric mKillerOrange, at 1.81 and 1.57 Å resolution, respectively. They are the first orange-emitting protein photosensitizers with a tryptophan-based chromophore (Gln65-Trp66-Gly67). Same as their red progenitors, both orange photosensitizers have a water-filled channel connecting the chromophore to the β-barrel exterior and enabling transport of ROS. In both proteins, Trp66 of the chromophore adopts an unusual trans-cis conformation stabilized by H-bond with the nearby Gln159. This trans-cis conformation along with the water channel was shown to be a key structural feature providing bright orange emission and phototoxicity of both examined orange photosensitizers. PMID:26699366
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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. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.
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Naito, Yasuhiro; Marotta, Francesco; Kantah, Makoto K; Zerbinati, Nicola; Kushugulova, Almagul; Zhumadilov, Zhaxybay; Illuzzi, Nicola; Sapienza, Chiara; Takadanohara, Hiroshi; Kobayashi, Riyichi; Catanzaro, Roberto
2014-04-01
The aim of this study was to assess the immunomodulatory effect of KC-1317 (a symbiotic mixture containing Saccharomyces boulardii lysate in a cranberry, colostrum-derived lactoferrin, fragaria, and lactose mixture) supplementation in immune-compromised but otherwise healthy elderly subjects. A liquid formulation of KC-1317 was administered in a randomized controlled trial (RCT) fashion to healthy volunteers (65-79 years) previously selected for low natural killer (NK) cell activity, and this parameter was checked at the completion of the study. A significant improvement in NK cell activity of KC-1317 consumers was observed as compared to placebo at the end of 2 months. Although preliminary, these beneficial immune-modulatory effects of KC-1317 in aged individuals might indicate its employment within a wider age-management strategy.
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Li, Yanan; Fu, Xiaorui; Wu, Jingjing; Yu, Chang; Li, Zhaoming; Sun, Zhenchang; Yan, Jiaqin; Nan, Feifei; Zhang, Xundong; Li, Ling; Li, Xin; Zhang, Lei; Li, Wencai; Wang, Guannan; Zhang, Mingzhi
2018-05-01
Extranodal natural killer/T-cell lymphoma (NKTL), nasal-type is one of the most aggressive lymphoid malignancies and is characterized by an extremely poor survival outcome. The present study reports the case of a 39-year-old Chinese male with history of extranodal NKTL who presented with a painless indurated mass in the glans penis. The results of an incisional biopsy revealed atypical cells that were positive for CD3, CD56, T-cell-restricted intracellular antigen-1, granzyme B and Epstein-Barr virus-encoded RNA, and negative for CD20. A diagnosis of metastatic NKTL was determined. The patient was treated with systemic chemotherapy consisting of cisplatin, dexamethasone, gemcitabine and pegaspargase, which resulted in remission and regression of the mass. In addition, a review of the literature was performed, and the data for 13 cases of non-B-cell penile lymphoma, including the present case, are presented. To the best of our knowledge, this is first review of this entity.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Lill, P.H.; Gangemi, D.
1986-01-01
Transient suppression of splenic natural killer (NK), natural cytotoxic (NC) and peritoneal macrophage cytotoxicity was observed following a single injection of 3-methylcholanthrene (3-MC) into C3H/HeN mice. Natural killer cell activity was depressed by 30-60% 4-6 d after injection of 1.0 mg 3-MC. Levels of NK reactivity returned to normal 8 d post 3-MC injection, and no suppression of natural killing was seen when tested 6 wk after 3-MC treatment. 3-MC did not affect propionibacterium acnes augmentation of NK cell activity when tested both 6 d and 6 wk after carcinogen injection. The results indicate that the observed suppression of naturallymore » cytotoxic cells may not be important in allowing 3-MC-induced tumors to grow, since suppression is not long-lasting. Therefore, any effect on tumor growth mediated by a suppression of naturally cytotoxic cells would have to be exerted at the earliest stages of tumor development.« less
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Dannemann, B.R.; Morris, V.A.; Araujo, F.G.
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 themore » 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.« less
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Wu, Zeguang; Sinzger, Christian; Frascaroli, Giada; Reichel, Johanna; Bayer, Carina; Wang, Li; Schirmbeck, Reinhold; Mertens, Thomas
2013-07-01
Recent studies indicate that expansion of NKG2C-positive natural killer (NK) cells is associated with human cytomegalovirus (HCMV); however, their activity in response to HCMV-infected cells remains unclear. We show that NKG2C(hi) CD57(hi) NK cells gated on CD3(neg) CD56(dim) cells can be phenotypically identified as HCMV-induced NK cells that can be activated by HCMV-infected cells. Using HCMV-infected autologous macrophages as targets, we were able to show that these NKG2C(hi) CD57(hi) NK cells are highly responsive to HCMV-infected macrophages only in the presence of HCMV-specific antibodies, whereas they are functionally poor effectors of natural cytotoxicity. We further demonstrate that NKG2C(hi) CD57(hi) NK cells are intrinsically responsive to signaling through CD16 cross-linking. Our findings show that the activity of pathogen-induced innate immune cells can be enhanced by adaptive humoral immunity. Understanding the activity of NKG2C(hi) CD57(hi) NK cells against HCMV-infected cells will be of relevance for the further development of adoptive immunotherapy.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Kwon, Hyeok-Ran; Lee, Ki Won; Dong, Zigang
2010-01-01
T-lymphokine-activated killer cell-originated protein kinase (TOPK) appears to be highly expressed in various cancer cells and to play an important role in maintaining proliferation of cancer cells. However, the underlying mechanism by which TOPK regulates growth of cancer cells remains elusive. Here we report that upregulated endogenous TOPK augments resistance of cancer cells to apoptosis induced by tumor necrosis factor-related apoptosis inducing ligand (TRAIL). Stable knocking down of TOPK markedly increased TRAIL-mediated apoptosis of human HeLa cervical cancer cells, as compared with control cells. Caspase 8 or caspase 3 activities in response to TRAIL were greatly incremented in TOPK-depleted cells.more » Ablation of TOPK negatively regulated TRAIL-mediated NF-{kappa}B activity. Furthermore, expression of NF-{kappa}B-dependent genes, FLICE-inhibitory protein (FLIP), inhibitor of apoptosis protein 1 (c-IAP1), or X-linked inhibitor of apoptosis protein (XIAP) was reduced in TOPK-depleted cells. Collectively, these findings demonstrated that TOPK contributed to TRAIL resistance of cancer cells via NF-{kappa}B activity, suggesting that TOPK might be a potential molecular target for successful cancer therapy using TRAIL.« less
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Stephens, Camilla; Moreno-Casares, Antonia; López-Nevot, Miguel-Ángel; García-Cortés, Miren; Medina-Cáliz, Inmaculada; Hallal, Hacibe; Soriano, German; Roman, Eva; Ruiz-Cabello, Francisco; Romero-Gomez, Manuel; Lucena, M Isabel; Andrade, Raúl J
2016-01-01
Natural killer cells are an integral part of the immune system and represent a large proportion of the lymphocyte population in the liver. The activity of these cells is regulated by various cell surface receptors, such as killer Ig-like receptors (KIR) that bind to human leukocyte antigen (HLA) class I ligands on the target cell. The composition of KIR receptors has been suggested to influence the development of specific diseases, in particularly autoimmune diseases, cancer and reproductive diseases. The role played in idiosyncratic drug-induced liver injury (DILI) is currently unknown. In this study, we examined KIR gene profiles and HLA class I polymorphisms in amoxicillin-clavulanate (AC) DILI patients in search for potential risk associations. One hundred and two AC DILI patients and 226 controls were genotyped for the presence or absence of 16 KIR loci, including the two pseudogenes 2DP1 and 3DP1. No significant differences were found in the distribution of individual KIRs between patients and controls, which were comparable to previously reported KIR data from ethnically similar cohorts. The 21.6 and 21.2% of the patients and controls, respectively, were homozygous haplotype A carriers, while 78.4 and 78.8%, respectively, contained at least one B haplotype (Bx). The genotypes translated into 27 (AC DILI) and 46 (controls) different gene profiles, with 19 being present in both groups. The most frequent Bx gene profile containing KIRs 2DS2, 2DL2, 2DL3, 2DP1, 2DL1, 3DL1, 2DS4, 3DL2, 3DL3, 2DL4, and 3PD1 was present in 16% of the DILI patients and 14% of the controls. The distribution of HLA class I epitopes did not differ significantly between AC DILI patients and controls. The most frequent receptor-ligand combinations in the DILI patients were 2DL3 + epitope C1 (67%) and 3DL1 + Bw4 motif (67%), while 2DL1 + epitope C2 (69%) and 3DL1 + Bw4 motif (69%) predominated in the controls. This is to our knowledge the first analysis of KIR receptor-HLA ligand associations in DILI, although our findings do not support evidence of these genetic variations playing a major role in AC DILI development.
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Stephens, Camilla; Moreno-Casares, Antonia; López-Nevot, Miguel-Ángel; García-Cortés, Miren; Medina-Cáliz, Inmaculada; Hallal, Hacibe; Soriano, German; Roman, Eva; Ruiz-Cabello, Francisco; Romero-Gomez, Manuel; Lucena, M. Isabel; Andrade, Raúl J.
