They were named "natural killers" because of the notion that they do not require activation to kill cells that are missing "self" markers of MHC class I.

[6][7] NK cells are known to differentiate and mature in the bone marrow, lymph nodes, spleen, tonsils, and thymus, where they then enter into the circulation.

NK cells also play a role in the adaptive immune response:[11] numerous experiments have demonstrated their ability to readily adjust to the immediate environment and formulate antigen-specific immunological memory, fundamental for responding to secondary infections with the same antigen.

The first published study to assert that untreated lymphoid cells were able to confer a natural immunity to tumors was performed by Dr. Henry Smith at the University of Leeds School of Medicine in 1966,[15] leading to the conclusion that the "phenomenon appear[ed] to be an expression of defense mechanisms to tumor growth present in normal mice."

[16] By 1973, 'natural killing' activity was established across a wide variety of species, and the existence of a separate lineage of cells possessing this ability was postulated.

The discovery that a unique type of lymphocyte was responsible for "natural" or spontaneous cytotoxicity was made in the early 1970s by doctoral student Rolf Kiessling and postdoctoral fellow Hugh Pross, in the mouse,[17] and by Hugh Pross and doctoral student Mikael Jondal in the human.

[18][19] The mouse and human work was carried out under the supervision of professors Eva Klein and Hans Wigzell, respectively, of the Karolinska Institute, Stockholm.

Later that same year, Ronald Herberman published similar data with respect to the unique nature of the mouse effector cell.

[20] The human data were confirmed, for the most part, by West et al.[21] using similar techniques and the same erythroleukemic target cell line, K562.

Using discontinuous density centrifugation, and later monoclonal antibodies, natural killing ability was mapped to the subset of large, granular lymphocytes known today as NK cells.

IFNγ activates macrophages for phagocytosis and lysis, and TNFα acts to promote direct NK tumor cell killing.

Patients deficient in NK cells prove to be highly susceptible to early phases of herpes virus infection.

This mode of NK cell target interaction is known as "missing-self recognition", a term coined by Klas Kärre and co-workers in the late 90s.

A number of cytokines are produced by NKs, including tumor necrosis factor α (TNFα), IFNγ, and interleukin (IL-10).

[28] NKG2D is a disulfide-linked homodimer which recognizes a number of ligands, including ULBP and MICA, which are typically expressed on tumor cells.

The role of dendritic cell—NK cell interface in immunobiology have been studied and defined as critical for the comprehension of the complex immune system.

[36] For example, in patients with Parkinson's disease, levels of Natural killer cells are elevated as they degrade alpha-synuclein aggregates, destroy senescent neurons, and attenuate the neuroinflammation by leukocytes in the central nervous system.

Such expansions were observed primarily in response to human cytomegalovirus (HCMV),[41] but also in other infections including Hantavirus, Chikungunya virus, HIV, or viral hepatitis.

Notably, recent research suggests that adaptive NK cells can use the activating receptor NKG2C (KLRC2) to directly bind to human cytomegalovirus-derived peptide antigens and respond to peptide recognition with activation, expansion, and differentiation,[43] a mechanism of responding to virus infections that was previously only known for T cells of the adaptive immune system.

[44] For example, IFN-γ dilates and thins the walls of maternal spiral arteries to enhance blood flow to the implantation site.

In addition, prostate cancer tumors can evade CD8 cell recognition due to their ability to downregulate expression of MHC class 1 molecules.

Two additional key components were added: 1) a high-affinity, non-cleavable Fc receptor CD16 (hnCD16) that enables tumor targeting and enhanced antibody-dependent cell cytotoxicity without negative regulation, combined with 2) a therapeutic monoclonal antibody targeting tumor cells and an IL-15/IL-15 receptor fusion protein (IL-15RF) promoting cytokine-independent persistence.

[56] Clinical studies have shown NK-92 cells to be safe and to exhibit anti-tumor activity in patients with lung or pancreatic cancer, melanoma, and lymphoma.

[74][66] PD-L1 targeted high affinity NK cells have been given to a number of patients with solid tumors in a phase I/II study, which is underway.

In a transplantation model of LMP1-fueled lymphomas, the NKG2D-Fc fusion proved capable of reducing tumor growth and prolonging survival of the recipients.

This indicates that the stimulation of TLR-8 and subsequent activation of inflammasome enhances the CD-16 mediated ADCC reaction in patients treated with cetuximab antibody.

[81] Recent research suggests specific KIR-MHC class I gene interactions might control innate genetic resistance to certain viral infections, including HIV and its consequent development of AIDS.

This is evident because patients expressing these HLA alleles are observed to have lower viral loads and a more gradual decline in CD4+ T cells numbers.

Despite considerable research and data collected measuring the genetic correlation of HLA alleles and KIR allotypes, a firm conclusion has not yet been drawn as to what combination provides decreased HIV and AIDS susceptibility.

[86][87] Tissue-resident NK cells have also been identified in sites like bone marrow, spleen and more recently, in lung, intestines and lymph nodes.