Editing Natural killer cell (section)

==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.