2016-01-01
Natural killer cells are an integral part of the immune system and represent a large proportion of the lymphocyte population in the liver. The activity of these cells is regulated by various cell surface receptors, such as killer Ig-like receptors (KIR) that bind to human leukocyte antigen (HLA) class I ligands on the target cell. The composition of KIR receptors has been suggested to influence the development of specific diseases, in particularly autoimmune diseases, cancer and reproductive diseases. The role played in idiosyncratic drug-induced liver injury (DILI) is currently unknown. In this study, we examined KIR gene profiles and HLA class I polymorphisms in amoxicillin-clavulanate (AC) DILI patients in search for potential risk associations. One hundred and two AC DILI patients and 226 controls were genotyped for the presence or absence of 16 KIR loci, including the two pseudogenes 2DP1 and 3DP1. No significant differences were found in the distribution of individual KIRs between patients and controls, which were comparable to previously reported KIR data from ethnically similar cohorts. The 21.6 and 21.2% of the patients and controls, respectively, were homozygous haplotype A carriers, while 78.4 and 78.8%, respectively, contained at least one B haplotype (Bx). The genotypes translated into 27 (AC DILI) and 46 (controls) different gene profiles, with 19 being present in both groups. The most frequent Bx gene profile containing KIRs 2DS2, 2DL2, 2DL3, 2DP1, 2DL1, 3DL1, 2DS4, 3DL2, 3DL3, 2DL4, and 3PD1 was present in 16% of the DILI patients and 14% of the controls. The distribution of HLA class I epitopes did not differ significantly between AC DILI patients and controls. The most frequent receptor-ligand combinations in the DILI patients were 2DL3 + epitope C1 (67%) and 3DL1 + Bw4 motif (67%), while 2DL1 + epitope C2 (69%) and 3DL1 + Bw4 motif (69%) predominated in the controls. This is to our knowledge the first analysis of KIR receptor-HLA ligand associations in DILI, although our findings do not support evidence of these genetic variations playing a major role in AC DILI development. PMID:27616993
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NK cell development requires Tsc1-dependent negative regulation of IL-15-triggered mTORC1 activation
Yang, Meixiang; Chen, Shasha; Du, Juan; He, Junming; Wang, Yuande; Li, Zehua; Liu, Guangao; Peng, Wanwen; Zeng, Xiaokang; Li, Dan; Xu, Panglian; Guo, Wei; Chang, Zai; Wang, Song; Tian, Zhigang; Dong, Zhongjun
2016-01-01
Activation of metabolic signalling by IL-15 is required for natural killer (NK) cell development. Here we show that Tsc1, a repressor of mTOR, is dispensable for the terminal maturation, survival and function of NK cells but is critical to restrict exhaustive proliferation of immature NK cells and activation downstream of IL-15 during NK cell development. Tsc1 is expressed in immature NK cells and is upregulated by IL-15. Haematopoietic-specific deletion of Tsc1 causes a marked decrease in the number of NK cells and compromises rejection of ‘missing-self' haematopoietic tumours and allogeneic bone marrow. The residual Tsc1-null NK cells display activated, pro-apoptotic phenotype and elevated mTORC1 activity. Deletion of Raptor, a component of mTORC1, largely reverses these defects. Tsc1-deficient NK cells express increased levels of T-bet and downregulate Eomes and CD122, a subunit of IL-15 receptor. These results reveal a role for Tsc1-dependent inhibition of mTORC1 activation during immature NK cell development. PMID:27601261
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Rodríguez-Cousiño, Nieves
2016-01-01
ABSTRACT Saccharomyces cerevisiae killer strains secrete a protein toxin active on nonkiller strains of the same (or other) yeast species. Different killer toxins, K1, K2, K28, and Klus, have been described. Each toxin is encoded by a medium-size (1.5- to 2.3-kb) M double-stranded RNA (dsRNA) located in the cytoplasm. M dsRNAs require L-A helper virus for maintenance. L-A belongs to the Totiviridae family, and its dsRNA genome of 4.6 kb codes for the major capsid protein Gag and a minor Gag-Pol protein, which form the virions that separately encapsidate L-A or the M satellites. Different L-A variants exist in nature; on average, 24% of their nucleotides are different. Previously, we reported that L-A-lus was specifically associated with Mlus, suggesting coevolution, and proposed a role of the toxin-encoding M dsRNAs in the appearance of new L-A variants. Here we confirm this by analyzing the helper virus in K2 killer wine strains, which we named L-A-2. L-A-2 is required for M2 maintenance, and neither L-A nor L-A-lus shows helper activity for M2 in the same genetic background. This requirement is overcome when coat proteins are provided in large amounts by a vector or in ski mutants. The genome of another totivirus, L-BC, frequently accompanying L-A in the same cells shows a lower degree of variation than does L-A (about 10% of nucleotides are different). Although L-BC has no helper activity for M dsRNAs, distinct L-BC variants are associated with a particular killer strain. The so-called L-BC-lus (in Klus strains) and L-BC-2 (in K2 strains) are analyzed. IMPORTANCE Killer strains of S. cerevisiae secrete protein toxins that kill nonkiller yeasts. The “killer phenomenon” depends on two dsRNA viruses: L-A and M. M encodes the toxin, and L-A, the helper virus, provides the capsids for both viruses. Different killer toxins exist: K1, K2, K28, and Klus, encoded on different M viruses. Our data indicate that each M dsRNA depends on a specific helper virus; these helper viruses have nucleotide sequences that may be as much as 26% different, suggesting coevolution. In wine environments, K2 and Klus strains frequently coexist. We have previously characterized the association of Mlus and L-A-lus. Here we sequence and characterize L-A-2, the helper virus of M2, establishing the helper virus requirements of M2, which had not been completely elucidated. We also report the existence of two specific L-BC totiviruses in Klus and K2 strains with about 10% of their nucleotides different, suggesting different evolutionary histories from those of L-A viruses. PMID:27940540
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AHR prevents human IL-1R1hi ILC3 differentiation to natural killer cells
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
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Restoring Natural Killer Cell Immunity against Multiple Myeloma in the Era of New Drugs
Pittari, Gianfranco; Vago, Luca; Festuccia, Moreno; Bonini, Chiara; Mudawi, Deena; Giaccone, Luisa; Bruno, Benedetto
2017-01-01
Transformed plasma cells in multiple myeloma (MM) are susceptible to natural killer (NK) cell-mediated killing via engagement of tumor ligands for NK activating receptors or “missing-self” recognition. Similar to other cancers, MM targets may elude NK cell immunosurveillance by reprogramming tumor microenvironment and editing cell surface antigen repertoire. Along disease continuum, these effects collectively result in a progressive decline of NK cell immunity, a phenomenon increasingly recognized as a critical determinant of MM progression. In recent years, unprecedented efforts in drug development and experimental research have brought about emergence of novel therapeutic interventions with the potential to override MM-induced NK cell immunosuppression. These NK-cell enhancing treatment strategies may be identified in two major groups: (1) immunomodulatory biologics and small molecules, namely, immune checkpoint inhibitors, therapeutic antibodies, lenalidomide, and indoleamine 2,3-dioxygenase inhibitors and (2) NK cell therapy, namely, adoptive transfer of unmanipulated and chimeric antigen receptor-engineered NK cells. Here, we summarize the mechanisms responsible for NK cell functional suppression in the context of cancer and, specifically, myeloma. Subsequently, contemporary strategies potentially able to reverse NK dysfunction in MM are discussed. PMID:29163516
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NKT Cell Networks in the Regulation of Tumor Immunity
Robertson, Faith C.; Berzofsky, Jay A.; Terabe, Masaki
2014-01-01
CD1d-restricted natural killer T (NKT) cells lie at the interface between the innate and adaptive immune systems and are important mediators of immune responses and tumor immunosurveillance. These NKT cells uniquely recognize lipid antigens, and their rapid yet specific reactions influence both innate and adaptive immunity. In tumor immunity, two NKT subsets (type I and type II) have contrasting roles in which they not only cross-regulate one another, but also impact innate immune cell populations, including natural killer, dendritic, and myeloid lineage cells, as well as adaptive populations, especially CD8+ and CD4+ T cells. The extent to which NKT cells promote or suppress surrounding cells affects the host’s ability to prevent neoplasia and is consequently of great interest for therapeutic development. Data have shown the potential for therapeutic use of NKT cell agonists and synergy with immune response modifiers in both pre-clinical studies and preliminary clinical studies. However, there is room to improve treatment efficacy by further elucidating the biological mechanisms underlying NKT cell networks. Here, we discuss the progress made in understanding NKT cell networks, their consequent role in the regulation of tumor immunity, and the potential to exploit that knowledge in a clinical setting. PMID:25389427
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Kang, Seung-Ji; Jin, Hye-Mi; Cho, Young-Nan; Kim, Seong Eun; Kim, Uh Jin; Park, Kyung-Hwa; Jang, Hee-Chang; Jung, Sook-In; Kee, Seung-Jung; Park, Yong-Wook
2017-07-01
Natural killer (NK) cells are essential immune cells against several pathogens. Not much is known regarding the roll of NK cells in Orientia tsutsugamushi infection. Thus, this study aims to determine the level, function, and clinical relevance of NK cells in patients with scrub typhus. This study enrolled fifty-six scrub typhus patients and 56 health controls (HCs). The patients were divided into subgroups according to their disease severity. A flow cytometry measured NK cell level and function in peripheral blood. Circulating NK cell levels and CD69 expressions were significantly increased in scrub typhus patients. Increased NK cell levels reflected disease severity. In scrub typhus patients, tests showed their NK cells produced higher amounts of interferon (IFN)-γ after stimulation with interleukin (IL)-12 and IL-18 relative to those of HCs. Meanwhile, between scrub typhus patients and HCs, the cytotoxicity and degranulation of NK cells against K562 were comparable. CD69 expressions were recovered to the normal levels in the remission phase. This study shows that circulating NK cells are activated and numerically increased, and they produced more IFN-γ in scrub typhus patients.
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Cho, Young-Nan; Kim, Seong Eun; Kim, Uh Jin; Park, Kyung-Hwa; Jang, Hee-Chang; Jung, Sook-In; Kee, Seung-Jung
2017-01-01
Background Natural killer (NK) cells are essential immune cells against several pathogens. Not much is known regarding the roll of NK cells in Orientia tsutsugamushi infection. Thus, this study aims to determine the level, function, and clinical relevance of NK cells in patients with scrub typhus. Methodology/Principal findings This study enrolled fifty-six scrub typhus patients and 56 health controls (HCs). The patients were divided into subgroups according to their disease severity. A flow cytometry measured NK cell level and function in peripheral blood. Circulating NK cell levels and CD69 expressions were significantly increased in scrub typhus patients. Increased NK cell levels reflected disease severity. In scrub typhus patients, tests showed their NK cells produced higher amounts of interferon (IFN)-γ after stimulation with interleukin (IL)-12 and IL-18 relative to those of HCs. Meanwhile, between scrub typhus patients and HCs, the cytotoxicity and degranulation of NK cells against K562 were comparable. CD69 expressions were recovered to the normal levels in the remission phase. Conclusions This study shows that circulating NK cells are activated and numerically increased, and they produced more IFN-γ in scrub typhus patients. PMID:28750012
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Dysfunctional Natural Killer Cells in the Aftermath of Cancer Surgery.
