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Special Issue "Natural Killer (NK) Cells"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 September 2017)

Special Issue Editors

Guest Editor
Prof. Dr. Nicholas Huntington

Department of Medical Biology, University of Melbourne, Melbourne, VIC, 3010, Australia
Website | E-Mail
Interests: natural killer (NK) cells; Innate Lymphocytes; IL-15; Immunotherapy; Cellular Immunology
Guest Editor
Prof. Dr. Sam Kung

Department of Immunology, University of Manitoba, 750 McDermont Avenue, Winnipeg, MB, Canada
Website | E-Mail
Interests: natural killer cells; dendritic cells; gene therapy; anti-tumor immunity

Special Issue Information

Dear Colleagues,

Natural killer (NK) cells, where discovered over 40 years ago, and are known for their spontaneous killing of foreign cells. We have made tremendous advances in the basic biology of NK cells, and, in doing so, have uncovered functional heterogeneity, plasticity and adaptivity within the lineage and are still confronted with questions concerning the precise roles of NK cells in pathogen and tumor immunity. This Special Issue on "Natural Killer (NK) Cells" will bring expert insight into these probing topics and present novel data on NK cell function in disease. We ask the experts in the field to contribute their latest research, perspective, or reviews on this fascinating and rapidly progressing topic.

Prof. Dr. Nicholas Huntington
Prof. Dr. Sam Kung
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Natural Killer (NK) cells

  • Innate immune system

  • NK cell receptors

  • NK cell inhibition/activation

  • Immunotherapy

Published Papers (11 papers)

