2016 Group 4 Project
- 1 Lymphocytic NK Cells
- 2 History
- 3 Structure
- 4 Function of NK cells
- 5 Abnormalities in Disease
- 6 Current Research
- 7 References
Lymphocytic NK Cells
Natural killer cells are lymphocytes which are characterized by their ability to destroy intracellular foreign bodies without needing the recognition of the specific antigen. They have no immunological memory and are part of the innate immune system, thus they are called "Natural killer cells". 5-15% of the total lymphocyte population in circulation are Natural killer cells.
Natural killer cells destroy their targets by injecting it with a toxin. This toxin creates holes in the membrane and is the start of a programmed cell death, apoptosis. The membrane is destroyed and the DNA is cleaved into many pieces.
They make up the bulk of the innate defense against viral infections and the surveillance of tumor cells. Natural killer cell function is abnormal in immunodeficiency diseases such as in HIV/AIDS. 
|1970||Prior to this date, Lymphocytes only had two types of classifications, either a T cell or a B cell. |
|1971||Dr Robert Leif conducts an experiment with sheep blood that show the distinct characteristics of the NK cell. It is yet to be distinguished from other lymphocytes. |
|1973||'Natural killing' activity was established across a wide variety of species|
|1975||Rolf Keissling and Hugh Pross identify a killer cell within mice, that seemed to be genetically regulated and with a natural cytotoxicity that killed many tumours. He coined this as the "natural" killer cell. |
|1975||Within the same year Hugh Pross and Mikael Jondal further establish the presence of natural killer cells in humans. |
|1980||Timonen and Saksela, first to visualize NK cells microscopically, and proved that large granular lymphocytes are the root of NK activity in humans. This was done initially through discontinuous density centrifugation then later through monoclonal antibodies. |
|2007||NK cells are now identifiable by surface expressions, NKp46 established to be present in Natural killer cells in all mammals. |
Natural killer cells are formed from common lymphoid progenitor cells which are then differentiated into the bone marrow allowing circulation around the body as peripheral blood after the homeostasis period at which point they contribute to approximately 10 to 15% of all peripheral blood lymphocytes in humans.  
Most commonly NK cells are large granular lymphocytes, meaning that have large round nueclei with an absence of a nucleoli surrounded by a large transparent cytoplasm. Granules can be seen throughout the cell giving the cell its name.
On an individual cellular level Natural killer cells can be divided in three simple ways:
- Genetically as either CD56 bright or CD56 dim. CD56 bright is the more common type contributing approximately 90% of NK cells in the blood whilst CD56 dim contributes approximately 5-15% of NK cells . Functionally this plays a pivotal role as CD56 bright allows for greater cytotoxity whilst CD56 dim cells allow for a greater range of cytokinesis. 
- Functionally natural killer cells can be differentiated into either exhibiting activating or inhibitory responses through the receptors on the cell surface. 
- Structurally, NK cells can be divided into the Immunoglobulin Super Family (IgSF) or Killer Cell Lectin-like Receptor family (KIRs) .
Immunoglobin Super Family (IgSF)
IgSF are a the largest superfamily in the human genome . They are a group of soluble, cell surface glycoproteins that play a role in the recognition, binding and adhesion of cells. All IgSF molecules consist of a structural domain called the immunoglobulin (Ig) domain, named according to the immunoglobulin type they consist of . The Ig domain consists of a characteristic Ig-fold, formed by two antiparallel beta sheets, sometimes referred to as a “beta-sandwich”. These sheets are linked by disulphide bonds that act to stabilise the Ig-fold .
There is a region of hypervariable loops or complementarity determining regions (CDRs) located at one end of the Ig-fold which has a role in determining the specificity of antibody-ligand mechanisms and the generation of diverse antibodies and T-cell receptors .
Immunoglobulins, known commonly as antibodies, have an important role in the immune system for neutralising antigens . Immunoglobulins are heterodimeric proteins composed of two heavy and two light chains . They have two domains; the variable (V) domain which binds antigens and the constant (C) domain which has a role in determining specificity via activation of complement or binding to Fc receptors .
