Metabolic regulation of natural killer cells

2015 ◽  
Vol 43 (4) ◽  
pp. 758-762 ◽  
Author(s):  
David K. Finlay
Keyword(s):  
Immune Responses ◽  
Nk Cells ◽  
Natural Killer ◽  
Metabolic Regulation ◽  
Immune Cell ◽  
Nk Cell ◽  
Cellular Metabolism ◽  
T Cell Subsets ◽  
Immune Cell Subsets ◽  
Mtor Complex 1

Natural killer (NK) cells have key roles in anti-viral and anti-tumour immune responses. Recent research demonstrates that cellular metabolism is an important determinant for the function of pro-inflammatory immune cells, including activated NK cells. The mammalian target of rapamcyin (mTOR) complex 1 (mTORC1) has been identified as a key metabolic regulator that promotes glycolytic metabolism in multiple immune cell subsets. Glycolysis is integrally linked to pro-inflammatory immune responses such that activated NK cells and effector T-cell subsets are reliant on sufficient glucose availability for maximal effector function. This article will discuss the regulation of cellular metabolism in NK cells as compared with that of T lymphocytes and discuss the implications for NK cell responses to viral infection and cancer.

scholarly journals The Natural Killer–Dendritic Cell Immune Axis in Anti-Cancer Immunity and Immunotherapy

2021 ◽  
Vol 11 ◽  
Author(s):  
Erin E. Peterson ◽  
Kevin C. Barry
Keyword(s):  
Immune Responses ◽  
Nk Cells ◽  
Natural Killer ◽  
Cross Talk ◽  
Immune Cell ◽  
Nk Cell ◽  
Cell Axis ◽  
Cancer Immunity ◽  
Anti Cancer ◽  
Patient Responses

Natural killer (NK) cells and dendritic cells (DCs) are crucial mediators of productive immune responses to infection and disease. NK cells and a subtype of DCs, the type 1 conventional DCs (cDC1s), are individually important for regulating immune responses to cancer in mice and humans. Recent work has found that NK cells and cDC1s engage in intercellular cross-talk integral to initiating and coordinating adaptive immunity to cancer. This NK cell–cDC1 axis has been linked to increased overall survival and responses to anti-PD-1 immunotherapy in metastatic melanoma patients. Here, we review recent findings on the role of NK cells and cDC1s in protective immune responses to cancer and immunotherapy, as well as current therapies targeting this NK cell–cDC1 axis. Further, we explore the concept that intercellular cross-talk between NK cells and cDC1s may be key for many of the positive prognostic associations seen with NK cells and DCs individually. It is clear that increasing our understanding of the NK cell–cDC1 innate immune cell axis will be critical for the generation of novel therapies that can modulate anti-cancer immunity and increase patient responses to common immunotherapies.

scholarly journals Natural Killer Cells Are Present in Rag1−/− Mice and Promote Tissue Damage During the Acute Phase of Ischemic Stroke

2021 ◽  
Author(s):  
Leoni Rolfes ◽  
Tobias Ruck ◽  
Christina David ◽  
Stine Mencl ◽  
Stefanie Bock ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Adoptive Transfer ◽  
Immune Cell ◽  
Nk Cell ◽  
Cell Subset ◽  
Neurological Deficits ◽  
In Vitro Assays ◽  
Experimental Stroke ◽  
Transfer Model

AbstractRag1−/− mice, lacking functional B and T cells, have been extensively used as an adoptive transfer model to evaluate neuroinflammation in stroke research. However, it remains unknown whether natural killer (NK) cell development and functions are altered in Rag1−/− mice as well. This connection has been rarely discussed in previous studies but might have important implications for data interpretation. In contrast, the NOD-Rag1nullIL2rgnull (NRG) mouse model is devoid of NK cells and might therefore eliminate this potential shortcoming. Here, we compare immune-cell frequencies as well as phenotype and effector functions of NK cells in Rag1−/− and wildtype (WT) mice using flow cytometry and functional in vitro assays. Further, we investigate the effect of Rag1−/− NK cells in the transient middle cerebral artery occlusion (tMCAO) model using antibody-mediated depletion of NK cells and adoptive transfer to NRG mice in vivo. NK cells in Rag1−/− were comparable in number and function to those in WT mice. Rag1−/− mice treated with an anti-NK1.1 antibody developed significantly smaller infarctions and improved behavioral scores. Correspondingly, NRG mice supplemented with NK cells were more susceptible to tMCAO, developing infarctions and neurological deficits similar to Rag1−/− controls. Our results indicate that NK cells from Rag1−/− mice are fully functional and should therefore be considered in the interpretation of immune-cell transfer models in experimental stroke. Fortunately, we identified the NRG mice, as a potentially better-suited transfer model to characterize individual cell subset-mediated neuroinflammation in stroke.

