scholarly journals Effect of Natural Compounds on NK Cell Activation

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Malgorzata Grudzien ◽  
Andrzej Rapak
Keyword(s):  
Nk Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
Death Receptor ◽  
Adaptive Immune Response ◽  
The Body ◽  
Target Cells ◽  
Surface Receptors ◽  
Microbial Infections ◽  
A Cell

Natural killer (NK) cells are lymphocytes of the innate immune system that survey the body for stressed and abnormal cells. The integration of signals that they receive through various inhibitory and activating cell surface receptors controls their activation and ability to kill target cells and produce cytokines. In this manner, phenotypically and functionally distinct subsets of NK cells help protect against microbial infections and cancer and shape the adaptive immune response. NK cells can use two different mechanisms to kill their targets, either by cytotoxic granule exocytosis or by induction of death receptor-mediated apoptosis. Death ligands belong to the tumor necrosis factor (TNF) family of ligands. Upon release in close proximity to a cell slated for killing, perforin forms pores in the cell membrane of the target cell through which granzymes and associated molecules can enter and induce apoptosis. NK cells are also involved in antibody-dependent cellular toxicity via the CD16 receptor. In addition to target recognition, NK cells can be also activated by treatment with multiple compounds with stimulatory properties. Apart from interleukins, which belong to the best characterized group of NK cell-stimulating compounds, vitamins and constituents extracted from plants also display the ability to activate NK cells. The current review characterizes several groups of NK cell-activating compounds: vitamins belonging to classes A, B, C, D, and E, polysaccharides, lectins, and a number of phytochemicals used in cancer research, exhibiting stimulatory properties when applied to NK cells. Although in most cases the exact mechanism of action is not known, constituents described in this review seem to be promising candidates for NK cell-stimulating drugs.

scholarly journals NT5E/CD73 as Correlative Factor of Patient Survival and Natural Killer Cell Infiltration in Glioblastoma

2019 ◽  
Vol 8 (10) ◽  
pp. 1526 ◽  
Author(s):  
Jiao Wang ◽  
Sandro Matosevic
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Activation ◽  
Patient Survival ◽  
Nk Cell ◽  
Killer Cell ◽  
Surface Protein ◽  
The Cancer Genome Atlas ◽  
Negative Prognostic Factor ◽  
A Cell

CD73, a cell-surface protein encoded by the gene NT5E, is overexpressed in glioblastoma (GBM), where it contributes to the tumor’s pathophysiology via the generation of immunosuppressive adenosine. Adenosinergic signaling, in turn, drives immunosuppression of natural killer (NK) cells through metabolic and functional reprogramming. The correlation of CD73 with patient survival in relation to GBM pathology and the intratumoral infiltration of NK cells has not been comprehensively studied before. Here, we present an analysis of the prognostic relevance of CD73 in GBM based on transcriptional gene expression from patient data from The Cancer Genome Atlas (TCGA) database. Utilizing bioinformatics data mining tools, we explore the relationship between GBM prognosis, NT5E expression, and intratumoral presence of NK cells. Our analysis demonstrates that CD73 is a negative prognostic factor for GBM and that presence of NK cells may associate with improved prognosis. Moreover, the interplay between expression of NT5E and specific NK genes hints to potential functional effects of CD73 on NK cell activation.

scholarly journals Understanding the Synergy of NKp46 and Co-Activating Signals in Various NK Cell Subpopulations: Paving the Way for More Successful NK-Cell-Based Immunotherapy

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 753 ◽  
Author(s):  
Loris Zamai ◽  
Genny Del Zotto ◽  
Flavia Buccella ◽  
Sara Gabrielli ◽  
Barbara Canonico ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cell Response ◽  
Cell Activation ◽  
Nk Cell ◽  
High Sensitivity ◽  
Leukemic Cells ◽  
Target Cells ◽  
Hematopoietic Stem ◽  
Oncologic Patients ◽  
The Way

