Submit to Cells Review for Cells Propose a Special Issue

Journal Browser

► Journal Browser

Regulation of Natural Killer Cell Development and Functions

Print Special Issue Flyer
Special Issue Editors
Special Issue Information
Keywords
Published Papers

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: closed (30 September 2021) | Viewed by 37475

Share This Special Issue

Special Issue Editors

Prof. Dr. Subramaniam Malarkannan

E-Mail Website
Guest Editor

1. Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
2. Laboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, Versiti, Milwaukee, WI 53226, USA
Interests: innate immunity; NK cells; signaling; single-cell transcriptome; cell therapy; CAR-T/NK therapy
Special Issues, Collections and Topics in MDPI journals

Dr. Anahid Jewett

E-Mail Website1 Website2 Website3
Guest Editor

1. Tumor Immunology Laboratory, Division of Oral Biology and Medicine, School of Dentistry and Medicine, Los Angeles, CA 90095, USA
2. Division of Advanced Prosthodontics and Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, CA 90095, USA
3. The Jonsson Comprehensive Cancer Center, UCLA School of Dentistry and Medicine, Los Angeles, CA 90095, USA
Interests: natural killer cells; differentiation; cancer stem cells; cell death; NK therapeutics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Natural killer (NK) cells are major innate lymphocytes. NK cells do not require prior antigen exposure to mediate antitumor cytotoxicity or pro-inflammatory cytokine production. NK cells only use non-clonotypic germline-encoded receptors that largely recognize “self-antigens”. The ability of NK cells to differentiate “missing-self” from “self” provides high clinical value in formulating immunotherapies against a broad spectrum of malignancies. Irrespective of these potentials, the signaling pathways and transcriptional regulation that govern NK cell development and functions remain far from fully defined. In this Special Issue of Cells, we invite authors to contribute original and review articles that focus on signaling molecules, transcription factors, developmental processes, functional analyses, and therapeutic formulations of murine or human NK cells. Through these broad-reaching goals of this Special Issue, we would like to provide an update on NK cell biology to the larger immunology community.

Prof. Subramaniam Malarkannan
Dr. Anahid Jewett
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 submissions that pass pre-check are 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. Cells is an international peer-reviewed open access semimonthly 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 2700 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

NK cells
development
effector functions
transcription factors
immunotherapy
CAR-NK
metabolic reprogramming
inflammatory cytokines
helper functions
NK–DC interactions
NK-T cell interactions

Published Papers (7 papers)

Download All Papers

Research

Jump to: Review

18 pages, 2099 KiB

Open AccessArticle

Defective Patient NK Function Is Reversed by AJ2 Probiotic Bacteria or Addition of Allogeneic Healthy Monocytes

by Meng-Wei Ko, Kawaljit Kaur, Tahmineh Safaei, Wuyang Chen, Christine Sutanto, Paul Wong and Anahid Jewett

Cells 2022, 11(4), 697; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11040697 - 16 Feb 2022

Cited by 3 | Viewed by 2448

Abstract

In this paper, we present the role of autologous and allogeneic monocytes from healthy individuals and those of the cancer patients, with a number of distinct cancers, in activating the function of natural killer (NK) cells, in particular, in induction of IFN-γ secretion by the NK cells and the functional capability of secreted IFN-γ in driving differentiation of the tumor cells. In addition, we compared the roles of CD16 signaling as well as sonicated probiotic bacteria AJ2 (sAJ2)-mediated induction and function of IFN-γ-mediated differentiation in tumor cells. We found that monocytes from cancer patients had lower capability to induce functional IFN-γ secretion by the autologous CD16 mAb-treated NK cells in comparison to those from healthy individuals. In addition, when patient monocytes were cultured with NK cells from healthy individuals, they had lower capability to induce functional IFN-γ secretion by the NK cells when compared to those from autologous monocyte/NK cultures from healthy individuals. Activation by sAJ2 or addition of monocytes from healthy individuals to patient NK cells increased the secretion of functional IFN-γ by the NK cells and elevated its functional capability to differentiate tumors. Monocytes from cancer patients were found to express lower CD16 receptors, providing a potential mechanism for their lack of ability to trigger secretion of functional IFN-γ. In addition to in vitro studies, we also conducted in vivo studies in which cancer patients were given oral supplementation of AJ2 and the function of NK cells were studied. Oral ingestion of AJ2 improved the secretion of IFN-γ by patient derived NK cells and resulted in the better functioning of NK cells in cancer patients. Thus, our studies indicate that for successful NK cell immunotherapy, not only the defect in NK cells but also those in monocytes should be corrected. In this regard, AJ2 probiotic bacteria may serve to provide a potential adjunct treatment strategy. Full article

(This article belongs to the Special Issue Regulation of Natural Killer Cell Development and Functions)

