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 growing group of innate lymphoid cells. In humans, they make up 5–20% of all circulating lymphocytes. Their function is similar to that of cytotoxic T cells in the adaptive immune response, but with a key difference: NK cells react quickly to virus-infected cells, stressed cells, tumor cells, and other intracellular pathogens by using signals from both activating and inhibitory receptors. While cytotoxic T cells need to detect antigens presented on MHC class I molecules to activate, NK cells recognize and destroy stressed cells that lack these MHC class I markers. They earned the name "natural killers" because they do not require prior activation to kill cells that are missing these "self" markers. This ability is crucial because harmful cells without MHC class I cannot be targeted by other immune cells, like T lymphocytes.

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 come from the same 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 terms of phenotype, origin, and function; NKT cells often boost NK cell activity by releasing interferon gamma. Unlike NKT cells, NK cells lack T-cell antigen receptors, the pan T marker CD3, and surface immunoglobulins (B cell receptors). Instead, they typically express CD16 (FcγRIII) and CD57 in humans, and NK1.1 or NK1.2 in certain mouse strains. The NKp46 surface marker is also commonly used to identify NK cells in humans, several mouse strains, and three monkey species.

Beyond innate immunity, NK cell receptors—both activating and inhibitory—help maintain self-tolerance and sustain NK cell activity. NK cells also contribute to adaptive immunity; experiments show they can adapt to their environment and form antigen-specific immunological memory, which is important for responding to secondary infections with the same antigen. This dual role in innate and adaptive immunity is increasingly relevant in research on NK cell-based therapies for cancer and HIV.

In early experiments on cell-mediated cytotoxicity against tumor cells, both in cancer patients and animal models, researchers noticed a "natural" reactivity—certain cells could destroy tumor cells without prior sensitization. The first published study suggesting that untreated lymphoid cells could provide natural immunity to tumors came from Dr. Henry Smith at the University of Leeds School of Medicine in 1966, who concluded 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 the idea of a distinct cell lineage responsible for it emerged. The discovery that a unique type of lymphocyte was behind this spontaneous cytotoxicity came in the early 1970s from doctoral student Rolf Kiessling and postdoctoral fellow Hugh Pross in mice, and from Hugh Pross and doctoral student Mikael Jondal in humans. The mouse and human work was supervised by professors Eva Klein and Hans Wigzell, respectively, at the Karolinska Institute in Stockholm. Kiessling’s research focused on how T lymphocytes attack tumor cells they had been immunized against, while Pross and Jondal studied cell-mediated cytotoxicity in normal human blood and the effects of removing receptor-bearing cells. Later that year, Ronald Herberman published similar findings on the unique nature of the mouse effector cell.

Human data were largely confirmed by West and colleagues using similar methods and the K562 erythroleukemic target cell line, which is highly sensitive to human NK cell lysis. Over the decades, the K562 chromium-release assay became the standard test for measuring human NK activity, allowing easy comparison of results across laboratories worldwide.

Using discontinuous density centrifugation and later monoclonal antibodies, natural killing activity was traced to the subset of large, granular lymphocytes now known as NK cells. In 1980, Timonen and Saksela demonstrated that density gradient-isolated large granular lymphocytes were responsible for human NK activity, marking the first microscopic visualization of NK cells and a major breakthrough in the field.

Natural killer cells are classified as either CD56bright or CD56dim. CD56bright NK cells act similarly to T helper cells by releasing cytokines. CD56bright NK cells make up the majority of NK cells.