scholarly journals When and how NK cell-induced programmed cell death benefits immunological protection against intracellular pathogen infection

2018 ◽  
Vol 24 (8) ◽  
pp. 452-465 ◽  
Author(s):  
José E Belizário ◽  
Jennifer M Neyra ◽  
Maria Fernanda Setúbal Destro Rodrigues
Keyword(s):  
Cell Death ◽  
Nk Cells ◽  
Cell Biology ◽  
Cell Activation ◽  
Nk Cell ◽  
Immune Surveillance ◽  
Lymphoid Cells ◽  
Activated T Cells ◽  
Infected Cells ◽  
Immunological Protection

NK cells are innate lymphoid cells that exert a key role in immune surveillance through the recognition and elimination of transformed cells and viral, bacterial, and protozoan pathogen-infected cells without prior sensitization. Elucidating when and how NK cell-induced intracellular microbial cell death functions in the resolution of infection and host inflammation has been an important topic of investigation. NK cell activation requires the engagement of specific activating, co-stimulatory, and inhibitory receptors which control positively and negatively their differentiation, memory, and exhaustion. NK cells secrete diverse cytokines, including IFN-γ, TNF-α/β, CD95/FasL, and TRAIL, as well as cytoplasmic cytotoxic granules containing perforin, granulysin, and granzymes A and B. Paradoxically, NK cells also kill other immune cells like macrophages, dendritic cells, and hyper-activated T cells, thus turning off self-immune reactions. Here we first provide an overview of NK cell biology, and then we describe and discuss the life–death signals that connect the microbial pathogen sensors to the inflammasomes and finally to cell death signaling pathways. We focus on caspase-mediated cell death by apoptosis and pro-inflammatory and non-caspase-mediated cell death by necroptosis, as well as inflammasome- and caspase-mediated pyroptosis.

scholarly journals Killing the Invaders: NK Cell Impact in Tumors and Anti-Tumor Therapy

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 595
Author(s):  
Martina Molgora ◽  
Victor S. Cortez ◽  
Marco Colonna
Keyword(s):  
Nk Cells ◽  
Cell Biology ◽  
Cell Activation ◽  
Cell Function ◽  
Nk Cell ◽  
Tumor Therapy ◽  
Tumor Immunotherapy ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
The Impact

Natural Killer cells belong to group 1 innate lymphoid cells, which also includes ILC1s. NK/ILC1s are highly heterogeneous cell types showing distinct phenotypes across tissues and conditions. NK cells have long been described as innate lymphocytes able to directly and rapidly kill tumor cells without antigen-restriction. Different mechanisms were shown to modulate NK cell activation and tumor resistance, mainly based on cytokine stimulation and receptor–ligand interactions, and several strategies have been developed to target NK cells in tumor immunotherapy to promote NK cell function and overcome tumor evasion. The characterization of ILC1 distinct phenotype and function and the specific role in tumors still needs further investigation and will be essential to better understand the impact of innate lymphoid cells in tumors. Here, we review key aspects of NK cell biology that are relevant in tumor immune surveillance, emphasizing the most recent findings in the field. We describe the novel therapeutical strategies that have been developed in tumor immunotherapy targeting NK cells, and we summarize some recent findings related to NK cell/ILC1 transition in tumor models.

scholarly journals Interaction of Fc receptor (CD16) ligands induces transcription of interleukin 2 receptor (CD25) and lymphokine genes and expression of their products in human natural killer cells.

1988 ◽  
Vol 167 (2) ◽  
pp. 452-472 ◽  
Author(s):  
I Anegón ◽  
M C Cuturi ◽  
G Trinchieri ◽  
B Perussia
Keyword(s):  
Nk Cells ◽  
Cell Biology ◽  
Cell Activation ◽  
De Novo ◽  
Nk Cell ◽  
Interleukin 2 ◽  
Transcriptional Level ◽  
Mrna Accumulation ◽  
Ifn Gamma ◽  
Fast Kinetics

