Natural killer (NK) cells 

What is a Natural killer (NK) cell? Large granular lymphocytes are the morphological description of natural killer (NK) cells. These cells are...

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This article writter by MN Editors on October 22, 2022

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Natural killer (NK) cells 
Natural killer (NK) cells 

What is a Natural killer (NK) cell?

  • Large granular lymphocytes are the morphological description of natural killer (NK) cells. These cells are referred to as natural killer cells due to their capacity to eliminate certain virally infected and tumour cells without prior sensitization.
  • Their actions are not improved by exposure and are not virus-specific.
  • 5–10% of peripheral lymphocytes are NK cells, which are located in the spleen and peripheral circulation.
  • NK cells originate in the bone marrow and lack TCR, but have killer activation receptors and killer inhibition receptors.
  • In addition, they possess NK T cells, a subpopulation of T cells that shares some functional properties with NK cells.
  • In contrast to NK cells, these NK T cells are triggered by lipids, glycolipids, and hydrophobic peptides provided by a nonclassical class I molecule CD1D, and they produce significant quantities of cytokines, particularly IL-4.
  • NK cells are primarily responsible for eliminating virus-infected cells and malignancies. They accomplish this via secreting cytotoxins such as perforins and granzymes comparable to those of cytotoxic T cells, as well as by FasL-mediated apoptosis.
  • They eliminate viruses without the presence of particular antibodies through a process known as ADCC. IL-12 and gamma interferons are both powerful NK cell activators.

Properties of natural killer cells

  • Large lymphocytes with granular structures.
  • Lack T-cell receptor, CD3 proteins, surface IgM and IgD, and surface IgM and IgD.
  • Prior exposure has no effect on the level of activity.
  • Thymus is not necessary for growth.
  • In a case of severe combined immunodeficiency, the number remains normal.

NK Cells and T Cells Share Some Features

  • NK cells are lymphoid cells generated from bone marrow that have a common early progenitor with T cells; however, their precise lineage is still being determined. They express membrane markers that are characteristic of monocytes and granulocytes, as well as T-cell-specific markers.
  • NK cells express distinct sets of membrane-bound chemicals. It is unknown whether this variability reflects subpopulations of NK cells or distinct activation or maturation stages of these cells.
  • CD2, the 75-kDa subunit of the IL-2 receptor, is one of the membrane molecules expressed by NK cells. Almost all NK cells also express CD16 (or FcRIII), a receptor for the Fc portion of IgG.
  • Anti-CD16 monoclonal antibody depletion eliminates nearly all NK-cell activity in peripheral blood.
  • Although NK cells share characteristics with T lymphocytes, they do not develop primarily in the thymus. The NK-cell populations of nude mice, which lack a thymus and have few or no T cells, are functioning. Unlike T and B cells, NK cells do not undergo receptor gene rearrangement. This is evidenced by the development of NK cells in mice in which the recombinase genes RAG-1 or RAG-2 have been deleted.
  • In addition, while SCID mice lack T and B cells, functioning populations of NK cells can be readily demonstrated.
  • The capacity of NK cells and other innate immune defence systems to defend animals devoid of adaptive immunity.

Structure of Natural Killer (NK) Cells

  • Natural killer cells are big, granular lymphocytes generated from bone marrow. The cytoplasm of the cell contains azurophilic granules containing hydrolytic and digesting enzymes.
  • NK cells are bigger in diameter than other lymphocytes of a similar kind. These lymphocytes lack the receptors seen on T and B cells.
  • The Wright-Giemsa stain reveals the presence of these cells, which account for around 5% of peripheral circulating lymphocytes.
  • Natural Killer cells exist in a variety of morphologies and display microvilli, particularly in the region of contact between effector and target.
  • These cells have granules with two separate compartments. The outer compartment contains trumetaphosphatase and lysosome-associated phosphatase acid enzymes.
  • The inner compartment is composed of structural components and is devoid of enzyme activity.
  • During degranulation, a specific region of the cytoplasm creates numerous vacuole-like regions made up of granules and granular debris.
  • Additionally, the cytoplasm contains organelles such as mitochondria and polysomes.
  • Against thick granules and pseudopodia, the nucleus is twisted with unique polarity.
  • Different activating and inhibiting receptors that detect distinct membrane proteins are located on the surface of natural killer cells.