The NK cell population is characterized by distinct NK cell subsets that respond differently to the various activating stimuli. For this reason, the determination of the optimal cytotoxic activation of the different NK cell subsets can be a crucial aspect to be exploited to counter cancer cells in oncologic patients. To evaluate how the triggering of different combination of activating receptors can affect the cytotoxic responses of different NK cell subsets, we developed a microbead-based degranulation assay. By using this new assay, we were able to detect CD107a+ degranulating NK cells even within the less cytotoxic subsets (i.e., resting CD56bright and unlicensed CD56dim NK cells), thus demonstrating its high sensitivity. Interestingly, signals delivered by the co-engagement of NKp46 with 2B4, but not with CD2 or DNAM-1, strongly cooperate to enhance degranulation on both licensed and unlicensed CD56dim NK cells. Of note, 2B4 is known to bind CD48 hematopoietic antigen, therefore this observation may provide the rationale why CD56dim subset expansion correlates with successful hematopoietic stem cell transplantation mediated by alloreactive NK cells against host T, DC and leukemic cells, while sparing host non-hematopoietic tissues and graft versus host disease. The assay further confirms that activation of LFA-1 on NK cells leads to their granule polarization, even if, in some cases, this also takes to an inhibition of NK cell degranulation, suggesting that LFA-1 engagement by ICAMs on target cells may differently affect NK cell response. Finally, we observed that NK cells undergo a time-dependent spontaneous (cytokine-independent) activation after blood withdrawal, an aspect that may strongly bias the evaluation of the resting NK cell response. Altogether our data may pave the way to develop new NK cell activation and expansion strategies that target the highly cytotoxic CD56dim NK cells and can be feasible and useful for cancer and viral infection treatment.

scholarly journals Potential Role of NK Cells in the Pathogenesis of Inflammatory Bowel Disease

2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
Praveen K. Yadav ◽  
Chi Chen ◽  
Zhanju Liu
Keyword(s):  
Inflammatory Bowel Disease ◽  
Nk Cells ◽  
Proinflammatory Cytokines ◽  
Bowel Disease ◽  
Cell Activation ◽  
Potential Role ◽  
Nk Cell ◽  
Target Cells ◽  
Intestinal Epithelial ◽  
Inflammatory Bowel

NK cells are a major component of the innate immune system and play an important role in the tissue inflammation associated with autoimmune diseases such as inflammatory bowel disease (IBD). NK cells are unique in bearing both stimulatory and inhibitory receptors specific for MHC class I molecules, and their function is regulated by a series of inhibiting or activating signals. The delicate balance between activation and inhibition that decides NK cell final action provides an opportunity for their possible modulatory effect on specific therapeutic settings. Intestinal NK cells are phenotypically distinct from their counterparts in the blood and resemble “helper” NK cells, which have potentially important functions both in promoting antipathogen responses and in the maintenance of intestinal epithelial homeostasis. NK cell activities have been found to be significantly below normal levels in both remissive and active stages of IBD patients. However, some proinflammatory cytokines (e.g., IL-15, IL-21, and IL-23) could potently induce NK cell activation to secret high levels of proinflammatory cytokines (e.g., IFN-γ and TNF) and promote the cytolytic activities against the target cells. This paper provides the characteristics of intestinal NK cells and their potential role in the pathogenesis of IBD.

scholarly journals Transient and persistent effects of IL-15 on lymphocyte homeostasis in nonhuman primates

Blood ◽  
2010 ◽  
Vol 116 (17) ◽  
pp. 3238-3248 ◽  
Author(s):  
Enrico Lugli ◽  
Carolyn K. Goldman ◽  
Liyanage P. Perera ◽  
Jeremy Smedley ◽  
Rhonda Pung ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
The Body ◽  
Effector Memory ◽  
Memory Cd8 T Cells