Angka, Leonard; Khan, Sarwat T; Kilgour, Marisa K; Xu, Rebecca; Kennedy, Michael A; Auer, Rebecca C
2017-08-17
The physiological changes that occur immediately following cancer surgeries initiate a chain of events that ultimately result in a short pro-, followed by a prolonged anti-, inflammatory period. Natural Killer (NK) cells are severely affected during this period in the recovering cancer patient. NK cells play a crucial role in anti-tumour immunity because of their innate ability to differentiate between malignant versus normal cells. Therefore, an opportunity arises in the aftermath of cancer surgery for residual cancer cells, including distant metastases, to gain a foothold in the absence of NK cell surveillance. Here, we describe the post-operative environment and how the release of sympathetic stress-related factors (e.g., cortisol, prostaglandins, catecholamines), anti-inflammatory cytokines (e.g., IL-6, TGF-β), and myeloid derived suppressor cells, mediate NK cell dysfunction. A snapshot of current and recently completed clinical trials specifically addressing NK cell dysfunction post-surgery is also discussed. In collecting and summarizing results from these different aspects of the surgical stress response, a comprehensive view of the NK cell suppressive effects of surgery is presented. Peri-operative therapies to mitigate NK cell suppression in the post-operative period could improve curative outcomes following cancer surgery.
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Halstead, E Scott; Carcillo, Joseph A; Schilling, Bastian; Greiner, Robert J; Whiteside, Theresa L
2013-10-01
Sepsis continues to be a leading cause of death in infants and children. Natural killer (NK) cells serve as a bridge between innate and adaptive immunity, yet their role in pediatric sepsis has not been well characterized. We tested the hypothesis that decreased NK cell cytotoxicity is a common feature of pediatric systemic inflammatory response syndrome (SIRS)/sepsis patients by measuring, using flow cytometry, NK cell cytotoxicity and cell surface phenotype in the peripheral blood of 38 pediatric intensive care patients who demonstrated signs and symptoms of SIRS and/or sepsis. NK cell cytotoxicity was significantly reduced in peripheral blood mononuclear cells (PBMCs) of pediatric SIRS/sepsis patients as compared with healthy controls, and the percentage of CD56(dim) CD16(+) cytotoxic NK cells in PBMCs was lower in patients with SIRS/sepsis than in normal donors. However, on a per cell basis, CD56(dim) CD16(+) NK cells in patients mediated cytotoxicity as well as those in normal donors. The NK cell dysfunction in pediatric SIRS/sepsis patients reflects a quantitative rather than a qualitative difference from healthy controls.
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Dysfunctional Natural Killer Cells in the Aftermath of Cancer Surgery
Khan, Sarwat T.; Kilgour, Marisa K.; Xu, Rebecca; Kennedy, Michael A.; Auer, Rebecca C.
2017-01-01
The physiological changes that occur immediately following cancer surgeries initiate a chain of events that ultimately result in a short pro-, followed by a prolonged anti-, inflammatory period. Natural Killer (NK) cells are severely affected during this period in the recovering cancer patient. NK cells play a crucial role in anti-tumour immunity because of their innate ability to differentiate between malignant versus normal cells. Therefore, an opportunity arises in the aftermath of cancer surgery for residual cancer cells, including distant metastases, to gain a foothold in the absence of NK cell surveillance. Here, we describe the post-operative environment and how the release of sympathetic stress-related factors (e.g., cortisol, prostaglandins, catecholamines), anti-inflammatory cytokines (e.g., IL-6, TGF-β), and myeloid derived suppressor cells, mediate NK cell dysfunction. A snapshot of current and recently completed clinical trials specifically addressing NK cell dysfunction post-surgery is also discussed. In collecting and summarizing results from these different aspects of the surgical stress response, a comprehensive view of the NK cell suppressive effects of surgery is presented. Peri-operative therapies to mitigate NK cell suppression in the post-operative period could improve curative outcomes following cancer surgery. PMID:28817109
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Aravindhan, Vivekanandhan; Anand, Gowrishankar
2017-12-01
Recent epidemiological studies have documented an inverse relationship between the decreasing prevalence of helminth infections and the increasing prevalence of metabolic diseases ("metabolic hygiene hypothesis"). Chronic inflammation leading to insulin resistance (IR) has now been identified as a major etiological factor for a variety of metabolic diseases other than obesity and Type-2 diabetes (metainflammation). One way by which helminth infections such as filariasis can modulate IR is by inducing a chronic, nonspecific, low-grade, immune suppression mediated by modified T-helper 2 (Th2) response (induction of both Th2 and regulatory T cells) which can in turn suppress the proinflammatory responses and promote insulin sensitivity (IS). This article provides evidence on how the cross talk between the innate and adaptive arms of the immune responses can modulate IR/sensitivity. The cross talk between innate (macrophages, dendritic cells, natural killer cells, natural killer T cells, myeloid derived suppressor cells, innate lymphoid cells, basophils, eosinophils, and neutrophils) and adaptive (helper T [CD4 + ] cells, cytotoxic T [CD8 + ] cells and B cells) immune cells forms two opposing circuits, one associated with IR and the other associated with IS under the conditions of metabolic syndrome and helminth-mediated immunomodulation, respectively.
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van der Ploeg, Kattria; Chang, Chiwen; Ivarsson, Martin A.; Moffett, Ashley; Wills, Mark R.; Trowsdale, John
2017-01-01
The interaction of inhibitory killer cell Ig-like receptors (KIRs) with human leukocyte antigen (HLA) class I molecules has been characterized in detail. By contrast, activating members of the KIR family, although closely related to inhibitory KIRs, appear to interact weakly, if at all, with HLA class I. KIR2DS1 is the best studied activating KIR and it interacts with C2 group HLA-C (C2-HLA-C) in some assays, but not as strongly as KIR2DL1. We used a mouse 2B4 cell reporter system, which carries NFAT-green fluorescent protein with KIR2DS1 and a modified DAP12 adaptor protein. KIR2DS1 reporter cells were not activated upon coculture with 721.221 cells transfected with different HLA-C molecules, or with interferon-γ stimulated primary dermal fibroblasts. However, KIR2DS1 reporter cells and KIR2DS1+ primary natural killer (NK) cells were activated by C2-HLA-C homozygous human fetal foreskin fibroblasts (HFFFs) but only after infection with specific clones of a clinical strain of human cytomegalovirus (HCMV). Active viral gene expression was required for activation of both cell types. Primary NKG2A−KIR2DS1+ NK cell subsets degranulated after coculture with HCMV-infected HFFFs. The W6/32 antibody to HLA class I blocked the KIR2DS1 reporter cell interaction with its ligand on HCMV-infected HFFFs but did not block interaction with KIR2DL1. This implies a differential recognition of HLA-C by KIR2DL1 and KIR2DS1. The data suggest that modulation of HLA-C by HCMV is required for a potent KIR2DS1-mediated NK cell activation. PMID:28424684
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Heymann, Felix; Niemietz, Patricia M; Peusquens, Julia; Ergen, Can; Kohlhepp, Marlene; Mossanen, Jana C; Schneider, Carlo; Vogt, Michael; Tolba, Rene H; Trautwein, Christian; Martin, Christian; Tacke, Frank
2015-03-24
Liver inflammation as a response to injury is a highly dynamic process involving the infiltration of distinct subtypes of leukocytes including monocytes, neutrophils, T cell subsets, B cells, natural killer (NK) and NKT cells. Intravital microscopy of the liver for monitoring immune cell migration is particularly challenging due to the high requirements regarding sample preparation and fixation, optical resolution and long-term animal survival. Yet, the dynamics of inflammatory processes as well as cellular interaction studies could provide critical information to better understand the initiation, progression and regression of inflammatory liver disease. Therefore, a highly sensitive and reliable method was established to study migration and cell-cell-interactions of different immune cells in mouse liver over long periods (about 6 hr) by intravital two-photon laser scanning microscopy (TPLSM) in combination with intensive care monitoring. The method provided includes a gentle preparation and stable fixation of the liver with minimal perturbation of the organ; long term intravital imaging using multicolor multiphoton microscopy with virtually no photobleaching or phototoxic effects over a time period of up to 6 hr, allowing tracking of specific leukocyte subsets; and stable imaging conditions due to extensive monitoring of mouse vital parameters and stabilization of circulation, temperature and gas exchange. To investigate lymphocyte migration upon liver inflammation CXCR6.gfp knock-in mice were subjected to intravital liver imaging under baseline conditions and after acute and chronic liver damage induced by intraperitoneal injection(s) of carbon tetrachloride (CCl4). CXCR6 is a chemokine receptor expressed on lymphocytes, mainly on Natural Killer T (NKT)-, Natural Killer (NK)- and subsets of T lymphocytes such as CD4 T cells but also mucosal associated invariant (MAIT) T cells1. Following the migratory pattern and positioning of CXCR6.gfp+ immune cells allowed a detailed insight into their altered behavior upon liver injury and therefore their potential involvement in disease progression.
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Schwartz, John C; Gibson, Mark S; Heimeier, Dorothea; Koren, Sergey; Phillippy, Adam M; Bickhart, Derek M; Smith, Timothy P L; Medrano, Juan F; Hammond, John A
2017-04-01
Natural killer (NK) cells are a diverse population of lymphocytes with a range of biological roles including essential immune functions. NK cell diversity is in part created by the differential expression of cell surface receptors which modulate activation and function, including multiple subfamilies of C-type lectin receptors encoded within the NK complex (NKC). Little is known about the gene content of the NKC beyond rodent and primate lineages, other than it appears to be extremely variable between mammalian groups. We compared the NKC structure between mammalian species using new high-quality draft genome assemblies for cattle and goat; re-annotated sheep, pig, and horse genome assemblies; and the published human, rat, and mouse lemur NKC. The major NKC genes are largely in the equivalent positions in all eight species, with significant independent expansions and deletions between species, allowing us to propose a model for NKC evolution during mammalian radiation. The ruminant species, cattle and goats, have independently evolved a second KLRC locus flanked by KLRA and KLRJ, and a novel KLRH-like gene has acquired an activating tail. This novel gene has duplicated several times within cattle, while other activating receptor genes have been selectively disrupted. Targeted genome enrichment in cattle identified varying levels of allelic polymorphism between the NKC genes concentrated in the predicted extracellular ligand-binding domains. This novel recombination and allelic polymorphism is consistent with NKC evolution under balancing selection, suggesting that this diversity influences individual immune responses and may impact on differential outcomes of pathogen infection and vaccination.
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Novel targets for natural killer/T-cell lymphoma immunotherapy.
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.