► Show Figures

Figure 1

16 pages, 1943 KiB

Open AccessArticle

Radiotherapy Combined with PD-1 Inhibition Increases NK Cell Cytotoxicity towards Nasopharyngeal Carcinoma Cells

by Anna Makowska, Nora Lelabi, Christina Nothbaum, Lian Shen, Pierre Busson, Tram Thi Bao Tran, Michael Eble and Udo Kontny

Cells 2021, 10(9), 2458; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10092458 - 17 Sep 2021

Cited by 16 | Viewed by 3000

Abstract

Background: Nasopharyngeal carcinoma (NPC) in endemic regions and younger patients is characterized by a prominent lymphomononuclear infiltration. Radiation is the principal therapeutic modality for patients with NPC. Recent data suggest that the efficacy of radiotherapy in various cancers can be augmented when combined with immune checkpoint blockade. Here, we investigate the effect of radiotherapy on the killing of NPC cells by Natural Killer (NK) cells. Methods: NPC cell lines and a patient-derived xenograft were exposed to NK cells in the context of radiotherapy. Cytotoxicity was measured using the calcein-release assay. The contribution of the PD-L1/PD-1 checkpoint and signaling pathways to killing were analyzed using specific inhibitors. Results: Radiotherapy sensitized NPC cells to NK cell killing and upregulated expression of PD-1 ligand (PD-L1) in NPC cells and PD-1 receptor (PD-1) in NK cells. Blocking of the PD-L1/PD-1 checkpoint further increased the killing of NPC cells by NK cells in the context of radiotherapy. Conclusion: Radiation boosts the killing of NPC cells by NK cells. Killing can be further augmented by blockade of the PD-L1/PD-1 checkpoint. The combination of radiotherapy with PD-L1/PD-1 checkpoint blockade could therefore increase the efficacy of radiotherapy in NPC tumors. Full article

(This article belongs to the Special Issue Regulation of Natural Killer Cell Development and Functions)

► Show Figures

Figure 1

Review

Jump to: Research

23 pages, 2571 KiB

Open AccessReview

The New Kid on the Block: HLA-C, a Key Regulator of Natural Killer Cells in Viral Immunity

by Sarah Vollmers, Annabelle Lobermeyer and Christian Körner

Cells 2021, 10(11), 3108; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10113108 - 10 Nov 2021

Cited by 10 | Viewed by 6344

Abstract

The human leukocyte antigen system (HLA) is a cluster of highly polymorphic genes essential for the proper function of the immune system, and it has been associated with a wide range of diseases. HLA class I molecules present intracellular host- and pathogen-derived peptides to effector cells of the immune system, inducing immune tolerance in healthy conditions or triggering effective immune responses in pathological situations. HLA-C is the most recently evolved HLA class I molecule, only present in humans and great apes. Differentiating from its older siblings, HLA-A and HLA-B, HLA-C exhibits distinctive features in its expression and interaction partners. HLA-C serves as a natural ligand for multiple members of the killer-cell immunoglobulin-like receptor (KIR) family, which are predominately expressed by natural killer (NK) cells. NK cells are crucial for the early control of viral infections and accumulating evidence indicates that interactions between HLA-C and its respective KIR receptors determine the outcome and progression of viral infections. In this review, we focus on the unique role of HLA-C in regulating NK cell functions and its consequences in the setting of viral infections. Full article

(This article belongs to the Special Issue Regulation of Natural Killer Cell Development and Functions)

► Show Figures

Figure 1

18 pages, 1372 KiB

Open AccessReview

NK Cell Regulation in Cervical Cancer and Strategies for Immunotherapy

by Adriana Gutiérrez-Hoya and Isabel Soto-Cruz

Cells 2021, 10(11), 3104; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10113104 - 10 Nov 2021

Cited by 26 | Viewed by 5254

Abstract

Cervical cancer is one of the most prevalent gynaecological malignancies worldwide and is related to human papillomavirus (HPV) infection, viral persistence, progression, and invasion. Therefore, the immune response is linked to HPV status. Natural killer (NK) cells play a central role against virus-infected cells and tumours through a delicate balance between activating and inhibitory receptors and secretion of cytokines and chemokines. These cells also play a crucial role in tumour immunosurveillance. For these reasons, there is growing interest in harnessing NK cells as an immunotherapy for cervical cancer. These studies are diverse and include many strategies such as transferring activated autologous or allogeneic NK cells, improving the activation and cytolytic activity of NK cells using cytokines or analogues and modifying chimeric antigen receptors to increase specificity and targeting NK cells. However, research regarding the application of NK cells in immunotherapy is limited. This article focuses on recent discoveries about using NK cells to prevent and treat cervical cancer and the possibility of cellular immunotherapy becoming one of the best strategies to exploit the immune system to fight tumours. Full article