scholarly journals 789 Generation of a Bicycle NK-TICA™, a novel NK cell engaging molecule to enhance targeted tumor cytotoxicity

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A824-A824
Author(s):  
Fay Dufort ◽  
Christopher Leitheiser ◽  
Gemma Mudd ◽  
Julia Kristensson ◽  
Alexandra Rezvaya ◽  
...  
Keyword(s):  
Phage Display ◽  
Nk Cells ◽  
Natural Killer ◽  
Tumor Antigen ◽  
Cell Activation ◽  
Immune Cell ◽  
Nk Cell ◽  
High Affinity ◽  
Tumor Cytotoxicity ◽  
Immune Oncology

BackgroundNatural killer (NK) cells are immune cells that can detect and eliminate tumor cells and bridge innate to adaptive immune responses. Tumor specific activation of NK cells is thus an area of active investigation in immune oncology, but to date has relied on complex biologic modalities (e.g., antibodies, fusion proteins, or cell therapies), each of which has inherent disadvantages in this application. Thus, alternative approaches are warranted. Bicycle® are small (ca. 1.5 kDa), chemically synthetic, structurally constrained peptides discovered via phage display and optimized using structure-driven design and medicinal chemistry approaches. We have now applied this technology to identify Bicycles that bind specifically to the key activating receptors, NKp46 and CD16a. When chemically coupled to tumor antigen binding Bicycles this results in highly potent, antigen-dependent receptor activation and NK cell activation. We term this new class of fully synthetic molecules Bicycle® natural killer- tumor-targeted immune cell agonists (NK-TICAs™) and we will describe their discovery and evaluation in this presentation.MethodsUsing our unique phage display screening platform, we have identified high affinity, selective binders to NKp46 and CD16a. By conjugating the Bicycle® NK cell-engaging binders to a model tumor antigen EphA2-binding Bicycle®, we have developed a bifunctional Bicycle NK-TICA™ molecule. In in vitro functional assays, we evaluated the ability of the Bicycle NK-TICAs™ to induce NK cell activation as well as cell-mediated cytotoxicity and cytokine production in NK-tumor co-culture assays.ResultsWe have developed a novel modular compound with high affinity and selectivity to NK cell receptors with specific tumor targeting capability. We demonstrate potent, selective binding of our Bicycles to receptor-expressing cells and the capability of the bifunctional molecule to induce NK cell function. With Bicycle's novel NK-TICA™ compound, we demonstrate engagement of NK cells, specific activation and function of NK cells, and enhanced EphA2-expressing tumor cytotoxicity, in a dose dependent manner.ConclusionsBicycle NK-TICAs™ are novel therapeutic agents capable of enhancing the landscape of immune oncology. We hypothesize that utilization of Bicycle NK-TICA™ as a multifunctional immune cell engager will promote modulation of NK cells, and infiltration and anti-tumor activity of NK cells in solid tumors. The data presented here provide initial proof of concept for application of the Bicycle technology to drive NK cell-mediated tumor immunity.

Natural killer cells and type II interferon in Ro/SSA and La/SSB autoantibody-exposed newborns at risk of congenital heart block

2020 ◽  
pp. annrheumdis-2019-216786
Author(s):  
Margarita Ivanchenko ◽  
Gudny Ella Thorlacius ◽  
Malin Hedlund ◽  
Vijole Ottosson ◽  
Lauro Meneghel ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Nk Cells ◽  
Natural Killer ◽  
Heart Block ◽  
Congenital Heart ◽  
Immune Cell ◽  
Nk Cell ◽  
Congenital Heart Block ◽  
Cell Populations ◽  
Type I

