View source for Natural killer cell

{{Short description|Type of cytotoxic lymphocyte}}
{{Distinguish|Natural killer T cell}}
{{Infobox cell|Name=Natural killer cell|Image=Human Natural Killer Cell (29120480442).jpg|Caption=Human natural killer cell, colorized scanning electron micrograph|System=[[Immune system]]|Function=Cytotoxic [[lymphocyte]]}}

'''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 lymphocytes<ref>{{Cite journal |last=Oshimi |first=Kazuo |date=2017 |title=Clinical Features, Pathogenesis, and Treatment of Large Granular Lymphocyte Leukemias |url=https://www.jstage.jst.go.jp/article/internalmedicine/56/14/56_56.8881/_article |journal=Internal Medicine |language=en |volume=56 |issue=14 |pages=1759–1769 |doi=10.2169/internalmedicine.56.8881 |issn=0918-2918|doi-access=free }}</ref><ref>{{Cite web |title=Large granular lymphocytic (LGL) leukemia |url=https://www.lls.org/leukemia/large-granular-lymphocytic-leukemia |access-date=2024-08-24 |website=www.lls.org}}</ref> (LGL), and belong to the rapidly expanding family of known [[innate lymphoid cell]]s (ILC) and represent 5–20% of all circulating lymphocytes in humans.<ref>{{cite journal | vauthors = Perera Molligoda Arachchige AS | title = Human NK cells: From development to effector functions | journal = Innate Immunity | volume = 27 | issue = 3 | pages = 212–229 | date = April 2021 | pmid = 33761782 | pmc = 8054151 | doi = 10.1177/17534259211001512 | doi-access = free }}</ref> The role of NK cells is analogous to that of [[cytotoxic T cell]]s 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.  Most [[immune cells]] detect the antigen presented on [[MHC class I|major histocompatibility complex I]] (MHC-I) on infected cell surfaces, but NK cells can recognize and kill stressed cells in the absence of [[antibodies]] and MHC, allowing for a much faster immune reaction.  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]].<ref name="Vivier2011">{{cite journal | vauthors = Vivier E, Raulet DH, Moretta A, Caligiuri MA, Zitvogel L, Lanier LL, Yokoyama WM, Ugolini S | display-authors = 6 | title = Innate or adaptive immunity? The example of natural killer cells | journal = Science | volume = 331 | issue = 6013 | pages = 44–49 | date = January 2011 | pmid = 21212348 | pmc = 3089969 | doi = 10.1126/science.1198687 | bibcode = 2011Sci...331...44V }}</ref> 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 [[Neural cell adhesion molecule|CD56]] and the absence of [[CD3 (immunology)|CD3]] (CD56<sup>+</sup>, CD3<sup>&minus;</sup>).<ref name="pmid32477340">{{cite journal | vauthors = Pfefferle A, Jacobs B, Haroun-Izquierdo A, Kveberg L, Sohlberg E, Malmberg KJ | title = Deciphering Natural Killer Cell Homeostasis | journal = Frontiers in Immunology | volume = 11 | pages = 812 | year = 2020 | pmid = 32477340 | pmc = 7235169 | doi = 10.3389/fimmu.2020.00812 | doi-access = free }}</ref> NK cells differentiate from [[Interleukin-7 receptor-α|CD127<sup>+</sup>]] common [[Innate lymphoid cell|innate lymphoid]] progenitor,<ref name=":7">{{cite journal | vauthors = Kansler ER, Li MO | title = Innate lymphocytes-lineage, localization and timing of differentiation | journal = Cellular & Molecular Immunology | volume = 16 | issue = 7 | pages = 627–633 | date = July 2019 | pmid = 30804475 | pmc = 6804950 | doi = 10.1038/s41423-019-0211-7 }}</ref> which is downstream of the [[Lymphopoiesis#The old model: lymphoid vs myeloid|common lymphoid progenitor]] from which [[B cell|B]] and [[T cell|T lymphocyte]]s are also derived.<ref name=":7" /><ref>{{cite journal | vauthors = Harly C, Cam M, Kaye J, Bhandoola A | title = Development and differentiation of early innate lymphoid progenitors | journal = The Journal of Experimental Medicine | volume = 215 | issue = 1 | pages = 249–262 | date = January 2018 | pmid = 29183988 | pmc = 5748853 | doi = 10.1084/jem.20170832 }}</ref> NK cells are known to differentiate and mature in the [[bone marrow]], [[lymph node]]s, [[spleen]], [[tonsil]]s, and [[thymus]], where they then enter into the circulation.<ref name=Lannello2008>{{cite journal | vauthors = Iannello A, Debbeche O, Samarani S, Ahmad A | title = Antiviral NK cell responses in HIV infection: I. NK cell receptor genes as determinants of HIV resistance and progression to AIDS | journal = Journal of Leukocyte Biology | volume = 84 | issue = 1 | pages = 1–26 | date = July 2008 | pmid = 18388298 | doi = 10.1189/jlb.0907650 | s2cid = 26975415 | citeseerx = 10.1.1.619.9639 }}</ref> NK cells differ from [[natural killer T cell]]s (NKTs) phenotypically, by origin and by respective effector functions; often, NKT cell activity promotes NK cell activity by secreting [[IFNγ|interferon gamma]]. In contrast to NKT cells, NK cells do not express [[T-cell antigen receptors]] (TCR) or pan T marker [[CD3 (immunology)|CD3]] or surface [[immunoglobulin]]s (Ig) [[B cell receptor]]s, but they usually express the surface markers [[CD16]] (FcγRIII) and [[CD57]] in humans, NK1.1 or NK1.2 in [[C57BL/6]] [[mouse|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 (including [[BALB/c|BALB/c mice]]) and in three common monkey species.<ref>{{cite journal | vauthors = Walzer T, Bléry M, Chaix J, Fuseri N, Chasson L, Robbins SH, Jaeger S, André P, Gauthier L, Daniel L, Chemin K, Morel Y, Dalod M, Imbert J, Pierres M, Moretta A, Romagné F, Vivier E | display-authors = 6 | title = Identification, activation, and selective in vivo ablation of mouse NK cells via NKp46 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 9 | pages = 3384–3389 | date = February 2007 | pmid = 17360655 | pmc = 1805551 | doi = 10.1073/pnas.0609692104 | doi-access = free | bibcode = 2007PNAS..104.3384W }}</ref><ref>{{cite journal | vauthors = Sivori S, Vitale M, Morelli L, Sanseverino L, Augugliaro R, Bottino C, Moretta L, Moretta A | display-authors = 6 | title = p46, a novel natural killer cell-specific surface molecule that mediates cell activation | journal = The Journal of Experimental Medicine | volume = 186 | issue = 7 | pages = 1129–1136 | date = October 1997 | pmid = 9314561 | pmc = 2211712 | doi = 10.1084/jem.186.7.1129 }}</ref>

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]]:<ref name=Arina2007>{{cite journal | vauthors = Arina A, Murillo O, Dubrot J, Azpilikueta A, Alfaro C, Pérez-Gracia JL, Bendandi M, Palencia B, Hervás-Stubbs S, Melero I | display-authors = 6 | title = Cellular liaisons of natural killer lymphocytes in immunology and immunotherapy of cancer | journal = Expert Opinion on Biological Therapy | volume = 7 | issue = 5 | pages = 599–615 | date = May 2007 | pmid = 17477799 | doi = 10.1517/14712598.7.5.599 | s2cid = 43003664 }}</ref> 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.<ref>{{cite book | vauthors = Watzl C | title = How to trigger a killer: modulation of natural killer cell reactivity on many levels | series = Advances in Immunology | volume = 124 | pages = 137–70 | date = 2014 | pmid = 25175775 | doi = 10.1016/B978-0-12-800147-9.00005-4 | isbn = 9780128001479 }}</ref>  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.<ref>{{Cite journal |last=Perera Molligoda Arachchige |first=Arosh S |date=2022-03-25 |title=NK cell-based therapies for HIV infection: Investigating current advances and future possibilities |url=https://academic.oup.com/jleukbio/article/111/4/921/6885120 |journal=Journal of Leukocyte Biology |language=en |volume=111 |issue=4 |pages=921–931 |doi=10.1002/JLB.5RU0821-412RR |issn=0741-5400|url-access=subscription }}</ref><ref>{{Cite journal |last=Arachchige |first=Arosh S. Perera Molligoda |date=2021 |title=A universal CAR-NK cell approach for HIV eradication |url=http://www.aimspress.com/rticle/doi/10.3934/Allergy.2021015 |journal=AIMS Allergy and Immunology |language=en |volume=5 |issue=3 |pages=192–194 |doi=10.3934/Allergy.2021015 |issn=2575-615X |doi-access=free }}{{Dead link|date=August 2024 |bot=InternetArchiveBot |fix-attempted=yes }}</ref>

==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,<ref>{{cite journal | vauthors = Smith HJ | title = Antigenicity of carcinogen-induced and spontaneous tumours in inbred mice | journal = British Journal of Cancer | volume = 20 | issue = 4 | pages = 831–837 | date = December 1966 | pmid = 5964614 | pmc = 2008147 | doi = 10.1038/bjc.1966.95 }}</ref> leading to the conclusion that the "phenomenon appear[ed] 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.<ref>{{cite journal | vauthors = Oldham RK | title = Natural killer cells: artifact to reality: an odyssey in biology | journal = Cancer and Metastasis Reviews | volume = 2 | issue = 4 | pages = 323–336 | year = 1983 | pmid = 6375859 | doi = 10.1007/BF00048565 | s2cid = 11301147 }}</ref>

