Natural Killer Cells: Characteristics and Functions

Natural Killer cells are a type of lymphocyte linked to the body's innate immunity. They destroy cancer cells and pathogens through a process called cytolysis.

Written and verified by el biólogo Samuel Antonio Sánchez Amador.

Last update: 14 March, 2021

Natural Killer (NK) cells are one of the types of lymphocytes, along with the B and T varieties, that spontaneously kill tumor cells and cell bodies infected by different pathogens. Due to their nature, they are essential components of the body’s innate immune system.

Unlike macrophages and other leukocytes, these cells don’t engulf pathogens; they eliminate them by attacking their membrane and causing a process called cytolysis. If you want to know everything about the characteristics and functions of NK cells, read on.

The immune system and its importance

Starting to talk about the peculiarities of NK cells without first describing the immune system in terms of functionality and components is like starting to build a house starting with the roof. For this reason, we’ll start this article off by discovering some basic knowledge about the subject.

The immune system is defined as a set of biological elements and processes that allow the body to maintain internal balance against 3 threats: pathogens (viruses, bacteria, fungi, and protozoa), harmful physical-chemical elements (toxins, poisons), and dangerous internal processes (cancer, for example).

This complex system includes cells, proteins, tissues, and organs. The function is complex, but, at the same time, very clear: to defend the body from external threats and from itself. We’re now going to tell you briefly about the two types of immunity present in human beings.

Innate immunity

As indicated in the Las Condes Clinical Medical Journal, the innate immune system is the host’s first line of defense. It comprises a series of pre-existing processes that are activated quickly and efficiently, but with very limited specificity. Within this category, we find both cells and biological barriers.

Something as innocuous as mucous membranes, saliva, sweat, and even external epithelia (such as the skin) are the innate immune barriers that prevent most attacks in the first place. These fluids, in addition to other properties, have defensins, lysozymes, special fatty acids, and other compounds that prevent the proliferation of pathogens.

Within this group, we also have leukocytes (white blood cells), such as neutrophils, macrophages, and Natural Killer cells – the ones we’ll be focusing on in this article. We’ll see their particular characteristics later on in this article.

Adaptive immunity

According to the Elsevier Connect medical portal, adaptive immunity arises in response to an infection, and then adapts to it – it’s highly specific to the life of the individual. Its main properties are the following:

1. Specificity and diversity: Acquired responses are specific for different antigens (substances produced by the pathogen that are recognized by antibodies).
2. Memory: Exposure of the immune system to a certain antigen helps its future response times to be faster and more effective. Memory lymphocytes are the main ones responsible for this.
3. Tolerance to self: Except for some pathologies, the adaptive immune system doesn’t attack the host’s vital cell bodies.

Within this group, we find the most representative cells of the immune system: B and T lymphocytes. Two types of response also differ – cellular and humoral – whose characteristics we’ll leave for another occasion.

More related than you might think

Although the innate and acquired immune systems are often thought of as two different elements, this isn’t the case at all. This classification is only didactic, since both systems work together for 2 main reasons:

1. The innate immune system activates the acquired immune system in response to infections.
2. The acquired immune system uses the effector mechanisms of innate immunity to eliminate pathogenic microorganisms from the body.

Where do Natural Killer cells fall?

This extensive explanation and review of the immune system is essential, as Natural Killer (NK) cells are one of the main figures of innate immunity. This cell type can be defined as a variety of lymphocytes produced in the bone marrow, whose function is mediated by the production of cytokines (regulatory proteins) and a cytotoxic activity.

They’re found in certain elements of the lymphatic system (lymphoid nodes) and blood, but can also be seen in the lungs, liver, and uterus. Next, we’ll see a series of peculiarities that characterize them.

An anatomy similar to that of a large lymphocyte

As indicated by medical documents, NK cells represent between 7 and 15% of all circulating leukocytes in the blood. Their anatomy is defined as that of a large and granular lymphocyte, as they have a large number of cytoplasmic granules of a secretory and lytic nature, which help them to destroy cells.

They’re a particular type of lymphocyte, as they don’t have BCR membrane receptors (typical of B lymphocytes) or TCR receptors (analog in T lymphocytes). The membrane proteins that characterize NKs are CD16 and CD56, whose proportion or presence varies according to the cell subpopulation.