Abstract Interleukin-15 (IL-15) is a cytokine with potential therapeutic application in individuals with cancer or immunodeficiency to promote natural killer (NK)– and T-cell activation and proliferation or in vaccination protocols to generate long-lived memory T cells. Here we report that 10-50 μg/kg IL-15 administered intravenously daily for 12 days to rhesus macaques has both short- and long-lasting effects on T-cell homeostasis. Peripheral blood lymphopenia preceded a dramatic expansion of NK cells and memory CD8 T cells in the circulation, particularly a 4-fold expansion of central memory CD8 T cells and a 6-fold expansion of effector memory CD8 T cells. This expansion is a consequence of their activation in multiple tissues. A concomitant inverted CD4/CD8 T-cell ratio was observed throughout the body at day 13, a result of preferential CD8 expansion. Expanded T- and NK-cell populations declined in the blood soon after IL-15 was stopped, suggesting migration to extralymphoid sites. By day 48, homeostasis appears restored throughout the body, with the exception of the maintenance of an inverted CD4/CD8 ratio in lymph nodes. Thus, IL-15 generates a dramatic expansion of short-lived memory CD8 T cells and NK cells in immunocompetent macaques and has long-term effects on the balance of CD4+ and CD8+ T cells.

AFM13 Is the Most Advanced Bispecific NK-Cell Engaging Antibody in Clinical Development Substantially Enhancing NK-Cell Effector Function and Proliferation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1764-1764 ◽  
Author(s):  
Jens Pahl ◽  
Uwe Reusch ◽  
Thorsten Gantke ◽  
Anne Kerber ◽  
Joachim Koch ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
Target Cells ◽  
Cell Cytotoxicity ◽  
Cell Receptors ◽  
Cell Responses ◽  
Nk Cell Receptors ◽  
Ifn Γ ◽  
Nk Cell Cytotoxicity

Abstract Introduction: AFM13 is an NK-cell engaging CD30/CD16A bispecific tetravalent TandAb antibody currently in phase 2 clinical development in Hodgkin lymphoma (HL) and other CD30+ malignancies. It engages NK-cells through CD16A with high affinity and specificity and confers significantly stronger NK-cell activation compared to other therapeutic antibodies. We have previously shown synergistic efficacy when NK-cell activation by AFM13 is combined with check-point modulation such as anti-PD-1 treatment, which is known to unleash T cell and NK-cell activity. The goal of this study was to identify further candidates for combination treatments and biomarkers that potentially indicate NK-cell responses to AFM13 treatment. Methods: AFM13-mediated NK-cell cytotoxicity and IFN-γ production after 4-hour interaction with HL cell lines was measured by 51Cr release assays and flow cytometry, respectively. Expression of NK-cell receptors, NK-cell proliferation (CFSE dilution) and expansion (absolute cell counts) was analyzed by flow cytometry. Results: The interaction of NK-cells with AFM13-coated tumor cells up-regulated the expression of NK-cell receptors such as CD25, CD69, CD137/4-1BB as well as molecules that may serve as NK-cell check-points when compared with the unrelated NK-cell binding TandAb AFM12 that does not bind to target cells. Importantly, CD16A engagement by AFM13 enhanced the proliferation and expansion potential of NK-cells when subsequently incubated with IL-15 or with particularly low doses of IL-2. NK-cell cytotoxicity and IFN-γ production was substantially increased towards CD30+ tumor cells in the presence of AFM13. Even target cells resistant to naïve and IL-2/IL-15-activated NK-cells were susceptible to AFM13-induced NK-cell cytotoxicity. AFM13 concentrations of as low as 10-2 µg/mL resulted in maximal activity while AFM13 was significantly more potent than native anti-CD30 IgG1 antibody. NK-cell activation by IL-2 or IL-15 had a synergistic effect on AFM13-mediated cytotoxicity. Conclusion: AFM13 specifically enhances the cytotoxic, proliferative and cytokine-producing potential of NK-cells. Our data indicate that the distinctive modulation of NK-cell receptors can be utilized to monitor NK-cell responses during AFM13 therapy and provides candidates for therapeutic combination strategies. Moreover, the combination with low doses of IL-2 or with IL-15 may expand the quantity of tumor-reactive NK-cells after AFM13 treatment and promote NK-cell functionality in the tumor microenvironment in cancer patients. Disclosures Reusch: Affimed: Employment, Patents & Royalties: Patents. Gantke:Affimed GmbH: Employment. Kerber:Affimed: Employment. Koch:Affimed: Employment. Treder:Affimed: Employment. Cerwenka:Affimed: Research Funding.

