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

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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TLR agonists enhance responsiveness of inflammatory innate immune cells in HLA-B*57-positive HIV patients

Journal of Molecular Medicine ◽

10.1007/s00109-020-01996-7 ◽

2020 ◽

Vol 99 (1) ◽

pp. 147-158

Author(s):

L. Dold ◽

L. Zimmer ◽

C. Schwarze-Zander ◽

C. Boesecke ◽

R. Mohr ◽

...

Keyword(s):

Hiv Infection ◽

Nk Cells ◽

Immune Cells ◽

Nk Cell ◽

Innate Immune ◽

Innate Immune Cells ◽

Double Positive ◽

Hiv Patients ◽

Ifn Gamma ◽

Tlr Agonists

Abstract HLA-B*57 affects the course of HIV infection. Under antiretroviral therapy, its effects cannot be explained by outstandingly efficient T cell responses alone but may also involve cells of innate immunity. Studying in vitro stimulation with Pam3CSK4, E. coli LPS-B5 and CpG-ODN-2216, we observed greater induction of IL-6/IL-1beta double-positive CD14+CD16++ monocytes as well as IFN-gamma-positive cytotoxic CD56highCD16neg NK cells in HLA-B*57- versus HLA-B*44-positive HIV patients, while TNF-alpha induction remained unchanged. Differences were not seen in the other monocyte and NK cell subsets or in HLA-matched healthy controls. Our findings show that, in virally suppressed HIV infection, HLA-B*57 is associated with enhanced responsiveness of inflammatory innate immune cells to TLR ligands, possibly contributing to increased vulnerability in sepsis. Key messages • HLA-B*57 is a host factor affecting clinical outcomes of HIV infection. • HLA-B*57 modifies inflammatory subsets of NK cells and monocytes in HIV infection. • In HLA-B*57-positive HIV patients TLR agonists induce enhanced IL-6/IL-1beta in monocytes. • NK cells from HLA-B*57 HIV patients release more IFN-gamma upon TLR costimulation. • HLA-B*57 is linked to enhanced inflammatory responsiveness to TLR ligands.

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Multidirectional interactions are bridging human NK cells with plasmacytoid and monocyte-derived dendritic cells during innate immune responses

Blood ◽

10.1182/blood-2006-02-004028 ◽

2006 ◽

Vol 108 (12) ◽

pp. 3851-3858 ◽

Cited By ~ 53

Author(s):

Mariella Della Chiesa ◽

Chiara Romagnani ◽

Andreas Thiel ◽

Lorenzo Moretta ◽

Alessandro Moretta

Keyword(s):

Dendritic Cells ◽

Immune Responses ◽

Nk Cells ◽

De Novo ◽

Nk Cell ◽

Innate Immune ◽

Dependent Manner ◽

B Cell Differentiation ◽

Innate Immune Responses ◽

Intrinsic Resistance

AbstractDuring innate immune responses, natural killer (NK) cells may interact with both plasmacytoid dendritic cells (pDCs) and monocyte-derived dendritic cells (MDDCs). We show that freshly isolated NK cells promote the release by pDCs of IFN-α, in a CpG-dependent manner, whereas they induce IL-6 production in a CpG-independent manner. In turn pDC-derived IFN-α up-regulates NK-mediated killing, whereas IL-6 could promote B-cell differentiation. We also show that exposure to exogenous IL-12 or coculture with maturing MDDCs up-regulates the NK-cell–dependent IFN-α production by pDCs. On the other hand, NK cells cocultured with pDCs acquire the ability to kill immature MDDCs, thus favoring their editing process. Finally, we show that activated NK cells are unable to lyse pDCs because these cells display an intrinsic resistance to lysis. The exposure of pDCs to IL-3 increased their susceptibility to NK-cell cytotoxicity resulting from a de novo expression of ligands for activating NK-cell receptors, such as the DNAM-1 ligand nectin-2. Thus, different cell-to-cell interactions and various cytokines appear to control a multidirectional network between NK cells, MDDCs, and pDCs that is likely to play an important role during the early phase of innate immune responses to viral infections and to tumors.

