Natural killer cell

Natural killer cells, or NK cells, are a type of cytotoxic lymphocyte that plays a key role in the innate immune system. They are classified as large granular lymphocytes and belong to the broader family of innate lymphoid cells. In humans, NK cells make up 5–20% of all circulating lymphocytes. Their function is similar to that of cytotoxic T cells in the adaptive immune response, but they act more quickly. NK cells respond to virus-infected cells, stressed cells, tumor cells, and other intracellular pathogens by using signals from both activating and inhibitory receptors. Unlike cytotoxic T cells, which require antigen presentation on MHC class I molecules to activate, NK cells can recognize and kill stressed cells that lack these MHC class I markers. This ability is crucial because cells missing MHC class I cannot be detected by T cells. The name "natural killers" comes from the idea that they do not need prior activation to destroy cells that lack these "self" markers.

NK cells are identified by the presence of CD56 and the absence of CD3 (CD56+, CD3−). They develop from CD127+ common innate lymphoid progenitors, which themselves come from the common lymphoid progenitor that also gives rise to B and T lymphocytes. NK cells mature in the bone marrow, lymph nodes, spleen, tonsils, and thymus before entering the bloodstream. They are distinct from natural killer T cells (NKT cells) in phenotype, origin, and function; NKT cells often boost NK cell activity by secreting interferon gamma. Unlike NKT cells, NK cells do not have T-cell antigen receptors, the pan T marker CD3, or surface immunoglobulins (B cell receptors). Instead, they typically express surface markers such as CD16 (FcγRIII) and CD57 in humans, and NK1.1 or NK1.2 in C57BL/6 mice. The NKp46 marker is also commonly used to identify NK cells in humans, several mouse strains (including BALB/c mice), and three monkey species.

Beyond innate immunity, NK cell receptors—both activating and inhibitory—are important for self-tolerance and maintaining NK cell activity. NK cells also contribute to the adaptive immune response; experiments have shown they can adapt to their environment and form antigen-specific immunological memory, which is key for responding to secondary infections with the same antigen. This dual role in innate and adaptive immunity is increasingly studied for potential cancer and HIV therapies.

**Early history** Early experiments on cell-mediated cytotoxicity against tumor cells, in both cancer patients and animal models, revealed a "natural" reactivity—cells that could destroy tumor cells without prior sensitization. The first published study suggesting that untreated lymphoid cells could provide natural immunity to tumors was by Dr. Henry Smith at the University of Leeds School of Medicine in 1966, concluding that this phenomenon appeared to be a defense mechanism against tumor growth in normal mice. Similar observations were made by others, but because they contradicted the established model, many initially dismissed them as artifacts. By 1973, natural killing activity had been confirmed across many species, and a separate lineage of cells responsible for it was proposed. The discovery that a unique lymphocyte type was behind this natural cytotoxicity came in the early 1970s: doctoral student Rolf Kiessling and postdoctoral fellow Hugh Pross worked in mice, while Pross and doctoral student Mikael Jondal worked in humans, under the supervision of professors Eva Klein and Hans Wigzell at the Karolinska Institute in Stockholm. Kiessling’s research focused on T lymphocytes attacking tumor cells they had been immunized against, while Pross and Jondal studied cell-mediated cytotoxicity in normal human blood and the effect of removing receptor-bearing cells. Later that year, Ronald Herberman published similar data on the unique nature of the mouse effector cell. Human data were largely confirmed by West et al. using similar techniques and the K562 erythroleukemic target cell line, which is highly sensitive to human NK cells. The K562 chromium-release assay became the standard test for human NK function, allowing easy comparison of data across laboratories. Using discontinuous density centrifugation and later monoclonal antibodies, natural killing was traced to the subset of large, granular lymphocytes now known as NK cells. In 1980, Timonen and Saksela demonstrated that these density gradient-isolated large granular lymphocytes were responsible for human NK activity, marking the first microscopic visualization of NK cells and a major breakthrough.

**Types** NK cells are classified as CD56bright or CD56dim. CD56bright NK cells resemble T helper cells in that they exert influence by releasing cytokines. They make up the majority of NK cells.