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Luger, Dror; Lipinski, Michael J; Westman, Peter C; Glover, David K; Dimastromatteo, Julien; Frias, Juan C; Albelda, M Teresa; Sikora, Sergey; Kharazi, Alex; Vertelov, Grigory; Waksman, Ron; Epstein, Stephen E
2017-05-12
Virtually all mesenchymal stem cell (MSC) studies assume that therapeutic effects accrue from local myocardial effects of engrafted MSCs. Because few intravenously administered MSCs engraft in the myocardium, studies have mainly utilized direct myocardial delivery. We adopted a different paradigm. To test whether intravenously administered MSCs reduce left ventricular (LV) dysfunction both post-acute myocardial infarction and in ischemic cardiomyopathy and that these effects are caused, at least partly, by systemic anti-inflammatory activities. Mice underwent 45 minutes of left anterior descending artery occlusion. Human MSCs, grown chronically at 5% O 2 , were administered intravenously. LV function was assessed by serial echocardiography, 2,3,5-triphenyltetrazolium chloride staining determined infarct size, and fluorescence-activated cell sorting assessed cell composition. Fluorescent and radiolabeled MSCs (1×10 6 ) were injected 24 hours post-myocardial infarction and homed to regions of myocardial injury; however, the myocardium contained only a small proportion of total MSCs. Mice received 2×10 6 MSCs or saline intravenously 24 hours post-myocardial infarction (n=16 per group). At day 21, we harvested blood and spleens for fluorescence-activated cell sorting and hearts for 2,3,5-triphenyltetrazolium chloride staining. Adverse LV remodeling and deteriorating LV ejection fraction occurred in control mice with large infarcts (≥25% LV). Intravenous MSCs eliminated the progressive deterioration in LV end-diastolic volume and LV end-systolic volume. MSCs significantly decreased natural killer cells in the heart and spleen and neutrophils in the heart. Specific natural killer cell depletion 24 hours pre-acute myocardial infarction significantly improved infarct size, LV ejection fraction, and adverse LV remodeling, changes associated with decreased neutrophils in the heart. In an ischemic cardiomyopathy model, mice 4 weeks post-myocardial infarction were randomized to tail-vein injection of 2×10 6 MSCs, with injection repeated at week 3 (n=16) versus PBS control (n=16). MSCs significantly increased LV ejection fraction and decreased LV end-systolic volume. Intravenously administered MSCs for acute myocardial infarction attenuate the progressive deterioration in LV function and adverse remodeling in mice with large infarcts, and in ischemic cardiomyopathy, they improve LV function, effects apparently modulated in part by systemic anti-inflammatory activities. © 2017 American Heart Association, Inc.
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Wada, Taizo; Yokoyama, Tadafumi; Nakagawa, Hiroyasu; Asai, Erika; Toga, Akiko; Sakakibara, Yasuhisa; Shibata, Fumie; Tone, Yumi; Shimizu, Masaki; Toma, Tomoko; Yachie, Akihiro
2009-12-01
In chronic active Epstein-Barr virus (EBV) infection (CAEBV), ectopic EBV infection has been described in T or natural killer (NK) cells. NK cell-type infection (NK-CAEBV) is characterized by large granular lymphocytosis, high IgE levels and unusual reactions to mosquito bites, including severe local skin reactions, fever and liver dysfunction. However, the mechanisms underlying these reactions remain undetermined. Herein, we describe a patient with NK-CAEBV whose blister fluid after mosquito bites was analyzed. The patient exhibited significant increases in the percentage of CD56(+) NK cells in the fluid compared with a simple mosquito allergy, in which the majority of infiltrated cells were CD203c(+) cells, indicating basophils and/or mast cells. His fluid also contained CD203c(+) cells, and his circulating basophils were activated by mosquito extracts in vitro. These results suggest that CD203c(+) cells as well as NK cells may play pathogenic roles in the severe skin reactions to mosquito bites in NK-CAEBV.
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Boudjerra, Nadia; Perry, Anamarija M; Audouin, Josée; Diebold, Jacques; Nathwani, Bharat N; MacLennan, Kenneth A; Müller-Hermelink, Hans K; Bast, Martin; Boilesen, Eugene; Armitage, James O; Weisenburger, Dennis D
2015-04-01
The relative distribution of non-Hodgkin lymphoma (NHL) subtypes differs markedly around the world. The aim of this study was to report this distribution in Algeria. A panel of four hematopathologists classified 197 consecutive cases according to the World Health Organization classification, including 87.3% B-cell and 12.7% T- or natural killer (NK)-cell NHLs. This series was compared with similar cohorts from Western Europe (WEU) and North America (NA). Algeria had a significantly higher frequency of diffuse large B-cell lymphoma (DLBCL: 52.8%) and a lower frequency of follicular lymphoma (FL: 13.2%) compared with WEU (DLBCL: 32.2%; FL: 20.0%) and NA (DLBCL: 29.3%; FL: 33.6%). The frequency of mantle cell lymphoma was lower in Algeria (2.5%) compared with WEU (8.3%). Smaller differences were also found among the NK/T-cell lymphomas. In conclusion, we found important differences between Algeria and Western countries, and further epidemiologic studies are needed to explain these differences.
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La Regina, Giuseppe; Bai, Ruoli; Coluccia, Antonio; Famiglini, Valeria; Pelliccia, Sveva; Passacantilli, Sara; Mazzoccoli, Carmela; Ruggieri, Vitalba; Verrico, Annalisa; Miele, Andrea; Monti, Ludovica; Nalli, Marianna; Alfonsi, Romina; Di Marcotullio, Lucia; Gulino, Alberto; Ricci, Biancamaria; Soriani, Alessandra; Santoni, Angela; Caraglia, Michele; Porto, Stefania; Da Pozzo, Eleonora; Martini, Claudia; Brancale, Andrea; Marinelli, Luciana; Novellino, Ettore; Vultaggio, Stefania; Varasi, Mario; Mercurio, Ciro; Bigogno, Chiara; Dondio, Giulio; Hamel, Ernest; Lavia, Patrizia; Silvestri, Romano
2015-08-13
We designed 39 new 2-phenylindole derivatives as potential anticancer agents bearing the 3,4,5-trimethoxyphenyl moiety with a sulfur, ketone, or methylene bridging group at position 3 of the indole and with halogen or methoxy substituent(s) at positions 4-7. Compounds 33 and 44 strongly inhibited the growth of the P-glycoprotein-overexpressing multi-drug-resistant cell lines NCI/ADR-RES and Messa/Dx5. At 10 nM, 33 and 44 stimulated the cytotoxic activity of NK cells. At 20-50 nM, 33 and 44 arrested >80% of HeLa cells in the G2/M phase of the cell cycle, with stable arrest of mitotic progression. Cell cycle arrest was followed by cell death. Indoles 33, 44, and 81 showed strong inhibition of the SAG-induced Hedgehog signaling activation in NIH3T3 Shh-Light II cells with IC50 values of 19, 72, and 38 nM, respectively. Compounds of this class potently inhibited tubulin polymerization and cancer cell growth, including stimulation of natural killer cell cytotoxic activity and repression of Hedgehog-dependent cancer.
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A microfluidics assay to study invasion of human placental trophoblast cells.
Abbas, Yassen; Oefner, Carolin Melati; Polacheck, William J; Gardner, Lucy; Farrell, Lydia; Sharkey, Andrew; Kamm, Roger; Moffett, Ashley; Oyen, Michelle L
2017-05-01
Pre-eclampsia, fetal growth restriction and stillbirth are major pregnancy disorders throughout the world. The underlying pathogenesis of these diseases is defective placentation characterized by inadequate invasion of extravillous placental trophoblast cells into the uterine arteries. How trophoblast invasion is controlled remains an unanswered question but is influenced by maternal uterine immune cells called decidual natural killer cells. Here, we describe an in vitro microfluidic invasion assay to study the migration of primary human trophoblast cells. Each experiment can be performed with a small number of cells making it possible to conduct research on human samples despite the challenges of isolating primary trophoblast cells. Cells are exposed to a chemical gradient and tracked in a three-dimensional microenvironment using real-time high-resolution imaging, so that dynamic readouts on cell migration such as directionality, motility and velocity are obtained. The microfluidic system was validated using isolated trophoblast and a gradient of granulocyte-macrophage colony-stimulating factor, a cytokine produced by activated decidual natural killer cells. This microfluidic model provides detailed analysis of the dynamics of trophoblast migration compared to previous assays and can be modified in future to study in vitro how human trophoblast behaves during placentation. © 2017 The Authors.
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Benson, Don M.; Yu, Jianhua; Becknell, Brian; Wei, Min; Freud, Aharon G.; Ferketich, Amy K.; Trotta, Rossana; Perrotti, Danilo; Briesewitz, Roger
2009-01-01
Stem cell factor (SCF) promotes synergistic cellular proliferation in combination with several growth factors, and appears important for normal natural killer (NK)–cell development. CD34+ hematopoietic precursor cells (HPCs) require interleukin-15 (IL-15) for differentiation into human NK cells, and this effect can be mimicked by IL-2. Culture of CD34+ HPCs or some primary human NK cells in IL-2/15 and SCF results in enhanced growth compared with either cytokine alone. The molecular mechanisms responsible for this are unknown and were investigated in the present work. Activation of NK cells by IL-2/15 increases expression of c-kit whose kinase activity is required for synergy with IL-2/15 signaling. Mitogen-activated protein kinase (MAPK) signaling intermediaries that are activated both by SCF and IL-2/15 are enhanced in combination to facilitate earlier cell-cycle entry. The effect results at least in part via enhanced MAPK-mediated modulation of p27 and CDK4. Collectively the data reveal a novel mechanism by which SCF enhances cellular proliferation in combination with IL-2/15 in primary human NK cells. PMID:19060242
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La Regina, Giuseppe; Bai, Ruoli; Coluccia, Antonio; Famiglini, Valeria; Pelliccia, Sveva; Passacantilli, Sara; Mazzoccoli, Carmela; Ruggieri, Vitalba; Verrico, Annalisa; Miele, Andrea; Monti, Ludovica; Nalli, Marianna; Alfonsi, Romina; Di Marcotullio, Lucia; Gulino, Alberto; Ricci, Biancamaria; Soriani, Alessandra; Santoni, Angela; Caraglia, Michele; Porto, Stefania; Pozzo, Eleonora Da; Martini, Claudia; Brancale, Andrea; Marinelli, Luciana; Novellino, Ettore; Vultaggio, Stefania; Varasi, Mario; Mercurio, Ciro; Bigogno, Chiara; Dondio, Giulio; Hamel, Ernest; Lavia, Patrizia; Silvestri, Romano
2015-01-01
We designed 39 new 2-phenylindole derivatives as potential anticancer agents bearing the 3,4,5-trimethox-yphenyl moiety with a sulfur, ketone, or methylene bridging group at position 3 of the indole and with halogen or methoxy substituent(s) at positions 4–7. Compounds 33 and 44 strongly inhibited the growth of the P-glycoprotein-overexpressing multi-drug-resistant cell lines NCI/ADR-RES and Messa/Dx5. At 10 nM, 33 and 44 stimulated the cytotoxic activity of NK cells. At 20–50 nM, 33 and 44 arrested >80% of HeLa cells in the G2/M phase of the cell cycle, with stable arrest of mitotic progression. Cell cycle arrest was followed by cell death. Indoles 33, 44, and 81 showed strong inhibition of the SAG-induced Hedgehog signaling activation in NIH3T3 Shh-Light II cells with IC50 values of 19, 72, and 38 nM, respectively. Compounds of this class potently inhibited tubulin polymerization and cancer cell growth, including stimulation of natural killer cell cytotoxic activity and repression of Hedgehog-dependent cancer. PMID:26132075
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Role for early-differentiated natural killer cells in infectious mononucleosis
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
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Role for early-differentiated natural killer cells in infectious mononucleosis.
