Potential Role of NK Cells in the Induction of Immune Responses: Implications for NK Cell–Based Immunotherapy for Cancers and Viral Infections

Severe sepsis and septic shock are still deadly conditions urging to develop novel therapies. A better understanding of the complex modifications of the immune system of septic patients is needed for the development of innovative immunointerventions. Natural killer (NK) cells are characterized as CD3−NKp46+CD56+cells that can be cytotoxic and/or produce high amounts of cytokines such as IFN-γ. NK cells are also engaged in crosstalks with other immune cells, such as dendritic cells, macrophages, and neutrophils. During the early stage of septic shock, NK cells may play a key role in the promotion of the systemic inflammation, as suggested in mice models. Alternatively, at a later stage, NK cells-acquired dysfunction could favor nosocomial infections and mortality. Standardized biological tools defining patients' NK cell status during the different stages of sepsis are mandatory to guide potential immuno-interventions. Herein, we review the potential role of NK cells during severe sepsis and septic shock.

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Role of KIR Receptor in NK Regulation during Viral Infections

Immuno ◽

10.3390/immuno1030021 ◽

2021 ◽

Vol 1 (3) ◽

pp. 305-331

Author(s):

Sabrina Rizzo ◽

Giovanna Schiuma ◽

Silvia Beltrami ◽

Valentina Gentili ◽

Roberta Rizzo ◽

...

Keyword(s):

Viral Infection ◽

Nk Cells ◽

Cell Activation ◽

Viral Infections ◽

Nk Cell ◽

Human Leukocyte ◽

Target Cells ◽

Inhibitory Receptors ◽

Receptor Repertoire

Natural Killer (NK) cells are key effectors of the innate immune system which represent the first line of defense against viral infections. NK cell activation depends on the engagement of a complex receptor repertoire expressed on their surface, consisting of both activating and inhibitory receptors. Among the known NK cell receptors, the family of killer Ig-like receptors (KIRs) consists in activating/inhibitory receptors that interact with specific human leukocyte antigen (HLA) molecules expressed on target cells. In particular, the expression of peculiar KIRs have been reported to be associated to viral infection susceptibility. Interestingly, a significant association between the development and onset of different human pathologies, such as tumors, neurodegeneration and infertility, and a clonal KIRs expression on NK cells has been described in presence of viral infections, supporting the crucial role of KIRs in defining the effect of viral infections in different tissues and organs. This review aims to report the state of art about the role of KIRs receptors in NK cell activation and viral infection control.

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Potential role of mushroom beta-glucans in immunity and inflammation in viral infections and COVID-19

Journal of Food Bioactives ◽

10.31665/jfb.2021.16288 ◽

2021 ◽

Vol 16 ◽

Author(s):

Valentina Konusova ◽

Eugene Vorbeychikov ◽

Mark Shamtsyan

Keyword(s):

Immune Response ◽

Immune Responses ◽

Immune Cells ◽

Potential Role ◽

Clinical Evidence ◽

Viral Infections ◽

Antiviral Responses ◽

Beta Glucans ◽

Secondary Stimulus

According to the concept of trained immunity (TRIM), by stimulating the immune response with one pathogen, one can strengthen it against infection by another. With this understanding, one can take advantage of such immune responses with a stimulant such as β-glucan, which does not actually cause disease in humans, but has the advantage of generating primed immune cells that will respond to a variety of deadly infections. Mushroom β-glucans are known to act as training agents that leads to an increase in immune responses when these trained cells are subjected to a secondary stimulus. Understanding whether the TRIM processes are responsible for antiviral responses will undoubtedly provide a deeper understanding of other potential antiviral strategies, as the new SARS-CoV-2 is not the first- or last-time humanity has to deal with viral pandemics. More studies and clinical evidence are necessary for better understanding of the role of β-glucans in viral infections and COVID-19.