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,<ref>{{cite journal | vauthors = Kiessling R, Klein E, Pross H, Wigzell H | title = "Natural" killer cells in the mouse. II. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Characteristics of the killer cell | journal = European Journal of Immunology | volume = 5 | issue = 2 | pages = 117–121 | date = February 1975 | pmid = 1086218 | doi = 10.1002/eji.1830050209 | s2cid = 2389610 }}</ref>  and by Hugh Pross and doctoral student Mikael Jondal in the human.<ref>{{cite journal | vauthors = Pross HF, Jondal M | title = Cytotoxic lymphocytes from normal donors. A functional marker of human non-T lymphocytes | journal = Clinical and Experimental Immunology | volume = 21 | issue = 2 | pages = 226–235 | date = August 1975 | pmid = 810282 | pmc = 1538269 }}</ref><ref>{{cite journal | vauthors = Jondal M, Pross H | title = Surface markers on human b and t lymphocytes. VI. Cytotoxicity against cell lines as a functional marker for lymphocyte subpopulations | journal = International Journal of Cancer | volume = 15 | issue = 4 | pages = 596–605 | date = April 1975 | pmid = 806545 | doi = 10.1002/ijc.2910150409 | s2cid = 30612835 }}</ref>  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 B. Herberman, M.D.|Ronald Herberman]] published similar data with respect to the unique nature of the mouse effector cell.<ref>{{cite journal | vauthors = Herberman RB, Nunn ME, Holden HT, Lavrin DH | title = Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic tumors. II. Characterization of effector cells | journal = International Journal of Cancer | volume = 16 | issue = 2 | pages = 230–239 | date = August 1975 | pmid = 1080480 | doi = 10.1002/ijc.2910160205 | s2cid = 24410880 }}</ref>
The human data were confirmed, for the most part, by West ''et al.''<ref>{{cite journal | vauthors = West WH, Cannon GB, Kay HD, Bonnard GD, Herberman RB | title = Natural cytotoxic reactivity of human lymphocytes against a myeloid cell line: characterization of effector cells | journal = Journal of Immunology | volume = 118 | issue = 1 | pages = 355–361 | date = January 1977 | pmid = 299761 | doi = 10.4049/jimmunol.118.1.355 | s2cid = 42635604 }}</ref>  using similar techniques and the same erythroleukemic target cell line, [[K562 cells|K562]]. K562 is highly sensitive to lysis by human NK cells and, over the decades, the K562  <sup>51</sup>chromium-release assay has become the most commonly used assay to detect human NK functional activity.<ref>{{cite journal | vauthors = Pross HF, Baines MG, Rubin P, Shragge P, Patterson MS | title = Spontaneous human lymphocyte-mediated cytotoxicity against tumor target cells. IX. The quantitation of natural killer cell activity | journal = Journal of Clinical Immunology | volume = 1 | issue = 1 | pages = 51–63 | date = January 1981 | pmid = 7334070 | doi = 10.1007/BF00915477 | s2cid = 24437710 }}</ref>  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,<ref>{{cite journal | vauthors = Timonen T, Saksela E | title = Isolation of human NK cells by density gradient centrifugation | journal = Journal of Immunological Methods | volume = 36 | issue = 3–4 | pages = 285–291 | year = 1980 | pmid = 7430655 | doi = 10.1016/0022-1759(80)90133-7 }}</ref> was the first time that NK cells had been visualized microscopically, and was a major breakthrough in the field.

==Types==
NK cells can be classified as CD56<sup>bright</sup> or CD56<sup>dim</sup>.<ref name="pmid32545516">{{cite journal | vauthors = Hashemi E, Malarkannan S | title = Tissue-Resident NK Cells: Development, Maturation, and Clinical Relevance | journal = Cancers | volume = 12 | issue = 6 | pages = 1553 | date = June 2020 | pmid = 32545516 | pmc = 7352973 | doi = 10.3390/cancers12061553 | doi-access = free }}</ref><ref name="pmid32762681">{{cite journal | vauthors = Wu SY, Fu T, Jiang YZ, Shao ZM | title = Natural killer cells in cancer biology and therapy | journal = Molecular Cancer | volume = 19 | issue = 1 | pages = 120 | date = August 2020 | pmid = 32762681 | pmc = 7409673 | doi = 10.1186/s12943-020-01238-x | doi-access = free }}</ref><ref name="pmid32477340" /> CD56<sup>bright</sup> NK cells are similar to [[T helper cell]]s in exerting their influence by releasing [[cytokine]]s.<ref name="pmid32762681" /> CD56<sup>bright</sup> NK cells constitute the majority of NK cells, being found in bone marrow, secondary lymphoid tissue, liver, and skin.<ref name="pmid32477340" /> CD56<sup>bright</sup> NK cells are characterized by their preferential killing of highly proliferative cells,<ref>{{Cite journal |last1=Lee |first1=Mercede |last2=Bell |first2=Charles JM |last3=Rubio García |first3=Arcadio |title=CD56bright natural killer cells preferentially kill proliferating CD4+ T cells |url=https://academic.oup.com/discovimmunology/advance-article/doi/10.1093/discim/kyad012/7241354 |journal=Discovery Immunology |date=2023 |pages=kyad012 |doi=10.1093/discim/kyad012|doi-access=free |pmc=10465185 }}</ref> and thus might have an immunoregulatory role. CD56<sup>dim</sup> NK cells are primarily found in the [[Venous blood|peripheral blood]],<ref name="pmid32477340" /> and are characterized by their cell killing ability.<ref name="pmid32762681" /> CD56<sup>dim</sup> NK cells are always [[CD16]] positive (CD16 is the key mediator of [[antibody-dependent cellular cytotoxicity]], or ADCC).<ref name="pmid32762681" /> CD56<sup>bright</sup> can transition into CD56<sup>dim</sup> by acquiring CD16.<ref name="pmid32477340" />

NK cells can eliminate virus-infected cells via CD16-mediated ADCC.<ref name="pmid32655581">{{cite journal | vauthors = Market M, Angka L, Martel AB, Bastin D, Olanubi O, Tennakoon G, Boucher DM, Ng J, Ardolino M, Auer RC | display-authors = 6 | title = Flattening the COVID-19 Curve With Natural Killer Cell Based Immunotherapies | journal = Frontiers in Immunology | volume = 11 | pages = 1512 | year = 2020 | pmid = 32655581 | pmc = 7324763 | doi = 10.3389/fimmu.2020.01512 | doi-access = free }}</ref> All [[coronavirus disease 2019]] (COVID-19) patients show depleted CD56<sup>bright</sup> NK cells, but CD56<sup>dim</sup> is only depleted in patients with severe COVID-19.<ref name="pmid32655581" />

==Receptors==
[[File:HLA-Cw4.png|150px|right|thumb|The HLA ligand for KIR]]

NK cell receptors can also be differentiated based on function. Natural [[cytotoxicity]] receptors directly induce [[apoptosis]] (cell death) after binding to [[Fas ligand]] that directly indicate infection of a cell. The MHC-independent receptors (described above) 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.<ref name=Terunuma2008>{{cite journal | vauthors = Terunuma H, Deng X, Dewan Z, Fujimoto S, Yamamoto N | title = Potential role of NK cells in the induction of immune responses: implications for NK cell-based immunotherapy for cancers and viral infections | journal = International Reviews of Immunology | volume = 27 | issue = 3 | pages = 93–110 | year = 2008 | pmid = 18437601 | doi = 10.1080/08830180801911743 | s2cid = 27557213 }}</ref>

[[File:PDB 1hq8 EBI.jpg|150px|thumb|right|Protein structure of NKG2D]]
NK cell receptor types (with inhibitory, as well as some activating members) are differentiated by structure, with a few examples to follow:
[[File:PDB 1hkf EBI.jpg|150px|thumb|Protein structure of NKp44]]