Azzi, Tarik; Lünemann, Anna; Murer, Anita; Ueda, Seigo; Béziat, Vivien; Malmberg, Karl-Johan; Staubli, Georg; Gysin, Claudine; Berger, Christoph; Münz, Christian; Chijioke, Obinna; Nadal, David
2014-10-16
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 CD56(dim) 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. © 2014 by The American Society of Hematology.
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Toxoplasma gondii-infected natural killer cells display a hypermotility phenotype in vivo.
Ueno, Norikiyo; Lodoen, Melissa B; Hickey, Graeme L; Robey, Ellen A; Coombes, Janine L
2015-01-01
Toxoplasma gondii is a highly prevalent intracellular protozoan parasite that causes severe disease in congenitally infected or immunocompromised hosts. T. gondii is capable of invading immune cells and it has been suggested that the parasite harnesses the migratory pathways of these cells to spread through the body. Although in vitro evidence suggests that the parasite further enhances its spread by inducing a hypermotility phenotype in parasitized immune cells, in vivo evidence for this phenomenon is scarce. Here we use a physiologically relevant oral model of T. gondii infection, in conjunction with two-photon laser scanning microscopy, to address this issue. We found that a small proportion of natural killer (NK) cells in mesenteric lymph nodes contained parasites. Compared with uninfected 'bystander' NK cells, these infected NK cells showed faster, more directed and more persistent migratory behavior. Consistent with this, infected NK cells showed impaired spreading and clustering of the integrin, LFA-1, when exposed to plated ligands. Our results provide the first evidence for a hypermigratory phenotype in T. gondii-infected NK cells in vivo, providing an anatomical context for understanding how the parasite manipulates immune cell motility to spread through the host.
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ID’ing Innate and Innate-like Lymphoid Cells
Verykokakis, Mihalis; Zook, Erin C.; Kee, Barbara L.
2014-01-01
Summary The immune system can be divided into innate and adaptive components that differ in their rate and mode of cellular activation, with innate immune cells being the first responders to invading pathogens. Recent advances in the identification and characterization of innate lymphoid cells have revealed reiterative developmental programs that result in cells with effector fates that parallel those of adaptive lymphoid cells and are tailored to effectively eliminate a broad spectrum of pathogenic challenges. However, activation of these cells can also be associated with pathologies such as autoimmune disease. One major distinction between innate and adaptive immune system cells is the constitutive expression of ID proteins in the former and inducible expression in the latter. ID proteins function as antagonists of the E protein transcription factors that play critical roles in lymphoid specification as well as B and T-lymphocyte development. In this review, we examine the transcriptional mechanisms controlling the development of innate lymphocytes, including natural killer cells and the recently identified innate lymphoid cells (ILC1, ILC2, and ILC3), and innate-like lymphocytes, including natural killer T cells, with an emphasis on the known requirements for the ID proteins. PMID:25123285
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ID'ing innate and innate-like lymphoid cells.
Verykokakis, Mihalis; Zook, Erin C; Kee, Barbara L
2014-09-01
The immune system can be divided into innate and adaptive components that differ in their rate and mode of cellular activation, with innate immune cells being the first responders to invading pathogens. Recent advances in the identification and characterization of innate lymphoid cells have revealed reiterative developmental programs that result in cells with effector fates that parallel those of adaptive lymphoid cells and are tailored to effectively eliminate a broad spectrum of pathogenic challenges. However, activation of these cells can also be associated with pathologies such as autoimmune disease. One major distinction between innate and adaptive immune system cells is the constitutive expression of ID proteins in the former and inducible expression in the latter. ID proteins function as antagonists of the E protein transcription factors that play critical roles in lymphoid specification as well as B- and T-lymphocyte development. In this review, we examine the transcriptional mechanisms controlling the development of innate lymphocytes, including natural killer cells and the recently identified innate lymphoid cells (ILC1, ILC2, and ILC3), and innate-like lymphocytes, including natural killer T cells, with an emphasis on the known requirements for the ID proteins. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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“Multi-Omics” Analyses of the Development and Function of Natural Killer Cells
Zhou, Yonggang; Xu, Xiuxiu; Tian, Zhigang; Wei, Haiming
2017-01-01
For over four decades, our understanding of natural killer (NK) cells has evolved from the original description of cluster of differentiation (CD)56+CD3− to establishing NK cells as an important subset of innate lymphocytes in the host’s surveillance against viral infections and malignancy. The progress of research on the fundamental properties and therapeutic prospects for translational medicine using NK cells excites immunologists and clinicians. Over the past decade, numerous advances in “-omics”-scale methods and new technological approaches have addressed many essential questions in the biology of NK cells. We now have further understanding of the overall molecular mechanisms of action that determine the development, function, plasticity, diversity, and immune reactivity of NK cells. These findings are summarized here, and our view on how to study NK cells using “multi-omics” is highlighted. We also describe “-omics” analyses of the relationships between NK cells and viral infection, tumorigenesis, and autoimmune diseases. Ultimately, a deeper and more comprehensive understanding of NK cells in multiple conditions will provide more effective strategies to manipulate NK cells for the treatment of human disease. PMID:28928751
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Determination of the reactivity of cytotoxic immune cells with preimplantation mouse embryos
DOE Office of Scientific and Technical Information (OSTI.GOV)
Ewoldsen, M.A.
1987-01-01
Cytotoxic immune cells were used in an assay, MELIA (mixed embryo leukocyte interaction assay) to test the ability of the cells to kill blastocyst stage embryos. The cytotoxic immune cells generated for use in this study, cytotoxic T lymphocytes (CTLs), natural killer (NK) cells, and lymphokine activated killer (LAK) cells were shown to have phenotypic and cytolytic characteristics similar to those reported by other investigators. The lysis of the blastocysts in the MELIA was determined by measuring the inhibition of blastocoel retention and/or by the inhibition of incorporation of tritiated thymidine (/sup 3/H-TdR) into embryonic DNA. Blastocysts which possess ormore » lack their zonae pellucidae were tested to determine whether the zona pellucida plays an immunoprotective role in preimplantation development. The results indicated that CTLs only lysed embryonic cells when the zona pellucida was absent, but NK and LAK cells lysed embryonic cells whether the zona pellucida was present or absent. The results suggest that the zona pellucida may protect the preimplantation mouse embryo from lysis by CTLs but what protects the embryo from lysis by NK and LAK cells is unclear.« less
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Clustered carbohydrates as a target for natural killer cells: a model system.
Kovalenko, Elena I; Abakushina, Elena; Telford, William; Kapoor, Veena; Korchagina, Elena; Khaidukov, Sergei; Molotkovskaya, Irina; Sapozhnikov, Alexander; Vlaskin, Pavel; Bovin, Nicolai
2007-03-01
Membrane-associated oligosaccharides are known to take part in interactions between natural killer (NK) cells and their targets and modulate NK cell activity. A model system was therefore developed using synthetic glycoconjugates as tools to modify the carbohydrate pattern on NK target cell surfaces. NK cells were then assessed for function in response to synthetic glycoconjugates, using both cytolysis-associated caspase 6 activation measured by flow cytometry and IFN-gamma production. Lipophilic neoglycoconjugates were synthesized to provide their easy incorporation into the target cell membranes and to make carbohydrate residues available for cell-cell interactions. While incorporation was successful based on fluorescence monitoring, glycoconjugate incorporation did not evoke artifactual changes in surface antigen expression, and had no negative effect on cell viability. Glycoconjugates contained Le(x), sulfated Le(x), and Le(y) sharing the common structure motif trisaccharide Le(x) were revealed to enhance cytotoxicity mediated specifically by CD16 +CD56+NK cells. The glycoconjugate effects were dependent on saccharide presentation in a polymeric form. Only polymeric, or clustered, but not monomeric glycoconjugates resulted in alteration of cytotoxicity in our system, suggesting that appropriate presentation is critical for carbohydrate recognition and subsequent biological effects.
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Ando, Shotaro; Kawada, Jun-Ichi; Watanabe, Takahiro; Suzuki, Michio; Sato, Yoshitaka; Torii, Yuka; Asai, Masato; Goshima, Fumi; Murata, Takayuki; Shimizu, Norio; Ito, Yoshinori; Kimura, Hiroshi
2016-11-22
Epstein-Barr virus (EBV) infects not only B cells, but also T cells and natural killer (NK) cells, and is associated with T or NK cell lymphoma. These lymphoid malignancies are refractory to conventional chemotherapy. We examined the activation of the JAK3/STAT5 pathway in EBV-positive and -negative B, T and NK cell lines and in cell samples from patients with EBV-associated T cell lymphoma. We then evaluated the antitumor effects of the selective JAK3 inhibitor, tofacitinib, against these cell lines in vitro and in a murine xenograft model. We found that all EBV-positive T and NK cell lines and patient samples tested displayed activation of the JAK3/STAT5 pathway. Treatment of these cell lines with tofacitinib reduced the levels of phospho-STAT5, suppressed proliferation, induced G1 cell-cycle arrest and decreased EBV LMP1 and EBNA1 expression. An EBV-negative NK cell line was also sensitive to tofacitinib, whereas an EBV-infected NK cell line was more sensitive to tofacitinib than its parental line. Tofacitinib significantly inhibited the growth of established tumors in NOG mice. These findings suggest that tofacitinib may represent a useful therapeutic agent for patients with EBV-associated T and NK cell lymphoma.