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Rapid dose-dependent Natural Killer (NK) cell modulation and cytokine responses following human rVSV-ZEBOV Ebolavirus vaccination

npj Vaccines ◽

10.1038/s41541-020-0179-4 ◽

2020 ◽

Vol 5 (1) ◽

Cited By ~ 1

Author(s):

David Pejoski ◽

◽

Casimir de Rham ◽

Paola Martinez-Murillo ◽

Francesco Santoro ◽

...

Keyword(s):

Immune Responses ◽

Nk Cells ◽

Nk Cell ◽

Protective Efficacy ◽

Innate Immune ◽

Receptor Expression ◽

Innate Immune Responses ◽

Plasma Cytokines ◽

Surface Receptor ◽

Dose Dependent

Abstract The rVSV-ZEBOV Ebolavirus vaccine confers protection within days after immunization, suggesting the contribution of innate immune responses. We report modulation of rVSV-ZEBOV vaccinee blood CD56+ NK cell numbers, NKG2D or NKp30 surface receptor expression, Killer Immunoglobulin-like Receptor (KIR)+ cell percentages and NK-cell-related genes on day 1 post immunization. Inverse correlations existed between the concentration of several plasma cytokines and inhibitory KIR+ CD56dim or cytokine-responsive CD56bright NK cells. Thus, NK cells may contribute to the early protective efficacy of rVSV-ZEBOV in humans.

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Lower blood lactate and higher circulating natural killer cells at admission predict spontaneous survival in non-acetaminophen induced acute Liver failure

10.1101/2020.11.27.20239731 ◽

2020 ◽

Author(s):

Tanvi Agrawal ◽

Rakhi Maiwall ◽

Rajan V ◽

Meenu Bajpai ◽

Rakesh Kumar Jagdish ◽

...

Keyword(s):

Nk Cells ◽

Natural Killer ◽

Immune Cells ◽

Nk Cell ◽

Innate Immune ◽

List Type ◽

Innate Immune Cells ◽

Cell Percentage ◽

Immune Mediated ◽

Lactate Levels

AbstractBackground and AimsMassive cellular necrosis in ALF is dominantly immune mediated and innate immune cells are major pathophysiological determinants in liver damage. Our aim was to investigate specific innate immune cells or damage associated molecular patterns (DAMPs) relating to the final outcome of patient.MethodsIn fifty ALF patients and in fifteen age-matched healthy controls (HC), DAMPs were measured in plasma using ELISA. Phenotypic analysis of neutrophils, monocytes, natural killer (NK) and NKT cells was done by flow-cytometry and correlated with clinical and biochemical parameters.ResultsALF patients (aged 27±9 yr, 56% males, 78% viral etiology) had MELD of 31.5±8, jaundice to hepatic encephalopathy (HE) of 4.6±3.2 days, HE grade III-IV, 82% with cerebral edema, 38% met KCH criteria, 56% had suspected sepsis. Percentage of intermediate monocytes (CD14+CD16+) was increased (p<0.01) and non-classical monocytes (CD14-CD16+) was decreased in ALF compared to HC. CD16+CD56+ NK cells in total lymphocytes was significantly lower in ALF patients compared to HC, but was higher in survivors {9.28% (0.5-20.3)} than non-survivors {5.1% (0.2-10.6)} (p<0.001). Higher percentage of circulating NK cells (>6.7%) at admission was a good predictor of survival. Non-survivors had higher levels of serum lactate (6.1 vs. 28, Odds ratio 2.23, CI 1.27-3.94) and granzymeB positive NK cells than survivors. Logistic regression model predicted the combination of lactate levels with NK cell percentage at admission for survival (AUROC of 0.94; sensitivity 95.8%, specificity of 78.5%).ConclusionCombination of NK cell frequency and lactate levels at admission can reliably predict survival of ALF patients.KEY POINTSALF is generally immune mediated and predominantly caused by viral infections or acetaminophen toxicity.Therapeutic options are limited in ALF, important to know key immune players for their survival.CD16+CD56+ NK cells were found to be higher in survivors than non survivors.Combination of lactate levels with NK cell percentage at the time of admission can reliably predict the survival of ALF patients.