===Activating receptors===
*'''[[Ly49]] '''(homodimers),  relatively ancient, C-type [[lectin]] family receptors, are of multigenic presence in mice, while humans have only one [[pseudogene|pseudogenic]] Ly49, the receptor for classical (polymorphic) [[MHC I]] molecules.
*'''NCR''' (natural cytotoxicity receptors), 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]] (FcγIIIA)''' plays a role in [[antibody-dependent cell-mediated cytotoxicity]]; in particular, they bind [[immunoglobulin G]].
*'''[[Toll-like receptor|TLR]]''' – Toll-like receptors are receptors that belong in the group of [[Pattern recognition receptor|pattern recognition receptors (PRR)]] which are typical for the cells of [[innate immunity]] but are expressed also on NK cells. They recognize [[Pathogen-associated molecular pattern|PAMPs]] (pathogen-associated molecular patterns) and [[Damage-associated molecular pattern|DAMPs]] (damage-associated molecular patterns) 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 [[cytokine]]s and [[chemokine]]s and ultimately leads to the activation of NK cell effector functions.<ref>{{cite book | vauthors = Maldonado-Bernal C, Sánchez-Herrera D | chapter = Toll-Like Receptors and Natural Killer Cells |date=2020-01-15 | chapter-url= https://www.intechopen.com/books/toll-like-receptors/toll-like-receptors-and-natural-killer-cells | title = Toll-like Receptors | veditors = Rezaei N |access-date=2023-06-15 |publisher=IntechOpen |language=en |doi=10.5772/intechopen.86393 |isbn=978-1-78984-523-5 |s2cid=191147609 }}</ref> So NK cells directly react to the presence of [[pathogen]]s in their surroundings. Apart from [[Toll-like receptor 10|TLR-10]], NK cells express all of the human TLR although in various levels. NK cells express high levels of [[Toll-like receptor 1|TLR-1]], moderate levels of [[Toll-like receptor 2|TLR-2]], [[Toll-like receptor 3|TLR-3]], [[Toll-like receptor 5|TLR-5]] and [[Toll-like receptor 6|TLR-6]], low levels of [[Toll-like receptor 4|TLR-4]], [[Toll-like receptor 8|TLR-8]] and TLR-9 and very low levels of [[Toll-like receptor 7|TLR-7]].<ref name=":4">{{cite journal | vauthors = Noh JY, Yoon SR, Kim TD, Choi I, Jung H | title = Toll-Like Receptors in Natural Killer Cells and Their Application for Immunotherapy | journal = Journal of Immunology Research | volume = 2020 | pages = 2045860 | date = 2020 | pmid = 32377528 | pmc = 7199539 | doi = 10.1155/2020/2045860 | doi-access = free }}</ref> 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.<ref>{{cite journal | vauthors = Sivori S, Carlomagno S, Pesce S, Moretta A, Vitale M, Marcenaro E | title = TLR/NCR/KIR: Which One to Use and When? | journal = Frontiers in Immunology | volume = 5 | pages = 105 | date = 2014 | pmid = 24678311 | pmc = 3958761 | doi = 10.3389/fimmu.2014.00105 | doi-access = free }}</ref> These receptors are expressed extracellularly on the cell surface or endosomally inside the [[endosome]]s. Apart from TLR-3 and TLR-4, all TLR signal through adaptor protein [[MYD88|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.<ref>{{cite journal | vauthors = Patel H, Shaw SG, Shi-Wen X, Abraham D, Baker DM, Tsui JC | title = Toll-like receptors in ischaemia and its potential role in the pathophysiology of muscle damage in critical limb ischaemia | journal = Cardiology Research and Practice | volume = 2012 | pages = 121237 | date = 2012 | pmid = 22454775 | pmc = 3290818 | doi = 10.1155/2012/121237 | doi-access = free }}</ref>

===Inhibitory receptors===
*[[Killer-cell immunoglobulin-like receptor]]s (KIRs) belong to a multigene family of more recently [[evolution|evolved]] Ig-like extracellular domain receptors; they are present in nonhuman primates, and are the main receptors for both classical MHC I ([[HLA-A]], [[HLA-B]], [[HLA-C]]) and nonclassical Mamu-G ([[HLA-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.<ref name=Lannello2008/>
* '''[[CD94/NKG2]]''' (heterodimers), a C-type lectin family receptor, is conserved in both rodents and primates and identifies nonclassical (also nonpolymorphic) 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 (polymorphic) HLA molecules.
*'''ILT''' or '''LIR''' (immunoglobulin-like receptor) – are recently discovered members of the Ig receptor family.	
* '''Ly49''' (homodimers) 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 (polymorphic) MHC I molecules.

== Function ==

===Cytolytic granule mediated cell apoptosis===
NK cells are [[cytotoxic]]; small [[Granulocytes|granules]] in their [[cytoplasm]] contain proteins such as [[perforin]] and [[protease]]s known as [[granzyme]]s. Upon release in close proximity to a cell slated for killing, perforin forms pores in the [[cell membrane]] of the target cell, creating an aqueous channel through which the granzymes and associated molecules can enter, inducing either [[apoptosis]] or osmotic cell lysis. The distinction between apoptosis and cell [[lysis]] is important in [[immunology]]: lysing a virus-infected cell could potentially release the [[virion]]s, whereas apoptosis leads to destruction of the virus inside. [[Alpha defensin|α-defensins]], antimicrobial molecules, are also secreted by NK cells, and directly kill bacteria by disrupting their cell walls in a manner analogous to that of [[neutrophil]]s.<ref name=Lannello2008/>

===Antibody-dependent cell-mediated cytotoxicity (ADCC)===
Infected cells are routinely [[opsonized]] with antibodies for detection by immune cells.  Antibodies that bind to antigens can be recognised by FcγRIII ([[CD16]]) receptors expressed on NK cells, resulting in NK activation, release of cytolytic granules and consequent cell [[apoptosis]]. This is a major killing mechanism of some [[monoclonal antibodies]] like [[Rituximab|rituximab (Rituxan)]], [[ofatumumab | ofatumumab (Azzera)]], and others. The contribution of antibody-dependent cell-mediated cytotoxicity to tumor cell killing can be measured with a specific test that uses [[NK-92]], an immortal line of NK-like cells licensed to [https://nantkwest.com NantKwest, Inc.]: the response of [https://nantkwest.com NK-92 cells] that have been transfected with a high-affinity [[Fc receptor]] are compared to that of the "wild type" NK-92 which does not express the Fc receptor.<ref name=Smyth2002>{{cite journal | vauthors = Smyth MJ, Hayakawa Y, Takeda K, Yagita H | title = New aspects of natural-killer-cell surveillance and therapy of cancer | journal = Nature Reviews. Cancer | volume = 2 | issue = 11 | pages = 850–861 | date = November 2002 | pmid = 12415255 | doi = 10.1038/nrc928 | s2cid = 1430364 }}</ref>

===Cytokine-induced NK and Cytotoxic T lymphocyte (CTL) activation===
[[Cytokine]]s play a crucial role in NK cell activation. As these are [[Stress (biology)|stress]] molecules released by cells upon viral infection, they serve to signal to the NK cell the presence of [[virus|viral pathogens]] in the affected area. Cytokines involved in NK activation include [[interleukin 12|IL-12]], [[interleukin 15|IL-15]], [[interleukin 18|IL-18]], [[interleukin 2|IL-2]], and [[CCL5]]. NK cells are activated in response to interferons or macrophage-derived cytokines. They serve to contain viral infections while the adaptive immune response generates antigen-specific [[cytotoxic T cells]] that can clear the infection. NK cells work to control viral infections by secreting [[IFNγ]] and [[TNFα]]. 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. [Citation needed]

===Missing 'self' hypothesis===
[[File:Missing self.svg|thumb|right|400px| Schematic diagram indicating the complementary activities of [[cytotoxic T cells]] and NK cells]]
For NK cells to defend the body against [[viruses]] and other [[pathogens]], they require mechanisms that enable the determination of whether a cell is infected or not. The exact mechanisms remain the subject of current investigation, but recognition of an "altered self" state is thought to be involved. To control their cytotoxic activity, NK cells possess two types of surface [[Receptor (biochemistry)|receptor]]s:  activating receptors and inhibitory receptors, including [[killer-cell immunoglobulin-like receptors]]. Most of these receptors are not unique to NK cells and can be present in some [[T cell]] subsets, as well.

The inhibitory receptors recognize [[MHC class I]] [[allele]]s, which could explain why NK cells preferentially kill cells that possess low levels of MHC class I molecules. 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. MHC class I molecules are the main mechanism by which cells display viral or tumor antigens to cytotoxic T cells. A common evolutionary adaptation to this is seen in both intracellular [[microbes]] and tumors: the chronic down-regulation of MHC I molecules, which makes affected cells invisible to T cells, allowing them to evade T cell-mediated immunity. NK cells apparently evolved as an evolutionary response to this adaptation (the loss of the MHC eliminates CD4/CD8 action, so another immune cell evolved to fulfill the function).<ref name=Lodoen>{{cite journal | vauthors = Lodoen MB, Lanier LL | title = Viral modulation of NK cell immunity | journal = Nature Reviews. Microbiology | volume = 3 | issue = 1 | pages = 59–69 | date = January 2005 | pmid = 15608700 | doi = 10.1038/nrmicro1066 | s2cid = 16655783 }}</ref>

===Tumor cell surveillance===
Natural killer cells often lack antigen-specific cell surface receptors, so are part of innate immunity, ''i.e.'' able to react immediately with no prior exposure to the pathogen.  In both mice and humans, NKs can be seen to play a role in tumor immunosurveillance by directly inducing the death of tumor cells (NKs act as cytolytic effector lymphocytes), even in the absence of surface adhesion molecules and antigenic peptides. This role of NK cells is critical to immune success particularly because T cells are unable to recognize pathogens in the absence of surface antigens.<ref name=Vivier2011/>  Tumor cell detection results in activation of NK cells and consequent cytokine production and release.