Killer cell lectin-like receptors (KIRs)
Killer-cell immunoglobulin-like receptors are a type I transmembrane glycoprotein expressed on the plasma membrane of NK cells. They have a role in regulating the activity of NK cells via their interactions with Major Histocompatibility (MHC) molecules. KIRs can distinguish between various classes of MHC molecules, allowing them the ability to recognise foreign or transformed cells such as viruses . Most KIRs act as an inhibition response to the recognition of MHC molecules, leading to suppression of the cytotoxic activity of the NK cell . These KIR molecules are a feature of polymorphism, meaning that the gene sequences that code for KIRs varies highly amongst two unrelated individuals .
Differentiation from NK T-cells
Differentiating NK cells from similar (but functionally different) immune cells such as NK T-cells and other similar cells is difficult due to a previously lacking consensus on the genetic definition of NK cells. Previously NK cells were not thought to have any similarities amongst all mammal species as well as to each other, this has changed due to the discovery of NKp46 which appears in all NK cells of all species whilst not being expressed by any other cell type.
How they work
NK cells are motile with activating or inhibitory signals being received at a zone of tight intercellular contact known as the immune synapse (IS). Nk cells comprise of an actin mesh which enables the cell the release of granules into the IS. first though the cell must transport these lytic granules to the microtubial organising centre which then undergoes polarisation. the cell then undergoes exocytosis to eliminate virus-infected or tumour cells. the cytotoxicity occurs due to a combination of granzymes and perforin in the cell with granzymes inducing apoptotic death and perforin inducing faster death due to the formation of large membrane protrusions.
There are a lot of receptors associated with natural killer cells which enable the cell to properly carry out their immunological function as shown in the table below. The two main groups of receptors are Activating and Inhibiting.
Activating receptors read positive responses whilst cycling through the body, whereby upon receiving a signal the cell will become cytotoxic and produce cytokines in order to kill the target cell.  Some examples of activating receptors are summarised in the table below.
|Ly49:||Is a homodimer, apart of the C-type lectin family. In humans, we have one pseudogenic Ly49 homodimer that is the classical receptor for MHC I molecules.|
|NCR:||Natural cytotoxicity receptors), upon stimulation, will mediate NK cytotoxicity and the release of IFN-γ.|
|CD94:||Is a C-type lectin family receptor.Is derived from the generation of signal peptide peptidases and proteasomes. |
|CD16:||Has a role in the antibody-dependent cell-mediated cytotoxicity, specifically binding IgG.|
The inhibitory receptors of NK cells enable the cell to self recognise and only attack cells that are under stress and altered. This is done by having receptors to recognise MHC class 1- a gene expressed in normal healthy cells. If an NK cell does not read this code it will lose its receptor when exposed to a MHC class 1-deficient cell. Carried with this are KIR (killer immunoglobulin-like receptors) and lectin like receptors important in the killing of tumour cells. When exposed to a cell that does express MHC class 1, the cell simply is inhibited and no response is elicited . Some examples of Inhibitory receptors are shown in the table below.
|Ly49:||Ly49 is not only an activating receptor, but also has an inhibitory isoform for classical MHC I molecules. |
|ILT/LIR:||Are included in the Ig receptor family and have a relatively recently discovered role in the inhibition NK cell signalling via actin cytoskeleton reorganisation. |
|KIRs:||Are a type I transmembrane glycoprotein expressed on the plasma membrane of NK cells. They are the main receptor type for classical MHC I (HLA-A, HLA-B, HLA-C) and non-classical Mamu-G (HLA-G) molecules. |
Relationship between Activating and Inhibitory receptors
There is a direct relationship between cell activity and receptors. When the NK cell receives more activating (positive) signal responses than inhibitory (negative) the cell will then actively kill the target cell or produce cytokines in order to aid in the killing of the target cell. If however there is a balanced or overall negative signal response that would lead to the NK cell having an overall inhibitory response and lead to no reaction. This is how an NK cell knows not to target healthy cells and instead self-recognizes abnormal and unhealthy cells.