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Raulet, David H; Marcus, Assaf; Coscoy, Laurent
2017-11-01
Natural killer (NK) cells recognize and kill cancer cells and infected cells by engaging cell surface ligands that are induced preferentially or exclusively on these cells. These ligands are recognized by activating receptors on NK cells, such as NKG2D. In addition to activation by cell surface ligands, the acquisition of optimal effector activity by NK cells is driven in vivo by cytokines and other signals. This review addresses a developing theme in NK cell biology: that NK-activating ligands on cells, and the provision of cytokines and other signals that drive high effector function in NK cells, are driven by abnormalities that arise from transformation or the infected state. The pathways include genomic damage, which causes self DNA to be exposed in the cytosol of affected cells, where it activates the DNA sensor cGAS. The resulting signaling induces NKG2D ligands and also mobilizes NK cell activation. Other key pathways that regulate NKG2D ligands include PI-3 kinase activation, histone acetylation, and the integrated stress response. This review summarizes the roles of these pathways and their relevance in both viral infections and cancer. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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NK cell-released exosomes: Natural nanobullets against tumors.
Fais, Stefano
2013-01-01
We have recently reported that human natural killer (NK) cells release exosomes that express both NK-cell markers and cytotoxic molecules. Similar results were obtained with circulating exosomes from human healthy donors. Both NK-cell derived and circulating exosomes exerted a full functional activity and killed both tumor and activated immune cells. These findings indicate that NK-cell derived exosomes might constitute a new promising therapeutic tool.
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Fais, Stefano
2013-01-01
We have recently reported that human natural killer (NK) cells release exosomes that express both NK-cell markers and cytotoxic molecules. Similar results were obtained with circulating exosomes from human healthy donors. Both NK-cell derived and circulating exosomes exerted a full functional activity and killed both tumor and activated immune cells. These findings indicate that NK-cell derived exosomes might constitute a new promising therapeutic tool. PMID:23482694
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2015-12-01
cells (HSCs) are multipotent cells that differentiate into myeloid, lymphoid and erythroid lineages, and have short-term or long-term regenerative...All rights reserved Nature Reviews | Rheumatology a b MPP CMP CLP Lymphoid cells NK cellB cell T cell Megakaryocyte and erythrocytes Macrophage and...into other cell types. CLP, common lymphoid progenitor; CMP, common myeloid progenitor; MPP, multipotent progenitor; NK cell , natural killer cell . R E
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Xing, Yawei; Yang, Junwen; Lian, Guanghui; Chen, Shuijiao; Chen, Linlin; Li, Fujun
2017-01-01
Abstract Rationale: Chronic active Epstein–Barr virus infection (CAEBV) associated with hemophagocytic syndrome (HPS) and extra-nodal natural killer (NK)/T-cell lymphoma (ENKL) is a rare life-threatening disorder. This disease is easily misdiagnosed because of its varied presentations. Patient concerns: An 18-year-old girl was admitted to our hospital with a history of edema in the lower limbs and intermittent fever lasting for more than 1 month. At admission, she had severe liver injury of unknown etiology. Laboratory test results revealed pancytopenia, hyperferritinemia, hypertriglyceridemia, and hypofibrinogenemia. Results of serologic tests for EBV were positive. Results of a skin biopsy indicated EBV-positive NK/T-cell lymphoma, and bone marrow aspiration revealed focal hemophagocytosis and atypical lymphoid cells. Diagnosis: On the basis of these findings, we diagnosed the case as extra-nodal NK/T-cell lymphoma-associated HPS (natural killer/T-cell lymphoma-associated hemophagocytic syndrome), which is commonly induced by CAEBV. Interventions: Treatment consisted of general management of hepatitis, supplemented with albumin and empirical antibiotic therapy. Outcomes: The patient died from massive gastrointestinal hemorrhage a week after she was discharged from the hospital. Lessons: ENKL and HPS present with varied features and are generally fatal; therefore, clinicians should proceed with caution in suspected cases. HPS should be considered when the patient presents with fever, hepatosplenomegaly, pancytopenia, and liver failure. When HPS is suspected, clinicians should determine the underlying cause, such as severe infection, including infection with viruses such as EBV; genetic predisposition; or underlying malignancies, especially lymphoma because of its strong association with HPS. PMID:28489771
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Distinct subtype distribution and somatic mutation spectrum of lymphomas in East Asia.
Ren, Weicheng; Li, Wei; Ye, Xiaofei; Liu, Hui; Pan-Hammarström, Qiang
2017-07-01
Here, we give an updated overview of the subtype distribution of lymphomas in East Asia and also present the genome sequencing data on two major subtypes of these tumors. The distribution of lymphoma types/subtypes among East Asian countries is very similar, with a lower proportion of B-cell malignancies and a higher proportion of T/natural killer (NK)-cell lymphomas as compared to Western populations. Extranodal NK/T-cell lymphoma is more frequently observed in East Asia, whereas follicular lymphoma and chronic lymphocytic leukemia, are proportionally lower. The incidence rate of lymphoma subtypes in Asians living in the US was generally intermediate to the general rate in US and Asia, suggesting that both genetic and environmental factors may underlie the geographical variations observed.Key cancer driver mutations have been identified in Asian patients with diffuse large B-cell lymphoma or extranodal NK/T-cell lymphoma through genome sequencing. A distinct somatic mutation profile has also been observed in Chinese diffuse large B-cell lymphoma patients. The incidence and distribution of lymphoma subtypes differed significantly between patients from East Asia and Western countries, suggesting subtype-specific etiologic mechanisms. Further studies on the mechanism underlying these geographical variations may give new insights into our understanding of lymphomagenesis.
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Role of Natural Killer T Cells in Immunogenic Chemotherapy for Breast Cancer
2013-09-01
critical in the control of tuberculosis, candidiasis , Escherichia coli and Staphylococcus aureus infections (5, 6). In these models, γδT cells have...naturally occurring interleukin-17A-producing gammadelta T cells in the lung at the early stage of systemic candidiasis in mice. Infect Immun 79(11
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Improving efficacy of cancer immunotherapy by genetic modification of natural killer cells.
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.
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Natural killer cell therapy in children with relapsed leukemia.
Rubnitz, Jeffrey E; Inaba, Hiroto; Kang, Guolian; Gan, Kwan; Hartford, Christine; Triplett, Brandon M; Dallas, Mari; Shook, David; Gruber, Tanja; Pui, Ching-Hon; Leung, Wing
2015-08-01
Novel therapies are needed for children with relapsed or refractory leukemia. We therefore tested the safety and feasibility of haploidentical natural killer cell therapy in this patient population. Twenty-nine children who had relapsed or refractory leukemia were treated with chemotherapy followed by the infusion of haploidentical NK cells. Cohort 1 included 14 children who had not undergone prior allogeneic hematopoietic cell transplantation (HCT), whereas Cohort 2 included 15 children with leukemia that had relapsed after HCT. Twenty-six (90%) NK donors were KIR mismatched (14 with one KIR and 12 with 2 KIRs). The peak NK chimerism levels were >10% donor in 87% of the evaluable recipients. In Cohort 1, 10 had responsive disease and 12 proceeded to HCT thereafter. Currently, 5 (36%) are alive without leukemia. In Cohort 2, 10 had responsive disease after NK therapy and successfully proceeded to second HCT. At present, 4 (27%) are alive and leukemia-free. The NK cell infusions and the IL-2 injections were well-tolerated. NK cell therapy is safe, feasible, and should be further investigated in patients with chemotherapy-resistant leukemia. © 2015 Wiley Periodicals, Inc.
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Natural killer cells and HLA-G expression in the basal decidua of human placenta adhesiva.
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. Copyright © 2010 Elsevier Ltd. All rights reserved.
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Activation of cell-mediated immunity by Morinda citrifolia fruit extract and its constituents.
Murata, Kazuya; Abe, Yumi; Futamura-Masudaa, Megumi; Uwaya, Akemi; Isami, Fumiyuki; Matsuda, Hideaki
2014-04-01
Morinda citrifolia, commonly known as noni, is a traditional natural medicine in French Polynesia and Hawaii. Functional foods derived from M. citrifolia fruit have been marketed to help prevent diseases and promote good health. The objective of this study was to assess the effects of M. citrifolia fruit on cell-mediated immunity. In the picryl chloride-induced contact dermatitis test, M. citrifolia fruit extract (Noni-ext) inhibited the suppression of cell-mediated immunity by immunosuppressive substances isolated from freeze-dried ascites of Ehrlich carcinoma-bearing mice (EC-sup). In addition, Noni-ext inhibited reduction of IL-2 production in EC-sup-treated mice and activated natural killer cells in normal mice. These results suggest that Noni-ext has multiple effects on the recovery of cell-mediated immunity. Furthermore, we investigated the active principles of Noni-ext and identified an iridoid glycoside, deacetylasperulosidic acid. Oral administration of deacetylasperulosidic acid inhibited the reduction of ear swelling, and also cancelled the suppression of IL-2 production along with the activation of natural killer cells in the same manner as that of Noni-ext.
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Clark, Sarah E; Schmidt, Rebecca L; McDermott, Daniel S; Lenz, Laurel L
2018-05-29
The bacterial pathogen Listeria monocytogenes (Lm) capitalizes on natural killer (NK) cell production of regulatory interleukin (IL)-10 to establish severe systemic infections. Here, we identify regulators of this IL-10 secretion. We show that IL-18 signals to NK cells license their ability to produce IL-10. IL-18 acts independent of IL-12 and STAT4, which co-stimulate IFNγ secretion. Dendritic cell (DC) expression of Nlrp3 is required for IL-18 release in response to the Lm p60 virulence protein. Therefore, mice lacking Nlrp3, Il18, or Il18R fail to accumulate serum IL-10 and are highly resistant to systemic Lm infection. We further show that cells expressing or dependent on Batf3 are required for IL-18-inducing IL-10 production observed in infected mice. These findings explain how Il18 and Batf3 promote susceptibility to bacterial infection and demonstrate the ability of Lm to exploit NLRP3 for the promotion of regulatory NK cell activity. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.
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Adoptive immunotherapy against ovarian cancer.