Natural killer (NK) cell activation, cytokine production, and cytotoxicity in human PBMC/myeloma cell co-culture exposed to elotuzumab (Elo) alone or in combination with lenalidomide (Len).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8087-8087 ◽  
Author(s):  
Balaji Balasa ◽  
Rui Yun ◽  
Nicole Belmar ◽  
Gary Starling ◽  
Audie Rice
Keyword(s):  
Nk Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
Myeloma Cell ◽  
Cell Killing ◽  
Cell Counting ◽  
Target Cells ◽  
Human Pbmc ◽  
Myeloma Cells ◽  
Ifn Γ

8087 Background: Elo is a monoclonal IgG1 antibody targeting CS1, a cell surface glycoprotein highly expressed on >95% of myeloma cells. In preclinical models Elo exerts anti-myeloma activity via NK cell-mediated antibody-dependent cellular cytotoxicity. Len is an immunomodulatory agent that may activate NK cells. The combination of Elo + Len synergistically enhanced anti-tumor activity in myeloma xenograft models. We investigated the mechanism of enhancing NK cell activation and myeloma cell killing with Elo + Len. Methods: Human PBMC/OPM-2 co-cultures were treated for 24-72h with Elo, Len, or Elo + Len. Activation markers and adhesion receptors were evaluated by flow cytometry. Cytokines were measured by Luminex and ELISpot assays. Cytotoxicity was assessed by cell counting. Results: Elo + Len increased IFN-γ secretion significantly more than Elo or Len alone. IFN-γ elevates ICAM-1 expression, and ICAM-1 surface expression on OPM-2 target cells increased synergistically with Elo + Len. Elo, Elo + Len but not Len increased expression of CD25 (IL-2Rα) on NK cells. Len increased the levels of IL-2, but those were decreased in the presence of Elo due to increased consumption by CD25 expressing NK cells. Blocking uptake of IL-2 with anti-CD25 resulted in higher IL-2 levels than with Len. ELISpot assays confirmed that Elo + Len significantly increased the number of IL-2-producing cell colonies compared with Elo or Len. Elo induced NK dependent myeloma cell killing, and the effect was significantly higher with Elo + Len. Conclusions: Elo alone activated NK cells and mediated the killing of myeloma cells in PBMC/OPM-2 co-cultures. Elo + Len synergistically enhanced myeloma cell killing and increased expression/production of IFN-γ, ICAM-1, IL-2, and CD25. [Table: see text]

scholarly journals NK-DC Crosstalk in Immunity to Microbial Infection

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Rony Thomas ◽  
Xi Yang
Keyword(s):  
Immune Responses ◽  
Cell Activation ◽  
Nk Cell ◽  
Adaptive Immune Response ◽  
Microbial Infection ◽  
Adaptive Immune ◽  
Microbial Infections ◽  
Cellular Components ◽  
Secondary Lymphoid Organs ◽  
Dc Maturation

The interaction between natural killer (NK) cell and dendritic cell (DC), two important cellular components of innate immunity, started to be elucidated in the last years. The crosstalk between NK cells and DC, which leads to NK cell activation, DC maturation, or apoptosis, involves cell-cell contacts and soluble factors. This interaction either in the periphery or in the secondary lymphoid organs acts as a key player linking innate and adaptive immune responses to microbial stimuli. This review focuses on the mechanisms of NK-DC interaction and their relevance in antimicrobial responses. We specifically aim to emphasize the ability of various microbial infections to differently influence NK-DC crosstalk thereby contributing to distinct adaptive immune response.