Function of NK cells
The are 3 main functions of NK cells
1. CD56(dim) in cytokinesis
2. CD56(bright) in cytotoxicity
3. Clonal properties for tumour growth inhibition
Function in Immunity
Function in the Innate Host Immune Response
NK cells are apart of the innate immune system and act as effector lymphocytes, with the primary function of limiting the spread of microbial invasion and the proliferation of tumour cells. They are distributed throughout lymphoid and non-lymphoid tissues in relatively small amounts compared to total lymphocyte aggregates. Three subtypes of NK cells have been described in mice. These subtypes are distinguishable by the expression of CD11b and CD27. In humans, NK cells are divided into CD56(dim) and CD56(bright). They differ in their ability to express perforin 
Perforin is a cytolytic protein located in the rough ER, Golgi complex, trans-Golgi reticulum and in the granules of Cytotoxic T Lymphocytes (CTLs) and NK cells. Degranulation of perforin leads to binding to the target cell plasma membrane, activating pro-apoptotic granzymes into the target cell. This leads to destruction of target cells by NK cells 
NK cells are able to discriminate target cells from 'self' cells. These interactions are regulated by activating and inhibitory receptors to create a dynamic equilibrium for NK cell function 
Activated NK cell receptors can also detect stress-induced ‘distress’ ligands, recognised by NKG2D. NK cells can be activated by such molecules as human ULBP, MIC, mouse RAE1, H60 and MULT1 molecules. NK cells are also activated by infectious non-self ligands and Toll-like receptor (TLR) ligands. When activated, NK cells induce production of interferon-gamma (IFN-γ) and Tumour Necrosis Factor (TNF) which enhances cytotoxicity. This response is amplified further in the presence of accessory cells such as mast cells  NK cells are inhibited by expression of MHC class 1-specific receptors. These inhibitory signals are dampened when NK cells encounter MHC class 1-deficient cells 
NK cells can also regulate the extent of immune responses; that is, they can exacerbate or dampen immune responses. Recent studies speculate that NK cells also play a role in regulation of dendritic cells, macrophages, T cells and endothelial cells; key components of the innate immune response. Examples of such MHC class 1-specific receptors include killer cell immunoglobulin-like receptors (KIRs) and lectin-like CD94-NKG2A heterodimers. 
Function in the Adaptive Immune Response
Historically, NK cells belong to the innate immune system which generally does not exhibit immunological memory. However, recent findings have shown the ability for NK cells to implement a long-lived effect via long-lasting functional alterations executed by cytokines. Thus NK cells can have a prolonged effect in their response to happiness or viruses. 
For NK cells to be able to recognise target cells with low MHC class 1-receptor expression, NK cells have to undergo a process known as tuning or licensing whereby NK cells learn to adapt to their new environment via priming. Priming gives NK cells a memory like ability similar to the role of T and B cells in adaptive immunity. Via priming, NK cells are able to respond more potently to second presentations of the an antigen previously exposed. Priming is done by cytokines such as IL-15, IL-18 and IL-12. 
Video of NK cell attacking target cell
Function in Cancer
Tumour cells are recognised by NK cells and are therefore viable target cells. Studies have shown the functional role of NK cells in tumour development. Lack of MHC Class 1 expression, up-regulation of NKG2D ligand or CD27 ligands lead to NK cell mediated lysis of targeted tumour cells. 
It is for this reason that depletion of NK cells leads to increased susceptibility to methylcholanthrene-induced sarcomas and B cell lymphomas raising from a background of perforin deficiency and 2-microglobulin deficiency. NK cells confer anti tumour properties via the effects of several recombinant cytokines, including IL-2, IL-12, IL-18 and IL-21.  
A Japanese study spanning a period of 11-years has shown that the level of NK cell activity in peripheral blood has a significant association with cancer risk in adults. That is, results suggested low NK cell activity is associated with increased cancer risk; and a possible role for NK cells in immunological host defences in cancer. 