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Immune Sensing of Candida albicans

Journal of Fungi ◽

10.3390/jof7020119 ◽

2021 ◽

Vol 7 (2) ◽

pp. 119 ◽

Cited By ~ 1

Author(s):

Ebrima Bojang ◽

Harlene Ghuman ◽

Pizga Kumwenda ◽

Rebecca A. Hall

Keyword(s):

Candida Albicans ◽

Immune Responses ◽

Immune Cells ◽

Oral Candidiasis ◽

Innate Immune ◽

Vaginal Mucosa ◽

Innate Immune Cells ◽

Innate Immune Responses ◽

Immune Sensing ◽

Infection Types

Candida albicans infections range from superficial to systemic and are one of the leading causes of fungus-associated nosocomial infections. The innate immune responses during these various infection types differ, suggesting that the host environment plays a key role in modulating the host–pathogen interaction. In addition, C. albicans is able to remodel its cell wall in response to environmental conditions to evade host clearance mechanisms and establish infection in niches, such as the oral and vaginal mucosa. Phagocytes play a key role in clearing C. albicans, which is primarily mediated by Pathogen Associated Molecular Pattern (PAMP)–Pattern Recognition Receptor (PRR) interactions. PRRs such as Dectin-1, DC-SIGN, and TLR2 and TLR4 interact with PAMPs such as β-glucans, N-mannan and O-mannan, respectively, to trigger the activation of innate immune cells. Innate immune cells exhibit distinct yet overlapping repertoires of PAMPs, resulting in the preferential recognition of particular Candida morphotypes by them. The role of phagocytes in the context of individual infection types also differs, with neutrophils playing a prominent role in kidney infections, and dendritic cells playing a prominent role in skin infections. In this review, we provide an overview of the key receptors involved in the detection of C. albicans and discuss the differential innate immune responses to C. albicans seen in different infection types such as vulvovaginal candidiasis (VVC) and oral candidiasis.

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Sialic Acids and Their Influence on Human NK Cell Function

Cells ◽

10.3390/cells10020263 ◽

2021 ◽

Vol 10 (2) ◽

pp. 263

Author(s):

Philip Rosenstock ◽

Thomas Kaufmann

Keyword(s):

Nk Cells ◽

Immune Cells ◽

Cell Function ◽

Nk Cell ◽

Sialic Acids ◽

Innate Immune ◽

Target Cells ◽

Carbon Backbone ◽

Nk Cell Receptors ◽

Cell Inhibition

Sialic acids are sugars with a nine-carbon backbone, present on the surface of all cells in humans, including immune cells and their target cells, with various functions. Natural Killer (NK) cells are cells of the innate immune system, capable of killing virus-infected and tumor cells. Sialic acids can influence the interaction of NK cells with potential targets in several ways. Different NK cell receptors can bind sialic acids, leading to NK cell inhibition or activation. Moreover, NK cells have sialic acids on their surface, which can regulate receptor abundance and activity. This review is focused on how sialic acids on NK cells and their target cells are involved in NK cell function.