ObjectiveCongenital heart block (CHB) with immune cell infiltration develops in the fetus after exposure to maternal Ro/La autoantibodies. CHB-related serology has been extensively studied, but reports on immune-cell profiles of anti-Ro/La-exposed neonates are lacking. In the current study, we characterised circulating immune-cell populations in anti-Ro/La+mothers and newborns, and explored potential downstream effects of skewed neonatal cell populations.MethodsIn total, blood from mothers (n=43) and neonates (n=66) was sampled at birth from anti-Ro/La+ (n=36) and control (n=30) pregnancies with or without rheumatic disease and CHB. Flow cytometry, microarrays and ELISA were used for characterising cells and plasma.ResultsSimilar to non-pregnant systemic lupus erythematosus and Sjögren-patients, anti-Ro/La+mothers had altered B-cell subset frequencies, relative T-cell lymphopenia and lower natural killer (NK)-cell frequencies. Surprisingly, their anti-Ro/La exposed neonates presented higher frequencies of CD56dimCD16hi NK cells (p<0.01), but no other cell frequency differences compared with controls. Type I and II interferon (IFN) gene-signatures were revealed in neonates of anti-Ro/La+ pregnancy, and exposure of fetal cardiomyocytes to type I IFN induced upregulation of several NK-cell chemoattractants and activating ligands. Intracellular flow cytometry revealed IFNγ production by NK cells, CD8+ and CD4+ T cells in anti-Ro/La exposed neonates. IFNγ was also detectable in their plasma.ConclusionOur study demonstrates an increased frequency of NK cells in anti-Ro/La exposed neonates, footprints of type I and II IFN and an upregulation of ligands activating NK cells in fetal cardiac cells after type I IFN exposure. These novel observations demonstrate innate immune activation in neonates of anti-Ro/La+pregnancy, which could contribute to the risk of CHB.

scholarly journals Leukocyte Immunoglobulin-Like Receptor 1-Expressing Human Natural Killer Cell Subsets Differentially Recognize Isolates of Human Cytomegalovirus through the Viral Major Histocompatibility Complex Class I Homolog UL18

2016 ◽  
Vol 90 (6) ◽  
pp. 3123-3137 ◽  
Author(s):  
Kevin C. Chen ◽  
Richard J. Stanton ◽  
Jareer J. Banat ◽  
Mark R. Wills
Keyword(s):  
Immune Responses ◽  
Nk Cells ◽  
Natural Killer ◽  
Cytomegalovirus Infection ◽  
Hcmv Infection ◽  
Nk Cell ◽  
Long Term Memory ◽  
Term Memory

ABSTRACTImmune responses of natural killer (NK) cell are controlled by the balance between activating and inhibitory receptors, but the expression of these receptors varies between cells within an individual. Although NK cells are a component of the innate immune system, particular NK cell subsets expressing Ly49H are positively selected and increase in frequency in response to cytomegalovirus infection in mice. Recent evidence suggests that in humans certain NK subsets also have an increased frequency in the blood of human cytomegalovirus (HCMV)-infected individuals. However, whether these subsets differ in their capacity of direct control of HCMV-infected cells remains unclear. In this study, we developed a novelin vitroassay to assess whether human NK cell subsets have differential abilities to inhibit HCMV growth and dissemination. NK cells expressing or lacking NKG2C did not display any differences in controlling viral dissemination. However, whenin vitro-expanded NK cells were used, cells expressing or lacking the inhibitory receptor leukocyte immunoglobulin-like receptor 1 (LIR1) were differentially able to control dissemination. Surprisingly, the ability of LIR1+NK cells to control virus spread differed between HCMV viral strains, and this phenomenon was dependent on amino acid sequences within the viral ligand UL18. Together, the results here outline anin vitrotechnique to compare the long-term immune responses of different human NK cell subsets and suggest, for the first time, that phenotypically defined human NK cell subsets may differentially recognize HCMV infections.IMPORTANCEHCMV infection is ubiquitous in most populations; it is not cleared by the host after primary infection but persists for life. The innate and adaptive immune systems control the spread of virus, for which natural killer (NK) cells play a pivotal role. NK cells can respond to HCMV infection by rapid, short-term, nonspecific innate responses, but evidence from murine studies suggested that NK cells may display long-term, memory-like responses to murine cytomegalovirus infection. In this study, we developed a new assay that examines human NK cell subsets that have been suggested to play a long-term memory-like response to HCMV infection. We show that changes in an HCMV viral protein that interacts with an NK cell receptor can change the ability of NK cell subsets to control HCMV while the acquisition of another receptor has no effect on virus control.

Inflammation restraining effects of prostaglandin E2 on natural killer–dendritic cell (NK-DC) interaction are imprinted during DC maturation

Blood ◽  
2011 ◽  
Vol 118 (9) ◽  
pp. 2473-2482 ◽  
Author(s):  
Catharina H. M. J. Van Elssen ◽  
Joris Vanderlocht ◽  
Tammy Oth ◽  
Birgit L. M. G. Senden-Gijsbers ◽  
Wilfred T. V. Germeraad ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Immune Responses ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
T Helper 1 ◽  
Ifn Γ ◽  
Dc Maturation