Natural killer (NK) cell receptors

  • NK cell receptors can also be distinguished according on their function. Natural cytotoxicity receptors trigger apoptosis (cell death) instantly after attaching to Fas ligands, which signify infection of a cell.
  • The MHC-independent receptors (explained above) trigger apoptosis in infected cells via an alternative mechanism.
  • The activation of natural killer cells is determined by the relative stimulation of inhibitory and activating receptors. If the inhibitory receptor signalling is more predominant, for example, NK cell activity will be repressed; if the activating signal is more apparent, NK cell activity will be activated.
  • NK cell receptor types (including inhibitory and some activating members) are distinguished by their structures, as illustrated by the following examples:

Activating receptors

  • Ly49 (homodimers), receptors belonging to the rather old C-type lectin family, are multigenic in mice, whereas humans have only one pseudogenic Ly49, the receptor for classical (polymorphic) MHC I molecules.
  • Upon stimulation, NCR (natural cytotoxicity receptors), which are type 1 transmembrane proteins of the immunoglobulin superfamily, induce NK death and IFN release. They bind viral ligands such as hemagglutinins and hemagglutinin neuraminidases, as well as certain bacterial ligands and cellular ligands associated with tumour formation, such as PCNA.
  • In particular, CD16 (FcIIIA) plays a role in antibody-dependent cell-mediated cytotoxicity by binding immunoglobulin G.

Inhibitory receptors

  • KIRs are the primary receptors for both classical MHC I (HLA-A, HLA-B, and HLA-C) and nonclassical Mamu-G (HLA-G) in nonhuman primates. Certain KIRs are unique to particular HLA subtypes. Most KIRs are dominant and inhibitory. Regular cells express MHC class 1, so KIR receptors recognise them and block NK cell destruction.
  • CD94/NKG2 (heterodimers), a receptor belonging to the C-type lectin family, is conserved in both rodents and primates and recognises nonclassical (also nonpolymorphic) MHC I molecules, such as HLA-E. Expression of HLA-E at the cell surface is dependent on the presence of a nonamer peptide epitope derived from the signal sequence of classical MHC class I molecules, which is produced sequentially by signal peptide peptidase and the proteasome. This is an indirect method for assessing the amounts of classical (polymorphic) HLA molecules.
  • ILT and LIR (immunoglobulin-like receptor) are newly found Ig receptor family members.
  • There are both activating and inhibiting isoforms of Ly49 homodimers. Although they are physically unrelated to KIRs, they are functional homologues of KIRs in mice, including their expression pattern. Ly49s are receptors for polymorphic (classical) MHC I molecules.

Recognition of Infected and Stressed Cells by NK Cells

Distinguish infected and stressed cells

  • NK cells discriminate infected and stressed cells from healthy cells, and NK cell activation is regulated by a balance of activating and inhibiting receptor signals.
  • Multiple families of these receptors exist. These receptors identify chemicals on the surface of other cells and provide activating or inhibiting signals that stimulate or suppress NK responses, respectively.
  • In general, activating receptors identify ligands on infected and damaged cells, whereas inhibitory receptors identify healthy normal cells.
  • The outcome of an interaction between an NK cell and another cell is controlled by the integration of signals created by the NK cell’s array of inhibitory and activating receptors, which interact with ligands on the other cell.
  • Due to the stochastic nature of their production, the spectrum of activating and inhibiting receptors expressed by various NK cells in a given individual is quite diverse.
  • Consequently, an individual’s NK cells will react to various types of bacteria or infected cells.
  • In addition, the genes encoding the majority of these receptors are polymorphic, meaning that there are multiple variants of the genes in the population, so that each individual expresses a slightly different form of the receptors.

