Natural killer cell


Natural killer cells, also known as NK cells, are a type of cytotoxic lymphocyte critical to the innate immune system. They are a kind of large granular lymphocyte, belong to the rapidly expanding family of known innate lymphoid cells, and represent 5–20% of all circulating lymphocytes in humans. The role of NK cells is analogous to that of cytotoxic T cells in the vertebrate adaptive immune response. NK cells provide rapid responses to virus-infected cells, stressed cells, tumor cells, and other intracellular pathogens based on signals from several activating and inhibitory receptors. While cytotoxic T cells can only activate by detecting the antigen presented on major histocompatibility complex class I molecules on infected cell surfaces, NK cells recognize and kill stressed cells that are lacking the MHC class I molecules. 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. This role is especially important because harmful cells that are missing MHC I markers cannot be detected and destroyed by other immune cells, such as T lymphocyte cells.
NK cells can be identified by the presence of CD56 and the absence of CD3. NK cells differentiate from CD127+ common innate lymphoid progenitor, which is downstream of the common lymphoid progenitor from which B and T lymphocytes are also derived. 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 differ from natural killer T cells phenotypically, by origin and by respective effector functions; often, NKT cell activity promotes NK cell activity by secreting interferon gamma. In contrast to NKT cells, NK cells do not express T-cell antigen receptors or pan T marker CD3 or surface immunoglobulins B cell receptors, but they usually express the surface markers CD16 and CD57 in humans, NK1.1 or NK1.2 in C57BL/6 mice. The NKp46 cell surface marker constitutes, at the moment, another NK cell marker of preference being expressed in both humans, several strains of mice and in three common monkey species.
Outside of innate immunity, both activating and inhibitory NK cell receptors play important functional roles in self tolerance and the sustaining of NK cell activity. NK cells also play a role in the adaptive immune response: 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 role of NK cells in both the innate and adaptive immune responses is becoming increasingly important in research using NK cell activity as a potential cancer therapy and HIV therapy.

Early history

In early experiments on cell-mediated cytotoxicity against tumor target cells, both in cancer patients and animal models, investigators consistently observed what was termed a "natural" reactivity; that is, a certain population of cells seemed to be able to destroy tumor cells without having been previously sensitized to them. 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, leading to the conclusion that the "phenomenon appear to be an expression of defense mechanisms to tumor growth present in normal mice." Other researchers had also made similar observations, but as these discoveries were inconsistent with the established model at the time, many initially considered these observations to be artifacts.
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, 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. Kiessling's research involved the well-characterized ability of T lymphocytes to attack tumor cells which they had been previously immunized against. Pross and Jondal were studying cell-mediated cytotoxicity in normal human blood and the effect of the removal of various receptor-bearing cells on this cytotoxicity. Later that same year, Ronald Herberman published similar data with respect to the unique nature of the mouse effector cell.
The human data were confirmed, for the most part, by West et al. using similar techniques and the same erythroleukemic target cell line, K562. K562 is highly sensitive to lysis by human NK cells and, over the decades, the K562 51chromium-release assay has become the most commonly used assay to detect human NK functional activity. Its almost universal use has meant that experimental data can be compared easily by different laboratories around the world.
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. The demonstration that density gradient-isolated large granular lymphocytes were responsible for human NK activity, made by Timonen and Saksela in 1980, was the first time that NK cells had been visualized microscopically, and was a major breakthrough in the field.

Types

Natural killer cells can be classified as CD56bright or CD56dim. CD56bright NK cells are similar to T helper cells in exerting their influence by releasing cytokines. CD56bright NK cells constitute the majority of NK cells, being found in bone marrow, secondary lymphoid tissue, liver, and skin. CD56bright NK cells are characterized by their preferential killing of highly proliferative cells, and thus might have an immunoregulatory role. CD56dim NK cells are primarily found in the peripheral blood, and are characterized by their cell killing ability. CD56dim NK cells are always CD16 positive. CD56bright can transition into CD56dim by acquiring CD16.
NK cells can eliminate virus-infected cells via CD16-mediated ADCC.

Receptors

NK cell receptors can also be differentiated based on function. Natural cytotoxicity receptors directly induce apoptosis after binding to Fas ligand that directly indicate infection of a cell. The MHC-independent receptors use an alternate pathway to induce apoptosis in infected cells. Natural killer cell activation is determined by the balance of inhibitory and activating receptor stimulation. For example, if the inhibitory receptor signaling is more prominent, then NK cell activity will be inhibited; similarly, if the activating signal is dominant, then NK cell activation will result.
NK cell receptor types are differentiated by structure, with a few examples to follow:

Activating receptors

  • Ly49 , relatively ancient, C-type lectin family receptors, are of multigenic presence in mice, while humans have only one pseudogenic Ly49, the receptor for classical MHC I molecules.
  • NCR, type 1 transmembrane proteins of the immunoglobulin superfamily, upon stimulation mediate NK killing and release of IFNγ. They bind viral ligands such as hemagglutinins and hemagglutinin neuraminidases, some bacterial ligands and cellular ligands related to tumour growth such as PCNA.
  • CD16 plays a role in antibody-dependent cell-mediated cytotoxicity; in particular, they bind immunoglobulin G.
  • TLR – Toll-like receptors are receptors that belong in the group of pattern recognition receptors which are typical for the cells of innate immunity but are expressed also on NK cells. They recognize PAMPs and DAMPs as their ligands. These receptors are crucial for the induction of the immune response. TLR induction amplifies the immune response by promoting the production of inflammatory cytokines and chemokines and ultimately leads to the activation of NK cell effector functions. So NK cells directly react to the presence of pathogens in their surroundings. Apart from TLR-10, NK cells express all of the human TLR although in various levels. NK cells express high levels of TLR-1, moderate levels of TLR-2, TLR-3, TLR-5 and TLR-6, low levels of TLR-4, TLR-8 and TLR-9 and very low levels of TLR-7. TLR receptors are constitutionally expressed independently of their state of activation and they cooperate with cytokines and chemokines on the activation of the natural killer cells. These receptors are expressed extracellularly on the cell surface or endosomally inside the endosomes. Apart from TLR-3 and TLR-4, all TLR signal through adaptor protein MyD88 which ultimately leads mainly to the activation of NF-κB. TLR-3 signals through the adaptor protein TRIF and TLR-4 can switch between signaling through MyD88 and TRIF respectively. Induction of different TLR leads to distinct activation of NK cell functions.

    Inhibitory receptors

  • Killer-cell immunoglobulin-like receptors belong to a multigene family of more recently evolved Ig-like extracellular domain receptors; they are present in nonhuman primates, and are the main receptors for both classical MHC I and nonclassical Mamu-G in primates. Some KIRs are specific for certain HLA subtypes. Most KIRs are inhibitory and dominant. Regular cells express MHC class 1, so are recognised by KIR receptors and NK cell killing is inhibited.
  • CD94/NKG2, a C-type lectin family receptor, is conserved in both rodents and primates and identifies nonclassical MHC I molecules such as HLA-E. Expression of HLA-E at the cell surface is dependent on the presence of nonamer peptide epitope derived from the signal sequence of classical MHC class I molecules, which is generated by the sequential action of signal peptide peptidase and the proteasome. Though indirect, this is a way to survey the levels of classical HLA molecules.
  • ILT or LIR – are recently discovered members of the Ig receptor family.
  • Ly49 have both activating and inhibitory isoforms. They are highly polymorphic on the population level; though they are structurally unrelated to KIRs, they are the functional homologues of KIRs in mice, including the expression pattern. Ly49s are receptor for classical MHC I molecules.