Tumour suppression pathways:
- Death-receptor Pathway
Activation of death receptors such as Fas, TNFαR, DR3, DR4, and DR5 by their respective ligands can generate an apoptotic response. To initiate this apoptotic response, death receptor ligands, through receptor oligomerisation, signal the recruitment of specialised adaptor proteins and caspases.  Binding of Fas ligands (FasL) initiates Fas trimerisation, signalling for caspase-8 and the FADD adaptor protein. Caspase-8 undergoes autocatalysis, which activates oligomerisation, making caspase-8 activated. Activated caspase-8 can stimulate two parallel cascades pathways: direct activation and cleavage of caspase-3 activation and cleavage of pro-apoptotic, Bid that is apart of the BCL-2 protein family. Cleavage of Bid results in the formation of ‘truncated Bid’ or tBid. tBid translocates to mitochondria where it activates cytochrome c release. This leads to the activation of caspase-9 and caspase-3.  In addition, TNF-α and DR-3L can initiate pro-apoptotic signals or anti-apoptotic signals PMC1868232. In the absence of caspase activation, death receptors stimulation can lead to the activation of an alternative programmed cell death pathway, necroptosis, via the formation of a complex, IIb.
- Perforin/granzyme-containing Granule-mediated Pathway
The classical granzyme B (GrB)/perforin-mediated apoptosis pathway involves GrB internalisation which is aided by the release of perforin. After internalisation, GrB initiates apoptosis via the cleavage of Bid to tBid. Similar to the death receptor pathway, this triggers mitochondrial cytochrome c release and apoptosome formation leading to the activation of appropriate caspases and apoptosis. 19770840 GrB can also directly activate caspases via cleavage of caspase substrates such as inhibitor of caspase-activated deoxyribonucleases (ICADs). Cleavage allows ICADs to translocate to the nucleus to fragment DNA. GrB also cleaves lamin B, resulting in deterioration of the integrity of the nuclear membrane. 
- IFN-γ-mediated Pathway
interferon (IFN)-γ leads to stimulation of the release of macrophages and the release of neopterin. This increases the activity of indoleamine 2,3-dioxygenase (IDO), leading to tryptophan degradation via the kynurenine pathway. 
Function in Pregnancy
Pregnancy involves temporary immunosuppression of the mother’s immune system. NK cells, or more appropriately, uterine NK cells (uNK cells) are suspected to have a key function in this process. uNK cells are the CD56(bright) NK cell subtype which have high cytokine secretion (including the secretion of TNF-α, IL-10, IFN-γ and TGF-ß) but low cytotoxic potential.  In particular, IFN-γ causes arteriolar dilation to allow increased blood flow to the implantation site, crucial for successful pregnancy. 
Abnormalities in Disease
Summary of NK Cells in Disease
|Cancer:||NK cells have a role in immune surveillance which is breached in invasive neoplastic (cancerous) conditions whereby immune surveillance by NK cells become relatively low. Normally, NK cells have anti-tumour properties enabling them to migrate to sites of metastasis and eliminate malignant cells, but spare host cells . This elimination is done via a variety of mechanisms, including the perforin/granzyme-containing granule-mediated pathway, death-receptor pathway and IFN-γ-mediated pathway .These mechanisms can be targeted therapeutically to up regulate NK cell activity and enhance activatory receptors.|
|Viral Infection:||NK cells are involved in immuno-protection. Generally, during the presence of viral infection, NK cells are found in low numbers and activity; having shifted from CD56(dim) to CD56(bright). Therapeutically, adoptive transfer of NK cells and CCR5 deficient hESC-NK cell transfer can be effective . Additionally, genetically engineered specific NK cell receptors such as HIV1 can proliferate and stay in the liver and spleen even after viral infection, conferring long-term immunity.|
|Asthma:||NK cells contribute to the IgE mediated immune-response, leading to the resolution of airway inflammation. In Asthma, NK cells migrate from circulation to the lung and surrounding lymphoid organs . Therapeutically, adoptive NK cell transfer, in vitro or in vivo, or proliferation of specific NK cell subtypes can alleviate symptoms of asthma.|
|Diabetes (Type 1):||NK cells have a destructive, disease enhancing role in type 1 diabetes. They migrate from the blood and is suspected to house in the pancreas. Here, transformation of expression of NKp30, NKp46 and NKG2D occurs corresponding with lowered levels of perforin in blood NK cells . Current therapies involve targeting NKp46 receptors to reduce auto-destruction of pancreatic ß-cells|
|Rheumatoid Arthritis (RA):||The role of NK cells in RA remains ambiguous; it is inconclusive whether NK cells contribute to or control RA. In RA, there is low numbers of NK cells active in the blood but increased NK activity in the synovial fluid . Therapeutically, blocking inhibitory NKG2A pathways are thought to have an enhanced RA response and blocking RANKL and M-CSF is thought to control RA.|
|Systemic Lupus Erythmatosus (SLE):||NK cells have a disease controlling function such as in SLE. In SLE, there are lowered levels of NK cell activity, increased CD56(bright) and lowered perforin levels. Therapeutic adoptive NK cell transfer can aid in disease control .|
Rheumatoid arthritis (RA) is a chronic, inflammatory, systemic, autoimmune disease that leads to progressive joint disease degeneration and functional disability, including the risk of cardiovascular diseases. 