(This article belongs to the Special Issue Regulation of Natural Killer Cell Development and Functions)

► Show Figures

Figure 1

15 pages, 2715 KiB

Open AccessReview

The Role of microRNAs in NK Cell Development and Function

by Arash Nanbakhsh and Subramaniam Malarkannan

Cells 2021, 10(8), 2020; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10082020 - 7 Aug 2021

Cited by 10 | Viewed by 2809

Abstract

The clinical use of natural killer (NK) cells is at the forefront of cellular therapy. NK cells possess exceptional antitumor cytotoxic potentials and can generate significant levels of proinflammatory cytokines. Multiple genetic manipulations are being tested to augment the anti-tumor functions of NK cells. One such method involves identifying and altering microRNAs (miRNAs) that play essential roles in the development and effector functions of NK cells. Unique miRNAs can bind and inactivate mRNAs that code for cytotoxic proteins. MicroRNAs, such as the members of the Mirc11 cistron, downmodulate ubiquitin ligases that are central to the activation of the obligatory transcription factors responsible for the production of inflammatory cytokines. These studies reveal potential opportunities to post-translationally enhance the effector functions of human NK cells while reducing unwanted outcomes. Here, we summarize the recent advances made on miRNAs in murine and human NK cells and their relevance to NK cell development and functions. Full article

(This article belongs to the Special Issue Regulation of Natural Killer Cell Development and Functions)

► Show Figures

Figure 1

27 pages, 3497 KiB

Open AccessFeature PaperReview

Implications of a ‘Third Signal’ in NK Cells

by Mohamed Khalil, Dandan Wang, Elaheh Hashemi, Scott S. Terhune and Subramaniam Malarkannan

Cells 2021, 10(8), 1955; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10081955 - 31 Jul 2021

Cited by 6 | Viewed by 7796

Abstract

Innate and adaptive immune systems are evolutionarily divergent. Primary signaling in T and B cells depends on somatically rearranged clonotypic receptors. In contrast, NK cells use germline-encoded non-clonotypic receptors such as NCRs, NKG2D, and Ly49H. Proliferation and effector functions of T and B cells are dictated by unique peptide epitopes presented on MHC or soluble humoral antigens. However, in NK cells, the primary signals are mediated by self or viral proteins. Secondary signaling mediated by various cytokines is involved in metabolic reprogramming, proliferation, terminal maturation, or memory formation in both innate and adaptive lymphocytes. The family of common gamma (γc) cytokine receptors, including IL-2Rα/β/γ, IL-7Rα/γ, IL-15Rα/β/γ, and IL-21Rα/γ are the prime examples of these secondary signals. A distinct set of cytokine receptors mediate a ‘third’ set of signaling. These include IL-12Rβ1/β2, IL-18Rα/β, IL-23R, IL-27R (WSX-1/gp130), IL-35R (IL-12Rβ2/gp130), and IL-39R (IL-23Rα/gp130) that can prime, activate, and mediate effector functions in lymphocytes. The existence of the ‘third’ signal is known in both innate and adaptive lymphocytes. However, the necessity, context, and functional relevance of this ‘third signal’ in NK cells are elusive. Here, we define the current paradigm of the ‘third’ signal in NK cells and enumerate its clinical implications. Full article

(This article belongs to the Special Issue Regulation of Natural Killer Cell Development and Functions)

► Show Figures

Figure 1

24 pages, 1090 KiB

Open AccessReview

NKG2D Natural Killer Cell Receptor—A Short Description and Potential Clinical Applications

by Jagoda Siemaszko, Aleksandra Marzec-Przyszlak and Katarzyna Bogunia-Kubik

Cells 2021, 10(6), 1420; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10061420 - 7 Jun 2021

Cited by 27 | Viewed by 8725

Abstract

Natural Killer (NK) cells are natural cytotoxic, effector cells of the innate immune system. They can recognize transformed or infected cells. NK cells are armed with a set of activating and inhibitory receptors which are able to bind to their ligands on target cells. The right balance between expression and activation of those receptors is fundamental for the proper functionality of NK cells. One of the best known activating receptors is NKG2D, a member of the CD94/NKG2 family. Due to a specific NKG2D binding with its eight different ligands, which are overexpressed in transformed, infected and stressed cells, NK cells are able to recognize and attack their targets. The NKG2D receptor has an enormous significance in various, autoimmune diseases, viral and bacterial infections as well as for transplantation outcomes and complications. This review focuses on the NKG2D receptor, the mechanism of its action, clinical relevance of its gene polymorphisms and a potential application in various clinical settings. Full article

(This article belongs to the Special Issue Regulation of Natural Killer Cell Development and Functions)

► Show Figures