Expression of inhibitory receptors

  • The majority of natural killer (NK) cells carry inhibitory receptors that detect class I major histocompatibility complex (MHC) molecules, which are ordinarily found on the cell surface of virtually all healthy cells in the body.
  • In addition to their involvement in regulating NK cell activation, class I MHC molecules show on the cell surface peptides originating from cytoplasmic proteins, including microbial proteins, for identification by CD8+ T lymphocytes.
  • For the time being, it is essential to realise that NK cells and T cells use fundamentally different types of receptors to recognise class I MHC molecules. In contrast to T cells, the majority of NK receptors for class I MHC suppress NK activation.
  • This is advantageous because normal cells express class I MHC molecules, but many viruses and other causes of cell stress inhibit class I MHC expression on the cell surface.
  • Consequently, NK cells perceive the presence of class I MHC molecules as indicators of a normal, healthy self, whereas their absence indicates infection or harm.
  • Infected or stressed cells will not transmit inhibitory signals to NK cells. NK cells are also likely to receive activating signals via activating receptors from the same infected cells.
  • In the end, the NK cell will be activated to emit cytokines and kill the infected or stressed cell. This capacity of NK cells to become activated by host cells lacking class I MHC is referred to as “recognition of missing self.”
Functions of activating and inhibitory receptors of NK cells
Functions of activating and inhibitory receptors of NK cells – A, NK activating receptors identify ligands on target cells and activate protein tyrosine kinase (PTK), the activity of which is regulated by inhibitory receptors that recognise class I MHC molecules and activate protein tyrosine phosphatases (PTP). NK cells cannot effectively eliminate healthy cells expressing class I MHC. B. If a virus infection or other stress inhibits class I MHC expression on infected cells and induces the expression of additional activating ligands, the NK cell inhibitory receptor is not activated and the activating receptor functions unopposed to trigger NK cell responses, such as killing of target cells and cytokine secretion. C. Cells stressed by infection or neoplastic transformation may express higher levels of activating ligands, which bind NK cell activating receptors and stimulate more tyrosine phosphorylation than can be eliminated by inhibitory receptor related phosphatases, leading in cell death. The structural characteristics and ligands of inhibiting and activating NK cell receptors.

Immunoreceptor tyrosine-based inhibition motif (ITIM)

  • Immunoreceptor tyrosine-based inhibition motif (ITIM) is a structural motif in the cytoplasmic tails of NK cell inhibitory receptors that interacts with substances that impede the signalling pathways of activating receptors.
  • ITIMs contain phosphorylated tyrosine residues upon ligand interaction to the inhibitory receptor. This results in the recruitment and activation of phosphatases, which remove phosphates from a number of signalling proteins or lipids produced by signalling pathways downstream of NK activating receptors.
  • In the end, the signalling functions of activating receptors are inhibited. ITIMs are located in the cytoplasmic tails of receptors other than NK inhibitory receptors.
  • The main group of NK inhibitory receptors is composed of killer cell immunoglobulin-like receptors (KIRs), which are immunoglobulin (Ig) superfamily members.
  • Antibody (also known as Ig) molecules were the first to possess a structural domain called an Ig fold, which is shared by all members of this family. KIRs bind diverse molecules of class I MHC.
  • As noted previously, a second major group of NK inhibitory receptors belongs to the C-type lectin family, which contains proteins with carbohydrate-binding capabilities.
  • One of these receptors is the heterodimer CD94/NKG2A, which detects the HLA-E molecule of class I MHC. Intriguingly, HLA-E shows peptides generated from other class I MHC molecules, so CD94/NKG2A is essentially a surveillance receptor for numerous class I MHC molecules.
  • Leukocyte Ig-like receptors (LIRs), a third family of NK inhibitory receptors, are likewise Ig superfamily members that bind class I MHC molecules, albeit with lesser affinity than the KIRs, and are more abundantly expressed on B cells than NK cells.
Structure and ligands of activating and inhibitory receptors of NK cells
Structure and ligands of activating and inhibitory receptors of NK cells – Examples of inhibitory and activating NK cell receptors and their ligands. CD16 and the natural cytotoxic receptors (NCRs) associate with ζ chain homodimers, FcεRIγ homodimers, or ζ-FcεRIγ heterodimers. There are multiple different KIRs, with varying ligand specificities.