We report evidence that FcR(CD16) on human NK cells are signal-transducing molecules that, upon ligand binding, induce transcription of genes encoding surface activation molecules [IL-2-R(CD25)] and cytokines (IFN-gamma and TNF) relevant to NK cell biology and functions. Homogeneous NK and T cell populations purified from short-term bulk cultures of PBMC with irradiated B lymphoblastoid cell lines were cultured in the presence of FcR ligands (particulate immune complexes or immobilized anti-CD16 antibodies) alone or with rIL-2. Upon 18 h of stimulation, NK cells express Tac, TfR, and 4F2 antigens and produce IFN-gamma and TNF; both effects are synergistically enhanced in the presence of rIL-2, which is itself ineffective. Treatment of NK cells with FcR(CD16) ligands induces accumulation of mRNA for IFN-gamma and TNF and, to a lesser extent, IL-2-R with fast kinetics also in the absence of de novo protein synthesis. rIL-2 and FcR(CD16) ligands synergize to induce mRNA accumulation. mRNA accumulation and transcription of TNF and IFN-gamma genes induced by FcR(CD16) ligands are greater than those induced by rIL-2, and the reverse is true for IL-2-R. The two stimuli do not synergize at the transcriptional level. These observations indicate that the mechanisms through which FcR(CD16) ligands and rIL-2 induce NK cell activation are, in part, distinct. Both operate at the transcriptional level, although other mechanisms are probably induced by the FcR ligand stimulus per se or in combination with other lymphokines and synergize at a post-transcriptional or translational level to enhance NK cell activation.

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.

scholarly journals NK cells orchestrate splenic cDC1 migration to potentiate antiviral protective CD8+ T cell responses

2020 ◽  
Author(s):  
Sonia Ghilas ◽  
Marc Ambrosini ◽  
Jean-Charles Cancel ◽  
Marion Massé ◽  
Hugues Lelouard ◽  
...  
Keyword(s):  
T Cell ◽  
Nk Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
Murine Cytomegalovirus ◽  
Gm Csf ◽  
Cell Responses ◽  
Infected Cells ◽  
The Right

SummaryA successful immune response relies on a tightly regulated delivery of the right signals to the right cells at the right time. Here we show that innate and innate-like lymphocytes use two mechanisms to orchestrate in time and space the functions of conventional type 1 dendritic cells (cDC1) in spleen. Early after murine cytomegalovirus infection, XCL1 production by lymphocytes with innate functions attracts red pulp cDC1 near IFN-γ-producing NK cells, generating superclusters around infected cells in the marginal zone. There, cDC1 and NK cells physically interact reinforcing their reciprocal activation. Targeted IL-12 delivery and IL-15/IL-15Rα transpresentation by cDC1 trigger NK cell activation and expansion. In return, activated NK cells deliver GM-CSF to cDC1, triggering their CCR7-dependent relocalization into the T cell zone. This NK cell-dependent licensing of cDC1 accelerates the priming of virus-specific CD8+ T cells. Our findings reveal a novel mechanism through which cDC1 bridge innate and adaptive immunity.

scholarly journals Prospects for NK Cell Therapy of Sarcoma

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3719
Author(s):  
Mieszko Lachota ◽  
Marianna Vincenti ◽  
Magdalena Winiarska ◽  
Kjetil Boye ◽  
Radosław Zagożdżon ◽  
...  
Keyword(s):  
Nk Cells ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Nk Cell ◽  
Immune Surveillance ◽  
Current Treatment ◽  
Lymphoid Cells ◽  
Current Evidence ◽  
Treatment Regimens ◽  
Novel Therapeutic Strategies

Natural killer (NK) cells are innate lymphoid cells with potent antitumor activity. One of the most NK cell cytotoxicity-sensitive tumor types is sarcoma, an aggressive mesenchyme-derived neoplasm. While a combination of radical surgery and radio- and chemotherapy can successfully control local disease, patients with advanced sarcomas remain refractory to current treatment regimens, calling for novel therapeutic strategies. There is accumulating evidence for NK cell-mediated immunosurveillance of sarcoma cells during all stages of the disease, highlighting the potential of using NK cells as a therapeutic tool. However, sarcomas display multiple immunoevasion mechanisms that can suppress NK cell function leading to an uncontrolled tumor outgrowth. Here, we review the current evidence for NK cells’ role in immune surveillance of sarcoma during disease initiation, promotion, progression, and metastasis, as well as the molecular mechanisms behind sarcoma-mediated NK cell suppression. Further, we apply this basic understanding of NK–sarcoma crosstalk in order to identify and summarize the most promising candidates for NK cell-based sarcoma immunotherapy.