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Toll-Like Receptors in Natural Killer Cells and Their Application for Immunotherapy

Journal of Immunology Research ◽

10.1155/2020/2045860 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9 ◽

Cited By ~ 6

Author(s):

Ji-Yoon Noh ◽

Suk Ran Yoon ◽

Tae-Don Kim ◽

Inpyo Choi ◽

Haiyoung Jung

Keyword(s):

Immune Responses ◽

Nk Cells ◽

Immune Cells ◽

Viral Infections ◽

Nk Cell ◽

Innate Immune ◽

Innate Immune Cells ◽

Innate Immune Responses ◽

Toll Like Receptors ◽

Microbial Infection

Innate immunity represents the first barrier for host defense against microbial infection. Toll-like receptors (TLRs) are the most well-defined PRRs with respect to PAMP recognition and induction of innate immune responses. They recognize pathogen-associated molecular patterns (PAMPs) and trigger innate immune responses by inducing inflammatory cytokines, chemokines, antigen-presenting molecules, and costimulatory molecules. TLRs are expressed either on the cell surface or within endosomes of innate immune cells. NK cells are one of the innate immune cells and also express TLRs to recognize or respond to PAMPs. TLRs in NK cells induce the innate immune responses against bacterial and viral infections via inducing NK cytotoxicity and cytokine production. In this review, we will discuss the expression and cellular function of TLRs in NK cells and also introduce some therapeutic applications of TLR agonists for NK cell-mediated immunotherapy.

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Immunomodulatory Role of NK Cells during Antiviral Antibody Therapy

Vaccines ◽

10.3390/vaccines9020137 ◽

2021 ◽

Vol 9 (2) ◽

pp. 137

Author(s):

Mar Naranjo-Gomez ◽

Marine Cahen ◽

Jennifer Lambour ◽

Myriam Boyer-Clavel ◽

Mireia Pelegrin

Keyword(s):

B Cell ◽

Nk Cells ◽

Protective Immunity ◽

Viral Infections ◽

Nk Cell ◽

Antibody Therapy ◽

Cell Depletion ◽

Immunomodulatory Activity ◽

Cell Functions

Monoclonal antibodies (mAbs) are now considered as a therapeutic approach to prevent and treat severe viral infections. Using a mouse retroviral model, we showed that mAbs induce protective immunity (vaccinal effects). Here, we investigated the role of natural killer (NK) cells on this effect. NK cells are effector cells that are crucial to control viral propagation upon mAb treatment. However, their immunomodulatory activity during antiviral mAb immunotherapies has been little studied. Our data reveal that the mAb treatment of infected mice preserves the functional activation of NK cells. Importantly, functional NK cells play an essential role in preventing immune dysfunction and inducing antiviral protective immunity upon mAb therapy. Thus, NK cell depletion in mAb-treated, viral-infected mice leads to the upregulation of molecules involved in immunosuppressive pathways (i.e., PD-1, PD-L1 and CD39) on dendritic cells and T cells. NK cell depletion also abrogates the vaccinal effects induced by mAb therapy. Our data also reveal a role for IFNγ-producing NK cells in the enhancement of the B-cell responses through the potentiation of the B-cell helper properties of neutrophils. These findings suggest that preserved NK cell functions and counts might be required for achieving mAb-induced protective immunity. They open new prospects for improving antiviral immunotherapies.

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NK cells activated by Interleukin-4 in cooperation with Interleukin-15 exhibit distinctive characteristics

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1600112113 ◽

2016 ◽

Vol 113 (36) ◽

pp. 10139-10144 ◽

Cited By ~ 11

Author(s):

Tsuyoshi Kiniwa ◽

Yutaka Enomoto ◽

Natsumi Terazawa ◽

Ai Omi ◽

Naoko Miyata ◽

...