Recognition of a heterogeneous group of ligands

  • Activating receptors on NK cells identify a heterogeneous array of ligands, some of which may be expressed on normal cells and others of which are produced primarily on stressed, infected, or altered cells.
  • For several of these receptors, the molecular characteristics of the ligands are inadequately defined.
  • The enhanced expression of ligands on unhealthy cells that bind to activating receptors on NK cells may result in signals that overwhelm the signals from inhibitory receptors, particularly if class I MHC is also diminished or absent from the unhealthy cell.

Promote target cell killing and cytokine secretion

  • The majority of activating NK receptors share a structural motif in their cytoplasmic tails known as an immunoreceptor tyrosine-based activation motif (ITAM) that engages in signalling processes that boost target cell death and cytokine production.
  • In some of these receptors, the ITAM as well as the extracellular ligand-binding region are included on a single polypeptide chain.
  • In other receptors, such as FcεRIγ, ζ,, and DAP12, the ITAMs are in distinct polypeptide chains that do not bind ligand but are noncovalently connected with the ligand-binding chain.
  • ITAMs are also found in the cytoplasmic tails of other multichain immunological signalling receptors, such as the antigen receptors on T and B cells.
  • After ligand attachment to NK cell activating receptors, cytoplasmic kinases phosphorylate tyrosine residues inside the ITAMs, other protein kinases are attracted to the changed ITAMs and activated, and these kinases contribute to further signalling by phosphorylating other proteins.
  • As previously noted, numerous NK cell activating receptors are members of the C-type lectin or KIR families, which also contain inhibitory receptors. Some of the activating receptors appear to bind class I MHC molecules, similar to the inhibitory receptors, although it is unknown how infected or injured cells selectively activate these receptors.

How NK Cells Kill infected cells and phagocytosed microbes?

  • NK cells have the effector activities of destroying infected cells and activating macrophages to eliminate phagocytosed microorganisms.
  • The NK cell–mediated cytotoxic mechanism is largely identical to that of CD8+ CTLs.
  • Similar to CTLs, NK cells contain granules carrying substances that facilitate the death of target cells. Granule exocytosis releases these proteins near to the target cells when NK cells are activated.
  • Perforin, a granule protein of NK cells, enhances the entry of granzymes, another granule protein, into the cytoplasm of target cells. Granzymes are enzymes that trigger a series of signalling events that result in the apoptotic death of target cells.
  • The signalling pathways responsible for apoptosis. By destroying infected viral and intracellular bacterial cells, NK cells eradicate infection reservoirs.
  • Some cancers, particularly those of hematopoietic origin, are targets for natural killer (NK) cells, possibly because tumour cells do not exhibit typical quantities or types of class I MHC molecules.
  • Similarly to IFN- produced by T cells, IFN- produced by NK cells activates macrophages and enhances their ability to destroy phagocytosed bacteria.
  • IFN- generated by NK cells in lymph nodes can also direct naive T cells to differentiate into TH1 cells.
  • NK cells play various critical roles in defence against intracellular pathogens. They eliminate virally infected cells before antigen-specific CTLs may become completely active, i.e., within the initial few days of viral infection.
  • Early in the course of a viral infection, IL-12 and IL-15 stimulate the expansion and activation of NK cells, which then destroy infected cells, particularly those with diminished amounts of class I MHC molecules.
  • Moreover, NK cell-secreted IFN-γ stimulates macrophages to kill phagocytosed microorganisms. This IFN-γ–dependent NK cell–macrophage response can control an intracellular bacterial infection, such as Listeria monocytogenes, for several days or weeks, allowing T cell–mediated immunity to develop and remove the infection.
  • NK cell depletion increases vulnerability to infection by some viruses and intracellular microorganisms. In the absence of T cell–mediated immunity, the NK cell response of T-cell-deficient mice may be adequate to control infection with such microorganisms for a time, but the animals eventually perish.
  • By eliminating infected cells that have evaded CTL-mediated immune attack by lowering production of class I MHC molecules, NK cells may also play a crucial role later in the body’s response to infection.
  • Because NK cells are capable of killing specific tumour cells in vitro, it has been hypothesised that they also serve to eliminate malignant clones in vivo.
Functions of NK cells.
Functions of NK cells – A, NK cells identify ligands on infected or otherwise stressed cells and eliminate the host cells. NK cells remove infectious reservoirs and defective cells in this manner. B, in response to IL-12 generated by macrophages, NK cells emit IFN-γ, which activates macrophages to destroy phagocytosed microorganisms.


