Role of Natural Killer Cells in the Innate Immune System

The immune system is a complex mechanism in charge of protecting the body from pathogens and other foreign substances. It has two main components: the innate and adaptive immune systems.

The innate immune system is the first line of defense against pathogens and comprises various cells, including natural killer (NK) cells. In this article, we will discuss the role of NK cells in the innate immune system.

What Are Natural Killer Cells?

NK cells are a type of lymphocyte, a white blood cell involved in the immune response. They were first discovered in the 1970s and were initially thought to be a type of cytotoxic T cell. However, further research revealed that they are a distinct cell type with unique functions.

NK cells are called “natural killer” cells because they do not require prior activation to recognize and kill infected or cancerous cells. Unlike T cells, which require the recognition of specific antigens presented by major histocompatibility complex (MHC) molecules on the surface of infected or cancerous cells, NK cells use a variety of receptors to identify and kill abnormal cells.

NK Cell Receptors

Natural killer cells express various receptors that allow them to recognize and respond to infection.

One of the most important receptors on NK cells is the killer immunoglobulin-like receptor (KIR). KIRs recognize MHC class I molecules on the surface of normal cells and inhibit NK cell activation. However, when infected or cancerous cells downregulate MHC class I expression, they become susceptible to NK cell-mediated killing.

NK cells also express various activating receptors, which are triggered by stress-induced ligands on the surface of infected cells. One of the most important activating receptors on NK cells is NKG2D, which recognizes stress-induced ligands such as MICA/B and ULBP1-6.

NK Cell Functions

When an NK recognizes an abnormal cell, it releases cytotoxic granules containing perforin and granzymes. Perforin creates pores in the target cell membrane, allowing granzymes to enter and induce apoptosis or programmed cell death.

Natural killer cells also produce cytokine signaling molecules that modulate the immune response. One of these is interferon-gamma (IFN-γ), which activates macrophages and enhances their ability to phagocytose (engulf and digest) pathogens.

Finally, NK cells are involved in the regulation of the adaptive immune response. They can interact with dendritic cells (DCs), specialized antigen-presenting cells critical in initiating the adaptive immune response. NK cells can enhance DC maturation and antigen presentation, leading to the activation of T cells.

NK Cells and Cancer

Cancer cells often downregulate MHC class I expression to escape recognition by cytotoxic T cells. However, this makes them susceptible to NK cell-mediated killing, as NK cells use a variety of receptors to identify and kill cells that lack MHC class I expression.

Studies have shown that NK cells are essential in controlling viral infections. For example, individuals with a genetic deficiency in NK cell function are more susceptible to viral diseases such as hepatitis C and HIV. Additionally, studies have shown that high levels of NK cell activation are associated with improved outcomes in viral infections such as hepatitis B and C.

NK Cells and Autoimmunity

While NK cells are critical to the immune response to infections and cancer, they also have a dark side.

Sometimes the immune system attacks healthy tissues and cells. This is what we refer to as an autoimmune response. NK cells have been shown to contribute to the development of multiple sclerosis, rheumatoid arthritis, and other autoimmune diseases.

NK cells can interact with other immune cells, such as T and B cells, modulating the adaptive immune response. In autoimmune diseases, NK cells can promote the activation of T and B cells, leading to the production of autoantibodies and tissue damage.

However, not all autoimmune diseases are driven by NK cells, and their role in autoimmune diseases is complex and context-dependent.


Natural killer cells are an essential component of the innate immune system. They are involved in recognizing and eliminating infected and cancerous cells, producing cytokines, and regulating the adaptive immune response.

Further research is needed to fully understand the complex role of NK cells in health and disease and to develop novel therapies targeting NK cells for the treatment of various conditions.