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1.
A calcium optimum for cytotoxic T lymphocyte and natural killer cell cytotoxicity.
Kaschek, L, Zöphel, S, Knörck, A, Hoth, M
Seminars in cell & developmental biology. 2021;:10-18
Abstract
Cytotoxic T lymphocytes (CTL) and natural killer (NK) cells are required for host defense. They destroy malignant target cells like cancer cells. Among metal cations, Ca2+ plays a prescinded role for CTL and NK cytotoxicity as it is the only cation used as ubiquitous second messenger. Measuring intracellular Ca2+ concentrations [Ca2+]int in single cells has greatly changed our understanding of Ca2+ signaling. Yet, comparing the role of Ca2+ in the pre-[Ca2+]int and [Ca2+]int measurement era reveals that even in the pre-[Ca2+]int measurement era (before 1980), the functions of Ca2+ and some other metal cations for the cytotoxic immune response were well established. It was even shown that Ca2+ influx across the plasma membrane but not Ca2+ release from intracellular sources is relevant for lymphocyte cytotoxicity and that very little Ca2+ is needed for efficient lymphocyte cytotoxicity against cancer cells. In the [Ca2+]int measurement era after 1980, many of the important findings were better and more quantitatively refined and in addition the molecules important for Ca2+ transport were defined. The unexpected finding that there is a Ca2+ optimum of CTL and NK cell cytotoxicity deserves some attention and may be important for anti-cancer therapy.
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2.
Probiotics in Health and Disease: Distinct Roles of Different Strains in Natural Killer Cell Activation and Regulation.
Kaur, K, Ko, MW, Chen, PC, Breznik, B, Senjor, E, Wong, P, Wang, Y, Chovatiya, N, Jewett, A
Critical reviews in immunology. 2021;(2):1-19
Abstract
Elucidating the role of probiotic bacteria in health and disease perhaps constitutes one of the most exciting and fastest growing fields in medicine as we uncover the beneficial roles of these bacteria in many disease processes including cancer. We and others have reported previously that probiotic bacteria play a significant role in the activation of many cells including the cancer fighting natural killer (NK) cells. NK cells are the key immune effectors which control tumor growth and metastasis due to their ability to mediate direct cytotoxicity and/or differentiation of cancer stem cells/undifferentiated tumors through secreted and membrane bound interferon-gamma and tumor necrosis factor-alpha. In this review, we present an overview of recent studies from our laboratory and those of the others on their beneficial effects on immune cell function in particular on NK cells. In addition, we also highlight the current understanding of the role of probiotics in enhancement of the effectiveness of cancer therapeutics. Moreover, we discuss the functional impairment of cancer patients' NK cells and the role of probiotics in reversal of such functional impairment. NK cell-based immuno-therapies in combination with well-selected strains of probiotic bacteria may probably represent one of the best adjunct therapeutic approaches to prevent and treat cancer in the future.
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3.
Maternal natural killer cells at the intersection between reproduction and mucosal immunity.
Shmeleva, EV, Colucci, F
Mucosal immunology. 2021;(5):991-1005
Abstract
Many maternal immune cells populate the decidua, which is the mucosal lining of the uterus transformed during pregnancy. Here, abundant natural killer (NK) cells and macrophages help the uterine vasculature adapt to fetal demands for gas and nutrients, thereby supporting fetal growth. Fetal trophoblast cells budding off the forming placenta and invading deep into maternal tissues come into contact with these and other immune cells. Besides their homeostatic functions, decidual NK cells can respond to pathogens during infection, but in doing so, they may become conflicted between destroying the invader and sustaining fetoplacental growth. We review how maternal NK cells balance their double duty both in the local microenvironment of the uterus and systemically, during toxoplasmosis, influenza, cytomegalovirus, malaria and other infections that threat pregnancy. We also discuss recent developments in the understanding of NK-cell responses to SARS-Cov-2 infection and the possible dangers of COVID-19 during pregnancy.
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4.
Cryopreservation of NK and T Cells Without DMSO for Adoptive Cell-Based Immunotherapy.
Yao, X, Matosevic, S
BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy. 2021;(5):529-545
Abstract
Dimethylsufoxide (DMSO) being universally used as a cryoprotectant in clinical adoptive cell-therapy settings to treat hematological malignancies and solid tumors is a growing concern, largely due to its broad toxicities. Its use has been associated with significant clinical side effects-cardiovascular, neurological, gastrointestinal, and allergic-in patients receiving infusions of cell-therapy products. DMSO has also been associated with altered expression of natural killer (NK) and T-cell markers and their in vivo function, not to mention difficulties in scaling up DMSO-based cryoprotectants, which introduce manufacturing challenges for autologous and allogeneic cellular therapies, including chimeric antigen receptor (CAR)-T and CAR-NK cell therapies. Interest in developing alternatives to DMSO has resulted in the evaluation of a variety of sugars, proteins, polymers, amino acids, and other small molecules and osmolytes as well as modalities to efficiently enable cellular uptake of these cryoprotectants. However, the DMSO-free cryopreservation of NK and T cells remains difficult. They represent heterogeneous cell populations that are sensitive to freezing and thawing. As a result, clinical use of cryopreserved cell-therapy products has not moved past the use of DMSO. Here, we present the state of the art in the development and use of cryopreservation options that do not contain DMSO toward clinical solutions to enable the global deployment of safer adoptively transferred cell-based therapies.