If tumor cells do not cause inflammation, they will also be regarded as self and will not induce a T cell response. A number of cytokines are produced by NKs, including tumor necrosis factor α ([[TNFα]]), [[IFNγ]], and [[interleukin]] ([[Interleukin 10|IL-10]]). TNFα and IL-10 act as proinflammatory and immunosuppressors, respectively. The activation of NK cells and subsequent production of cytolytic effector cells impacts [[macrophages]], [[dendritic cells]], and [[neutrophils]], which subsequently enables antigen-specific T and B cell responses. Instead of acting via antigen-specific receptors, lysis of tumor cells by NK cells is mediated by alternative receptors, including [[NKG2D]], NKp44, NKp46, NKp30, and DNAM.<ref name=Terunuma2008/> [[NKG2D]] is a [[disulfide bond|disulfide]]-linked [[homodimer]] which recognizes a number of ligands, including ULBP and [[MHC class I polypeptide-related sequence A|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.{{Citation needed|date=December 2019|reason=removed citation to predatory publisher content}}

NK cells, along with [[macrophage]]s and several other cell types, express the Fc receptor (FcR) molecule (FC-gamma-RIII = CD16), an activating biochemical [[receptor (biochemistry)|receptor]] that binds the [[Fragment crystallizable region|Fc]] portion of IgG class [[Antibody|antibodies]]. This allows NK cells to target cells against which there has been a [[Humoral immunity|humoral response]] and to [[lysis|lyse]] cells through antibody-dependant cytotoxicity (ADCC). This response depends on the affinity of the Fc receptor expressed on NK cells, which can have high, intermediate, and low affinity for the Fc portion of the antibody. This affinity is determined by the amino acid in position 158 of the protein, which can be phenylalanine (F allele) or valine (V allele). Individuals with high-affinity FcRgammRIII (158 V/V allele) respond better to antibody therapy. This has been shown for lymphoma patients who received the antibody Rituxan. Patients who express the 158 V/V allele had a better antitumor response. Only 15–25% of the population expresses the 158 V/V allele. To determine the ADCC contribution of monoclonal antibodies, NK-92 cells (a "pure" NK cell line) has been transfected with the gene for the high-affinity FcR.

===Clearance of senescent cells===
Natural killer cells (NK cells) and [[macrophage]]s play a major role in clearance of [[Cellular senescence|senescent cells]].<ref name="pmid30811627">{{cite journal | vauthors = Antonangeli F, Zingoni A, Soriani A, Santoni A | title = Senescent cells: Living or dying is a matter of NK cells | journal = Journal of Leukocyte Biology | volume = 105 | issue = 6 | pages = 1275–1283 | date = June 2019 | pmid = 30811627 | doi = 10.1002/JLB.MR0718-299R | s2cid = 73469394 }}</ref> Natural killer cells directly kill senescent cells, and produce [[cytokine]]s which activate macrophages which remove senescent cells.<ref name="pmid30811627" />

Natural killer cells can use [[NKG2D]] receptors to detect senescent cells, and kill those cells using [[perforin]] pore-forming [[cytolysis|cytolytic]] protein.<ref name="pmid31088710">{{cite journal | vauthors = Prata LG, Ovsyannikova IG, Tchkonia T, Kirkland JL | title = Senescent cell clearance by the immune system: Emerging therapeutic opportunities | journal = Seminars in Immunology | volume = 40 | pages = 101275 | date = December 2018 | pmid = 31088710 | pmc = 7061456 | doi = 10.1016/j.smim.2019.04.003 }}</ref> [[Cytotoxic T cell|CD8+ cytotoxic T-lymphocytes]] also use NKG2D receptors to detect senescent cells, and promote killing similar to NK cells.<ref name="pmid31088710" /> 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.<ref>{{cite journal | vauthors = Earls RH, Lee JK | title = The role of natural killer cells in Parkinson's disease | journal = Experimental & Molecular Medicine | volume = 52 | issue = 9 | pages = 1517–1525 | date = September 2020 | pmid = 32973221 | pmc = 8080760 | doi = 10.1038/s12276-020-00505-7 }}</ref>

===Adaptive features of NK cells—"memory-like", "adaptive" and memory NK cells===
{{Main|Adaptive NK cells}}
The ability to generate memory cells following a primary infection and the consequent rapid immune activation and response to succeeding infections by the same antigen is fundamental to the role that T and B cells play in the adaptive immune response.  For many years, NK cells have been considered to be a part of the innate immune system. However, recently increasing evidence suggests that NK cells can display several features that are usually attributed to adaptive immune cells (e.g. T cell responses) such as dynamic expansion and contraction of subsets, increased longevity and a form of immunological memory, characterized by a more potent response upon secondary challenge with the same antigen.<ref>{{cite journal | vauthors = Rölle A, Pollmann J, Cerwenka A | title = Memory of infections: an emerging role for natural killer cells | journal = PLOS Pathogens | volume = 9 | issue = 9 | pages = e1003548 | date = September 2013 | pmid = 24086127 | pmc = 3784484 | doi = 10.1371/journal.ppat.1003548 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Pyzik M, Vidal SM | title = Natural killer cells: NK cells stroll down the memory lane | journal = Immunology and Cell Biology | volume = 87 | issue = 4 | pages = 261–263 | year = 2009 | pmid = 19290015 | doi = 10.1038/icb.2009.10 | s2cid = 42943696 | doi-access = free }}</ref>
In mice, the majority of research was carried out with murine cytomegalovirus (MCMV) and in models of hapten-hypersensitivity reactions. Especially, in the MCMV model, protective memory functions of MCMV-induced NK cells were discovered<ref name="SunBeilke2009">{{cite journal | vauthors = Sun JC, Beilke JN, Lanier LL | title = Adaptive immune features of natural killer cells | journal = Nature | volume = 457 | issue = 7229 | pages = 557–561 | date = January 2009 | pmid = 19136945 | pmc = 2674434 | doi = 10.1038/nature07665 | bibcode = 2009Natur.457..557S }}</ref>
and direct recognition of the MCMV-ligand m157 by the receptor Ly49 was demonstrated to be crucial for the generation of adaptive NK cell responses.<ref name="SunBeilke2009"/>  
In humans, most studies have focused on the expansion of an NK cell subset carrying the activating receptor [[NKG2C]] ([[KLRC2]]). Such expansions were observed primarily in response to [[human cytomegalovirus]] (HCMV),<ref>{{cite journal | vauthors = Gumá M, Angulo A, Vilches C, Gómez-Lozano N, Malats N, López-Botet M | title = Imprint of human cytomegalovirus infection on the NK cell receptor repertoire | journal = Blood | volume = 104 | issue = 12 | pages = 3664–3671 | date = December 2004 | pmid = 15304389 | doi = 10.1182/blood-2004-05-2058 | doi-access = free }}</ref> but also in other infections including [[Hantavirus]], [[Chikungunya virus]], [[HIV]], or viral [[hepatitis]]. However, whether these virus infections trigger the expansion of adaptive NKG2C+ NK cells or whether other infections result in re-activation of latent HCMV (as suggested for hepatitis
<ref>{{cite journal | vauthors = Malone DF, Lunemann S, Hengst J, Ljunggren HG, Manns MP, Sandberg JK, Cornberg M, Wedemeyer H, Björkström NK | display-authors = 6 | title = Cytomegalovirus-Driven Adaptive-Like Natural Killer Cell Expansions Are Unaffected by Concurrent Chronic Hepatitis Virus Infections | journal = Frontiers in Immunology | volume = 8 | issue = 8 | pages = 525 | year = 2017 | pmid = 28533779 | pmc = 5421146 | doi = 10.3389/fimmu.2017.00525 | doi-access = free }}</ref>), remains a field of study. 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,<ref name="HammerRuckert2018">{{cite journal | vauthors = Hammer Q, Rückert T, Borst EM, Dunst J, Haubner A, Durek P, Heinrich F, Gasparoni G, Babic M, Tomic A, Pietra G, Nienen M, Blau IW, Hofmann J, Na IK, Prinz I, Koenecke C, Hemmati P, Babel N, Arnold R, Walter J, Thurley K, Mashreghi MF, Messerle M, Romagnani C | display-authors = 6 | title = Peptide-specific recognition of human cytomegalovirus strains controls adaptive natural killer cells | journal = Nature Immunology | volume = 19 | issue = 5 | pages = 453–463 | date = May 2018 | pmid = 29632329 | doi = 10.1038/s41590-018-0082-6 | s2cid = 4718187 }}</ref> a mechanism of responding to virus infections that was previously only known for [[T cells]] of the [[adaptive immune system]].

===NK cell function in pregnancy===
As the majority of pregnancies involve two parents who are not tissue-matched, successful [[pregnancy]] requires the mother's immune system to be [[Immune tolerance in pregnancy|suppressed]]. NK cells are thought to be an important cell type in this process.<ref name="pmid20061017">
{{cite journal | vauthors = Lash GE, Robson SC, Bulmer JN | title = Review: Functional role of uterine natural killer (uNK) cells in human early pregnancy decidua | journal = Placenta | volume = 31 | issue = Suppl | pages = S87–S92 | date = March 2010 | pmid = 20061017 | doi = 10.1016/j.placenta.2009.12.022 }}</ref> These cells are known as "[[Uterine Natural Killer Cells|uterine NK cells]]" (uNK cells) and they differ from peripheral NK cells. They are in the [[CD56|CD56<sup>bright</sup>]] NK cell subset, potent at cytokine secretion, but with low cytotoxic ability and relatively similar to peripheral CD56<sup>bright</sup> NK cells, with a slightly different receptor profile.<ref name="pmid20061017" /> These uNK cells are the most abundant [[leukocyte]]s present ''in utero'' in early pregnancy, representing about 70% of leukocytes here, but from where they originate remains controversial.<ref name="pmid19876837">
{{cite journal | vauthors = Bulmer JN, Williams PJ, Lash GE | title = Immune cells in the placental bed | journal = The International Journal of Developmental Biology | volume = 54 | issue = 2–3 | pages = 281–294 | year = 2010 | pmid = 19876837 | doi = 10.1387/ijdb.082763jb | doi-access = free }}</ref>