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Research

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Open AccessArticle Identification of Novel Human NK Cell Progenitor Subsets
Int. J. Mol. Sci. 2017, 18(12), 2716; https://doi.org/10.3390/ijms18122716
Received: 31 October 2017 / Revised: 8 December 2017 / Accepted: 8 December 2017 / Published: 15 December 2017
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Abstract
Understanding the pathways and regulation of human haematopoiesis, in particular, lymphopoiesis, is vital to manipulation of these processes for therapeutic purposes. However, although haematopoiesis has been extensively characterised in mice, translation of these findings to human biology remains rudimentary. Here, we describe the
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Understanding the pathways and regulation of human haematopoiesis, in particular, lymphopoiesis, is vital to manipulation of these processes for therapeutic purposes. However, although haematopoiesis has been extensively characterised in mice, translation of these findings to human biology remains rudimentary. Here, we describe the isolation of three progenitor subsets from human foetal bone marrow that represent differential stages of commitment to the natural killer (NK) cell lineage based on IL-15 responsiveness. We identify CD7 as a marker of IL-15 responsive progenitors in human bone marrow and find that this expression is maintained throughout commitment and maturation. Within the CD7+ fraction, we focussed on the lineage potential of three subsets based on CD127 and CD117 expression and observed restricted lymphoid and biased NK cell potential amongst subsets. We further demonstrate the presence of subsets similar in both phenotype and function in umbilical cord blood and the bone marrow of humanised mice, validating these as appropriate sources of progenitors for the investigation of human haematopoiesis. Overall, we describe several stages in the process of lymphopoiesis that will form the basis of investigating the regulators of this process in humans. Full article
(This article belongs to the Special Issue Natural Killer (NK) Cells)
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Open AccessArticle The Effects of Artemisinin on the Cytolytic Activity of Natural Killer (NK) Cells
Int. J. Mol. Sci. 2017, 18(7), 1600; https://doi.org/10.3390/ijms18071600
Received: 3 June 2017 / Revised: 13 July 2017 / Accepted: 21 July 2017 / Published: 24 July 2017
Cited by 5 | PDF Full-text (1658 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Artemisinin, a chemical compound used for the treatment of malaria, has been known to show anti-cancer activity. However, the effect of this chemical on natural killer (NK) cells, which are involved in tumor killing, remains unknown. Here, we demonstrate that artemisinin exerts a
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Artemisinin, a chemical compound used for the treatment of malaria, has been known to show anti-cancer activity. However, the effect of this chemical on natural killer (NK) cells, which are involved in tumor killing, remains unknown. Here, we demonstrate that artemisinin exerts a potent anti-cancer effect by activating NK cells. NK-92MI cells pre-treated with artemisinin were subjected to a cytotoxicity assay using K562 cells. The results showed that artemisinin significantly enhances the cytolytic activity of NK cells in a dose-dependent manner. Additionally, the artemisinin-enhanced cytotoxic effect of NK-92MI cells on tumor cells was accompanied by the stimulation of granule exocytosis, as evidenced by the detection of CD107a expression in NK cells. Moreover, this enhancement of cytotoxicity by artemisinin was also observed in human primary NK cells from peripheral blood. Our results suggest that artemisinin enhances human NK cell cytotoxicity and degranulation. This is the first evidence that artemisinin exerts antitumor activity by enhancing NK cytotoxicity. Therefore, these results provide a deeper understanding of the action of artemisinin and will contribute to the development and application of this class of compounds in cancer treatment strategies. Full article
(This article belongs to the Special Issue Natural Killer (NK) Cells)
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Open AccessArticle Amphotericin B, an Anti-Fungal Medication, Directly Increases the Cytotoxicity of NK Cells
Int. J. Mol. Sci. 2017, 18(6), 1262; https://doi.org/10.3390/ijms18061262
Received: 9 May 2017 / Revised: 2 June 2017 / Accepted: 9 June 2017 / Published: 13 June 2017
Cited by 1 | PDF Full-text (2342 KB) | HTML Full-text | XML Full-text
Abstract
Immunomodulatory drugs (IMiDs) present one example of immunomodulatory agents that improve cancer immunotherapy. Based on the cytotoxic activity of natural killer (NK) cells against cancer cells, a high throughput screening method for the identification of novel immunomodulatory molecules with the potential to stimulate
