Functions of natural killer cells. Natural killer (NK) cells are effector lymphocytes of the innate immune system that control several types of tumors and microbial infections by limiting their spread and subsequent tissue damage. Natural killer (NK) cells, with a predominant morphology of large granular lymphocytes, represent a lineage of lymphoid cells with constitutive ability to mediate cytotoxicity toward pathologic target cells and secrete cytokines.
Forgotten your password? Natural killer NK cells are effector lymphocytes that play protective roles against both infectious pathogens and cancer. Although NK cells contribute to the innate immune system, they have a number of similarities to cells of the adaptive immune system, including T and B what is nepali date today. Recent discoveries have also shown that NK cells are capable of adapting and developing into long-lived memory cells, providing new functional insights into the roles of innate immune cells.
In this article, the author provides an overview of human and murine NK cell development, function, and memory, as well as their role in viral infection and cancer. Receive our free quarterly newsletters and your choice of journal publication alerts, straight to your inbox. Natural killer NK cells were originally described in the s as large granular lymphocytes able to develop natural cytotoxicity against tumour cells without a prior encounter.
They are also found in mucosal tissues, including the lungs, small and large intestines, and colon. In response to sex hormones, there is a substantial increase in uterine NK cells, which are thought to promote placental growth and provide maternal—fetal immunomodulation; 7 however, both peripheral NK cells and uterine NK cells have been associated with infertility and miscarriage.
ILC were classified into three main groups based on their cell surface marker expression, functionality, and transcriptional regulation. NK cells have been classified as components of the innate immune system; however, they have also been shown to possess numerous developmental and functional characteristics similar to cells of the adaptive immune system, including T and B cells.
During five stages of development, there are a number of changes in expression levels of CD56, CD94, and CD16, and, much like how to last longer in sex mice, human NK cells become responsive to and require the cytokine IL Maturing human NK cells can differentiate into CD56 bright cells, which usually remain in the lymphoid tissue to interact with dendritic cells DC and CD56 dim cells that return to how to get smarter in school fast via the lymphatics.
Transcription factors also play important roles in governing lymphocyte fate from the CLP. A simplified list of transcription factors driving the NK cell lineage is shown in the box and the numbers on the diagram indicate where they have been identified at the different stages during development.
Along with the expression of various cell surface markers and receptors, there are complex networks of transcription factors that can help dictate lymphocyte lineage commitments and give rise to distinct cell fates.
Thymocytes can be diverted into an NK cell-like lineage if Bcb, a Notchdependent transcription factor, is ablated during T cell development. The effector function of NK cells is determined by an integration of numerous signals. To sense their environment, NK cells use a tightly regulated balance of activating and inhibitory germline-encoded receptors, and initiation of an NK cell response is dependent on signalling via these receptors Figure 2. Under physiological conditions, circulating NK cells are mostly in a resting state; however, activation by an array of cytokines can lead to the infiltration of these cells into pathogen-infected or cancerous tissues.
K cells are able to recognise and kill target cells by an integrated balance of activating and inhibitory signals, which allow them to distinguish between healthy cells and target cells those virally infected or transformed.
The inhibitory signals are delivered by self-MHC class I in this setting. MHC: major histocompatibility complex; NK: natural killer. Killer cell immunoglobulin-like receptors in humans or members of the Ly49 family in mice make up the main inhibitory receptor profile of NK cells that bind MHC I molecules and maintain a tolerance for healthy host cells.
The quick response capabilities and enhanced host protection against a previously encountered pathogen make up the classical definition of immunological memory. During different educational routes, the formation of NK cell memory can occur in two ways: via antigen-dependent virus or hapten-induced or antigen-independent in mba what is finance mechanisms. The memory formation process in T cells has been well characterised and is usually distributed into three main phases.
These memory T cells persist throughout the organs of the host and maintain their longevity through self-renewal until they encounter their cognate ligand, where they display enhanced host protection and effector function. These NK cells can be recovered months after the initial infection in a number of peripheral tissues.
NK cells play an important role in viral clearance but their responses were initially thought to be non-specific and lacking an immune memory response. As discussed previously, NK cells possess a large number of activating and inhibitory receptors that are known to play important roles in controlling viral infection. Along with stress-induced receptor signals, other activating receptors are expressed to precisely sense viral signals including NK1.
NK cells were first identified for their ability to kill tumour cells without prior sensitisation. They are able to directly kill tumour cells through the release of cytotoxic granules containing granzyme and perforin. NK cells can be activated by various stimuli, including contact with DC. DC are the main antigen-presenting cells of the immune system and play a fundamental role in sensing pathogens and what are puffy eyes a symptom of an immune response.
A bi-directional crosstalk between DC and NK cells has been observed in secondary lymphoid tissues and in the periphery via cell—cell contacts or the release of soluble factors.
