Natural killer cell

Natural killer (NK) cells form part of the innate immune system. Their function involves the recognition and destruction of tumour and virally infected cells.

Function
The majority of lymphocytes, a leucocyte subgroup, are B or T cells but approximately 15% of the lymphocyte population lack B or T cell receptors; these are NK cells. The latter develop in the bone marrow and have a half-life of approximately 7 days. Most NK cells are found in the blood, spleen or liver and enter tissues at sites of inflammation following infection. There are two NK cell subgroups dependent on the expression of either CD16 (FcγRIII) or CD56 cell surface receptors.

NK cells play a major role in eliminating virally infected cells. Following infection, viruses block cell synthesis of major histocompatibility complex class I (MHCI) molecules. Presentation of MHC class I molecules at an infected cell’s surface is used by cytotoxic T cells (Tc cells) to target and destroy the cell. By preventing MHC class I presentation, viruses ensure the cell is unrecognised and escapes elimination by Tc cells: this is where NK cells prove vitally important in the body’s immune response. NK cells express specialised receptors – killer inhibitory receptors (KIRs), which can identify MHC class I molecules. Following recognition of the MHC class I molecule, the KIR inhibits NK cell cytotoxic activity and destruction of the target. Virally infected cells, lacking the surface expression of MHC class I molecules, can be targeted and eliminated by NK cells.

NK cells can also target virally infected cells via expression of the IgG receptor CD16. This receptor binds antibodies attached to viral molecules on infected cell surfaces in a process called antibody-dependent cell mediated cytotoxicity (ADCC).

NK Cell Cytotoxic Mechanisms

NK cells can terminate an infected cell via several mechanisms including:

•	Direct cell-to-cell contact

•	Cytokine synthesis and release

As LGLs, NK cells utilise their granular structure to kill infected cells. On fusing with virally infected cells’ plasma membranes, granules release their contents into the cell. These contents include the protein perforin, which perforates the infected cell's membrane, enabling entry of specialized ‘suicide’ enzymes, including granzyme B, into the virally infected cell; these initiate apoptosis (programmed cell death). Granzymes can also damage the infected cell directly and play a vital role in virally infected cell destruction. Apoptosis can also be triggered via the attachment of Fas ligands (FasL) on the NK cell surface to Fas proteins on the target cell, activating apoptosis-inducing signalling.

NK cells express two receptor types:

•	Activating

•	Inhibitory

Activating receptors induce NK cells to eliminate infected cells, while inhibitory receptors block killing mechanisms. Resting NK cells synthesize cytokines and are capable of destroying virally infected cells but activated NK cells produce higher numbers of cytokines and are more efficient at eliminating infected cells.

Factors Leading to NK cell Activation

Several elements can produce NK cell activation, including:

•	The detection of lipopolysaccharide (LPS, a bacterial cell wall constituent)

•	The release of various cytokines, e.g. IFN-α and IFN-β, when cells are infected with viruses

LPS is bound by NK cell surface receptors, inducing responses including IFN-γ synthesis, which can prepare macrophages for activation. Following activation, macrophages synthesize TNF (tumour necrosis factor), which binds a macrophage’s own surface receptors. This initiates IL-12 (interleukin-12) activation. The combination of TNF and IL-12 expression induces increased NK cell synthesis of IFN-γ leading to more macrophage priming, an example of an enhanced immune response via a positive feedback loop. TNF synthesis by macrophages also upregulates IL-2 expression on NK cell surfaces, NK cells respond to their own IL-2 synthesis and undergo rapid division.

Evidence
Numerous studies of Chronic Fatigue Syndrome have found evidence of reduced natural killer cell function. Some studies have showed natural killer cell function correlates with illness severity. One study found increased differentiation in NK cells. Inconsistency in laboratory preparation and analysis have made it difficult to compare results between laboratories or use NK function as a consistent biomarker.

Probiotics
Some probiotics have been shown to increase NK function, including Lactobacillus rhamnosus HN001, Bifidobacterium lactis HN019 and Lactobacillus casei Shirota

AHCC
In animal models, Active Hexose Correlated Compound (AHCC) has been show to increase NK activity. Other studies have found no significant increase in NK function.

Stress
There is evidence in humans and animal models that psychological stress and physical stress, for example surgery,  decreases NK function and promotes tumor development and metastasis. Mindfulness based meditation or stress reduction may increase natural killer cell function.

Smoking
Smoking decreases natural killer cell function.

Notable studies

 * 2016, MicroRNAs hsa-miR-99b, hsa-miR-330, hsa-miR-126 and hsa-miR-30c: Potential Diagnostic Biomarkers in Natural Killer (NK) Cells of Patients with Chronic Fatigue Syndrome (CFS)/ Myalgic Encephalomyelitis (ME)

Learn more

 * Wikipedia - Natural killer cell
 * Crash Course - The Immune System Part 1
 * 2016, Immune cell 'switch' discovery raises hopes in cancer fight