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Immunomodulatory drugs (IMiDs) present one example of immunomodulatory agents that improve cancer immunotherapy. Based on the cytotoxic activity of natural killer (NK) cells against cancer cells, a high throughput screening method for the identification of novel immunomodulatory molecules with the potential to stimulate NK cell cytotoxicity against cancer cells was designed and tested using an approved drug library. Among the primary hit compounds, the anti-fungal drug amphotericin B (AMP-B) increased the cytotoxicity of NK cell line and human primary NK cells in a direct manner. The increase in NK cell activity was related to increased formation of NK-target cell conjugates and the subsequent granule polarization toward target cells. The results of the present study indicate that AMP-B could serve a dual function as an anti-fungal and immunomodulatory drug. Full article
(This article belongs to the Special Issue Natural Killer (NK) Cells)
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Open AccessArticle Natural Killer Cells Response to IL-2 Stimulation Is Distinct between Ascites with the Presence or Absence of Malignant Cells in Ovarian Cancer Patients
Int. J. Mol. Sci. 2017, 18(5), 856; https://doi.org/10.3390/ijms18050856
Received: 23 February 2017 / Revised: 10 April 2017 / Accepted: 13 April 2017 / Published: 17 May 2017
Cited by 3 | PDF Full-text (1886 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Peritoneal ascites are a distinguishable feature of patients with advanced epithelial ovarian cancer (EOC). The presence of different lymphocyte subsets has been reported in EOC-associated ascites, which also can or not contain malignant cells. The goal of this study was to analyze the
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Peritoneal ascites are a distinguishable feature of patients with advanced epithelial ovarian cancer (EOC). The presence of different lymphocyte subsets has been reported in EOC-associated ascites, which also can or not contain malignant cells. The goal of this study was to analyze the functional characteristics of natural killer (NK) cells from EOC-associated ascites in terms of their expression of activating receptors and ascites’ contents of lymphocyte subtypes, cytokine profile and presence of EOC cells. NK cell function was evaluated by the expression of the degranulation marker CD107a in resting and interleukin (IL)-2 stimulated NK cells from ascites and blood. Degranulation of NK cells from EOC cell-free ascites was significantly (p < 0.05) higher than all the other groups, either in their resting state or after IL-2 stimulation, suggesting a previous local stimulation. In contrast, treatment with IL-2 had no effect on NK cells from ascites with EOC cells. The amount of regulatory T cells was significantly higher in ascites with EOC cells compared to EOC cell-free ascites. Ascites with EOC cells also had higher levels of tumor necrosis factor (TNF)-α, suggesting inflammation related to the malignancy. In conclusion, the functional performance of NK cells was distinct between EOC cell-free ascites and ascites with EOC cells. The impairment of NK cell response to IL-2 in ascites with EOC cells was consistent with an immunosuppressive tumor microenvironment. Full article
(This article belongs to the Special Issue Natural Killer (NK) Cells)
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Open AccessArticle Natural Killer Cell Assessment in Peripheral Circulation and Bronchoalveolar Lavage Fluid of Patients with Severe Sepsis: A Case Control Study
Int. J. Mol. Sci. 2017, 18(3), 616; https://doi.org/10.3390/ijms18030616
Received: 3 February 2017 / Revised: 2 March 2017 / Accepted: 7 March 2017 / Published: 12 March 2017
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Abstract
Sepsis is a complex systemic inflammatory syndrome, the most common cause of which is attributed to systemic underlying bacterial infection. The complete mechanisms of the dynamic pro- and anti-inflammatory processes underlying the pathophysiology of sepsis remain poorly understood. Natural killer (NK) cells play
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Sepsis is a complex systemic inflammatory syndrome, the most common cause of which is attributed to systemic underlying bacterial infection. The complete mechanisms of the dynamic pro- and anti-inflammatory processes underlying the pathophysiology of sepsis remain poorly understood. Natural killer (NK) cells play a crucial role in the pathophysiology of sepsis, leading to exaggerated inflammation due their rapid response and production of pro-inflammatory cytokines such as interferon gamma (IFN-γ). Several studies have already shown that NK cells undergo lymphopenia in the peripheral blood of patients with sepsis. However, our understanding of the mechanisms behind its cellular trafficking and its role in disease development is restricted to studies in animal models. In this study, we aimed to compare the human NK cell subset (CD56bright or dim) levels in the peripheral blood and bronchoalveolar lavage (BAL) fluid of sepsis patients. We conducted a case-control study with a sample size consisting of 10 control patients and 23 sepsis patients enrolled at the Hospital Cajuru (Curitiba/PR, Brazil) from 2013 to 2015. Although we were able to confirm previous observations of peripheral blood lymphopenia, no significant differences were detected in NK cell levels in the BAL fluid of these patients. Overall, these findings strengthened the evidence that peripheral blood lymphopenia is likely to be associated with cell death as a consequence of sepsis. Full article
(This article belongs to the Special Issue Natural Killer (NK) Cells)
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Review

