Natural killer cell

Lore & Background

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, and by Hugh Pross and doctoral student Mikael Jondal in the human. The mouse and human work was carried out under the supervision of professors Eva Klein and Hans Wigzell, respectively, of the Karolinska Institute, Stockholm. 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.

Reader's Guide

Natural killer cells are significant as a critical component of the innate immune system, providing rapid responses to virus-infected cells, stressed cells, tumor cells, and other intracellular pathogens. Their ability to recognize and kill cells lacking MHC class I molecules fills a crucial gap in immune surveillance, as such harmful cells cannot be detected by T lymphocytes. NK cells also play a role in the adaptive immune response, demonstrating the ability to formulate antigen-specific immunological memory. The role of NK cells in both innate and adaptive immunity is becoming increasingly important in research using NK cell activity as a potential cancer therapy and HIV therapy. Their classification into CD56bright and CD56dim subtypes, with distinct functions and locations, further highlights their versatility. The discovery of NK cells resolved earlier inconsistencies in observations of natural cytotoxicity and established a new lineage of immune cells.

Did You Know?

• NK cells represent 5–20% of all circulating lymphocytes in humans.
• NK cells can be identified by the presence of CD56 and the absence of CD3 (CD56+, CD3−).
• The K562 51chromium-release assay is the most commonly used assay to detect human NK functional activity.
• NK cells differ from natural killer T cells (NKTs) phenotypically, by origin and by respective effector functions.

The Long Road to Discovery

The story of NK cell discovery began in the mid-1960s when researchers studying cell-mediated cytotoxicity against tumor targets noticed that certain lymphoid cells could destroy them without prior sensitization. Dr. Henry Smith at the University of Leeds School of Medicine published the first formal assertion of this natural tumor immunity in 1966, attributing it to defense mechanisms present in normal mice. Although others had made similar observations, the findings contradicted the prevailing immunological model and were largely dismissed as artifacts. The definitive identification came in the early 1970s at the Karolinska Institute in Stockholm, where Rolf Kiessling and Hugh Pross characterized the mouse effector cell, and Pross with Mikael Jondal did the same in humans, under supervision of Eva Klein and Hans Wigzell. Ronald Herberman independently reported parallel mouse findings that year. The K562 chromium-release assay, validated by West and colleagues, became the standard functional test, enabling consistent cross-laboratory comparisons worldwide.

Missing-Self Recognition and Cytotoxic Logic

NK cells occupy a unique niche in vertebrate immunity by serving a cytotoxic function analogous to adaptive cytotoxic T cells, yet operating on fundamentally different recognition logic. Cytotoxic T cells require antigen presentation on MHC class I molecules to become activated, meaning they can only engage cells displaying foreign peptides in that specific context. NK cells, by contrast, detect and eliminate stressed, virus-infected, or tumor cells that have downregulated or lost MHC class I expression entirely. This missing-self recognition is precisely why they were termed natural killers—they need no prior antigen-specific activation to destroy cells lacking self markers. This capability is especially critical because malignant or pathogen-compromised cells that shed MHC I would be invisible to conventional T-cell surveillance. NK cells integrate signals from multiple activating and inhibitory receptors to make their kill-or-spare decision, providing a rapid, non-specific first line of defense against intracellular pathogens, stressed cells, and neoplastic growth. They constitute roughly five to twenty percent of all circulating human lymphocytes, underscoring their numerical significance in the blood.

Surface Markers, Lineage, and Functional Subsets

NK cells are immunologically defined by surface expression of CD56 alongside the absence of CD3, a combination that distinguishes them from T and B lymphocytes. They lack T-cell antigen receptors, pan-T marker CD3, and surface immunoglobulins, yet typically express CD16 (FcγRIII) and CD57 in humans, or NK1.1 and NK1.2 in C57BL/6 mice. The NKp46 marker has emerged as another preferred identifier across humans, several mouse strains including BALB/c, and three common monkey species. Developmentally, NK cells arise from a CD127-positive common innate lymphoid progenitor, which sits downstream of the common lymphoid progenitor that also gives rise to B and T cells. Maturation occurs in bone marrow, lymph nodes, spleen, tonsils, and thymus before cells enter circulation. Functionally, NK cells split into CD56bright and CD56dim subsets. The bright population, predominant in bone marrow, secondary lymphoid tissue, liver, and skin, resembles T helper cells in its cytokine-release strategy and preferentially targets highly proliferative cells. The dim subset, concentrated in peripheral blood, is the principal cytotoxic arm and is invariably CD16-positive, making it key in antibody-dependent cellular cytotoxicity. CD56bright cells can transition into the dim form.

Bridging Innate and Adaptive Immunity for Therapy

Beyond their classical role as rapid-response innate effectors, NK cells have revealed a surprising capacity to bridge innate and adaptive immunity. Numerous experimental studies have demonstrated that NK cells can adjust to their immediate microenvironment and generate antigen-specific immunological memory, a trait once considered exclusive to T and B lymphocytes. This memory function is fundamental for mounting more effective responses during secondary encounters with the same pathogen. In addition, both activating and inhibitory NK receptors contribute to self-tolerance and the sustained regulation of NK cell activity, preventing inappropriate autoaggression. These dual roles have propelled NK cells into the spotlight of translational research. Current investigations explore NK cell activity as a potential therapeutic strategy against cancer and HIV, leveraging their ability to recognize stressed or infected cells without requiring MHC-restricted antigen presentation. The fact that NKT cells can promote NK cell activity by secreting interferon gamma further highlights the interconnectedness of lymphoid lineages in shaping protective immunity. As understanding of NK cell biology deepens, their therapeutic potential in oncology and infectious disease continues to expand.