The cytokine production triggers tumour cell—cycle arrest. Although it has been known for some time that NK cells play a key role in fighting tumour development and progression, in more recent years NK cell-based immunotherapy has become a how to stop smelly urine and promising approach to treating tumours. NK cells are a key component of the immune response and play vital roles in controlling and eliminating both virally-infected and cancer cells.
Although our knowledge of basic NK cell biology and innate immunity continues to grow rapidly and many studies have shown that the development and function of NK cells is highly dynamic, there is still much to be investigated. The effector function of these NK cells must be further studied, with a predominant focus on immunotherapies along with the prevention of infectious diseases and cancer.
Login to continue x Members Forgotten your password? Create Account Create your own personal healthcare feed, full of the latest content from across our divisions. Abstract Natural killer NK cells are effector lymphocytes that play protective roles against both infectious pathogens and cancer. Figure 1: An overview of natural killer cell development. Related To This Subject. Read More. More articles.
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Jul 18, · Natural killer (NK) cells are effector lymphocytes that play protective roles against both infectious pathogens and cancer. Although NK cells contribute to the innate immune system, they have a number of similarities to cells of the adaptive immune system, including T and B cells. Recent discoveries have also shown that NK cells are capable of. May 10, · Natural killer cells (also known as NK cells, K cells, and killer cells) are a type of lymphocyte (a white blood cell) and a component of innate immune system. NK cells play a major role in the host-rejection of both tumours and virally infected cells. Click to see full answer Regarding this, what are natural killer cells and how do they function? Natural killer (NK) cells are granular lymphocytes that play important roles in immunity against viruses and in the immune surveillance of tumors. In addition to being a potent innate source of IFN-?, NK cells hold cytoplasmic granula that contain perforin and granzymes involved in cell-mediated cytotoxicity.
There is a growing appreciation that cellular metabolism is important in determining the course of lymphocyte responses. Additionally, changes in metabolic processes have been linked to dysfunctional lymphocyte functions in a number of different diseases. While most early studies of metabolic regulation of lymphocyte function focused on T lymphocytes, an understanding of how metabolic pathways impact upon natural killer NK cell responses is now starting to emerge.
In this review article, we will discuss how cellular metabolism influences lymphocyte function with a particular focus upon NK cells. Natural killer NK cells are important effector lymphocytes that are best characterized for their antiviral and anticancer activities 1 , 2. In addition to their effector functions, NK cells can also regulate development of the adaptive immune response in a variety of ways including production of immune modulating cytokines and regulating DC maturation 3.
As NK cell responses can be detected very rapidly after infection within hours , they have historically been classified as cells of the innate immune system. However, this textbook viewpoint has changed with the discovery of long-lived and sustained functional NK cells, and the demonstration of intrinsic innate immune memory 4 — 6.
Natural killer cells are also clinically important and represent a good target for anticancer immune therapy in which the host immune system is harnessed for anticancer activities. Currently, NK cells are being investigated in clinical trials using a range of different approaches.
Recently, one such trial investigating an anti-KIR antibody as a single agent for the treatment of acute myelogenous leukemia AML did not reach its primary efficacy endpoint and was halted. However, given the promising results in preclinical studies 7 , it will be interesting to see the results of several other trials still on-going that use these antibodies in combination with other agents for a range of cancer types. Natural killer cells allogeneic, haploidentical are also successfully being used for adoptive transfer treatment of AML 8 — Adoptive transfer therapy allows the potential to genetically manipulate NK cells prior to infusion.
This concept is being explored in a number of clinical trials NCT and NCT that have generated chimeric antigen receptor CAR NK cells, designed to recognize and treat B cell acute lymphoblastic leukemic. While these trials are using primary NK cells, there is also some evidence that CAR-modified NK cell lines NK can provide benefit in different preclinical models 11 , Finally, NK cells are important in particular antibody-mediated immunotherapy settings, for instance for the treatment of neuroblastoma or lymphoma where they mediate antibody-dependent cellular cytotoxicity ADCC against tumor cells Understanding the relevance of metabolism to NK cell effector functions will provide new mechanisms to enhance these therapeutic approaches but also opens up the potential for new avenues of NK cell-based therapies as discussed below.
It is becoming clear that metabolism is profoundly important for immune function, to the extent that manipulation of metabolism can alter immune cell fate and function. Immune responses involve highly dynamic changes in immune cell function, which often encompass robust cellular growth and proliferation. Therefore, it is not surprising that there are corresponding changes in metabolism that match the dynamic nature of immune cells.
Quiescent lymphocytes have limited biosynthetic demands and metabolic pathways are tuned toward efficiently metabolizing glucose through glycolysis coupled to oxidative phosphorylation oxphos to make energy, i.