NK cell functions

According to the Medical Journal of Chile, the main function of NK cells is cytotoxic in nature and linked to the secretion of cytokines. We’ll now quickly and simply break down each of these tasks.

Cytotoxic function

Cytotoxicity is defined as the quality of certain cells to be toxic compared to other ones that are altered. NK cells exert this capacity on different cell types, such as tumor cells, those infected or transformed by viruses, and those affected by bacteria etc. This function is divided into two types.

1. Natural cytotoxicity

The NK cell doesn’t require prior activation in order to act. This type of activity is independent of the typical antigenic recognition of B and T lymphocytes and, in turn, of the antibodies or immunoglobulins circulating in the blood. For this reason, NKs are part of the first cellular barriers to infection.

2. Antibody-mediated cytotoxicity

This variant is known as antibody-dependent cell-mediated cytotoxicity (ADDC). The lymphocytes included here are capable of attacking pathogenic cell bodies, but these must first be marked by specific immunoglobulins, that is to say, antibodies.

We aren’t going to dwell too much on complex terminology, as it’s enough for us to know the following: the CD16 and CD56 membrane proteins of NK cells adhere to a fraction of the antibody, which is bound to the antigen (which is part of the infectious agent). As a result, the NK interprets that this foreign element is dangerous and destroys it.

Mechanism of cytotoxicity

Once the pathogenic potential has been recognized, NK cells release granzymes and perforins, protein substances whose function is to form pores in the cell membrane of the harmful microorganism and induce its cell death. Osmotic lysis and caspase activation are some of the mechanisms carried out by these protein substances.

All these effects cause the pathogenic cell to lose its osmotic balance, thus causing it to die quickly and effectively.

Cytokine secretion

To understand this function, it’s enough for us to know that NK cells secrete a series of proteins and cytokines, essential for cell communication and the inflammatory response, among other processes.

As indicated by the Mi Sistema Inmune portal, some of the cytokines secreted by this cell type are tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), and granulocyte and monocyte colony-stimulating factor (GM-CSF). These substances are essential for the differentiation and proliferation of various cells of the immune system.

Inhibition and activation

These “programmed to kill” cells must be highly regulated, as the body can’t allow them to attack healthy cells. According to the British Society for Immunology, this is why they have a series of activation and inhibition receptors. They consist of the following:

1. Strong inhibition: Healthy cells have a sufficient concentration of MHC I molecules (major histocompatibility complexes) in order to inactivate the NK cell lysis process. They are, therefore, protected against its attack.
2. Reduced inhibition: Tumor or virus-infected cells usually reduce their number of surface MHC I molecules. They’re unable to emit a powerful inactivation signal, so the NKs interpret them as threats and destroy them.
3. Strong activation: In addition to having fewer MHC I molecules, infected cells show various ligands that are recognizable by NKs. These incite them to act quickly and skillfully, destroying the threat.

Natural Killer cells in medicine

Understanding the role of Natural Killer cells in cancer processes and other diseases is a very complex issue. In part, this is because the mechanisms that encode their natural cytotoxicity haven’t yet been discovered. It’s clear that they’re essential cells for our well-being but they also seem to have a negative potential.

According to the Medisur portal, the long-term activation of NK cells could favor the appearance of certain types of cancer. Studies cited in this portal show that, for example, women who had more inhibitory than activating signals with respect to NK were less likely to suffer from cervical cancer.

This type of neoplasm is associated with infection with the human papillomavirus (HPV). As NK cells continually fight the pathogen, their responses to local inflammation and tissue destruction could favor the development of the cancer itself.

Although these results should be taken with extreme caution, they underline the double meaning of many of our immune mechanisms. In most cases, they’re a source of salvation, but, on rare occasions, the remedy could be worse than the disease.

Summary

As you may have seen, NK cells represent a type of lymphocyte outside of the norm. They’re essential for the immune response and, in many cases, act without prior antibody-mediated activation. This is a true rarity in the world of highly specialized white blood cells.

While much is known about these curious cell types, we still have a lot to learn about them. Perhaps, with knowledge and perseverance, we can use the cytotoxic characteristics of NKs to put an end to such dangerous diseases as cancer, once and for all.