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Basics Of The Natural Killer Cell

What are Natural Killer Cells?

Natural Killer (NK) cells are a type of innate white blood cell capable of mediating immune-surveillance and killing ‘non-self’ cells, such as viral infected cells and tumor-transformed cells. They are named ‘natural killers’ as they do not require activation to kill cells and can identify missing ‘self’ markers, the MHC class 1, found on harmful cells. This role is especially important because other immune white blood cells, such as T-cells, are unable to detect the missing MHC class 1 marker. NK cells utilize a large family of various inhibitory and activating receptors that balance cell signals to decide whether they are encountering friend or foe and can activate antibody and T-cell adaptive immune responses.


Super-resolution microscopy images of an inactive (right) and an active (left) NK cell [1]


Attacking a tumour cell [2]


Aggressive destruction of non-tumour cells [3]

NK cells develop from common lymphoid progenitor cells primarily in the bone marrow and are primed to become self-tolerant by recognition of self MHC class I molecules. Mature NK cells migrate to the liver, uterus, thymus, and peripheral lymphoid organs where they give rise to tissue-specific, functionally distinct mature NK cell subsets. NK cells constitute 10% to 30% of mononuclear cells in blood and lymphoid organs.

NK cells express a large number of receptors that deliver either activating or inhibitory signals, and the relative balance of these signals control NK cell activity


Receptor families on the NK cells involved in cell identification and immune system mediation

Known NK Anti-tumor Receptors

As innate immune cells, NK cells are unique and play pivotal functions in cancer immune surveillance. NK cells can eliminate a variety of abnormal or stressed cells without prior sensitization, while maintaining tolerance to normal cells.


Receptor-ligand interactions between the NK cell and tumour cell. Tumour cells are recognised by NK cells through high ligand expression for the activating receptors of NK cells and low expression for its inhibitory receptors. [4]

Note: KIR genes display an extraordinary level of polymorphism. [5]

Anti-Cancer Stem Cell Capability

NK cells have long been known for their ability to reject allogenic hematopoietic stem cells, and there is increasing data demonstrating that NK cells can selectively identify and kill cancer stem cells.

Cancer stem cells (CSCs) are a subpopulation of tumor cells that have renewal ability and can differentiate into several distinct lineages. CSCs play a crucial role in the initiation and the maintenance of cancer. A single neoplasm stem cell makes a wide variation of neoplasm cells to form a large size tumor and can survive radiation and anti-cancer drugs. [6, 7]

3 Main killing trigger methods

NK cells are activated following the detection of abnormalities in target cells such as the loss of MHC class I expression or up-regulation of stress-induced ligands that occurs in response to infection or malignant transformation.

1. Killing by granule-dependent killing

a) Triggered by synthesizing various inhibitory and activating receptors to determine if they are encountering friend or foe


Types of receptors present on target cell determine if the NK cell is activated

When NK cells are activated through the interactions between the NK and tumor cells, they release cytotoxic granules containing enzymes such as perforin and granzymes. Perforin creates small pores in the target cell to create a channel by changing the osmotic pressure of target cells, through which granzymes are transferred into the cell and induce cell death by apoptosis.

b) Triggered by antibody-dependent cell-mediated cytotoxicity 

Target cells are killed by antibody-dependent cell-mediated cytotoxicity (ADCC). This is the   process of targeted NK cell killing target cells with IgG as the intermediate bridge. NK cells can recognize tumor cells that specifically bind to IgG antibodies through surface CD16 molecules, and CD16 interacts with corresponding adaptor proteins containing "immunoreceptor tyrosine activation motifs" in NK cells to phosphorylate adaptor proteins, thereby initiating intracellular signaling, activating NK cells to release perforin and granzymes to kill target cells.


2. Killing by death receptor-induced apoptosis

Another process by which NK cells mediate killing of target cells involves the activation of death receptors of the tumor necrosis factor receptor (TNFR) superfamily that are expressed on the target cells. Apoptosis is induced when the two most prominent apoptosis-inducing TNFR family members, Fas (CD95) and TNF-related apoptosis-inducing ligand-receptor (TRAIL-R) on target cells bind with their respective ligands, Fas ligand (FasL) and TRAIL, that can be present on NK cell surface or secreted by NK-derived exosomes.


3. Killing by activating the adaptive immune system (e.g. T cells)

In addition to the direct killing effect of NK cells themselves on tumor cells, activated NK cells can secrete a variety of cytokines, such as TNF, IFN, etc., which synergistically inhibit or kill tumor cells.


Early Response Time

While studies have shown that the decrease in the number of NK cells in mice renders them more susceptible to infection to several types of viruses, the opposite has been proven in humans, where NK cells are able to control virus burden prior to adaptive immune response. Furthermore, a low NK cell count increased the rate of progression and recurrence towards a particular immunodeficiency syndrome.

Note: NK cells do not play a role in all types of viral infections.


Days following influenza infection [8]

Comparing NK cell cytotoxicity and the immune response to influenza infection in young and aged mice, the graph shows a decrease in influenza-induced NK cell cytotoxicity in aged mice (dashed line) precedes an early and prolonged virus titer in lung and a reduced and delayed cytotoxic T lymphocyte (CTL) response, as compared to young mice (solid line), confirming the effects of the NK cell in immune response to infections. [9]



1. Killing Cancer From the Inside by Kathryn Largue, Daniel M. Davis (download)

2. The Natural Killer Cell: A Historical Perspective and the Use of Supplements to Enhance NKC Activity by Jerry T. Thornthwaite, Hare Shah, Pashupati Shah, Henry Respess (download)

3. Advances in Cancer Detection - My Discovery of the Natural Killer Cell by Jerry T. Thornthwaite, Ph.D. (download)

4. NK cells sense tumors, course of disease and treatments by Giulia Fregni,Aurélie Perier,Marie-Françoise Avril &Anne Caignard (download)

5. Killer Ig-Like Receptors (KIRs): Their Role in NK Cell Modulation and Developments Leading to Their Clinical Exploitation by Daniela Pende, Michela Falco, Massimo Vitale, Claudia Cantoni, Chiara Vitale, Enrico Munari, Alice Bertaina, Francesca Moretta, Genny Del Zotto, Gabriella Pietra, Maria Cristina Mingari, Franco Locatelli and Lorenzo Moretta (download)

6. Osteosarcoma: Cells-of-Origin, Cancer Stem Cells, and Targeted Therapies by Ander Abarrategi, Juan Tornin, Lucia Martinez-Cruzado, Ashley Hamilton, Enrique Martinez-Campos, Juan P. Rodrigo, M. Victoria González, Nicola Baldini, Javier Garcia-Castro, and Rene Rodriguez (download)

7. Targeting Cancer Stem Cells with Natural Killer Cell Immunotherapy by Jesus I. Luna, Steven K. Grossenbacher, William J. Murphy & Robert J. Canter (download)

8. Nutritional modulation of the innate immune response to influenza infection by Barry W. Ritz (download)

9. Fundamental Immunology by William E. Paul, M.D. (download)

Additional Supplementary Information

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