Keyword(s):

Immune Responses ◽

Nk Cells ◽

Nk Cell ◽

Parasitic Infection ◽

Interleukin 4 ◽

Gm Csf ◽

Interleukin 15 ◽

Ifn Γ ◽

High Cytotoxicity

Natural killer (NK) cells are known to be activated by Th1-type cytokines, such as IL-2, -12, or -18, and they secrete a large amount of IFN-γ that accelerates Th1-type responses. However, the roles of NK cells in Th2-type responses have remained unclear. Because IL-4 acts as an initiator of Th2-type responses, we examined the characteristics of NK cells in mice overexpressing IL-4. In this study, we report that IL-4 overexpression induces distinctive characteristics of NK cells (B220high/CD11blow/IL-18Rαlow), which are different from mature conventional NK (cNK) cells (B220low/CD11bhigh/IL-18Rαhigh). IL-4 overexpression induces proliferation of tissue-resident macrophages, which contributes to NK cell proliferation via production of IL-15. These IL-4–induced NK cells (IL4-NK cells) produce higher levels of IFN-γ, IL-10, and GM-CSF, and exhibit high cytotoxicity compared with cNK cells. Furthermore, incubation of cNK cells with IL-15 and IL-4 alters their phenotype to that similar to IL4-NK cells. Finally, parasitic infection, which typically causes strong Th2-type responses, induces the development of NK cells with characteristics similar to IL4-NK cells. These IL4-NK–like cells do not develop in IL-4Rα KO mice by parasitic infection. Collectively, these results suggest a novel role of IL-4 in immune responses through the induction of the unique NK cells.

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Immunosurveillance of Cancer and Viral Infections with Regard to Alterations of Human NK Cells Originating from Lifestyle and Aging

Biomedicines ◽

10.3390/biomedicines9050557 ◽

2021 ◽

Vol 9 (5) ◽

pp. 557

Author(s):

Xuewen Deng ◽

Hiroshi Terunuma ◽

Mie Nieda

Keyword(s):

Nk Cells ◽

Viral Infections ◽

Nk Cell ◽

Healthy Lifestyle ◽

Cell Activity ◽

Nk Cell Activity ◽

Effector Cells ◽

Cell Dysfunction ◽

Forest Bathing ◽

Infected Cells

Natural killer (NK) cells are cytotoxic immune cells with an innate capacity for eliminating cancer cells and virus- infected cells. NK cells are critical effector cells in the immunosurveillance of cancer and viral infections. Patients with low NK cell activity or NK cell deficiencies are predisposed to increased risks of cancer and severe viral infections. However, functional alterations of human NK cells are associated with lifestyles and aging. Personal lifestyles, such as cigarette smoking, alcohol consumption, stress, obesity, and aging are correlated with NK cell dysfunction, whereas adequate sleep, moderate exercise, forest bathing, and listening to music are associated with functional healthy NK cells. Therefore, adherence to a healthy lifestyle is essential and will be favorable for immunosurveillance of cancer and viral infections with healthy NK cells.

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GSK-3α Inhibition in Drug-Resistant CML Cells Promotes Susceptibility to NK Cell-Mediated Lysis in an NKG2D- and NKp30-Dependent Manner

Cancers ◽

10.3390/cancers13081802 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1802

Author(s):

Nayoung Kim ◽

Mi Yeon Kim ◽

Woo Seon Choi ◽

Eunbi Yi ◽

Hyo Jung Lee ◽

...

Keyword(s):