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5.
Unconventional Peptide Presentation by Classical MHC Class I and Implications for T and NK Cell Activation.
Zajonc, DM
International journal of molecular sciences. 2020;(20)
Abstract
T cell-mediated immune recognition of peptides is initiated upon binding of the antigen receptor on T cells (TCR) to the peptide-MHC complex. TCRs are typically restricted by a particular MHC allele, while polymorphism within the MHC molecule can affect the spectrum of peptides that are bound and presented to the TCR. Classical MHC Class I molecules have a confined binding groove that restricts the length of the presented peptides to typically 8-11 amino acids. Both N- and C-termini of the peptide are bound within binding pockets, allowing the TCR to dock in a diagonal orientation above the MHC-peptide complex. Longer peptides have been observed to bind either in a bulged or zig-zag orientation within the binding groove. More recently, unconventional peptide presentation has been reported for different MHC I molecules. Here, either N- or C-terminal amino acid additions to conventionally presented peptides induced a structural change either within the MHC I molecule that opened the confined binding groove or within the peptide itself, allowing the peptide ends to protrude into the solvent. Since both TCRs on T cells and killer immunoglobulin receptors on Natural Killer (NK) cells contact the MHC I molecule above or at the periphery of the peptide binding groove, unconventionally presented peptides could modulate both T cell and NK cell responses. We will highlight recent advances in our understanding of the functional consequences of unconventional peptide presentation in cellular immunity.
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6.
KIR specificity and avidity of standard and unusual C1, C2, Bw4, Bw6 and A3/11 amino acid motifs at entire HLA:KIR interface between NK and target cells, the functional and evolutionary classification of HLA class I molecules.
Gwozdowicz, S, Nestorowicz, K, Graczyk-Pol, E, Szlendak, U, Rogatko-Koros, M, Mika-Witkowska, R, Pawliczak, D, Zubala, M, Malinowska, A, Witkowska, A, et al
International journal of immunogenetics. 2019;(4):217-231
Abstract
Natural killer (NK) cells make vital contributions to the immune system and the reproductive system. Notably, NK cells of donor origin can recognize and kill residual leukaemic cells and cure malignant patients in hematopoietic stem cell (HSC) transplant setting. NK cell function is regulated by KIRs that recognize cognate HLA class I molecules on target cells, depending on their amino acid residues. In review, we addressed the question of binding capacity and avidity of HLA class I molecules to different killer cell immunoglobulin-like receptors (KIRs) depending on all interacting amino acid residues both on HLA and KIR side. We searched PubMed database and analysed available HLA:KIR crystallographic data for amino acid residues in HLA molecules, those physically involved in binding KIRs (termed here the "entire KIR interface"). Within entire KIR interface, we selected five functional sequence motifs (14-19, 66-76, 77-84, 88-92 and 142-151) and classified them according to the conservation of their amino acid sequences among 8,942 HLA class I molecules. Although some conserved amino acid motifs were shared by different groups of KIR ligands, the HLA motif combinations were exclusive for the ligand groups. In 135 common HLA class I molecules with known HLA:KIR recognition, we found 54 combinations of five motifs in each of the KIR-binding interfaces (C1, C2, Bw4, A3/11) and conserved non-KIR-binding interfaces. Based on the entire KIR interface, this analysis allowed to classify 8,942 HLA class I molecules into KIR specificity groups. This functional and evolutionary classification of entire KIR interfaces provides a tool for unambiguously predicting HLA:KIR interactions for common and those HLA molecules that have not yet been functionally tested. Considering the entire KIR interface in HLA class I molecules, functional interactions of HLA and KIR can be predicted in immune responses, reproduction and allotransplantation. Further functional studies are needed on the HLA:KIR interaction variations caused by the repertoires of peptides presented by HLA molecules and KIR polymorphisms at allelic level.
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7.
Update of syncytiotrophoblast derived extracellular vesicles in normal pregnancy and preeclampsia.