The killing activity of NK cell is shown to have significantly decreased in patients with RA compared to healthy controls through a study. Lytic units produced by NK cells from RA patients are also proven to be significantly lesser than the lytic units produced by NK cells from the healthy controls, presenting the impairment of NK activity in RA patients. The percentage of NKG2D (surface molecule that could activate NK cells) were also found to significantly decrease in RA patient, whereas percentage of CD244, CD2, and CD16 (other surface molecules that could also activate NK cells) expressions were similar to healthy control group. The mean fluorescent intensity of CD244 and CD16 expression however, significantly decreased in RA patients in comparison to healthy control group. Results suggested the impaired NK cell activity could be due to a result of low CD16 expression in RA patients, along with the low expression of NKG2D and CD244 as well. IL-6 (serum cytokine level) however might be one of the causes to the decreased NK cell number, resulting in the low NK activity in RA patients, as suggested in this study. 
On the other hand, high proportion of CD3-CD56+NKp44+ NK cells (NKp44+NK cells), CD56bright NK cells subset have been detected in RA patients. These cells partake in tissue-protection and proinflammatory role by overexpressing interleukin 22 (IL-22), which has already been identified on fibroblast-like synoviocytes (FLS) in patients with RA. Previous studies have also showed a subset of NKp44+NK cells, NK-22 cells, with a significantly greater proportion in patients with RA; and these cells were found to play a role in pathogenesis of RA. Futhermore, IL-22 is an IL-10 family cytokine member produced by several different cellular sources including Th17, Th22, and NKp44+NK cells. It plays a critical role in the inflammation and proliferation cascade of various autoimmune disease like RA, primary Sjogren syndrome, and psoriasis. In RA, this study confirmed that NKp44+NK cells could secrete high concentrations of IL-22 when compared with NK cells.
Ikeuchi et al have reported that IL-22, produced by synovial fibroblasts and macrophages, is also expressed as a proinflammatory cytokine which promotes inflammatory responses through the expression of IL-22 receptor 1 on FLS in patients with RA.  Ren et al have also partially reported that NKp44+NK cells play the role of synovial proliferation and inflammation in RA. 
In conclusion, STAT3 is found to be an essential pathway in mediating the effects of IL-22 secreted by NKp44+NK cells on the proliferation of FLS in patients with RA.
NK cells are potent cytotoxic effector cells for cancer therapy and potentially for severe viral infections. One of the studies proved that NK cells can provide effective immunotherapy for ovarian cancer cells through evaluating the ability of NK cells isolated from peripheral blood (PB) and NK cells derived from induced pluripotent stem cell (iPSC) to mediate killing of ovarian cancer cells in a mouse xenograft model.
This study has also previously proved and demonstrated that iPSC-NK cells are effective against leukemia and HIV infection. Since NK cells are not human leukocyte antigen (HLA) restricted, NK cells derived from iPSCs can be used as an allogenic "off-the-shell" immunotherapy for the treatment of cancer.