Mittica, Gloria; Capellero, Sonia; Genta, Sofia; Cagnazzo, Celeste; Aglietta, Massimo; Sangiolo, Dario; Valabrega, Giorgio
2016-05-17
The standard front-line therapy for epithelial ovarian cancer (EOC) is combination of debulking surgery and platinum-based chemotherapy. Nevertheless, the majority of patients experience disease recurrence. Although extensive efforts to find new therapeutic options, cancer cells invariably develop drug resistance and disease progression. New therapeutic strategies are needed to improve prognosis of patients with advanced EOC.Recently, several preclinical and clinical studies investigated feasibility and activity of adoptive immunotherapy in EOC. Our aim is to highlight prospective of adoptive immunotherapy in EOC, focusing on HLA-restricted Tumor Infiltrating Lymphocytes (TILs), and MHC-independent immune effectors such as natural killer (NK), and cytokine-induced killer (CIK). Adoptive cell therapy (ACT) has shown activity in several pre-clinical models. Available preclinical and clinical data suggest that adoptive cell therapy may provide the best benefit in settings of low tumor burden, minimal residual disease, or maintenance therapy. Further studies are needed to better define the optimal clinical setting.
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Interferon-γ-Mediated Natural Killer Cell Activation by an Aqueous Panax ginseng Extract
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
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Yang, Guozi; Kong, Qingyu; Wang, Guanjun; Jin, Haofan; Zhou, Lei; Yu, Dehai; Niu, Chao; Han, Wei; Li, Wei; Cui, Jiuwei
2014-12-01
Recent evidence indicates that limited availability and cytotoxicity have restricted the development of natural killer (NK) cells in adoptive cellular immunotherapy (ACI). While it has been reported that low-dose ionizing radiation (LDIR) could enhance the immune response in animal studies, the influence of LDIR at the cellular level has been less well defined. In this study, the authors aim to investigate the direct effects of LDIR on NK cells and the potential mechanism, and explore the application of activation and expansion of NK cells by LDIR in ACI. The authors found that expansion and cytotoxicity of NK cells were markedly augmented by LDIR. The levels of IFN-γ and TNF-α in the supernatants of cultured NK cells were significantly increased after LDIR. Additionally, the effect of the P38 inhibitor (SB203580) significantly decreased the expanded NK cell cytotoxicity, cytokine levels, and expression levels of FasL and perforin. These findings indicate that LDIR induces a direct expansion and activation of NK cells through possibly the P38-MAPK pathway, which provides a potential mechanism for stimulation of NK cells by LDIR and a novel but simplified approach for ACI.
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Morikawa, Yuko; Kitaoka-Higashiguchi, Kazuyo; Tanimoto, Chie; Hayashi, Midori; Oketani, Reiko; Miura, Katsuyuki; Nishijo, Muneko; Nakagawa, Hideaki
2005-09-01
The present study investigated the effects of job stress on cellular immune function, such as NK cell activity and NK cell subsets. The participants were 61 female nurses aged 23-59, who worked in a public psychiatric hospital in Ishikawa, Japan. Each subject completed the Nursing Job Stressor Scale (NJSS) and their NK cell activity and lymphocyte surface antigens (CD16+56+) were evaluated as immune system parameters. The NJSS has seven subscales: conflict with other nursing staff, nursing role conflict, conflict with physicians or autonomy, conflict with death or dying, quantitative work load, qualitative work load and conflict with patients. Factors influencing NK cell activity, and the proportion and cell counts of CD16+56+ lymphocytes were evaluated. Increase in quantitative work load significantly decreased NK cell activity. Conversely, no linear relationship was observed between qualitative work load and immunological variables, with the highest percentage of CD16+56+ lymphocytes observed among participants in the medium work load group. The other five NJSS subscales did not relate to immune parameters. In conclusion, the results suggest that perceived job strains, particularly quantitative work load, decreased NK cell function.
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Production of EUV mask blanks with low killer defects
NASA Astrophysics Data System (ADS)
Antohe, Alin O.; Kearney, Patrick; Godwin, Milton; He, Long; John Kadaksham, Arun; Goodwin, Frank; Weaver, Al; Hayes, Alan; Trigg, Steve
2014-04-01
For full commercialization, extreme ultraviolet lithography (EUVL) technology requires the availability of EUV mask blanks that are free of defects. This remains one of the main impediments to the implementation of EUV at the 22 nm node and beyond. Consensus is building that a few small defects can be mitigated during mask patterning, but defects over 100 nm (SiO2 equivalent) in size are considered potential "killer" defects or defects large enough that the mask blank would not be usable. The current defect performance of the ion beam sputter deposition (IBD) tool will be discussed and the progress achieved to date in the reduction of large size defects will be summarized, including a description of the main sources of defects and their composition.
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Wong, Emily S W; Sanderson, Claire E; Deakin, Janine E; Whittington, Camilla M; Papenfuss, Anthony T; Belov, Katherine
2009-08-01
Natural killer (NK) cell receptors belong to two unrelated, but functionally analogous gene families: the immunoglobulin superfamily, situated in the leukocyte receptor complex (LRC) and the C-type lectin superfamily, located in the natural killer complex (NKC). Here, we describe the largest NK receptor gene expansion seen to date. We identified 213 putative C-type lectin NK receptor homologs in the genome of the platypus. Many have arisen as the result of a lineage-specific expansion. Orthologs of OLR1, CD69, KLRE, CLEC12B, and CLEC16p genes were also identified. The NKC is split into at least two regions of the genome: 34 genes map to chromosome 7, two map to a small autosome, and the remainder are unanchored in the current genome assembly. No NK receptor genes from the LRC were identified. The massive C-type lectin expansion and lack of Ig-domain-containing NK receptors represents the most extreme polarization of NK receptors found to date. We have used this new data from platypus to trace the possible evolutionary history of the NK receptor clusters.
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Mechanisms of Invariant Natural Killer T Cell-Mediated Immunoregulation in Cancer
2012-05-01
by mesenchymal stem cells . Intriguingly, the increased metastatic ability was dependent on the production of CCL5 by mesenchymal stem cells , which...Tubo, R., &Weinberg, R.A.(2007) Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature. Vol. 449:pp557-563. Breast...can induce preferential secretion of immunosuppressive cytokines ; 2) iNKT cells inhibit effector T cell priming by killing dendritic cells that
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Natural Killer Cell Immunotherapy Targeting Cancer Stem Cells
Luna, Jesus I; Grossenbacher, Steven K.; Murphy, William J; Canter, Robert J
2017-01-01
Introduction 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. In this report, we 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 are able to 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. PMID:27960589
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Yamamoto, Kana; Furuya, Kanon; Yamada, Kazuki; Takahashi, Fuka; Hamajima, Chisato; Tanaka, Sachi
2018-04-01
Certain food components possess immunomodulatory effects. The aim of this study was to elucidate the mechanism of the immunostimulatory activity of Brassica rapa L. We demonstrated an enhancement of natural killer (NK) activity and interferon (IFN)-γ production in mice that were orally administered an insoluble fraction of B. rapa L. The insoluble fraction of B. rapa L. significantly induced IFN-γ production in mouse spleen cells in an interleukin (IL)-12-dependent manner, and NK1.1 + cells were the main cells responsible for producing IFN-γ. Additionally, the results suggested that the active compounds in the insoluble fraction were recognized by Toll-like receptor (TLR) 2, TLR4, and C-type lectin receptors on dendritic cells, and they activated signaling cascades such as MAPK, NF-κB, and Syk. These findings suggest that B. rapa L. is a potentially promising immuno-improving material, and it might be useful for preventing immunological disorders such as infections and cancers by activating innate immunity.
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Rousset, F; Souillet, G; Roncarolo, M G; Lamelin, J P
1986-02-01
Two X-linked lymphoproliferative syndrome (XLP) patients with the hypogammaglobulinemia phenotype were investigated at a time remote from their primary infection with the Epstein-Barr virus (EBV). The lymphoblastoid cell lines derived from these patients expressed the phenotypic markers characteristic of normal mature B lymphocytes and produced normal levels of immunoglobulins (Ig). These observations imply that at least some of their B cells are phenotypically normal. The natural killer (NK) activity of the two patients was low. In one patient, activated lymphocyte killer (ALK) activity was inefficient. These two XLP patients expressed a normal EBV-specific, HLA-restricted cytotoxic activity. It thus appears, from the present findings and those in cases published previously (6/11 patients expressing normal EBV-specific cytotoxic activity), that the notion of poor specific T cell memory for EBV may not be as pivotal ass suggested or, alternatively, that this defect may not be common in hypogammaglobulinemic survivors.
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Dotiwala, Farokh; Sen Santara, Sumit; Binker-Cosen, Andres Ariel; Li, Bo; Chandrasekaran, Sriram; Lieberman, Judy
2017-11-16
Human cytotoxic lymphocytes kill intracellular microbes. The cytotoxic granule granzyme proteases released by cytotoxic lymphocytes trigger oxidative bacterial death by disrupting electron transport, generating superoxide anion and inactivating bacterial oxidative defenses. However, they also cause non-oxidative cell death because anaerobic bacteria are also killed. Here, we use differential proteomics to identify granzyme B substrates in three unrelated bacteria: Escherichia coli, Listeria monocytogenes, and Mycobacteria tuberculosis. Granzyme B cleaves a highly conserved set of proteins in all three bacteria, which function in vital biosynthetic and metabolic pathways that are critical for bacterial survival under diverse environmental conditions. Key proteins required for protein synthesis, folding, and degradation are also substrates, including multiple aminoacyl tRNA synthetases, ribosomal proteins, protein chaperones, and the Clp system. Because killer cells use a multipronged strategy to target vital pathways, bacteria may not easily become resistant to killer cell attack. Copyright © 2017 Elsevier Inc. All rights reserved.