Tannetta, D, Masliukaite, I, Vatish, M, Redman, C, Sargent, I
Journal of reproductive immunology. 2017;:98-106
Abstract
The release of extracellular vesicles (EV) by the syncytiotrophoblast (STB) may be an important mechanism by which the placenta signals to the mother. STB derived EV (STBEV) are comprised predominantly of exosomes (50-150nm) and microvesicles (100-1000nm) that contain bioactive mediators such as proteins, nucleic acids and lipids. They, along with larger syncytial nuclear aggregates are released by the STB into the maternal circulation throughout gestation in normal pregnancy where they appear to have an immunoregulatory role, inhibiting T cell and NK cell responses. In pre-eclampsia (PE) STBEV are released in significantly increased numbers and have pro-inflammatory, anti-angiogenic and procoagulant activity, implicating them in the maternal systemic inflammation, endothelial dysfunction and activation of the clotting system which typifies the disorder. Research has focused on understanding the biological significance of STBEV by measuring their size and repertoire of molecules carried and how they differ in normal pregnancy and PE, using techniques such as Nanoparticle Tracking Analysis, flow cytometry and mass spectrometry. We have also found alterations in STBEV surface glycans associated with PE. The goal is to better understand the role STBEV play in normal pregnancy and PE and whether they are potential biomarkers of placental pathology and therapeutic targets in PE.
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8.
Regulation and control of nitric oxide (NO) in macrophages: Protecting the "professional killer cell" from its own cytotoxic arsenal via MRP1 and GSTP1.
Kovacevic, Z, Sahni, S, Lok, H, Davies, MJ, Wink, DA, Richardson, DR
Biochimica et biophysica acta. General subjects. 2017;(5 Pt A):995-999
Abstract
We recently demonstrated that a novel storage and transport mechanism for nitric oxide (NO) mediated by glutathione-S-transferase P1 (GSTP1) and multidrug resistance protein 1 (MRP1/ABCC1), protects M1-macrophage (M1-MØ) models from large quantities of endogenous NO. This system stores and transports NO as dinitrosyl-dithiol-iron complexes (DNICs) composed of iron, NO and glutathione (GSH). Hence, this gas with contrasting anti- and pro-tumor effects, which has been assumed to be freely diffusible, is a tightly-regulated species in M1-MØs. These control systems prevent NO cytotoxicity and may be responsible for delivering cytotoxic NO as DNICs via MRP1 from M1-MØs, to tumor cell targets.
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9.
Traditional Oriental Herbal Medicine and Natural Killer Cells for Cancer Patients: A Systematic Review and Meta-analysis.
Bae, K, Park, JH, Kim, J, Cho, CK, Oh, B, Costa, D, Lim, S, Deng, G, Yoo, HS
Phytotherapy research : PTR. 2017;(4):519-532
Abstract
Traditional oriental herbal medicine (HM) is used by cancer patients to improve immunity. Natural killer (NK) cells are associated with development and progression of tumor and survival of cancer patients. This literature review examined randomized controlled trials (RCTs) in four electronic databases until October 2015 to evaluate the effects of oral HM on NK cells in cancer patients. Data were pooled and computed in a meta-analysis. The methodological quality was assessed according to the Cochrane risk of bias tool. Sixteen RCTs involving 1326 cancer patients were identified. Combination of HM and conventional treatment was associated with significantly higher level of NK cells compared with conventional cancer treatments (standardized mean difference, 1.218; 95% confidence interval 0.719-1.717; p < 0.001). Eight RCTs reported statistically significant improvements in the proportions or activity of NK cells in patient groups who received both HM and conventional treatment compared with patients who received conventional treatment alone, while eight RCTs reported no statistically significant differences between the two groups. Studies (n = 16) included in this review had insufficient quality of evidence with unclear (n = 1) and high (n = 15) values of the risk of bias. Although traditional oriental HM may have the positive effects on preserving the level of NK cells in cancer patients receiving conventional treatments, current evidence is inconclusive because of lack of high-quality evidence. Copyright © 2017 John Wiley & Sons, Ltd.
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10.
The bidirectional crosstalk between human dendritic cells and natural killer cells.
Wehner, R, Dietze, K, Bachmann, M, Schmitz, M
Journal of innate immunity. 2011;(3):258-63
Abstract
Dendritic cells (DCs) are professional antigen-presenting cells, which display an extraordinary capacity to induce T-cell responses. Recent findings revealed that DCs also play a crucial role in the activation of natural killer (NK) cells representing important effectors in the innate immune defense against viruses and tumors. Here, we summarize various studies investigating the bidirectional crosstalk between human DCs and NK cells. In this context, it has been reported that DCs efficiently enhance CD69 expression, proliferation, interferon (IFN)-γ secretion and cytotoxic activity of NK cells. Cell membrane-associated molecules as well as soluble factors such as interleukin-12, tumor necrosis factor-α and type I IFNs contributed to DC-mediated NK cell activation. Reciprocally, the ability of human NK cells to enhance the immunostimulatory capacity of DCs was shown. Thus, NK cells promoted the maturation of DCs and markedly augmented their capacity to produce proinflammatory cytokines and to stimulate T-cell responses. The NK cell-mediated effects on DCs were dependent on cell membrane-associated molecules such as NKp30 and soluble factors such as tumor necrosis factor-α and IFN-γ. In conclusion, the reciprocal activating interaction between human DCs and NK cells may play a pivotal role in the immune defense against viruses and tumors.