Abstract Among prostaglandins (PGs), PGE2 is abundantly expressed in various malignancies and is probably one of many factors promoting tumor growth by inhibiting tumor immune surveillance. In the current study, we report on a novel mechanism by which PGE2 inhibits in vitro natural killer–dendritic cell (NK-DC) crosstalk and thereby innate and adaptive immune responses via its effect on NK-DC crosstalk. The presence of PGE2 during IFN-γ/membrane fraction of Klebsiella pneumoniae DC maturation inhibits the production of chemokines (CCL5, CCL19, and CXCL10) and cytokines (IL-12 and IL-18), which is cAMP-dependent and imprinted during DC maturation. As a consequence, these DCs fail to attract NK cells and show a decreased capacity to trigger NK cell IFN-γ production, which in turn leads to reduced T-helper 1 polarization. In addition, the presence of PGE2 during DC maturation impairs DC-mediated augmentation of NK-cell cytotoxicity. Opposed to their inhibitory effects on peripheral blood–derived NK cells, PGE2 matured DCs induce IL-22 secretion of inflammation constraining NKp44+ NK cells present in mucosa-associated lymphoid tissue. The inhibition of NK-DC interaction is a novel regulatory property of PGE2 that is of possible relevance in dampening immune responses in vivo.

scholarly journals A natural killer cell gene signature predicts melanoma patient survival

2018 ◽  
Author(s):  
Joseph Cursons ◽  
Fernando Souza-Fonseca-Guimaraes ◽  
Ashley Anderson ◽  
Momeneh Foroutan ◽  
Soroor Hediyeh-Zadeh ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Solid Tumors ◽  
Immune Cell ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Activity ◽  
Human Tumors ◽  
The Cancer Genome Atlas ◽  
Cell Gene

AbstractAnimal models have demonstrated that natural killer (NK) cells can limit the metastatic dissemination of tumors, however their ability to combat established human tumors has been difficult to investigate.A number of computational methods have been developed for the deconvolution of immune cell types within solid tumors. We have taken the NK cell gene signatures from several tools, then curated and expanded this list using recent reports from the literature. Using a gene set scoring method to investigate RNA-seq data from The Cancer Genome Atlas (TCGA) we show that patients with metastatic cutaneous melanoma have an improved survival rate if their tumor shows evidence of greater NK cell infiltration. Furthermore, these survival effects are enhanced in tumors which have a higher expression of NK cell stimuli such as IL-15, suggesting NK cells are part of a coordinated immune response within these patients. Using this signature we then examine transcriptomic data to identify tumor and stromal components which may influence the penetrance of NK cells into solid tumors.These data support a role for NK cells in the regulation of human tumors and highlight potential survival effects associated with increased NK cell activity. Furthermore, our computational analysis identifies a number of potential targets which may help to unleash the anti-tumor potential of NK cells as we enter the age of immunotherapy.

scholarly journals The Role of Natural Killer Cells in Autoimmune Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Umut Can Kucuksezer ◽  
Esin Aktas Cetin ◽  
Fehim Esen ◽  
Ilhan Tahrali ◽  
Nilgun Akdeniz ◽  
...  
Keyword(s):  
Immune Responses ◽  
Nk Cells ◽  
Natural Killer ◽  
Lupus Erythematosus ◽  
Cell Biology ◽  
Nk Cell ◽  
Cell Activity ◽  
Cell Subset ◽  
Therapeutic Interventions ◽  
Surface Receptors

Natural killer (NK) cells, the large granular lymphocytes differentiated from the common lymphoid progenitors, were discovered in early 1970’s. They are members of innate immunity and were initially defined by their strong cytotoxicity against virus-infected cells and by their important effector functions in anti-tumoral immune responses. Nowadays, NK cells are classified among the recently discovered innate lymphoid cell subsets and have capacity to influence both innate and adaptive immune responses. Therefore, they can be considered as innate immune cells that stands between the innate and adaptive arms of immunity. NK cells don’t express T or B cell receptors and are recognized by absence of CD3. There are two major subgroups of NK cells according to their differential expression of CD16 and CD56. While CD16+CD56dim subset is best-known by their cytotoxic functions, CD16-CD56bright NK cell subset produces a bunch of cytokines comparable to CD4+ T helper cell subsets. Another subset of NK cells with production of interleukin (IL)-10 was named as NK regulatory cells, which has suppressive properties and could take part in immune-regulatory responses. Activation of NK cells is determined by a delicate balance of cell-surface receptors that have either activating or inhibitory properties. On the other hand, a variety of cytokines including IL-2, IL-12, IL-15, and IL-18 influence NK cell activity. NK-derived cytokines and their cytotoxic functions through induction of apoptosis take part in regulation of the immune responses and could contribute to the pathogenesis of many immune mediated diseases including ankylosing spondylitis, Behçet’s disease, multiple sclerosis, rheumatoid arthritis, psoriasis, systemic lupus erythematosus and type-1 diabetes. Dysregulation of NK cells in autoimmune disorders may occur through multiple mechanisms. Thanks to the rapid developments in biotechnology, progressive research in immunology enables better characterization of cells and their delicate roles in the complex network of immunity. As NK cells stand in between innate and adaptive arms of immunity and “bridge” them, their contribution in inflammation and immune regulation deserves intense investigations. Better understanding of NK-cell biology and their contribution in both exacerbation and regulation of inflammatory disorders is a requisite for possible utilization of these multi-faceted cells in novel therapeutic interventions.