Aerobic glycolysis is adopted by cells engaging in robust growth and proliferation because it provides the biosynthetic precursors that are essential for the synthesis of nucleotides, amino acids, and lipids Figure 1 18 , Therefore, for cells engaged in aerobic glycolysis, the primary function of glucose has shifted from a fuel to generate energy to a source of carbon that can be used for biosynthetic purposes Figure 1.
The differing metabolic phenotypes of quiescent versus activated lymphocytes. A Adenosine triphosphate ATP is the key molecule that provides energy for cellular processes. Maintaining cellular ATP levels is essential for bioenergetic homeostasis and cell survival. Glucose, a key fuel source for mammalian cells, can be metabolized via two integrated metabolic pathways, glycolysis and oxidative phosphorylation oxphos , that efficiently generate ATP.
Glycolysis converts glucose to pyruvate that, following transportation into the mitochondria, is further metabolized to CO 2 by the Krebs cycle fueling oxphos and ATP synthesis. B Aerobic glycolysis supports biosynthetic processes of the cell as it allows the uptake of larger amounts of glucose and the maintenance of elevated glycolytic flux.
Glycolytic intermediates are then diverted into various pathways for the synthesis of biomolecules that support biosynthetic processes.
For instance, glucosephosphate G6P generated by the first step in glycolysis can feed into the pentose phosphate pathway PPP to support nucleotide synthesis. This pathway also generates NADPH, a cofactor that is essential for various biosynthetic processes including lipid synthesis. Glucose can also be converted into cytoplasmic acetyl-CoA via citrate in the Krebs cycle for the production of cholesterol and fatty acids for lipid synthesis.
Other glycolytic intermediates can also be converted into biomolecules used for protein and lipid synthesis. During aerobic glycolysis a significant proportion of pyruvate is also converted to lactate and secreted from the cell.
Lactate export is important as it allows glycolysis to be sustained at an elevated rate. Alternative fuels including glutamine feed into the Krebs cycle and can also supply biomolecules for biosynthetic processes under certain conditions. Beyond the biochemistry of energy production and cellular biosynthesis, it has emerged that metabolism also plays a direct role in controlling immune signaling and immune cell effector functions In addition, certain metabolic intermediates have emerged as important signaling molecules, e.
Immature cells had higher expression of nutrient receptors CD71 transferrin receptor and CD98 l -amino acid transporter , and higher uptake of 2-NBDG a fluorescent glucose analog presumably to facilitate the metabolic demands of proliferation and differentiation Keppel et al. Short-term activation 4—6 h with either cytokines or receptor ligation did not significantly alter the metabolic pathways used by NK cells However, when NK cells are stimulated with cytokine over longer periods of time, as might be expected in vivo in response to infection, changes in NK cell metabolism become apparent.
Although both pathways were upregulated, there was a preferential increase in glycolysis, a finding that parallels metabolic changes in CD8 effector T cells. Whether other fuels such as fatty acids and glutamine are important for NK cell metabolism and function is, to date, largely unexplored.
The mammalian target of rapamycin complex 1 mTORC1 is considered a master regulator of immunology and metabolism. Increasingly, the delineation between these activities blurs as the importance of metabolism on immune cell function is appreciated. Interestingly, while Akt regulates cellular metabolism in various cell types, this is not the case in IL2-maintained CD8 cytotoxic T cells It is clear that NK cells alter their metabolism in tandem with acquisition of enhanced effector functions but this does not necessarily imply a direct relationship between the two.
A range of experimental approaches have been used to interfere with particular metabolic pathways to test the impact on NK cell function. These approaches demonstrated that direct metabolic restriction of glycolysis results in decreased NK cell effector function 14 , Natural killer cells are part of a wider family of innate lymphoid cells ILCs and to date nothing is known about how cellular metabolism impacts upon the other ILC subsets.
However, one study has highlighted a role for mTORC1 for cytokine production in type 2 ILCs, which might suggest that metabolic changes are involved While less is known about human NK cell metabolism, it is likely that distinct phenotypic and functional NK cell subsets will have characteristic metabolic signatures.
CD56 expression levels have long been used to define peripheral blood NK cells subsets in humans. By contrast, CD56 bright cells predominate in tissues. Although there is strong evidence demonstrating that CD56 bright cells can differentiate into CD56 dim cells, both populations are maintained at a steady state in the peripheral blood of normal healthy individuals, suggesting that CD56 brights are not merely a precursor in a developmental pathway and that they may have particular specialized functions, possibly related to tissue trafficking and immunosurveillance.