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Evidence for Differential Roles for NKG2D Receptor Signaling in Innate Host Defense against Coronavirus-Induced Neurological and Liver Disease

Journal of Virology ◽

10.1128/jvi.02032-07 ◽

2007 ◽

Vol 82 (6) ◽

pp. 3021-3030 ◽

Cited By ~ 16

Author(s):

Kevin B. Walsh ◽

Melissa B. Lodoen ◽

Robert A. Edwards ◽

Lewis L. Lanier ◽

Thomas E. Lane

Keyword(s):

Liver Disease ◽

Immune Responses ◽

Host Defense ◽

Nk Cell ◽

Hepatitis Virus ◽

Innate Immune ◽

Liver Pathology ◽

Innate Immune Responses ◽

Ifn Γ ◽

The Brain

ABSTRACT Infection of SCID mice with a recombinant murine coronavirus (mouse hepatitis virus [MHV]) expressing the T-cell chemoattractant CXC chemokine ligand 10 (CXCL10) resulted in increased survival and reduced viral burden within the brain and liver compared to those of mice infected with an isogenic control virus (MHV), supporting an important role for CXCL10 in innate immune responses following viral infection. Enhanced protection in MHV-CXCL10-infected mice correlated with increased gamma interferon (IFN-γ) production by infiltrating natural killer (NK) cells within the brain and reduced liver pathology. To explore the underlying mechanisms associated with protection from disease in MHV-CXCL10-infected mice, the functional contributions of the NK cell-activating receptor NKG2D in host defense were examined. The administration of an NKG2D-blocking antibody to MHV-CXCL10-infected mice did not reduce survival, dampen IFN-γ production in the brain, or affect liver pathology. However, NKG2D neutralization increased viral titers within the liver, suggesting a protective role for NKG2D signaling in this organ. These data indicate that (i) CXCL10 enhances innate immune responses, resulting in protection from MHV-induced neurological and liver disease; (ii) elevated NK cell IFN-γ expression in the brain of MHV-CXCL10-infected mice occurs independently of NKG2D; and (iii) NKG2D signaling promotes antiviral activity within the livers of MHV-infected mice that is not dependent on IFN-γ and tumor necrosis factor alpha secretion.

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STING Requires the Adaptor TRIF to Trigger Innate Immune Responses to Microbial Infection

Cell Host & Microbe ◽

10.1016/j.chom.2016.08.002 ◽

2016 ◽

Vol 20 (3) ◽

pp. 329-341 ◽

Cited By ~ 29

Author(s):

Xin Wang ◽

Tanmay Majumdar ◽

Patricia Kessler ◽

Evgeny Ozhegov ◽

Ying Zhang ◽

...

Keyword(s):

Immune Responses ◽

Innate Immune ◽

Innate Immune Responses ◽

Microbial Infection

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Mitochondria surveillance systems trigger innate immune responses to bacterial pathogens via AMPK pathway in C. elegans

10.1101/2020.09.17.301036 ◽

2020 ◽

Author(s):

Shouyong Ju ◽

Hanqiao Chen ◽

Shaoying Wang ◽

Jian Lin ◽

Raffi V Aroian ◽

...

Keyword(s):

Immune System ◽

Immune Responses ◽

Innate Immune ◽

Surveillance Systems ◽

Innate Immune Responses ◽

Energy Status ◽

Microbial Infection ◽

C Elegans ◽

Host Interaction ◽

Intracellular Energy

AbstractPathogen recognition and triggering pattern of host innate immune system is critical to understanding pathogen-host interaction. It is generally accepted that the microbial infection can be recognized by host via pattern-triggered immunity (PTI) or effector-triggered immunity (ETI) responses. Recently, non-PRR-mediated cellular surveillance systems have been reported as an important supplement strategy to PTI and ETI responses. However, the mechanism of how surveillance systems sense pathogens and trigger innate immune responses is largely unknown. In the present study, using Bacillus thuringiensis-Caenorhabditis elegans as a model, we found a new approach for surveillance systems to sense the pathogens through no-PPRs patterns. We reported C. elegans can monitor intracellular energy status through the mitochondrial surveillance system to triggered innate immune responses against pathogenic attack via AMP-activated protein kinase (AMPK). Consider that the mitochondria surveillance systems and AMPK are conserved components from worms to mammals, our study suggests that disrupting mitochondrial homeostasis to activate the immune system through AMPK-dependent pathways may widely existing in animals.

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