  • Eliminate both virus-infected and cancerous cells.
  • The indiscriminate destruction of virus-infected and cancerous cells.
  • The killing process is unrelated to antigen presentation by MHC proteins.
  • The target cell is killed by perforins and granzymes, which induce apoptosis.
  • Killing is triggered when a cell fails to deliver antigen with class I MHC or when class I MHC proteins are reduced on the cell surface.

Natural killer (NK) cells Summary

  • Immunologists found natural killer cells by accident while assessing the in vitro activity of tumor-specific cells isolated from animals with tumours.
  • Mice that had not been inoculated and mice with unrelated tumours served as negative controls.
  • To the investigators’ consternation, the controls also demonstrated considerable tumour cell lysis. Characterization revealed that a population of big granular lymphocytes was responsible for this nonspecific tumour cell death.
  • The cells, dubbed natural killer (NK) cells due to their nonspecific cytotoxicity, account for 5–10% of the recirculating lymphocyte population.
  • These cells contribute to the immune system’s defence against viruses and malignancies. Due to the fact that NK cells produce a variety of immunologically significant cytokines, they play crucial functions in immune regulation and have a significant impact on both innate and adaptive immunity.
  • Specifically, IFN-γ production by NK cells can influence macrophage participation in innate immunity by stimulating phagocytic and microbicidal activities.
  • IFN-γ generated from NK cells can affect the TH1 vs TH2 commitment of helper T cell populations by inhibiting TH2 expansion and stimulating TH1 development via macrophage and dendritic cell production of IL-12.
  • The Chediak-Higashi syndrome described in the Clinical Focus exemplifies the catastrophic effects of an NK cell deficiency.
  • NK cells participate in the first immune response to some viruses and intracellular bacteria. IFN-, IFN-, and IL-12 each promote NK activity.
  • In the course of a viral infection, the concentration of these cytokines increases rapidly, followed by a wave of NK cells that reaches its peak in around three days.
  • NK cells are the initial line of defence against virus infection, limiting viral replication for approximately 7 days while CTL-P cells undergo activation, proliferation, and differentiation into functional CTLs.
  • A young woman who was completely devoid of NK cells exemplifies the significance of these cells in the fight against viral infections. Despite having normal T- and B-cell counts, this patient suffered from severe varicella virus and life-threatening CMV infections.


Where Are Natural Killer Cells Found?

Natural killer cells are sentinels of the immune system that patrol the body in search of contaminated and malignant cells. Consequently, NK cells are ubiquitous and present in the majority of human organs. The largest quantities are found in the bloodstream, the uterus, the lungs, and the liver.

From where NK cells are Originated?

Stem cells in the bone marrow, lymph nodes, spleen, or tonsils differentiate into natural killer cells. 5 to 20% of circulating white blood cells in the human body are mature NK cells.


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  • Addou-Klouche, L. (2017). NK Cells in Cancer Immunotherapy. In  (Ed.), Natural Killer Cells. IntechOpen.
  • Hu W, Wang G, Huang D, Sui M, Xu Y. Cancer Immunotherapy Based on Natural Killer Cells: Current Progress and New Opportunities. Front Immunol. 2019 May 31;10:1205. doi: 10.3389/fimmu.2019.01205. PMID: 31214177; PMCID: PMC6554437.
  • Vivier, E., Tomasello, E., Baratin, M. et al. Functions of natural killer cells. Nat Immunol 9, 503–510 (2008).
  • Abel, A. M., Yang, C., Thakar, M. S., & Malarkannan, S. (2018). Natural Killer Cells: Development, Maturation, and Clinical Utilization. Frontiers in Immunology, 9. doi:10.3389/fimmu.2018.01869 
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  • Cichocki, Frank & Miller, Jeffrey & Anderson, Stephen & Bryceson, Yenan. (2013). Epigenetic regulation of NK cell differentiation and effector functions. Frontiers in immunology. 4. 55. 10.3389/fimmu.2013.00055. 
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