This study found that using aAPC (artificial antigen presenting cells) expanded PB-NK cells or iPSC-derived NK cells is superior to the use of CD3/CD19 (T cells and B cells) depleted aphresis cell product. The pure (>97%) NK cell populations provided a better overall tumor reduction in vivo. It is also possible to achieve higher doses of NK cells, and the administration of multiple doses, proving that the cells could be banked to provide more immediate treatment options.
Viral infection such as herpes simplex virus-1, influenza virus or the ectromelia poxvirus, can be controlled by NK cells. Perhaps, the best documented evidence showing the important role of NK cells in viral pathogenesis is in the case of the herpesvirus MCMV, also known as cytomegalovirus (CMV). In hosts where NK cells were depleted, there is greater susceptibility to CMV. Defects in NK cell activity which lead to decreased production of IFN-γ and which lead to increased cytotoxicity also increased susceptibility to CMV infection. 
Allergic asthma is a chronic inflammatory disease that is associated with airway obstruction, inflammation and hyperactivity and inflammation. So far no study has yet evaluated the kinetics and migratory behavior of NK cells in allergic asthma. However, Ple et al demonstrated that NK cells were involved in the regulation of lung eosinophilia in OVA-induced airway allergic reaction.  NK cells have also been showed to play a pro-inflammatory role in the development of allergic disease, regulate the progress of airway eosinophilia and the production of TH2 cytokine. 
Type 1 Diabetes
Type 1 diabetes is an autoimmune disease where insulin-producing pancreatic β-cells are being destroyed by T-cell in the body, resulting in little or no insulin production that is vital for converting glucose into energy.
NKp46 is one of the primary activating receptors of NK cells, involving in the development of type 1 diabetes (T1D). A study has successfully shows that the treatment of mice with NCR1.15, a monoclonal antibodies (mAb) which specifically recognizes recombinant mouse NKp46 (mNKp46), reduces NKp46 membrane-associated expression by NK cells. 
The use of NCR1.15 treatment in the study did not reduce the fraction of NK cells in the blood or in the spleen and NKG2D-mediated function of NK cells were not affected as well. This proves that the use of targeted immunotherapy involving treatment with antibodies to activate immune cellular receptors and immune molecules can be used for the treatment and maybe cure of autoimmune and inflammatory diseases.
On another study, NK cells from type 1 diabetes subjects were found to be reduced in cell numbers compared with age-matched, nondiabetic control subjects and had diminished responses to the interleukin (IL)-2 and IL-15. NK cells from type 1 diabetic subjects were also found failed to downregulate activating NK cell receptor (NKG2D) ligands.
Systemic Lupus Erythematosus
Systemic Lupus Erythematosus (SLE) is a multisystem autoimmune rheumatic disorder where the immune system starts mistakenly attacking body's own tissues and organ causing inflammation and damage. It is more prevalent in women of childbearing age compare to children, adolescents and men, with unknown cause associated with genetic, environmental and infections. 
Two studies found out that both the total number of NK cells and the percentage of lymphocytes in peripheral blood were reduced significantly in SLE patients in both active and inactive disease compared to controls. However, the proportions of CD56(bright) NK cells and CD56(dim) NK cells were unaffected.   NK cells from patients with active SLE also have the potential to produce huge amounts of interferon-γ (IFN-γ) and serum IFNγ, indicating the possible successful idea on the development of immunotherapeutic strategies based on anti-IFNγ treatment in patients with active SLE. 
