A natural killer cell, usually abbreviated NK cell, is a lymphocyte of the immune system that can kill susceptible infected or malignant cells without prior antigen-specific sensitization. NK cells belong principally to innate immunity, but they also interact with adaptive immune responses and can acquire memory-like properties. Their activity depends on the combined signals from activating and inhibitory receptors, rather than on indiscriminate recognition of anything foreign. They also secrete signaling molecules that influence other immune cells. (pmc.ncbi.nlm.nih.gov)
Identity and development
NK cells are a type of white blood cell. Conventional human NK cells are commonly identified as CD3-negative, CD56-positive lymphocytes: they lack the CD3 complex associated with the T-cell receptor and express the surface marker CD56. This definition is useful but not absolute, because some NK populations have little or no CD56, while other lymphocyte populations can express it. Identification therefore depends on combinations of markers and biological context. (pmc.ncbi.nlm.nih.gov)
Unlike T cells and B cells, NK cells do not generate their characteristic recognition receptors through V(D)J recombination. Their receptors are encoded in the inherited genome, although receptor expression varies substantially among individual NK cells. They are distinct from natural killer T cells, which belong to the T-cell lineage despite sharing some NK-associated markers. (pmc.ncbi.nlm.nih.gov)
NK cells arise from hematopoietic stem cells. Their development involves the bone marrow and other tissues, including secondary lymphoid organs. Interleukin-15 is particularly important for their development, survival, and maintenance. NK cells occur in blood and in numerous organs, where local environments influence their phenotype and function. (pmc.ncbi.nlm.nih.gov)
Recognition of target cells
NK-cell recognition is governed by a balance of receptor signals. Inhibitory receptors help protect healthy cells, while activating receptors detect molecules associated with cellular stress, infection, or transformation. Neither a single activating marker nor the absence of one inhibitory signal invariably determines the outcome. (pmc.ncbi.nlm.nih.gov)
Missing-self recognition describes sensitivity to reduced expression of major histocompatibility complex class I molecules, or MHC I. Many healthy cells express MHC I, which engages inhibitory NK-cell receptors. In humans, these include inhibitory killer-cell immunoglobulin-like receptors, or KIRs, and CD94–NKG2A. When a target loses relevant MHC I molecules, inhibition can diminish, making the cell more vulnerable if sufficient activating signals are present. (pmc.ncbi.nlm.nih.gov)
This mechanism complements cytotoxic T-cell recognition. Some infected or malignant cells reduce MHC I expression and thereby evade T cells that recognize peptide–MHC complexes; the same change can increase their susceptibility to NK cells. However, missing self is not sufficient by itself to guarantee killing. (pmc.ncbi.nlm.nih.gov)
Activating receptors include NKG2D and the natural cytotoxicity receptors NKp30, NKp44, and NKp46. These receptors recognize particular ligands, including molecules whose expression can increase during cellular stress. Different receptor combinations allow NK cells to respond to diverse targets without requiring a unique antigen-specific receptor for each one. (pmc.ncbi.nlm.nih.gov)
Education and self-tolerance
NK cells undergo functional tuning commonly called education or licensing. Interactions between inhibitory receptors and an individual's own MHC I molecules influence how strongly an NK cell subsequently responds to stimulation. Cells possessing appropriate self-recognizing inhibitory receptors generally show greater responsiveness in missing-self assays. (pmc.ncbi.nlm.nih.gov)
NK cells lacking such receptor–ligand interactions are not necessarily autoreactive. They often respond less strongly to activating-receptor stimulation, although inflammatory signals can increase their responsiveness. Education therefore links functional competence with immune tolerance; it is not simply a permanent permission to kill. (pmc.ncbi.nlm.nih.gov)
Effector mechanisms
NK cells kill targets mainly by releasing cytotoxic granules at the contact site between the two cells. These granules contain perforin, which facilitates delivery of granzymes, enzymes that activate intracellular death pathways. The target commonly undergoes apoptosis, or regulated cell death. NK cells can also engage death receptors through molecules such as Fas ligand and TRAIL. (pmc.ncbi.nlm.nih.gov)
A second important mechanism is antibody-dependent cellular cytotoxicity, or ADCC. The NK-cell receptor CD16 recognizes the Fc region of immunoglobulin G attached to a target. Receptor engagement can trigger killing of the antibody-coated cell. This connects NK-cell effector activity with the specificity supplied by an antibody response. (pmc.ncbi.nlm.nih.gov)
NK cells also produce cytokines, particularly interferon-γ, and chemokines that influence recruitment and activation of other immune cells. Their functions therefore extend beyond direct cytotoxicity to coordination of immune responses. (pmc.ncbi.nlm.nih.gov)
Major populations
Two broad populations are commonly distinguished in human peripheral blood:
- CD56-dim NK cells constitute approximately 90% of circulating NK cells. They usually express substantial CD16 and have strong immediate cytotoxic capacity.
