Editing Natural killer cell (section)

==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.