These NK cells have the ability to elicit cell cytotoxicity ''in vitro'', but at a lower level than peripheral NK cells, despite containing [[perforin]].<ref name="PMCid1266146">
{{cite journal | vauthors = Kopcow HD, Allan DS, Chen X, Rybalov B, Andzelm MM, Ge B, Strominger JL | title = Human decidual NK cells form immature activating synapses and are not cytotoxic | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 43 | pages = 15563–15568 | date = October 2005 | pmid = 16230631 | pmc = 1266146 | doi = 10.1073/pnas.0507835102 | doi-access = free | bibcode = 2005PNAS..10215563K }}</ref> Lack of cytotoxicity ''in vivo'' may be due to the presence of ligands for their inhibitory receptors. [[Trophoblast]] cells downregulate [[HLA-A]] and [[HLA-B]] to defend against [[cytotoxic T cell]]-mediated death. This would normally trigger NK cells by missing self recognition; however, these cells survive. The selective retention of [[HLA-E]] (which is a ligand for NK cell inhibitory receptor [[NKG2|NKG2A]]) and [[HLA-G]] (which is a ligand for NK cell inhibitory receptor [[KIR2DL4]]) by the trophoblast is thought to defend it against NK cell-mediated death.<ref name="pmid20061017" />

Uterine NK cells have shown no significant difference in women with [[recurrent miscarriage]] compared with controls. However, higher peripheral NK cell percentages occur in women with recurrent miscarriages than in control groups.<ref name="SeshadriSunkara2013">{{cite journal | vauthors = Seshadri S, Sunkara SK | title = Natural killer cells in female infertility and recurrent miscarriage: a systematic review and meta-analysis | journal = Human Reproduction Update | volume = 20 | issue = 3 | pages = 429–438 | year = 2013 | pmid = 24285824 | doi = 10.1093/humupd/dmt056 | doi-access = free }}</ref>

NK cells secrete a high level of cytokines which help mediate their function. NK cells interact with [[HLA-C]] to produce cytokines necessary for trophoblastic proliferation. Some important cytokines they secrete include [[TNF-α]], [[Interleukin 10|IL-10]], [[IFN-γ]], [[GM-CSF]] and [[TGF-β]], among others.<ref name="pmid20061017" /> For example, IFN-γ dilates and thins the walls of maternal [[spiral arteries]] to enhance blood flow to the implantation site.<ref>{{cite journal | vauthors = Ashkar AA, Di Santo JP, Croy BA | title = Interferon gamma contributes to initiation of uterine vascular modification, decidual integrity, and uterine natural killer cell maturation during normal murine pregnancy | journal = The Journal of Experimental Medicine | volume = 192 | issue = 2 | pages = 259–270 | date = July 2000 | pmid = 10899912 | pmc = 2193246 | doi = 10.1084/jem.192.2.259 }}</ref>

===NK cell evasion by tumor cells===
By shedding decoy [[NKG2D]] soluble ligands, tumor cells may avoid immune responses.  These soluble NKG2D ligands bind to NK cell NKG2D receptors, activating a false NK response and consequently creating competition for the receptor site.<ref name=Vivier2011/>  This method of evasion occurs in [[prostate cancer]].  In addition, prostate cancer tumors can evade CD8 cell recognition due to their ability to downregulate expression of MHC class 1 molecules. This example of immune evasion actually highlights NK cells' importance in tumor surveillance and response, as CD8 cells can consequently only act on tumor cells in response to NK-initiated cytokine production (adaptive immune response).<ref>{{cite journal | vauthors = O'Leary JG, Goodarzi M, Drayton DL, von Andrian UH | title = T cell- and B cell-independent adaptive immunity mediated by natural killer cells | journal = Nature Immunology | volume = 7 | issue = 5 | pages = 507–516 | date = May 2006 | pmid = 16617337 | doi = 10.1038/ni1332 | s2cid = 1459858 }}</ref>

===Excessive NK cells===
Experimental treatments with NK cells have resulted in excessive cytokine production, and even [[septic shock]]. Depletion of the inflammatory cytokine [[interferon gamma]] reversed the effect.{{citation needed|date=November 2020}}

==Applications==

===Anticancer therapy===

Tumor-infiltrating NK cells have been reported to play a critical role in promoting drug-induced cell death in human triple-negative breast cancer.<ref name="pmid33077554">{{cite journal | vauthors = Smalley M, Natarajan SK, Mondal J, Best D, Goldman D, Shanthappa B, Pellowe M, Dash C, Saha T, Khiste S, Ramadurai N, Eton EO, Smalley JL, Brown A, Thayakumar A, Rahman M, Arai K, Kohandel M, Sengupta S, Goldman A | display-authors = 6 | title = Nanoengineered Disruption of Heat Shock Protein 90 Targets Drug-Induced Resistance and Relieves Natural Killer Cell Suppression in Breast Cancer | journal = Cancer Research | volume = 80 | issue = 23 | pages = 5355–5366 | date = December 2020 | pmid = 33077554 | pmc = 7718318 | doi = 10.1158/0008-5472.CAN-19-4036 }}</ref> Since NK cells recognize target cells when they express nonself HLA antigens (but not self), autologous (patients' own) NK cell infusions have not shown any antitumor effects. Instead, investigators are working on using allogeneic cells from peripheral blood, which requires that all T cells be removed before infusion into the patients to remove the risk of [[Graft-versus-host disease|graft versus host disease]], which can be fatal. This can be achieved using an immunomagnetic column (CliniMACS). In addition, because of the limited number of NK cells in blood (only 10% of lymphocytes are NK cells), their number needs to be expanded in culture. This can take a few weeks and the yield is donor-dependent.

=== CAR-NK cells ===
[[Chimeric antigen receptor]]s (CARs) are genetically modified receptors targeting cell surface [[antigen]]s that provide a valuable approach to enhance effector cell efficacy. CARs induce high-affinity binding of effector cells carrying these [[Receptors (biochemistry)|receptors]] to cells expressing the target antigen, thereby lowering the threshold for cellular activation and inducing effector functions.<ref name=":5">{{cite journal | vauthors = Sivori S, Pende D, Quatrini L, Pietra G, Della Chiesa M, Vacca P, Tumino N, Moretta F, Mingari MC, Locatelli F, Moretta L | display-authors = 6 | title = NK cells and ILCs in tumor immunotherapy | journal = Molecular Aspects of Medicine | volume = 80 | pages = 100870 | date = August 2021 | pmid = 32800530 | doi = 10.1016/j.mam.2020.100870 | s2cid = 221143327 | hdl = 11573/1480427 | hdl-access = free }}</ref>

[[CAR T cell]]s are now a fairly well-known [[cell therapy]]. However, wider use is limited by several fundamental problems: The high cost of CAR T cell therapy, which is due to the need to generate specific CAR T cells for each patient; the necessity to use only autologous T cells, due to the high risk of [[GvHD]] if allogeneic T cells are used; the inability to reinfuse CAR T cells if the patient relapses or low CAR T cell survival is observed; CAR T therapy also has a high toxicity, mainly due to [[Interferon type I|IFN-γ]] production and subsequent induction of CRS ([[cytokine release syndrome]]) and/or [[neurotoxicity]].<ref name=":6">{{cite journal | vauthors = Sivori S, Meazza R, Quintarelli C, Carlomagno S, Della Chiesa M, Falco M, Moretta L, Locatelli F, Pende D | display-authors = 6 | title = NK Cell-Based Immunotherapy for Hematological Malignancies | journal = Journal of Clinical Medicine | volume = 8 | issue = 10 | pages = 1702 | date = October 2019 | pmid = 31623224 | pmc = 6832127 | doi = 10.3390/jcm8101702 | doi-access = free }}</ref>

The use of CAR NK cells is not limited by the need to generate patient-specific cells, and at the same time, GvHD is not caused by NK cells, thus obviating the need for autologous cells.<ref>{{cite journal | vauthors = Daher M, Rezvani K | title = Next generation natural killer cells for cancer immunotherapy: the promise of genetic engineering | journal = Current Opinion in Immunology | volume = 51 | pages = 146–153 | date = April 2018 | pmid = 29605760 | pmc = 6140331 | doi = 10.1016/j.coi.2018.03.013 }}</ref> Toxic effects of CAR T therapy, such as CSR, have not been observed with the use of CAR NK cells. Thus, NK cells are considered an interesting "off-the-shelf" product option. Compared to CAR T cells, CAR NK cells retain unchanged expression of NK cell activating receptors. Thus, NK cells recognize and kill tumor cells even if, due to a tumor-escape strategy on tumor cells, ligand expression for the CAR receptor is downregulated.<ref name=":6" />

NK cells derived from umbilical cord blood have been used to generate CAR.CD19 NK cells. These cells are capable of self-producing the cytokine [[Interleukin 15|IL-15]], thereby enhancing autocrine/paracrine expression and persistence [[in vivo]]. Administration of these modified NK cells is not associated with the development of CSR, neurotoxicity, or GvHD.<ref name=":5" />

