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1.
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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2.
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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3.
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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4.
Immune activation of Bio-Germanium in a randomized, double-blind, placebo-controlled clinical trial with 130 human subjects: Therapeutic opportunities from new insights.
Cho, JM, Chae, J, Jeong, SR, Moon, MJ, Shin, DY, Lee, JH
PloS one. 2020;(10):e0240358
Abstract
[NCT03677921]; www.clinicaltrials.gov [KCT0002726]; https://cris.nih.go.kr.
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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.
High Metabolic Function and Resilience of NKG2A-Educated NK Cells.
Highton, AJ, Diercks, BP, Möckl, F, Martrus, G, Sauter, J, Schmidt, AH, Bunders, MJ, Körner, C, Guse, AH, Altfeld, M
Frontiers in immunology. 2020;:559576
Abstract
Natural killer (NK) cells are an important component of the innate immune system for the control of intracellular pathogens and cancer cells. NK cells demonstrate heterogeneous expression of inhibitory surface receptors. Signaling through these various receptors during NK cell development promotes functionality, referred to as NK cell education. Here we investigated the impact of education on NK cell metabolism through functional assessment of critical metabolic pathways and calcium signaling. Educated NK cells had an increased uptake of the metabolic substrates 2-NBDG, a fluorescent glucose analog, and BODIPY FL C16, a fluorescent palmitate, compared to uneducated NK cells. Comparison of NK cells educated via KIRs or NKG2A showed that NKG2A-educated NK cells were the main contributor to these differences in uptake of metabolites, and that NKG2A-educated NK cells were functionally more resilient in response to metabolic blockade of oxidative phosphorylation. Furthermore, NKG2A-educated NK cells exhibited higher peak calcium concentration following stimulation, indicating stronger signaling events taking place in these educated NK cells. These results demonstrate that cellular metabolism plays an important role in the functional differences observed between educated and uneducated NK cells, and show that NKG2A-educated NK cells remain more functionally competent than KIR-educated NK cells when oxidative phosphorylation is restricted. Understanding metabolic programming during NK cell education may unveil future targets to manipulate NK cell function for use in clinical settings, such as cancer therapies.
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7.
Effect of vitamin D supplementation on N-glycan branching and cellular immunophenotypes in MS.
Bäcker-Koduah, P, Infante-Duarte, C, Ivaldi, F, Uccelli, A, Bellmann-Strobl, J, Wernecke, KD, Sy, M, Demetriou, M, Dörr, J, Paul, F, et al
Annals of clinical and translational neurology. 2020;(9):1628-1641
Abstract
OBJECTIVE To investigate the effect of cholecalciferol (vitamin D3) supplementation on peripheral immune cell frequency and N-glycan branching in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS Exploratory analysis of high-dose (20 400 IU) and low-dose (400 IU) vitamin D3 supplementation taken every other day of an 18-month randomized controlled clinical trial including 38 RRMS patients on stable immunomodulatory therapy (NCT01440062). We investigated cholecalciferol treatment effects on N-glycan branching using L-PHA stain (phaseolus vulgaris leukoagglutinin) at 6 months and frequencies of T-, B-, and NK-cell subpopulations at 12 months with flow cytometry. RESULTS High-dose supplementation did not change CD3+ T cell subsets, CD19+ B cells subsets, and NK cells frequencies, except for CD8+ T regulatory cells, which were reduced in the low-dose arm compared to the high-dose arm at 12 months. High-dose supplementation decreased N-glycan branching on T and NK cells, measured as L-PHA mean fluorescence intensity (MFI). A reduction of N-glycan branching in B cells was not significant. In contrast, low-dose supplementation did not affect N-glycan branching. Changes in N-glycan branching did not correlate with cell frequencies. INTERPRETATION Immunomodulatory effect of vitamin D may involve regulation of N-glycan branching in vivo. Vitamin D3 supplementation did at large not affect the frequencies of peripheral immune cells.
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8.
Short-term probiotic supplementation enhances cellular immune function in healthy elderly: systematic review and meta-analysis of controlled studies.
Miller, LE, Lehtoranta, L, Lehtinen, MJ
Nutrition research (New York, N.Y.). 2019;:1-8
Abstract
Immune function declines with advancing age. Probiotic supplementation has been proposed to slow or reverse these age-related changes. The primary objective of this study was to evaluate the effect of probiotic supplementation on cellular innate immune activity in healthy elderly subjects. We hypothesized that probiotic supplementation would enhance immune function. We performed a systematic review and meta-analysis of controlled trials that reported polymorphonuclear cell phagocytic capacity or natural killer (NK) cell tumoricidal activity following short-term probiotic supplementation in the elderly. Effect size was reported as the standardized mean difference (SMD) between probiotic and control groups, where values of 0.2, 0.5, 0.8, and 1.0 corresponded to small, medium, large, and very large effect sizes, respectively. A total of 17 prospective controlled studies (18 comparisons) of 733 subjects were included. Probiotic supplementation duration ranged from 3 to 12 weeks. Probiotic supplementation increased polymorphonuclear phagocytic capacity (SMD = 1.37, 95% confidence interval: 0.86-1.88, P < .001) and NK cell tumoricidal activity (SMD = 0.55, 95% confidence interval: 0.37-0.73, P < .001) relative to controls. In a subgroup analysis of NK cell activity, heterogeneity among studies was not explained by variability in study design or probiotic characteristics. Main limitations of this research were short-term supplementation durations and unclear clinical benefit of the immune changes. In conclusion, short-term probiotic supplementation enhances cellular immune function in healthy elderly adults.
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9.
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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10.
Relationship between natural killer cell activity and glucose control in patients with type 2 diabetes and prediabetes.
Kim, JH, Park, K, Lee, SB, Kang, S, Park, JS, Ahn, CW, Nam, JS
Journal of diabetes investigation. 2019;(5):1223-1228
Abstract
AIMS/INTRODUCTION Natural killer (NK) cells are cytotoxic lymphocytes critical to human immunity. Previous studies showed correlations between NK cell function and blood glucose concentrations. The purpose of the present study was to assess the NK cell activity and various metabolic parameters in people with type 2 diabetes, prediabetes and normal glucose tolerance. MATERIALS AND METHODS A total of 49 participants were enrolled in the study. Anthropometric and biochemical parameters including age, sex, body mass index, smoking status, blood pressure, fasting plasma glucose, C-peptide, insulin, glycated hemoglobin, total cholesterol, triglyceride, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol were assessed. The 75 g oral glucose tolerance test was carried out for 2-h postload glucose level. Homeostatic model assessment was calculated for insulin resistance and β-cell function. NK cell activity was measured by detecting the circulating interferon-gamma level secreted from NK cells. RESULTS NK cell activity was lower in patients with type 2 diabetes (768.01 ± 650.35) compared with those with prediabetes (2,396.08 ± 653.76, P < 0.001) and normal glucose tolerance (2,435.31 ± 633.22, P < 0.001). In patients with type 2 diabetes, there was a significant inverse linear relationship between NK cell activity and fasting plasma glucose, glycated hemoglobin, and 2-h postload glucose level (all P < 0.001). Multiple regression analysis showed glycated hemoglobin to be an independent predictor of NK cell activity in patients with type 2 diabetes. CONCLUSIONS Compared with individuals with normal glucose tolerance or prediabetes, type 2 diabetes patients have a reduced NK cell activity, and it is significantly related to glucose control.