scholarly journals The Traffic of the NKG2D/Dap10 Receptor Complex during Natural Killer (NK) Cell Activation

2009 ◽  
Vol 284 (24) ◽  
pp. 16463-16472 ◽  
Author(s):  
Pedro Roda-Navarro ◽  
Hugh T. Reyburn
Keyword(s):  
Cell Surface ◽  
Nk Cells ◽  
Cell Activation ◽  
Cell Function ◽  
Nk Cell ◽  
Receptor Expression ◽  
Cell Surface Expression ◽  
Target Cells ◽  
Receptor Complex ◽  
Secretory Lysosomes

NKG2D is an important activating receptor for triggering the NK cell cytotoxic activity, although chronic engagement of specific ligands by NKG2D is also known to provoke decreased cell surface expression of the receptor and compromised NK cell function. We have studied the dynamics of surface NKG2D expression and how exposure to the specific ligand major histocompatibility complex class I chain-related molecule B (MICB) affects receptor traffic and fate. While in the NKL cell line and “resting” NK cells NKG2D was found principally at the cell surface, in activated primary NK cells an intracellular pool of receptor could also be found recycling to the plasma membrane. Exposure of NK cells to targets expressing MICB resulted in degradation of ∼50% of total NKG2D protein and lysosomal degradation of the DAP10 adaptor molecule. Consistent with these observations, confocal microscopy experiments demonstrated that DAP10 trafficked to secretory lysosomes in both transfected NKL cells and in activated primary NK cells upon interaction with MICB-expressing target cells. Interestingly, polarization to the synapse of secretory lysosomes containing DAP10 was also observed. The implications of the intracellular traffic of the NKG2D/DAP10 receptor complex for NK cell activation are discussed. We propose that the rapid degradation of NKG2D/DAP10 observed coincident with recruitment of the receptor to the cytotoxic immune synapse may explain the loss of NKG2D receptor expression after chronic exposure to NKG2D ligands.

scholarly journals The human cytomegalovirus protein UL147A downregulates the most prevalent MICA allele: MICA*008, to evade NK cell-mediated killing

2021 ◽  
Vol 17 (5) ◽  
pp. e1008807
Author(s):  
Einat Seidel ◽  
Liat Dassa ◽  
Corinna Schuler ◽  
Esther Oiknine-Djian ◽  
Dana G. Wolf ◽  
...  
Keyword(s):  
Nk Cells ◽  
Human Cytomegalovirus ◽  
Cell Activation ◽  
Hcmv Infection ◽  
Nk Cell ◽  
Innate Immune ◽  
Target Cells ◽  
Histocompatibility Complex ◽  
Immunosuppressed Patients ◽  
Infected Cells

Natural killer (NK) cells are innate immune lymphocytes capable of killing target cells without prior sensitization. One pivotal activating NK receptor is NKG2D, which binds a family of eight ligands, including the major histocompatibility complex (MHC) class I-related chain A (MICA). Human cytomegalovirus (HCMV) is a ubiquitous betaherpesvirus causing morbidity and mortality in immunosuppressed patients and congenitally infected infants. HCMV encodes multiple antagonists of NK cell activation, including many mechanisms targeting MICA. However, only one of these mechanisms, the HCMV protein US9, counters the most prevalent MICA allele, MICA*008. Here, we discover that a hitherto uncharacterized HCMV protein, UL147A, specifically downregulates MICA*008. UL147A primarily induces MICA*008 maturation arrest, and additionally targets it to proteasomal degradation, acting additively with US9 during HCMV infection. Thus, UL147A hinders NKG2D-mediated elimination of HCMV-infected cells by NK cells. Mechanistic analyses disclose that the non-canonical GPI anchoring pathway of immature MICA*008 constitutes the determinant of UL147A specificity for this MICA allele. These findings advance our understanding of the complex and rapidly evolving HCMV immune evasion mechanisms, which may facilitate the development of antiviral drugs and vaccines.

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