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Open AccessReview Type 1 Diabetes and Its Multi-Factorial Pathogenesis: The Putative Role of NK Cells
Int. J. Mol. Sci. 2018, 19(3), 794; https://doi.org/10.3390/ijms19030794
Received: 7 February 2018 / Revised: 6 March 2018 / Accepted: 7 March 2018 / Published: 10 March 2018
Cited by 3 | PDF Full-text (1060 KB) | HTML Full-text | XML Full-text
Abstract
Type 1 diabetes (T1D) affects millions of people worldwide and is the prevalent form of all pediatric diabetes diagnoses. T1D is recognized to have an autoimmune etiology, since failure in specific self-tolerance mechanisms triggers immune reactions towards self-antigens and causes disease onset. Among
[...] Read more.
Type 1 diabetes (T1D) affects millions of people worldwide and is the prevalent form of all pediatric diabetes diagnoses. T1D is recognized to have an autoimmune etiology, since failure in specific self-tolerance mechanisms triggers immune reactions towards self-antigens and causes disease onset. Among all the different immunocytes involved in T1D etiopathogenesis, a relevant role of natural killer cells (NKs) is currently emerging. NKs represent the interface between innate and adaptive immunity; they intervene in the defense against infections and present, at the same time, typical features of the adaptive immune cells, such as expansion and generation of memory cells. Several recent studies, performed both in animal models and in human diabetic patients, revealed aberrations in NK cell frequency and functionality in the peripheral blood and in damaged tissues, suggesting their possible redirection towards affected tissues. NKs oscillate from a quiescent to an activated state through a delicate balance of activating and inhibitory signals transduced via surface receptors. Further accurate investigations are needed to elucidate the exact role of NKs in T1D, in order to develop novel immune-based therapies able to reduce the disease risk or delay its onset. Full article
(This article belongs to the Special Issue Natural Killer (NK) Cells)
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Open AccessReview View Point: Semaphorin-3E: An Emerging Modulator of Natural Killer Cell Functions?
Int. J. Mol. Sci. 2017, 18(11), 2337; https://doi.org/10.3390/ijms18112337
Received: 29 September 2017 / Revised: 21 October 2017 / Accepted: 1 November 2017 / Published: 5 November 2017
Cited by 1 | PDF Full-text (815 KB) | HTML Full-text | XML Full-text
Abstract
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
[...] Read more.
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. Full article
(This article belongs to the Special Issue Natural Killer (NK) Cells)
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Open AccessReview Control of NK Cell Activation by Immune Checkpoint Molecules
Int. J. Mol. Sci. 2017, 18(10), 2129; https://doi.org/10.3390/ijms18102129
Received: 19 September 2017 / Revised: 4 October 2017 / Accepted: 9 October 2017 / Published: 12 October 2017
Cited by 7 | PDF Full-text (252 KB) | HTML Full-text | XML Full-text
Abstract
The development of cancer and chronic infections is facilitated by many subversion mechanisms, among which enhanced expression of immune checkpoints molecules, such as programmed death-1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), on exhausted T cells. Recently, immune checkpoint inhibitors have shown
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The development of cancer and chronic infections is facilitated by many subversion mechanisms, among which enhanced expression of immune checkpoints molecules, such as programmed death-1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), on exhausted T cells. Recently, immune checkpoint inhibitors have shown remarkable efficiency in the treatment of a number of cancers. However, expression of immune checkpoints on natural killer (NK) cells and its functional consequences on NK cell effector functions are much less explored. In this review, we focus on the current knowledge on expression of various immune checkpoints in NK cells, how it can alter NK cell-mediated cytotoxicity and cytokine production. Dissecting the role of these inhibitory mechanisms in NK cells is critical for the full understanding of the mode of action of immunotherapies using checkpoint inhibitors in the treatment of cancers and chronic infections. Full article
(This article belongs to the Special Issue Natural Killer (NK) Cells)
Open AccessReview Natural Killer Cells: Angels and Devils for Immunotherapy
Int. J. Mol. Sci. 2017, 18(9), 1868; https://doi.org/10.3390/ijms18091868
Received: 1 August 2017 / Revised: 16 August 2017 / Accepted: 19 August 2017 / Published: 29 August 2017
Cited by 5 | PDF Full-text (1961 KB) | HTML Full-text | XML Full-text
Abstract
In recent years, the relevance of the immune system to fight cancer has led to the development of immunotherapy, including the adoptive cell transfer of immune cells, such as natural killer (NK) cells and chimeric antigen receptors (CAR)-modified T cells. The discovery of
[...] Read more.
In recent years, the relevance of the immune system to fight cancer has led to the development of immunotherapy, including the adoptive cell transfer of immune cells, such as natural killer (NK) cells and chimeric antigen receptors (CAR)-modified T cells. The discovery of donor NK cells’ anti-tumor activity in acute myeloid leukemia patients receiving allogeneic stem cell transplantation (allo-SCT) was the trigger to conduct many clinical trials infusing NK cells. Surprisingly, many of these studies did not obtain optimal results, suggesting that many different NK cell parameters combined with the best clinical protocol need to be optimized. Various parameters including the high array of activating receptors that NK cells have, the source of NK cells selected to treat patients, different cytotoxic mechanisms that NK cells activate depending on the target cell and tumor cell survival mechanisms need to be considered before choosing the best immunotherapeutic strategy using NK cells. In this review, we will discuss these parameters to help improve current strategies using NK cells in cancer therapy. Moreover, the chimeric antigen receptor (CAR) modification, which has revolutionized the concept of immunotherapy, will be discussed in the context of NK cells. Lastly, the dark side of NK cells and their involvement in inflammation will also be discussed. Full article
(This article belongs to the Special Issue Natural Killer (NK) Cells)
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Open AccessReview Dysfunctional Natural Killer Cells in the Aftermath of Cancer Surgery
Int. J. Mol. Sci. 2017, 18(8), 1787; https://doi.org/10.3390/ijms18081787
Received: 25 July 2017 / Revised: 13 August 2017 / Accepted: 14 August 2017 / Published: 17 August 2017
Cited by 3 | PDF Full-text (668 KB) | HTML Full-text | XML Full-text
Abstract
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.
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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. Full article
(This article belongs to the Special Issue Natural Killer (NK) Cells)
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Open AccessReview Regulation of NKG2D-Dependent NK Cell Functions: The Yin and the Yang of Receptor Endocytosis
Int. J. Mol. Sci. 2017, 18(8), 1677; https://doi.org/10.3390/ijms18081677
Received: 12 July 2017 / Revised: 27 July 2017 / Accepted: 30 July 2017 / Published: 2 August 2017
Cited by 4 | PDF Full-text (743 KB) | HTML Full-text | XML Full-text
Abstract
Natural-killer receptor group 2, member D (NKG2D) is a well characterized natural killer (NK) cell activating receptor that recognizes several ligands poorly expressed on healthy cells but up-regulated upon stressing stimuli in the context of cancer or viral infection. Although NKG2D ligands represent
[...] Read more.
Natural-killer receptor group 2, member D (NKG2D) is a well characterized natural killer (NK) cell activating receptor that recognizes several ligands poorly expressed on healthy cells but up-regulated upon stressing stimuli in the context of cancer or viral infection. Although NKG2D ligands represent danger signals that render target cells more susceptible to NK cell lysis, accumulating evidence demonstrates that persistent exposure to ligand-expressing cells causes the decrease of NKG2D surface expression leading to a functional impairment of NKG2D-dependent NK cell functions. Upon ligand binding, NKG2D is internalized from the plasma membrane and sorted to lysosomes for degradation. However, receptor endocytosis is not only a mechanism of receptor clearance from the cell surface, but is also required for the proper activation of signalling events leading to the functional program of NK cells. This review is aimed at providing a summary of current literature relevant to the molecular mechanisms leading to NKG2D down-modulation with particular emphasis given to the role of NKG2D endocytosis in both receptor degradation and signal propagation. Examples of chronic ligand-induced down-regulation of NK cell activating receptors other than NKG2D, including natural cytotoxicity receptors (NCRs), DNAX accessory molecule-1 (DNAM1) and CD16, will be also discussed. Full article
(This article belongs to the Special Issue Natural Killer (NK) Cells)
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