The FT596 product is the first "Off-the-Shelf", universal, and allogenic CAR NK cellular product derived from [[Induced pluripotent stem cell|iPSCs]] to be authorized for use in clinical studies in the USA.<ref>{{Cite journal | vauthors = Goodridge JP, Mahmood S, Zhu H, Gaidarova S, Blum R, Bjordahl R, Cichocki F, Chu HY, Bonello G, Lee T, Groff B | display-authors = 6 |date=2019-11-13 |title=FT596: Translation of First-of-Kind Multi-Antigen Targeted Off-the-Shelf CAR-NK Cell with Engineered Persistence for the Treatment of B Cell Malignancies |journal=Blood |volume=134 |issue=Supplement_1 |pages=301 |doi=10.1182/blood-2019-129319 | s2cid = 209578805 |issn=0006-4971|doi-access=free }}</ref> It consists of an anti-CD19 CAR optimized for NK cells with a transmembrane domain for the [[NKG2D]] activation receptor, a 2B4 costimulatory domain and a CD3ζ signaling domain. 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.<ref>{{Cite journal | vauthors = Bachanova V, Cayci Z, Lewis D, Maakaron JE, Janakiram M, Bartz A, Payne S, Wong C, Cooley S, Valamehr B, Chu YW | display-authors = 6 |date=2020-11-05 |title=Initial Clinical Activity of FT596, a First-in-Class, Multi-Antigen Targeted, Off-the-Shelf, iPSC-Derived CD19 CAR NK Cell Therapy in Relapsed/Refractory B-Cell Lymphoma |url=https://ashpublications.org/blood/article/136/Supplement%201/8/472050/Initial-Clinical-Activity-of-FT596-a-First-in |journal=Blood |language=en |volume=136 |issue=Supplement 1 |pages=8 |doi=10.1182/blood-2020-141606 | s2cid = 228912346 |issn=0006-4971|doi-access=free |url-access=subscription }}</ref>

=== NK-92 cells ===
A more efficient way to obtain high numbers of NK cells is to expand [[NK-92|NK-92 cells]], an NK cell line with all the characteristics of highly active blood Natural Killer (NK) cells but with much broader and higher cytotoxicity. NK-92 cells grow continuously in culture and can be expanded to clinical-grade numbers in bags or bioreactors.<ref>Gong JH, Maki G, Klingemann HG (April 1994). "Characterization of a human cell line (NK-92) with phenotypical and functional characteristics of activated natural killer cells". Leukemia. 8 (4): 652–8. PMID 8152260.</ref> 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.<ref>{{cite journal | vauthors = Arai S, Meagher R, Swearingen M, Myint H, Rich E, Martinson J, Klingemann H | title = Infusion of the allogeneic cell line NK-92 in patients with advanced renal cell cancer or melanoma: a phase I trial | journal = Cytotherapy | volume = 10 | issue = 6 | pages = 625–632 | year = 2008 | pmid = 18836917 | doi = 10.1080/14653240802301872 }}</ref><ref>{{cite journal | vauthors = Tonn T, Becker S, Esser R, Schwabe D, Seifried E | title = Cellular immunotherapy of malignancies using the clonal natural killer cell line NK-92 | journal = Journal of Hematotherapy & Stem Cell Research | volume = 10 | issue = 4 | pages = 535–544 | date = August 2001 | pmid = 11522236 | doi = 10.1089/15258160152509145 }}</ref>  When NK-92 cells originate from a patient with lymphoma, they must be irradiated prior to infusion.<ref>{{cite journal | vauthors = Maki G, Klingemann HG, Martinson JA, Tam YK | title = Factors regulating the cytotoxic activity of the human natural killer cell line, NK-92 | journal = Journal of Hematotherapy & Stem Cell Research | volume = 10 | issue = 3 | pages = 369–383 | date = June 2001 | pmid = 11454312 | doi = 10.1089/152581601750288975 }}</ref><ref>{{cite journal | vauthors = Navarrete-Galvan L, Guglielmo M, Cruz Amaya J, Smith-Gagen J, Lombardi VC, Merica R, Hudig D | title = Optimizing NK-92 serial killers: gamma irradiation, CD95/Fas-ligation, and NK or LAK attack limit cytotoxic efficacy | journal = Journal of Translational Medicine | volume = 20 | issue = 1 | pages = 151 | date = April 2022 | pmid = 35366943 | pmc = 8976335 | doi = 10.1186/s12967-022-03350-6 | doi-access = free }}</ref> Efforts, however, are being made to engineer the cells to eliminate the need for irradiation. The irradiated cells maintain full cytotoxicity. NK-92 are allogeneic (from a donor different from the recipient), but in clinical studies have not been shown to elicit significant host reaction.<ref>{{cite journal | vauthors = Williams BA, Law AD, Routy B, denHollander N, Gupta V, Wang XH, Chaboureau A, Viswanathan S, Keating A | display-authors = 6 | title = A phase I trial of NK-92 cells for refractory hematological malignancies relapsing after autologous hematopoietic cell transplantation shows safety and evidence of efficacy | journal = Oncotarget | volume = 8 | issue = 51 | pages = 89256–89268 | date = October 2017 | pmid = 29179517 | pmc = 5687687 | doi = 10.18632/oncotarget.19204 }}</ref><ref>{{cite journal | vauthors = Tonn T, Schwabe D, Klingemann HG, Becker S, Esser R, Koehl U, Suttorp M, Seifried E, Ottmann OG, Bug G | display-authors = 6 | title = Treatment of patients with advanced cancer with the natural killer cell line NK-92 | journal = Cytotherapy | volume = 15 | issue = 12 | pages = 1563–1570 | date = December 2013 | pmid = 24094496 | doi = 10.1016/j.jcyt.2013.06.017 }}</ref>

Unmodified NK-92 cells lack CD-16, making them unable to perform antibody-dependent cellular cytotoxicity (ADCC); however, the cells have been engineered to express a high affinity Fc-receptor (CD16A, 158V) genetically linked to IL-2 that is bound to the endoplasmic reticulum (ER).<ref>{{cite journal | vauthors = Jochems C, Hodge JW, Fantini M, Fujii R, Morillon YM, Greiner JW, Padget MR, Tritsch SR, Tsang KY, Campbell KS, Klingemann H, Boissel L, Rabizadeh S, Soon-Shiong P, Schlom J | display-authors = 6 | title = An NK cell line (haNK) expressing high levels of granzyme and engineered to express the high affinity CD16 allele | journal = Oncotarget | volume = 7 | issue = 52 | pages = 86359–86373 | date = December 2016 | pmid = 27861156 | pmc = 5341330 | doi = 10.18632/oncotarget.13411 | s2cid = 3464303 }}</ref><ref>{{cite journal | vauthors = Snyder KM, Hullsiek R, Mishra HK, Mendez DC, Li Y, Rogich A, Kaufman DS, Wu J, Walcheck B | display-authors = 6 | title = Expression of a Recombinant High Affinity IgG Fc Receptor by Engineered NK Cells as a Docking Platform for Therapeutic mAbs to Target Cancer Cells | journal = Frontiers in Immunology | volume = 9 | pages = 2873 | year = 2018 | pmid = 30574146 | pmc = 6291448 | doi = 10.3389/fimmu.2018.02873 | doi-access = free }}</ref> These high affinity NK-92 cells can perform ADCC and have greatly expanded therapeutic utility.<ref>Klingemann H. "Engineered, Off the Shelf, NK Cell Lines for Targeted Cancer Immuno-therapy." Frontiers in Cancer Immunotherapy, NYAS April 26–27, 2018. www.nyas.org/Immunotherapy2018</ref><ref name="ReferenceA">{{cite journal | vauthors = Boissel L, Betancur-Boissel M, Lu W, Krause DS, Van Etten RA, Wels WS, Klingemann H | title = Retargeting NK-92 cells by means of CD19- and CD20-specific chimeric antigen receptors compares favorably with antibody-dependent cellular cytotoxicity | journal = Oncoimmunology | volume = 2 | issue = 10 | pages = e26527 | date = October 2013 | pmid = 24404423 | pmc = 3881109 | doi = 10.4161/onci.26527 }}</ref><ref>{{cite web | url=https://www.onclive.com/view/nk-cell-targeting-strategies-come-into-their-own | title=NK Cell–Targeting Strategies Come into Their Own | date=16 April 2021 }}</ref><ref>{{cite journal | vauthors = Fabian KP, Hodge JW | title = The emerging role of off-the-shelf engineered natural killer cells in targeted cancer immunotherapy | journal = Molecular Therapy Oncolytics | volume = 23 | pages = 266–276 | date = December 2021 | pmid = 34761106 | pmc = 8560822 | doi = 10.1016/j.omto.2021.10.001 | s2cid = 239089319 }}</ref>