We have recently described that CD56 bright and CD56 dim subsets can also be distinguished in terms of their metabolism Interestingly, mTORC1 was much more strongly activated in CD56 bright cells and these cells responded more strongly to cytokine in terms of nutrient receptor expression and 2-NBDG uptake. Interestingly, in line with the observations that CD56 bright NK cells are more metabolically responsive to cytokine stimulation, metabolic restriction had a greater impact upon the function of CD56 bright versus CD56 dim NK cells Cell surface, intracellular markers, and epigenetic signatures have been defined and important functional differences have been defined 30 , It is likely that these subsets will be characterized by different metabolic pathway usage and based on similarities between adaptive NK cells and memory T cells, it seems reasonable to predict that adaptive NK cells may be characterized by preferential use of FAO metabolism to fuel oxphos In mice, using Ly49H to identify cytomegalovirus CMV -experienced NK cells will also be informative in terms of metabolic analyses and data are already starting to emerge to support that NK cell metabolic responses will play a role in the formation of NK cell memory see below.
Finally, it will be interesting to investigate if there are differences between licensed and unlicensed NK cells in terms of their metabolism If normal responsive NK cells, i. Most of what is known about metabolic changes in lymphocytes during viral infections come from studies on CD8 T cells and thusfar, very little is known about metabolic changes that occur in NK cells during viral infection. The underlying principles of CD8 T cells metabolism during viral infection are likely to be similar in NK cells, though there may be differences in particular NK cell subsets The CD8 T cell response to virus consists of an initial expansion of virus-specific T cells that carry out effector functions against virally infected cells.
As expected, mitochondrial mass, ATP levels, and spare respiratory capacity SRC can all be increased in effector cells After immune control has been established by elimination of the pathogen, the expanded effector population contracts to generate a small pool of long-lived memory cells that have the capacity to react quickly and more effectively upon subsequent exposure to the same virus.
These memory cells preferentially use FAO to fuel oxphos to provide energy 32 , However, sometimes the immune system fails to control the pathogen and chronic viral infections can ensue that are associated with increased long-term morbidity and mortality in patients, e. Metabolically, exhausted cells have impaired mitochondrial responses that paradoxically include increased mitochondrial mass but reduced oxphos, SRC, and mitochondrial membrane potential 38 , There is a general consensus that defective mitochondrial function is a characteristic of chronic infection and that the reduced mitochondrial activity may force the cells to ineffectively utilize glycolysis under conditions where glucose availability is limited.
Thus, while we do not fully understand the why and how, it is clear that different T cell subsets are characterized by using different metabolic pathways for their survival and function. Although little is yet known about how metabolism in NK cells impacts upon viral infections, information is starting to emerge, albeit indirectly. As these effector cells died back to generate a pool of memory cells in a mitophagy-dependent manner, mitochondrial potential in memory NK cells was restored, concomitant with reduced mtROS, suggesting a role for metabolic regulation of innate immune memory as has been seen for memory CD8 cells Furthermore, Marcais et al.
Metabolism remains an unexplored landscape that holds great potential for therapeutic manipulation of NK cells in a variety of diseases including cancer and chronic viral infection. There are several potential ways in which metabolism of NK cells could be targeted to improve outcome for cancer patients. It has been known for a long time that NK cell functions are impaired in many different forms of cancer 46 — Indeed, various mouse models have shown that NK cells become exhausted during cancer 49 , In addition to no longer being effective against cancer, reduced NK activity also leaves patients susceptible to infections.
Therefore, activation of NK cells in vivo is an attractive therapeutic strategy. We predict that NK cell metabolism in these patients will be severely compromised and restoring normal metabolism might be key to restoring function. Check-point blockade inhibitors including anti-PD1 and -PDL1 have revolutionized many cancer treatments.
They function in part by restoring immune activity in exhausted T cells and a recent report suggests that restoring metabolism in T cells can contribute to this There is some evidence that NK cells from multiple myeloma patients expressed PD1 and that blocking PD1 enhanced NK cell functions against tumor cells Indeed, anti-PD1 blockade increased expression of genes associated with NK cell cytotoxicity during in vivo therapy for cancer There is also evidence that anti-Tim3 restored NK cell function in NK cells from patients with metastatic melanoma However, the impact of check-point inhibitors on NK cell functions during cancer treatment has not yet been extensively investigated.
Understanding how NK cell metabolism is altered in cancer will provide valuable information regarding how best to restore metabolism and function in exhausted NK cells. As mentioned earlier, NK cells are used therapeutically in a variety of settings including adoptive transfer therapy and antibody-mediated immunotherapy for cancer.
Adoptive transfer of allogeneic haploidentical NK cells is currently used as a treatment for AML 54 — One benefit of allogeneic NK cells is the ability to culture the cells ex vivo , e. Understanding how metabolism contributes to NK cell function will provide the opportunity to strategically manipulate metabolism of NK cells, which will translate into more effective anticancer activity in vivo.
Proof of principle for this comes from preclinical studies in which altering T cell metabolism improved cancer outcome in an adoptive cellular immunotherapy setting.