scholarly journals Natural Killer Cells Protect against Mucosal and Systemic Infection with the Enteric Pathogen Citrobacter rodentium

2012 ◽  
Vol 81 (2) ◽  
pp. 460-469 ◽  
Author(s):  
Lindsay J. Hall ◽  
Carola T. Murphy ◽  
Grainne Hurley ◽  
Aoife Quinlan ◽  
Fergus Shanahan ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Bacterial Infections ◽  
Immune Cell ◽  
Nk Cell ◽  
Systemic Infection ◽  
Citrobacter Rodentium ◽  
Content Type

ABSTRACTNatural killer (NK) cells are traditionally considered in the context of tumor surveillance and viral defense, but their role in bacterial infections, particularly those caused by enteric pathogens, is less clear. C57BL/6 mice were orally gavaged withCitrobacter rodentium, a murine pathogen related to human diarrheagenicEscherichia coli. We used polyclonal anti-asialo GM1 antibody to actively deplete NK cellsin vivo. Bioluminescent imaging and direct counts were used to follow infection. Flow cytometry and immunofluorescence microscopy were used to analyze immune responses. DuringC. rodentiuminfection, NK cells were recruited to mucosal tissues, where they expressed a diversity of immune-modulatory factors. Depletion of NK cells led to higher bacterial loads but less severe colonic inflammation, associated with reduced immune cell recruitment and lower cytokine levels. NK cell-depleted mice also developed disseminated systemic infection, unlike control infected mice. NK cells were also cytotoxic toC. rodentiumin vitro.

scholarly journals Mapping and Characterization of HCMV-Specific Unconventional HLA-E-Restricted CD8 T Cell Populations and Associated NK and T Cell Responses Using HLA/Peptide Tetramers and Spectral Flow Cytometry

2021 ◽  
Vol 23 (1) ◽  
pp. 263
Author(s):  
Amélie Rousselière ◽  
Laurence Delbos ◽  
Céline Bressollette ◽  
Maïlys Berthaume ◽  
Béatrice Charreau
Keyword(s):  
Flow Cytometry ◽  
T Cell ◽  
Immune Responses ◽  
Nk Cells ◽  
Hcmv Infection ◽  
Immune Cell ◽  
Nk Cell ◽  
Spectral Flow ◽  
Cell Responses

HCMV drives complex and multiple cellular immune responses, which causes a persistent immune imprint in hosts. This study aimed to achieve both a quantitative determination of the frequency for various anti-HCMV immune cell subsets, including CD8 T, γδT, NK cells, and a qualitative analysis of their phenotype. To map the various anti-HCMV cellular responses, we used a combination of three HLApeptide tetramer complexes (HLA-EVMAPRTLIL, HLA-EVMAPRSLLL, and HLA-A2NLVPMVATV) and antibodies for 18 surface markers (CD3, CD4, CD8, CD16, CD19, CD45RA, CD56, CD57, CD158, NKG2A, NKG2C, CCR7, TCRγδ, TCRγδ2, CX3CR1, KLRG1, 2B4, and PD-1) in a 20-color spectral flow cytometry analysis. This immunostaining protocol was applied to PBMCs isolated from HCMV- and HCMV+ individuals. Our workflow allows the efficient determination of events featuring HCMV infection such as CD4/CD8 ratio, CD8 inflation and differentiation, HCMV peptide-specific HLA-EUL40 and HLA-A2pp65CD8 T cells, and expansion of γδT and NK subsets including δ2-γT and memory-like NKG2C+CD57+ NK cells. Each subset can be further characterized by the expression of 2B4, PD-1, KLRG1, CD45RA, CCR7, CD158, and NKG2A to achieve a fine-tuned mapping of HCMV immune responses. This assay should be useful for the analysis and monitoring of T-and NK cell responses to HCMV infection or vaccines.

Sign in / Sign up

Export Citation Format

Share Document