NK-92 cells have also been engineered to expressed chimeric antigen receptors (CARs), in an approach similar to that used for T cells. An example of this is an NK-92 derived cell engineered with both a CD16 and an anti-PD-L1 CAR; currently in clinical development for oncology indications.<ref>{{cite web | url=https://www.clinicaltrials.gov/ct2/show/NCT04050709?term=t-haNK&cond=cancer&draw=2&rank=1 | title=Open-Label Phase 1 Study of PD-L1 t-haNK in Subjects with Locally Advanced or Metastatic Solid Cancers | date=9 May 2022 }}</ref><ref>{{cite journal | vauthors = Robbins Y, Greene S, Friedman J, Clavijo PE, Van Waes C, Fabian KP, Padget MR, Abdul Sater H, Lee JH, Soon-Shiong P, Gulley J, Schlom J, Hodge JW, Allen CT | display-authors = 6 | title = Tumor control via targeting PD-L1 with chimeric antigen receptor modified NK cells | journal = eLife | volume = 9 | date = July 2020 | pmid = 32633234 | pmc = 7340502 | doi = 10.7554/eLife.54854 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Fabian KP, Padget MR, Donahue RN, Solocinski K, Robbins Y, Allen CT, Lee JH, Rabizadeh S, Soon-Shiong P, Schlom J, Hodge JW | display-authors = 6 | title = PD-L1 targeting high-affinity NK (t-haNK) cells induce direct antitumor effects and target suppressive MDSC populations | journal = Journal for Immunotherapy of Cancer | volume = 8 | issue = 1 | pages = e000450 | date = May 2020 | pmid = 32439799 | pmc = 7247398 | doi = 10.1136/jitc-2019-000450 }}</ref> A clinical grade NK-92 variant that expresses a CAR for HER2 (ErbB2) has been generated<ref>{{cite journal | vauthors = Zhang C, Burger MC, Jennewein L, Genßler S, Schönfeld K, Zeiner P, Hattingen E, Harter PN, Mittelbronn M, Tonn T, Steinbach JP, Wels WS | display-authors = 6 | title = ErbB2/HER2-Specific NK Cells for Targeted Therapy of Glioblastoma | journal = Journal of the National Cancer Institute | volume = 108 | issue = 5 | date = May 2016 | pmid = 26640245 | doi = 10.1093/jnci/djv375 | doi-access = free }}</ref> and is in a clinical study in patients with HER2 positive [[glioblastoma]].<ref>{{cite journal | vauthors = Burger MC, Zhang C, Harter PN, Romanski A, Strassheimer F, Senft C, Tonn T, Steinbach JP, Wels WS | display-authors = 6 | title = CAR-Engineered NK Cells for the Treatment of Glioblastoma: Turning Innate Effectors Into Precision Tools for Cancer Immunotherapy | journal = Frontiers in Immunology | volume = 10 | pages = 2683 | year = 2019 | pmid = 31798595 | pmc = 6868035 | doi = 10.3389/fimmu.2019.02683 | doi-access = free }}</ref> Several other clinical grade clones have been generated expressing the CARs for PD-L1, CD19, HER-2, and EGFR.<ref>{{cite journal | vauthors = Romanski A, Uherek C, Bug G, Seifried E, Klingemann H, Wels WS, Ottmann OG, Tonn T | display-authors = 6 | title = CD19-CAR engineered NK-92 cells are sufficient to overcome NK cell resistance in B-cell malignancies | journal = Journal of Cellular and Molecular Medicine | volume = 20 | issue = 7 | pages = 1287–1294 | date = July 2016 | pmid = 27008316 | pmc = 4929308 | doi = 10.1111/jcmm.12810 }}</ref><ref name="ReferenceA"/> 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.<ref>{{cite web | url=https://immunitybio.com/immunitybio-announces-nih-led-research-affirming-that-pd-l1-t-hank-therapy-overcomes-t-cell-escape-in-multiple-types-of-resistant-tumors/ | title=ImmunityBio Announces NIH-Led Research Affirming that PD-L1 T-haNK Therapy Overcomes T-Cell Escape in Multiple Types of Resistant Tumors | date=22 March 2021 }}</ref>

=== NKG2D-Fc fusion protein ===
In a study at Boston Children's Hospital, in coordination with [[Dana–Farber Cancer Institute]], in which immunocompromised mice had contracted [[lymphomas]] from [[Epstein-Barr virus|EBV]] infection, an NK-activating receptor called [[NKG2D]] was fused with a stimulatory [[Fc region|Fc]] portion of the EBV antibody.  The NKG2D-Fc fusion proved capable of reducing tumor growth and prolonging survival of the recipients.  In a transplantation model of LMP1-fueled lymphomas, the NKG2D-Fc fusion proved capable of reducing tumor growth and prolonging survival of the recipients.

In Hodgkin lymphoma, in which the malignant Hodgkin Reed-Sternberg cells are typically HLA class I deficient, immune evasion is in part mediated by skewing towards an exhausted PD-1hi NK cell phenotype, and re-activation of these NK cells appears to be one mechanism of action induced by checkpoint-blockade.<ref name="pmid29449276">{{cite journal | vauthors = Vari F, Arpon D, Keane C, Hertzberg MS, Talaulikar D, Jain S, Cui Q, Han E, Tobin J, Bird R, Cross D, Hernandez A, Gould C, Birch S, Gandhi MK | display-authors = 6 | title = Immune evasion via PD-1/PD-L1 on NK cells and monocyte/macrophages is more prominent in Hodgkin lymphoma than DLBCL | journal = Blood | volume = 131 | issue = 16 | pages = 1809–1819 | date = April 2018 | pmid = 29449276 | pmc = 5922274 | doi = 10.1182/blood-2017-07-796342 }}</ref>

=== TLR ligands ===
Signaling through [[Toll-like receptor|TLR]] can effectively activate NK cell effector functions ''in vitro'' and ''in vivo''. TLR ligands are then potentially able to enhance NK cell effector functions during NK cell anti-tumor [[immunotherapy]].<ref name=":4" />

[[Trastuzumab]] is a [[Monoclonal antibody|monoclonal]] anti-HER2 [[antibody]] that is used as a treatment of the [[HER2|HER2+]] [[breast cancer]].<ref>{{cite journal | vauthors = Baselga J, Perez EA, Pienkowski T, Bell R | title = Adjuvant trastuzumab: a milestone in the treatment of HER-2-positive early breast cancer | journal = The Oncologist | volume = 11 | issue = Suppl 1 | pages = 4–12 | date = 2006-09-01 | pmid = 16971734 | doi = 10.1634/theoncologist.11-90001-4 | doi-access = free }}</ref> NK cells are an important part of the therapeutical effect of trastzumab as NK cells recognize the antibody coated cancer cells which induces [[Antibody-dependent cellular cytotoxicity|ADCC]] (antibody-dependent cellular cytotoxicity) reaction. TLR ligand is used in addition to trastuzumab as a means to enhance its effect. The [[Polysaccharide-K|polysaccharide krestin]], which is extracted from ''[[Trametes versicolor]]'', is a potent ligand of [[Toll-like receptor 2|TLR-2]] and so activates NK cells, induces the production of [[IFNG|IFNg]] and enhances the [[Antibody-dependent cellular cytotoxicity|ADCC]] caused by recognition of trastuzumab-coated cells.<ref>{{cite journal | vauthors = Lu H, Yang Y, Gad E, Inatsuka C, Wenner CA, Disis ML, Standish LJ | title = TLR2 agonist PSK activates human NK cells and enhances the antitumor effect of HER2-targeted monoclonal antibody therapy | journal = Clinical Cancer Research | volume = 17 | issue = 21 | pages = 6742–6753 | date = November 2011 | pmid = 21918170 | pmc = 3206987 | doi = 10.1158/1078-0432.CCR-11-1142 }}</ref>

Stimulation of [[Toll-like receptor 7|TLR-7]] induces the expression of [[Interferon type I|IFN type I]] and other pro-inflammatory cytokines like [[IL-1B|IL-1b]], [[Interleukin 6|IL-6]] and [[Interleukin 12|IL-12]]. Mice suffering with [[NK cell-sensitive lymphoma RMA-S]] were treated with SC1 molecule. SC1 is novel small-molecule TLR-7 agonist and its repeated administration reportedly activated NK cells in TLR-7- and IFN type I- dependent manner thus reversing the NK cell [[anergy]] which ultimately lead to [[lysis]] of the tumor.<ref>{{cite journal | vauthors = Wiedemann GM, Jacobi SJ, Chaloupka M, Krächan A, Hamm S, Strobl S, Baumgartner R, Rothenfusser S, Duewell P, Endres S, Kobold S | display-authors = 6 | title = A novel TLR7 agonist reverses NK cell anergy and cures RMA-S lymphoma-bearing mice | journal = Oncoimmunology | volume = 5 | issue = 7 | pages = e1189051 | date = July 2016 | pmid = 27622045 | pmc = 5006928 | doi = 10.1080/2162402X.2016.1189051 }}</ref>

[[VTX-2337]] is a selective [[Toll-like receptor 8|TLR-8]] agonist and together with [[monoclonal antibody]] [[cetuximab]] it was used as a potential therapy for the treatment of recurrent or metastatic [[SCCHN]]. Results have shown that the NK cells had become more reactive to the treatment with [[cetuximab]] antibody upon pretreatment with VTX-2337. This indicates that the stimulation of TLR-8 and subsequent activation of [[inflammasome]] enhances the [[Fc receptor|CD-16]] mediated [[Antibody-dependent cellular cytotoxicity|ADCC]] reaction in patients treated with [[cetuximab]] antibody.<ref>{{cite journal | vauthors = Dietsch GN, Lu H, Yang Y, Morishima C, Chow LQ, Disis ML, Hershberg RM | title = Coordinated Activation of Toll-Like Receptor8 (TLR8) and NLRP3 by the TLR8 Agonist, VTX-2337, Ignites Tumoricidal Natural Killer Cell Activity | journal = PLOS ONE | volume = 11 | issue = 2 | pages = e0148764 | date = 2016 | pmid = 26928328 | pmc = 4771163 | doi = 10.1371/journal.pone.0148764 | doi-access = free | bibcode = 2016PLoSO..1148764D }}</ref>