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Wu, Junjie; Waxman, David J
2015-01-01
Cancer chemotherapy using cytotoxic drugs can induce immunogenic tumor cell death; however, dosing regimens and schedules that enable single-agent chemotherapy to induce adaptive immune-dependent ablation of large, established tumors with activation of long-term immune memory have not been identified. Here, we investigate this issue in a syngeneic, implanted GL261 glioma model in immune-competent mice given cyclophosphamide on a 6-day repeating metronomic schedule. Two cycles of metronomic cyclophosphamide treatment induced sustained upregulation of tumor-associated CD8+ cytotoxic T lymphocyte (CTL) cells, natural killer (NK) cells, macrophages, and other immune cells. Expression of CTL- and NK–cell-shared effectors peaked on Day 6, and then declined by Day 9 after the second cyclophosphamide injection and correlated inversely with the expression of the regulatory T cell (Treg) marker Foxp3. Sustained tumor regression leading to tumor ablation was achieved after several cyclophosphamide treatment cycles. Tumor ablation required CD8+ T cells, as shown by immunodepletion studies, and was associated with immunity to re-challenge with GL261 glioma cells, but not B16-F10 melanoma or Lewis lung carcinoma cells. Rejection of GL261 tumor re-challenge was associated with elevated CTLs in blood and increased CTL infiltration in tumors, consistent with the induction of long-term, specific CD8+ T-cell anti-GL261 tumor memory. Co-depletion of CD8+ T cells and NK cells did not inhibit tumor regression beyond CD8+ T-cell depletion alone, suggesting that the metronomic cyclophosphamide-activated NK cells function via CD8a+ T cells. Taken together, these findings provide proof-of-concept that single-agent chemotherapy delivered on an optimized metronomic schedule can eradicate large, established tumors and induce long-term immune memory. PMID:26137402
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Micro-encapsulated sensors for in vivo assessment of the oxidative stress in aquatic organisms
NASA Astrophysics Data System (ADS)
Sadovoy, Anton; Teh, Cathleen; Escobar, Marco; Meglinski, Igor; Korzh, Vladimir
2011-10-01
Oxidative stress results from an imbalance between the production and detoxification of reactive oxygen spices (ROS). ROS are natural byproducts of normal metabolism of oxygen and have important roles in cell signaling and homeostasis. Many heart related diseases like heart failure and myocardial infarction develop as a result of oxidative stress. Current treatment cannot improve the progressive decline in heart function experienced by all patients. Therefore heart failure is the cause of around 25% of all deaths in the Asia Pacific region. Thus any step taken to address the oxidative stress problem is essential for enhancing human health and improve their quality of life. Current approach is dedicated to develop micron-size oxidation stress-sensor for in-vivo measuring level of ROS in KillerRed expressing transgenic zebrafish larvae. Central to our investigation is the light-inducible heart failure animal model we developed in zebrafish that expressed KillerRed in the heart. By utilizing the photosensitizer properties of KillerRed to produce ROS upon green light illumination, heart failure can be repeatedly induced in a non-invasive manner. Importantly, the use of this biological platform permits the development of physiologically sensitive ROS sensor and identifies efficient antioxidants that improve heart contractility. The biosensor approach is based on utilizing biocompatible polyelectrolyte microcapsules as a carry of fluorescent dyes sensitive to amount of reactive oxygen spices. Microcapsule prevents dye diffusion in tissue that makes use toxic dyes possible. Microcapsule's wall is permeable for environment with size less than 500 Da. The oxidation stress-sensors are injected directly in zebrafish pericardium with further circulation along blood system. Detecting of ROS is obtained by using laser scanning microscopy by illuminating oxidation stress-sensors and detecting changing excitation signal from the fluorescent dye.
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Micro-encapsulated sensors for in vivo assessment of the oxidative stress in aquatic organisms
NASA Astrophysics Data System (ADS)
Sadovoy, Anton; Teh, Cathleen; Escobar, Marco; Meglinski, Igor; Korzh, Vladimir
2012-03-01
Oxidative stress results from an imbalance between the production and detoxification of reactive oxygen spices (ROS). ROS are natural byproducts of normal metabolism of oxygen and have important roles in cell signaling and homeostasis. Many heart related diseases like heart failure and myocardial infarction develop as a result of oxidative stress. Current treatment cannot improve the progressive decline in heart function experienced by all patients. Therefore heart failure is the cause of around 25% of all deaths in the Asia Pacific region. Thus any step taken to address the oxidative stress problem is essential for enhancing human health and improve their quality of life. Current approach is dedicated to develop micron-size oxidation stress-sensor for in-vivo measuring level of ROS in KillerRed expressing transgenic zebrafish larvae. Central to our investigation is the light-inducible heart failure animal model we developed in zebrafish that expressed KillerRed in the heart. By utilizing the photosensitizer properties of KillerRed to produce ROS upon green light illumination, heart failure can be repeatedly induced in a non-invasive manner. Importantly, the use of this biological platform permits the development of physiologically sensitive ROS sensor and identifies efficient antioxidants that improve heart contractility. The biosensor approach is based on utilizing biocompatible polyelectrolyte microcapsules as a carry of fluorescent dyes sensitive to amount of reactive oxygen spices. Microcapsule prevents dye diffusion in tissue that makes use toxic dyes possible. Microcapsule's wall is permeable for environment with size less than 500 Da. The oxidation stress-sensors are injected directly in zebrafish pericardium with further circulation along blood system. Detecting of ROS is obtained by using laser scanning microscopy by illuminating oxidation stress-sensors and detecting changing excitation signal from the fluorescent dye.
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Sha, Wei Hong; Zeng, Xiao Hui; Min, Lu
2014-05-01
This study aimed to detect the expression of natural killer (NK) cell receptor natural killer group 2D (NKG2D) in the peripheral blood of patients with primary hepatocellular carcinoma and to discuss the correlation between NK cell cytotoxicity and liver function. The number of NK cells and the expression of NK cell receptor NKG2D in peripheral blood were determined by flow cytometry in patients with primary hepatocellular carcinoma, hepatitis B cirrhosis, chronic hepatitis B, and healthy controls. When compared with patients in the healthy and the chronic hepatitis B groups, the primary hepatocellular carcinoma group showed significant decreases in all parameters, including the cytotoxicity of NK cells on K562 cells, expression rate of NKG2D in NK cells, number of NKG2D(+) NK cells, expression level of NKG2D, and number of NK cells (p<0.05). The activity of NK cells showed a positive correlation, whereas the Child-Pugh scores in the primary hepatocellular carcinoma and the hepatitis B cirrhosis groups showed a negative correlation with all parameters detected above. The decrease of NK cell activity in patients with primary hepatocellular carcinoma is closely related to their lower expression of NKG2D. Liver function affects the expression of NKG2D and the activity of NK cells.
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Natural Killer (NK) Cells in Antibacterial Innate Immunity: Angels or Devils?
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
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[Functional activity of the natural killers and macrophages in patients with breast tumors].
Andrianov, I G; Voronov, S M; Dobkin, A N; Okulov, V B; Orlov, A B
1988-01-01
The activity of natural killers (NK) and macrophages of peripheral blood was studied in 37 female donors, 40 patients with benign and 43 with malignant tumors of the breast of various stages prior to treatment. Also the effect of Soviet-made recombinant interleukin-2 on NK activity was assessed. Natural killer activity (cytotoxic index) was 34.1 +/- 1.42 in healthy donors, 44.2 +/- 3.64 in cases of fibroadenomatosis, 43.1 +/- 5.6 in patients with stages I-IIa, 64.4 +/- 3.93--stage IIb, 45.8 +/- 6.32--stage III and 16.6 +/- 7.21% in cases of stage IV breast cancer, the scatter of values being greater in the tumor group. As many as 40% of patients with stages I-IIa and III cancer showed increased NK-activity values. An in vitro stimulating effect of NK activity of peripheral blood mononuclear cells by Soviet-made recombinant interleukin-2 was established.
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Pichia anomala DBVPG 3003 Secretes a Ubiquitin-Like Protein That Has Antimicrobial Activity▿
De Ingeniis, Jessica; Raffaelli, Nadia; Ciani, Maurizio; Mannazzu, Ilaria
2009-01-01
The yeast strain Pichia anomala DBVPG 3003 secretes a killer toxin (Pikt) that has antifungal activity against Brettanomyces/Dekkera sp. yeasts. Pikt interacts with β-1,6-glucan, consistent with binding to the cell wall of sensitive targets. In contrast to that of toxin K1, secreted by Saccharomyces cerevisiae, Pikt killer activity is not mediated by an increase in membrane permeability. Purification of the toxin yielded a homogeneous protein of about 8 kDa, which showed a marked similarity to ubiquitin in terms of molecular mass and N-terminal sequences. Pikt is also specifically recognized by anti-bovine ubiquitin antibodies and, similar to ubiquitin-like peptides, is not absorbed by DEAE-cellulose. However, Pikt differs from ubiquitin in its sensitivity to proteolytic enzymes. Therefore, Pikt appears to be a novel ubiquitin-like peptide that has killer activity. PMID:19114528
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NASA Astrophysics Data System (ADS)
Warner, John F.; Dennert, Gunther
1982-11-01
Natural killer (NK) cells cloned in vitro have been transferred into NK-deficient hosts. These cells have been shown to have a role in the rejection of allogeneic bone marrow grafts, resistance to both radiation-induced thymic leukaemia and challenge with melanoma tumour cells. It appears that NK cells have an important role in immune surveillance.
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USDA-ARS?s Scientific Manuscript database
We have identified Severe Combined Immunodeficiency (SCID) in a line of Yorkshire pigs at Iowa State University. These SCID pigs lack B-cells and T-cells, but possess Natural Killer (NK) cells. This SCID phenotype is caused by recessive mutations in the Artemis gene. Interestingly, two human tumor c...
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Shin, Dong-Jun; Park, Ji-Yun; Jang, Youn-Young; Lee, Je-Jung; Lee, Youn-Kyung; Shin, Myung-Geun; Jung, Ji-Youn; Carson, William E; Cho, Duck; Kim, Sang-Ki
2013-06-15
Canine NK cells still are not well-characterized due to the lack of information concerning specific NK cell markers and the fact that NK cells are not an abundant cell population. In this study, we selectively expanded the canine cytotoxic large granular lymphocytes (CLGLs) that exhibit morphologic, genetic, and functional characteristics of NK cells from normal donor PBMCs. The cultured CLGLs were characterized by a high proportion of CD5(dim) expressing cells, of which the majority of cells co-expressed CD3 and CD8, but did not express TCRαβ and TCRγδ. The phenotype of the majority of the CLGLs was CD5(dim)CD3(+)CD8(+) TCRαβ(-)TCRγδ(-)CD4(-)CD21(-)CD11c(+/-)CD11d(+/-)CD44(+). The expression of mRNAs for NK cell-associated receptors (NKG2D, NKp30, NKp44, Ly49, perforin, and granzyme B) were highly upregulated in cultured CLGLs. Specifically, NKp46 was remarkably upregulated in the cultured CLGLs compared to PBMCs. The mRNAs for the NKT-associated iTCRα gene in CLGLs was present at a basal level. The cytotoxic activity of the CLGLs against canine NK cell-sensitive CTAC cells was remarkably elevated in a dose-dependent manner, and the CLGLs produced large amounts of IFN-γ. The antitumor activity of CLGLs extended to different types of canine tumor cells (CF41.Mg and K9TCC-pu-AXC) without specific antigen recognition. These results are consistent with prior reports, and strongly suggest that the selectively expanded CLGLs represent a population of canine NK cells. The results of this study will contribute to future research on canine NK cells as well as NK cell-based immunotherapy. Copyright © 2013 Elsevier B.V. All rights reserved.