scholarly journals DNAM-1 controls NK cell activation via an ITT-like motif

2015 ◽  
Vol 212 (12) ◽  
pp. 2165-2182 ◽  
Author(s):  
Zhanguang Zhang ◽  
Ning Wu ◽  
Yan Lu ◽  
Dominique Davidson ◽  
Marco Colonna ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cd8 T Cells ◽  
Actin Polymerization ◽  
Cell Activation ◽  
Cytokine Production ◽  
Nk Cell ◽  
Phosphatidylinositol 3 Kinase ◽  
Specific Memory ◽  
Downstream Effectors ◽  
Infected Cells

DNAM-1 (CD226) is an activating receptor expressed on natural killer (NK) cells, CD8+ T cells, and other immune cells. Upon recognition of its ligands, CD155 and CD112, DNAM-1 promotes NK cell–mediated elimination of transformed and virus-infected cells. It also has a key role in expansion and maintenance of virus-specific memory NK cells. Herein, the mechanism by which DNAM-1 controls NK cell–mediated cytotoxicity and cytokine production was elucidated. Cytotoxicity and cytokine production triggered by DNAM-1 were mediated via a conserved tyrosine- and asparagine-based motif in the cytoplasmic domain of DNAM-1. Upon phosphorylation by Src kinases, this motif enabled binding of DNAM-1 to adaptor Grb2, leading to activation of enzymes Vav-1, phosphatidylinositol 3′ kinase, and phospholipase C-γ1. It also promoted activation of kinases Erk and Akt, and calcium fluxes. Although, as reported, DNAM-1 promoted adhesion, this function was signal-independent and insufficient to promote cytotoxicity. DNAM-1 signaling was also required to enhance cytotoxicity, by increasing actin polymerization and granule polarization. We propose that DNAM-1 promotes NK cell activation via an immunoreceptor tyrosine tail (ITT)–like motif coupling DNAM-1 to Grb2 and other downstream effectors.

scholarly journals Receptor-induced death in human natural killer cells: involvement of CD16.

1995 ◽  
Vol 181 (1) ◽  
pp. 339-344 ◽  
Author(s):  
J R Ortaldo ◽  
A T Mason ◽  
J J O'Shea
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Nk Cells ◽  
Natural Killer ◽  
Tyrosine Kinases ◽  
Nk Cell ◽  
Interleukin 2 ◽  
Activated T Cells ◽  
Human Natural Killer Cells ◽  
Induced Apoptosis

Propriocidal regulation of T cells refers to apoptosis induced by interleukin 2 (IL-2) activation with subsequent antigen receptor stimulation. We examined whether natural killer (NK) cells exhibited cytokine- and ligand-induced death similar to activated T cells. Peripheral NK cells were examined for ligand-induced death using antibodies to surface moieties (CD2, CD3, CD8, CD16, CD56), with and without prior activation of IL-2. Only those NK cells stimulated first with IL-2 and then with CD16 exhibited ligand-induced death; none of the other antibody stimuli induced this phenomenon. Next we examined various cytokines (IL-2, IL-4, IL-6, IL-7, IL-12, IL-13, interferon alpha and gamma) that can activate NK cells and determined if CD16-induced killing occurred. Only IL-2 and IL-12 induced NK cell death after occupancy of this receptor by aggregated immunoglobulin or by cross-linking with antireceptor antibody. The CD16-induced death was inhibited by herbimycin A, indicating that cell death was dependent upon protein tyrosine kinases. Identical to T cells, the form of cell death for NK cells was demonstrated to be receptor-induced apoptosis. Overall these data indicate that highly activated NK cells mediate ligand-induced apoptosis via signaling molecules like CD16. Whereas the propriocidal regulation of T cells is antigen specific, this is not the case for NK cells due to the nature of the receptor. The clinical implications of this finding are considered.

scholarly journals Targeting NK Cells to Enhance Melanoma Response to Immunotherapies

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1363
Author(s):  
Hansol Lee ◽  
Inês Pires Da Silva ◽  
Umaimainthan Palendira ◽  
Richard A. Scolyer ◽  
Georgina V. Long ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Nk Cells ◽  
Cell Biology ◽  
Cell Activation ◽  
Nk Cell ◽  
Antitumor Effects ◽  
Cell Responses ◽  
Adaptive Immune ◽  
Nk Cell Receptors ◽  
Immunosuppressive Cells