NK cells play a role in controlling [[HIV-1]] infection. TLR are potent enhancers of innate antiviral immunity and potentially can reverse HIV-1 latency. Incubation of [[peripheral blood mononuclear cell]]s with novel potent [[Toll-like receptor 9|TLR-9]] ligand [[MGN1703]] have resulted in enhancement of NK cell effector functions, thus significantly inhibiting the spread of HIV-1 in culture of [[autologous]] [[Cd4+ t cells|CD4+ T-cells]]. The stimulation of TLR-9 in NK cells induced a strong antiviral innate immune response, an increase in HIV-1 [[Transcription (biology)|transcription]] (indicating the reverse in latency of the virus) and it also boosted the NK cell-mediated suppression of HIV-1 infections in autologous CD4+ T cells.<ref>{{cite journal | vauthors = Offersen R, Nissen SK, Rasmussen TA, Østergaard L, Denton PW, Søgaard OS, Tolstrup M | title = A Novel Toll-Like Receptor 9 Agonist, MGN1703, Enhances HIV-1 Transcription and NK Cell-Mediated Inhibition of HIV-1-Infected Autologous CD4+ T Cells | journal = Journal of Virology | volume = 90 | issue = 9 | pages = 4441–4453 | date = May 2016 | pmid = 26889036 | pmc = 4836316 | doi = 10.1128/JVI.00222-16 }}</ref>

==New findings==

===Innate resistance to HIV===
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]].<ref name=Lannello2008/> Certain HLA allotypes have been found to determine the progression of HIV to AIDS; an example is the [[HLA-B57]] and [[HLA-B27]] alleles, which have been found to delay progression from HIV to AIDS. This is evident because patients expressing these HLA alleles are observed to have lower viral loads and a more gradual decline in [[T helper cell|CD4<sup>+</sup> 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. <!-- Future research will aim to pinpoint relevant KIR/HLA interactions, to develop a vaccine against HIV/AIDS. -->

NK cells can impose immune pressure on HIV, which had previously been described only for T cells and antibodies.<ref name="Alter et al.">{{cite journal | vauthors = Alter G, Heckerman D, Schneidewind A, Fadda L, Kadie CM, Carlson JM, Oniangue-Ndza C, Martin M, Li B, Khakoo SI, Carrington M, Allen TM, Altfeld M | display-authors = 6 | title = HIV-1 adaptation to NK-cell-mediated immune pressure | journal = Nature | volume = 476 | issue = 7358 | pages = 96–100 | date = August 2011 | pmid = 21814282 | pmc = 3194000 | doi = 10.1038/nature10237 }}</ref> HIV mutates to avoid NK cell detection.<ref name="Alter et al."/>

=== Tissue-resident NK cells ===
Most of our current knowledge is derived from investigations of mouse splenic and human peripheral blood NK cells. However, in recent years tissue-resident NK cell populations have been described.<ref name=":0">{{cite journal | vauthors = Yokoyama WM, Sojka DK, Peng H, Tian Z | title = Tissue-resident natural killer cells | journal = Cold Spring Harbor Symposia on Quantitative Biology | volume = 78 | pages = 149–156 | date = 2013-01-01 | pmid = 24584057 | doi = 10.1101/sqb.2013.78.020354 | doi-access = free }}</ref><ref name=":1">{{cite journal | vauthors = Sojka DK, Plougastel-Douglas B, Yang L, Pak-Wittel MA, Artyomov MN, Ivanova Y, Zhong C, Chase JM, Rothman PB, Yu J, Riley JK, Zhu J, Tian Z, Yokoyama WM | display-authors = 6 | title = Tissue-resident natural killer (NK) cells are cell lineages distinct from thymic and conventional splenic NK cells | journal = eLife | volume = 3 | pages = e01659 | date = January 2014 | pmid = 24714492 | pmc = 3975579 | doi = 10.7554/elife.01659 | doi-access = free }}</ref> These tissue-resident NK cells share transcriptional similarity to tissue-resident memory T cells described previously. However, tissue-resident NK cells are not necessarily of the memory phenotype, and in fact, the majority of the tissue-resident NK cells are functionally immature.<ref name = Dogra2020>{{cite journal | vauthors = Dogra P, Rancan C, Ma W, Toth M, Senda T, Carpenter DJ, Kubota M, Matsumoto R, Thapa P, Szabo PA, Li Poon MM, Li J, Arakawa-Hoyt J, Shen Y, Fong L, Lanier LL, Farber DL | display-authors = 6 | title = Tissue Determinants of Human NK Cell Development, Function, and Residence | journal = Cell | volume = 180 | issue = 4 | pages = 749–763.e13 | date = February 2020 | pmid = 32059780 | pmc = 7194029 | doi = 10.1016/j.cell.2020.01.022 }}</ref> These specialized NK-cell subsets can play a role in organ homeostasis. For example, NK cells are enriched in the human liver with a specific phenotype and take part in the control of liver fibrosis.<ref name=":2">{{cite journal | vauthors = Hudspeth K, Donadon M, Cimino M, Pontarini E, Tentorio P, Preti M, Hong M, Bertoletti A, Bicciato S, Invernizzi P, Lugli E, Torzilli G, Gershwin ME, Mavilio D | display-authors = 6 | title = Human liver-resident CD56(bright)/CD16(neg) NK cells are retained within hepatic sinusoids via the engagement of CCR5 and CXCR6 pathways | journal = Journal of Autoimmunity | volume = 66 | pages = 40–50 | date = January 2016 | pmid = 26330348 | pmc = 4718768 | doi = 10.1016/j.jaut.2015.08.011 }}</ref><ref name=":3">{{cite journal | vauthors = Fasbender F, Widera A, Hengstler JG, Watzl C | title = Natural Killer Cells and Liver Fibrosis | language = English | journal = Frontiers in Immunology | volume = 7 | pages = 19 | date = 2016 | pmid = 26858722 | pmc = 4731511 | doi = 10.3389/fimmu.2016.00019 | doi-access = free }}</ref> Tissue-resident NK cells have also been identified in sites like bone marrow, spleen and more recently, in lung, intestines and lymph nodes. In these sites, tissue-resident NK cells may act as reservoir for maintaining immature NK cells in humans throughout life.<ref name = Dogra2020 />

=== Adaptive NK cells against leukemia targets ===
Natural killer cells are being investigated as an emerging treatment for patients with acute myeloid leukemia (AML), and cytokine-induced memory-like NK cells have shown promise with their enhanced antileukemia functionality.<ref name="Romee2016"/> It has been shown that this kind of NK cell has enhanced interferon-γ production and cytotoxicity against leukemia cell lines and primary AML blasts in patients.<ref name="Romee2016"/> During a phase 1 clinical trial, five out of nine patients exhibited clinical responses to the treatment, and four patients experienced a complete remission, which suggests that these NK cells have major potential as a successful translational immunotherapy approach for patients with AML in the future.<ref name="Romee2016">{{cite journal | vauthors = Romee R, Rosario M, Berrien-Elliott MM, Wagner JA, Jewell BA, Schappe T, Leong JW, Abdel-Latif S, Schneider SE, Willey S, Neal CC, Yu L, Oh ST, Lee YS, Mulder A, Claas F, Cooper MA, Fehniger TA | display-authors = 6 | title = Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia | journal = Science Translational Medicine | volume = 8 | issue = 357 | pages = 357ra123 | date = September 2016 | pmid = 27655849 | pmc = 5436500 | doi = 10.1126/scitranslmed.aaf2341 }}</ref>

== See also ==
* [[Active hexose correlated compound]]
* [[Granzyme]]s
* [[Hematopoiesis]]
* [[Immune system]]
* [[Interleukin]]
* [[Lymphatic system]]
* [[List of distinct cell types in the adult human body]]

== References ==
{{Reflist}}

== Further reading ==
{{refbegin}}
* {{cite journal | vauthors = Perera Molligoda Arachchige AS | title = Human NK cells: From development to effector functions | journal = Innate Immunity | volume = 27 | issue = 3 | pages = 212–229 | date = April 2021 | pmid = 33761782 | pmc = 8054151 | doi = 10.1177/17534259211001512 }}
* {{cite book | title = Cellular and Molecular Immunology | vauthors = Abbas AK, Lichtman A | publisher = Saunders | date = 2003 }}
* {{cite book | title = How the Immune System Works | edition = 2nd | vauthors = Sompayrac L | publisher = Blackwell Publishing | date = 2003 }}
* {{cite book | title = Immunobiology: The Immune System In Health And Disease | edition = 5th | vauthors = Janeway Jr CA, Travers P, Walport M, Shlomchik MJ | isbn = 0-8153-3642-X | date = 2001 | publisher = Garland Science | url = https://www.ncbi.nlm.nih.gov/books/NBK10757/ }}
* {{cite book | title = Kuby Immunology | edition = 6th | vauthors = Kindt TJ, Goldsby RA, Osborne BA | publisher = W.H. Freeman and Company | location = New York }}
{{refend}}

== External links ==
{{Commons category|NK cells| natural killer cell}}
* {{MeshName|Natural+Killer+Cells}}

{{Lymphocytes}}
{{Immune system}}
{{Authority control}}

[[Category:Human cells]]
[[Category:Immune system]]
[[Category:Lymphocytes]]