Nk Cells ◽

Nk Cell ◽

Negative Regulator ◽

Target Cells ◽

Dependent Manner ◽

Cell Functions ◽

Cell Based Therapy ◽

Activating Receptors ◽

Gsk 3Β

Natural killer (NK) cells are innate cytotoxic lymphocytes that provide early protection against cancer. NK cell cytotoxicity against cancer cells is triggered by multiple activating receptors that recognize specific ligands expressed on target cells. We previously demonstrated that glycogen synthase kinase (GSK)-3β, but not GSK-3α, is a negative regulator of NK cell functions via diverse activating receptors, including NKG2D and NKp30. However, the role of GSK-3 isoforms in the regulation of specific ligands on target cells is poorly understood, which remains a challenge limiting GSK-3 targeting for NK cell-based therapy. Here, we demonstrate that GSK-3α rather than GSK-3β is the primary isoform restraining the expression of NKG2D ligands, particularly ULBP2/5/6, on tumor cells, thereby regulating their susceptibility to NK cells. GSK-3α also regulated the expression of the NKp30 ligand B7-H6, but not the DNAM-1 ligands PVR or nectin-2. This regulation occurred independently of BCR-ABL1 mutation that confers tyrosine kinase inhibitor (TKI) resistance. Mechanistically, an increase in PI3K/Akt signaling in concert with c-Myc was required for ligand upregulation in response to GSK-3α inhibition. Importantly, GSK-3α inhibition improved cancer surveillance by human NK cells in vivo. Collectively, our results highlight the distinct role of GSK-3 isoforms in the regulation of NK cell reactivity against target cells and suggest that GSK-3α modulation could be used to enhance tumor cell susceptibility to NK cells in an NKG2D- and NKp30-dependent manner.

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Microfluidic tumor-on-a-chip model to evaluate the role of tumor environmental stress on NK cell exhaustion

Science Advances ◽

10.1126/sciadv.abc2331 ◽

2021 ◽

Vol 7 (8) ◽

pp. eabc2331 ◽

Cited By ~ 1

Author(s):

Jose M. Ayuso ◽

Shujah Rehman ◽

Maria Virumbrales-Munoz ◽

Patrick H. McMinn ◽

Peter Geiger ◽

...

Keyword(s):

Nk Cells ◽

Immune Cells ◽

Molecular Mechanisms ◽

Nk Cell ◽

Checkpoint Inhibitors ◽

Waste Product ◽

Extended Period ◽

Cell Exhaustion

Solid tumors generate a suppressive environment that imposes an overwhelming burden on the immune system. Nutrient depletion, waste product accumulation, hypoxia, and pH acidification severely compromise the capacity of effector immune cells such as T and natural killer (NK) cells to destroy cancer cells. However, the specific molecular mechanisms driving immune suppression, as well as the capacity of immune cells to adapt to the suppressive environment, are not completely understood. Thus, here, we used an in vitro microfluidic tumor-on-a-chip platform to evaluate how NK cells respond to the tumor-induced suppressive environment. The results demonstrated that the suppressive environment created by the tumor gradually eroded NK cell cytotoxic capacity, leading to compromised NK cell surveillance and tumor tolerance. Further, NK cell exhaustion persisted for an extended period of time after removing NK cells from the microfluidic platform. Last, the addition of checkpoint inhibitors and immunomodulatory agents alleviated NK cell exhaustion.

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Natural Killer–Dendritic Cell Interactions in Liver Cancer: Implications for Immunotherapy

Cancers ◽

10.3390/cancers13092184 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2184

Author(s):

Valentina Cazzetta ◽

Sara Franzese ◽

Claudia Carenza ◽

Silvia Della Bella ◽

Joanna Mikulak ◽

...

Keyword(s):

Liver Cancer ◽

Immune Responses ◽

Nk Cells ◽

Natural Killer ◽

Tumor Cells ◽

Primary Liver Cancer ◽

Circulating Antigens ◽

Direct Cytotoxicity ◽

Immune Changes

Natural killer (NK) and dendritic cells (DCs) are innate immune cells that play a crucial role in anti-tumor immunity. NK cells kill tumor cells through direct cytotoxicity and cytokine secretion. DCs are needed for the activation of adaptive immune responses against tumor cells. Both NK cells and DCs are subdivided in several subsets endowed with specialized effector functions. Crosstalk between NK cells and DCs leads to the reciprocal control of their activation and polarization of immune responses. In this review, we describe the role of NK cells and DCs in liver cancer, focusing on the mechanisms involved in their reciprocal control and activation. In this context, intrahepatic NK cells and DCs present unique immunological features, due to the constant exposure to non-self-circulating antigens. These interactions might play a fundamental role in the pathology of primary liver cancer, namely hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Additionally, the implications of these immune changes are relevant from the perspective of improving the cancer immunotherapy strategies in HCC and ICC patients.

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