Natural killer (NK) cells are a key component of an innate immune system. They are important not only in initiating, but also in augmenting adaptive immune responses. NK cell activation is mediated by a carefully orchestrated balance between the signals from inhibitory and activating NK cell receptors. NK cells are potent producers of proinflammatory cytokines and are also able to elicit strong antitumor responses through secretion of perforin and granzyme B. Tumors can develop many mechanisms to evade NK cell antitumor responses, such as upregulating ligands for inhibitory receptors, secreting anti-inflammatory cytokines and recruiting immunosuppressive cells. Enhancing NK cell responses will likely augment the effectiveness of immunotherapies, and strategies to accomplish this are currently being evaluated in clinical trials. A comprehensive understanding of NK cell biology will likely provide additional opportunities to further leverage the antitumor effects of NK cells. In this review, we therefore sought to highlight NK cell biology, tumor evasion of NK cells and clinical trials that target NK cells.

scholarly journals The Interplay of Exosomes and NK Cells in Cancer Biology

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 473
Author(s):  
Inês A. Batista ◽  
Sofia T. Quintas ◽  
Sónia A. Melo
Keyword(s):  
Nk Cells ◽  
Cancer Progression ◽  
Cell Biology ◽  
Cancer Biology ◽  
Immune Escape ◽  
Nk Cell ◽  
Lymphoid Cells ◽  
Tumor Immune Escape ◽  
Immunotherapeutic Strategy ◽  
Open Question

Natural killer (NK) cells are innate lymphoid cells involved in tumor surveillance. These immune cells have the potential to fight cancer growth and metastasis, as such, their deregulation can result in tumor immune escape. Recently exosomes were described as mediators of intercellular communication between cancer and NK cells. The exact role of this subclass of extracellular vesicles (EVs), which transport genetic and molecular material to recipient cells, in NK cell biology in the context of cancer, is still an open question. Several reports have demonstrated that tumor-derived exosomes (TDEs) can exert immunomodulatory activities, including immunosuppression, thus promoting cancer progression. Some reports demonstrate that the interplay between cancer exosomes and NK cells allows tumors to escape immune regulation. On the other hand, tumor exosomes were also described to activate NK cells. Additionally, studies show that NK cell exosomes can modulate the immune system, opening up their potential as an immunotherapeutic strategy for cancer treatment. Our review will focus on the reprogramming effect of cancer exosomes on NK cells, and the immunotherapeutic potential of NK cells-derived exosomes.

scholarly journals The Role of NK Cells in EBV Infection and EBV-Associated NPC

Viruses ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 300
Author(s):  
Yi Tian Png ◽  
Audrey Zhi Yi Yang ◽  
Mei Ying Lee ◽  
Magdalene Jahn May Chua ◽  
Chwee Ming Lim
Keyword(s):  
Nk Cells ◽  
Cell Biology ◽  
Nk Cell ◽  
Southern China ◽  
Epithelial Cancers ◽  
Barr Virus ◽  
Ebv Infection ◽  
Highly Sensitive ◽  
Infected Cells ◽  
Epstein Barr

A vast majority of the population worldwide are asymptomatic carriers of Epstein-Barr Virus (EBV). However, some infected individuals eventually develop EBV-related cancers, including Nasopharyngeal Carcinoma (NPC). NPC is one of the most common EBV-associated epithelial cancers, and is highly prevalent in Southern China and Southeast Asia. While NPC is highly sensitive to radiotherapy and chemotherapy, there is a lack of effective and durable treatment among the 15%–30% of patients who subsequently develop recurrent disease. Natural Killer (NK) cells are natural immune lymphocytes that are innately primed against virus-infected cells and nascent aberrant transformed cells. As EBV is found in both virally infected and cancer cells, it is of interest to examine the NK cells’ role in both EBV infection and EBV-associated NPC. Herein, we review the current understanding of how EBV-infected cells are cleared by NK cells, and how EBV can evade NK cell-mediated elimination in the context of type II latency in NPC. Next, we summarize the current literature about NPC and NK cell biology. Finally, we discuss the translational potential of NK cells in NPC. This information will deepen our understanding of host immune interactions with EBV-associated NPC and facilitate development of more effective NK-mediated therapies for NPC treatment.

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