Natural Killer (NK) cells are a type of lymphocyte that functions within the innate immune system, representing one of the body’s first lines of defense. These cells circulate throughout the body, acting as sentinels that can rapidly identify and respond to various threats like cancerous or virus-infected cells.
Unlike the adaptive immune system, which requires time to build a specific response, NK cells are primed for immediate action. They can recognize stressed cells without prior exposure or activation, a feature that led to their name as “natural killers.” This capability allows them to control infections and malignancies before a more tailored immune defense can be mounted.
Identifying NK Cell Subsets with Surface Markers
To distinguish between different types of immune cells, scientists use proteins on the cell surface known as surface markers. These markers function like cellular identification cards, with each combination of proteins indicating a specific cell type and its potential role.
The most widely used nomenclature for these proteins is the Cluster of Differentiation (CD) system. Each unique surface protein is assigned a CD number, allowing for precise identification using a technique called flow cytometry. This technology uses lasers and fluorescent antibodies that bind to specific CD markers, enabling researchers to count and sort cells based on their unique protein signatures.
Within the family of NK cells, two surface markers are important for classification: CD56 and CD16. The relative amount of each of these proteins on an NK cell’s surface—whether it is high or low—is the primary determinant for categorizing the major NK cell populations in human blood. This distinction directly corresponds to the specialized functions each subset performs.
The Two Primary Human NK Cell Subsets
The majority of NK cells in human peripheral blood can be divided into two groups based on the expression of CD56 and CD16 markers. The most common subset, making up about 90% of all NK cells in circulation, is defined by low expression of CD56 and high expression of CD16. This population is referred to as CD56dim CD16bright, where “dim” signifies low protein levels and “bright” indicates high levels.
Conversely, the second major subset is characterized by high expression of CD56 and low to nonexistent levels of CD16, earning it the designation CD56bright CD16dim/-. This group is less common in the blood, making up only about 10% of the circulating NK cell population. Instead, these cells are found in greater numbers within secondary lymphoid organs like the tonsils, lymph nodes, and spleen. These cells are thought to be precursors to the more mature CD56dim cells.
Distinct Functions of Primary Subsets
The differences in surface marker expression between the two NK cell subsets directly correlate with their specialized functions. The CD56dim CD16bright cells are the principal cytotoxic effectors of the NK cell family. Their high concentration of the CD16 receptor is central to their ability to kill target cells through a process called Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC). In ADCC, antibodies coat a target cell, and the CD16 receptor on the NK cell binds to these antibodies, triggering a lethal attack.
Upon activation, CD56dim cells release cytotoxic granules containing proteins like perforin and granzymes. Perforin creates pores in the target cell’s membrane, allowing granzymes to enter and initiate programmed cell death, or apoptosis.
In contrast, the CD56bright CD16dim/- subset excels in a different capacity, acting as prolific producers of cytokines. These cells are poor killers due to their low levels of the CD16 receptor and smaller quantities of cytotoxic granules. Cytokines are signaling proteins that orchestrate the broader immune response by communicating with and activating other immune cells.
Upon activation, CD56bright cells release a powerful array of cytokines, most notably interferon-gamma (IFN-γ). IFN-γ enhances the activity of other immune players, like macrophages and dendritic cells, and helps shape the subsequent adaptive immune response.
Specialized NK Cells in Tissues and Memory
Beyond the two main subsets circulating in the blood, the body hosts specialized NK cells residing within specific tissues. These tissue-resident NK cells possess unique characteristics tailored to the microenvironment of the organs they inhabit, such as the liver, skin, uterus, and lungs. Their functions often differ from their blood-borne counterparts.
A prominent example is in the uterus, where a unique population of uterine NK cells is important for a successful pregnancy. Rather than focusing on killing, these cells play a developmental role, helping to remodel maternal arteries to ensure an adequate blood supply to the fetus.
Researchers have also identified NK cells that exhibit features of immunological memory, a trait once thought to be exclusive to the adaptive immune system. These “adaptive” or “memory” NK cells can “remember” a previous encounter with a pathogen, such as a virus. Upon re-exposure, they mount a more robust and rapid response than standard NK cells, challenging the traditional boundaries between innate and adaptive immunity.