- CD56-bright NK cells are less numerous in blood and typically express little or no CD16. They are particularly responsive to cytokine stimulation and can produce abundant immunoregulatory cytokines.
These are tendencies, not exclusive functions: CD56-dim cells also produce cytokines, and activated CD56-bright cells can become cytotoxic. (pmc.ncbi.nlm.nih.gov)
The blood-based division does not capture all tissue diversity. For example, single-cell analysis of the early human maternal–fetal interface identified three major decidual NK-cell populations with different receptor, chemokine, and immunomodulatory profiles. These cells participate in specialized interactions with placental and maternal tissues rather than behaving simply as circulating killer cells relocated to the uterus. (nature.com)
Memory-like responses
Although NK cells are classified as innate lymphocytes, previous stimulation can alter their later responses. In mouse experiments, brief cytokine activation produced cells that retained enhanced interferon-γ responses after transfer and subsequent restimulation. Related experiments demonstrated cytokine-induced memory-like behavior in human NK cells. (pmc.ncbi.nlm.nih.gov)
Such findings broaden the concept of immunological memory, but do not make NK-cell memory identical to classical adaptive immunity. Cytokine-induced memory-like responses need not depend on recognition of a particular antigen, and different experimental forms of NK-cell memory involve different mechanisms. (pmc.ncbi.nlm.nih.gov)
Discovery
Experiments in the early 1970s revealed that lymphocytes from animals or people without prior exposure to particular tumors could nevertheless kill certain tumor-cell targets. In 1975, Rolf Kiessling and colleagues introduced the name “natural killer” for this activity and its associated lymphocyte population. Ronald Herberman's group independently reported closely related findings that year. Later work established receptor-mediated recognition, missing-self responses, and the distinction between NK cells and antigen-specific cytotoxic T cells. (pmc.ncbi.nlm.nih.gov)
Research and clinical significance
NK cells are studied for their roles in defense against viruses and cancer. Rare deficiencies affecting NK-cell numbers or function are associated particularly with susceptibility to certain viral infections, including herpesvirus infections. (pmc.ncbi.nlm.nih.gov)
Their cytotoxicity also provides a basis for experimental cancer immunotherapy. Approaches include transferring NK cells and engineering them to express chimeric antigen receptors, or CARs. A phase 1–2 study published in 2020 treated 11 patients with CD19-positive lymphoid malignancies using cord-blood-derived CAR-NK cells; eight patients responded. No cytokine release syndrome, neurotoxicity, or graft-versus-host disease was observed in that cohort. The small study did not establish universal safety or efficacy, and additional treatments given after response limited assessment of response durability attributable to CAR-NK cells alone. (nejm.org)
References
- NK cell biology: An update and future directionspmc.ncbi.nlm.nih.gov
- Human natural killer cells: form, function, and developmentpmc.ncbi.nlm.nih.gov
- Deciphering Natural Killer Cell Homeostasispmc.ncbi.nlm.nih.gov
- Human natural killer cellspmc.ncbi.nlm.nih.gov
- Natural killer cell regulation - beyond the receptorspmc.ncbi.nlm.nih.gov
- Single-cell reconstruction of the early maternal–fetal interface in humansnature.com
- Cytokine-induced memory-like natural killer cellspmc.ncbi.nlm.nih.gov
- Cytokine activation induces human memory-like NK cellspmc.ncbi.nlm.nih.gov
- Five decades of natural killer cell discoverypmc.ncbi.nlm.nih.gov
- Natural Killer Activity: Early Days, Advances, and Seminal Observationspmc.ncbi.nlm.nih.gov