Severe Aplastic Anemia
Severe aplastic anaemia (SAA) is a rare and potentially life threatening autoimmune disease caused by bone marrow failure, where it is unable to produce sufficient blood cells for the body. Natural Killer (NK) cells are lymphocytes that play an important role in the pathogenesis of autoimmune disease, which host defence against malignancies, viruses and allogenic cells. They either kill target cells directly or encourage production of cytokines and chemokines. A study also showed that the percentage of NK cells and its subsets in peripheral blood lymphocytes was decreased in SAA patients, but increased dramatically after immunosuppresive therapy (IST). However, the ratio of NK cells increased and restored to normal levels in patients after intensive immunosuppressive therapy (IIST), suggesting the involvement NK cells in the processess of SAA. A postulation was stated, that the function of DC and T cells were failed to be suppressed may due to the lower numbers of NK cells. This study also showed that the median expression of NKp46 on NK cells of newly diagnosed SAA patients was higher than that of healthy individuals. Similar, the expression of perforin in newly diagnosed SAA patients was also higher than of controls. The expression of CD158b and the median expression of granzyme B in NK cells however, had no statistical difference between two groups. Thus, the high expression of NKp46 and perforin on the NK cells from these patients might be the cause of hematopoiesis failure in SAA. NK cells were also thought to be more protective than harmful to SAA patients. 
Schistosomiasis japonica is a parasitic disease, caused by the infection with human schistosomes (trematode flatworms). During infection, the deposition of its eggs can lead to immunopathological reactions such as granuloma and fibrosis formation, which are the main contributors to the host lesions.  By using mice that are infected with Schistosoma japonicum , a certain study aim to investigate the charactheristics of NK cells in affected mice. The result showed no significant different in NK cell percentages between the normal and infected groups but NK cell numbers significantly increased after infection. It is found that NK cells from C57BL/6 mouse spleens were activated and produced more specific cytokines like IL-2, IL-4, IL-10 and IL-17 and less IFN- γ during the host defense process against S.japonicum infection. 
NK cells have a role in innate immunity; specifically their critical involvement in the viral infection, murine cytomegalovirus. NK cells and their receptors were initially classified according to tumor killing ability in vitro, however, the NK cell activation receptor, Ly-49H is also involved in providing innate immunity against murine cytomegalovirus. Ly-49H couples with immunoreceptor tyrosine-based activation motifs (ITAMs) which contains the transmembrane molecule required for signal transduction. So, NK cells use receptors with functional resemblance to the ITAM-coupled T and B cell antigen receptors that are involved in innate host defence. 
Recently, there has been much research on the role of NK cells in multiple myeloma (MM). There is a suggested role for NK cells in MM since the IL-2–primed peripheral blood mononuclear cells (PBMCs) treated with thalidomide (Thal) and thalidomide analogue, immunomodulatory drugs (IMiDs) demonstrated significantly increased lysis of MM cells. Inhibition assays revealed that NK-cell mediating killing was responsible for all cell lysis in MM; more critical than LAK-cell mediated killing, previously thought. This suggests that modulation of NK cell numbers may be important in MM and possibly other angiogenic disorders. 
There is also a suspected role of NK cells in human HLA haplotype-mismatched haematopoietic stem cell transplantation. Specifically, the roles of the three major NK alleles; HLA-C group 1, HLA-C group 2, and HLA-Bw4. A recent study has revealed that out of 60 donor recipient pairs, a prediction of 20 donor recipient pairs would cause graft versus host (GVH)/graft versus leukemia (GVL) reactions. There was an absence of GVH disease, however, there were high frequencies of NK clones detected which killed recipient’s target cells. These same NK clones also killed allogeneic leukemia. Hence, GVL effectors may be operational in HLA mismatched haematopoietic cell transplants. 
NK cell activation is controlled by a dynamic balance of promotive and inhibitory pathways, both of which are initiated when potential target cells are identified. Activating cell surface receptors on NK cells can lead to cytokine or chemokine secretion. Some cell surface receptors on NK cells initiate protein tyrosine kinase (PTK) -dependent pathways coupled with transmembrane signalling adaptors consisting of ITAMs. There are also additional cell surface receptors that are not directly coupled with ITAMs but also contribute to NK cell activation. Such molecules include NKG2D, integrins and cytokine receptors. NK cells also express cell surface inhibitory receptors that have an inhibitory effect on activating pathways. This inhibitory effect is achieved via protein tyrosine phosphatases (PTPs). The dynamic nature of NK signalling must be understood to better manipulate NK cell effector signaling pathways in future research. 
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