Natural cytotoxicity triggering receptor 3 is aprotein that in humans is encoded by theNCR3gene.[3][4][5] NCR3 has also been designated asCD337 (cluster of differentiation 337) and asNKp30. NCR3 belongs to the family of NCR membrane receptors together withNCR1 (NKp46) andNCR2 (NKp44).[6]
NKp30 receptor was first identified in 1999. According toWestern blot analysis specific monoclonal antibodies reacted with 30kDa molecule, therefore was the protein named NKp30.[7]
Gene for NKp30 is located in theMHC class III region of the human MHC locus and encodes 190 amino acid long type I transmembrane receptor which belongs toimmunoglobulin super family (IgSF).[7][8] NKp30 has a mass of 30 kDa and includes oneIg-like extracellular domain which is 138 amino acids long, a 19 amino acidtransmembrane (TM) domain and a 33 amino acid cytoplasmic tail.[7][6][9] The Ig-like domain consists of 2 antiparallelbeta-sheets linked by adisulphide bond.[9][10] The extracellular domain contains two potential sites forN-linked glycosylation involved in ligand binding.[7] The TM domain contains a positivelly chargedarginine residue, which associates with negatively chargedaspartate in TM domain ofITAMadaptor moleculesCD3ζ andFCεRIγ. This is a common feature of other NK cell activating receptors as well.[7][9][11] Accordingly the cytoplasmic tail lacks typical ITAM consensus sequence.
Six different splicing variants can be found on the cell surface. NKp30a, NKp30b and NKp30c encode molecules with extracellular V-type Ig domain. NKp30d, NKp30e and NKp30f encode extracellular C-type Ig domain. Splicing variants also differ in their cytosolic intracellular domains depending on the translation of variants of exon 4 (NKp30a,b or c).[6][8]
The distribution of splicing variants of NKp30 varies in tissues and results in different NK cell responses. NKp30a/b engagement stimulates the release of high amounts of IFN-γ, whereas activation of NKp30c induces IL-10 production and only small amounts of IFN-γ. First two are therefore considered as immunostimulatory isoforms which enhance Th1 immune response, while NKp30c mediates immunosuppressive signaling most likely because of reduced association with CD3ζ adaptor after cross-linking with ligand.[8]
Gastrointestinal stromal tumor patients who express NKp30c isoform have worse prognosis compared with patients expressing other isoforms, mainly as a consequence of NK cell immunosuppressive character.[8][12]
NCR3 is expressed mainly oncytoplasmic membrane of matureNK cells and functions as an activatingreceptor of NK cells. However it is also expressed on surface ofCD8+ T cells,γδ T cells with Vδ1TCR andILC2.[6][11] The presence ofIL-15 stimulates the expression of NKp30+ CD8+ T cells with anti-tumor activity.[6][13] Expression of NKp30 in γδ T cells is induced byIL-2 or IL-15.[6][14] After progesteron stimulation NKp30 can be found on the cytoplasmic membrane ofendometrial epithelial cells as well.[8]
Heparan sulfate epitopes are in healthy tissue as well as on tumor cells, where HS GAGs are changed or differ in ligands (HMGB1,S100A8/A9) in contrast to healthy tissue. In addition, interaction of NCR with HS GAGs can facilitate binding to other cellular ligands. Thus via heparan sulfate epitopes NCRs can bind to the same ligands and exert similar reactions and at the same time also have their own unique interacting partners. It is also known that heparan sulfate epitopes lead to better signaling through growth factor receptors, NCRs could be thus evolved to recognize unusual HS GAGs on malignant cells as transformed cell patterns.[15]
Human cytomegalovirus proteinpp65 is another ligand of NKp30. The ligation leads to disruption of the interaction between NKp30 and CD3ζ and thus decreases the activation of NK cells and its cytotoxicity. This is a mechanism of HMCV to evade NK cell surveillance.[8][9][17]
Patients with primarySjögren's syndrome express higher levels of NKp30+ NK cells (and its ligation with B7-H6 expressed in salivary glands) in comparison to healthy controls.[6]
Immature dendritic cells can be lysed upon stimulation of NKp30 on NK cells.[8] Accordingly. patients withacute myeloid leukemia (AML), who often show downregulation in NKp30 expression, were incapable of effectively lysing both autologous and allogeneic immature dendritic cells. The ability of NK cells to kill immature dendritic cells may serve to check the quality of dendritic cell maturation process.[16] Interestingly at the same time immunostimulatory capacity of dendritic cells can be enhanced via interaction with NKp30 with ligands expressed on immature dendritic cells.[8] Upon such stimulation NK cells produceTNFα which is capable of inducing dendritic cell maturation.[16]
Uterine NK cells (uNK) are the most abundantlymphocyte population inuterus duringpregnancy on the maternal-fetal interface. These cells are responsible forangiogenesis and vascular remodelling introphoblast.[18][19] uNK cells express NKp30 and its ligands are expressed by trophoblast cells. Though these ligands have not yet been identified, this interaction has a potential to regulate fetal-maternal interface.[20][6] The uNK cells dominantly express the inhibitory NKp30c isoform.[21]
^Sato M, Ohashi J, Tsuchiya N, Tadokoro K, Juji T, Hanaoka K, et al. (October 2001). "Identification of novel single nucleotide substitutions in the NKp30 gene expressed in human natural killer cells".Tissue Antigens.58 (4):255–8.doi:10.1034/j.1399-0039.2001.580406.x.PMID11782277.
^Correia DV, Fogli M, Hudspeth K, da Silva MG, Mavilio D, Silva-Santos B (July 2011). "Differentiation of human peripheral blood Vδ1+ T cells expressing the natural cytotoxicity receptor NKp30 for recognition of lymphoid leukemia cells".Blood.118 (4):992–1001.doi:10.1182/blood-2011-02-339135.hdl:2434/223196.PMID21633088.
^abcMoretta A, Bottino C, Vitale M, Pende D, Cantoni C, Mingari MC, et al. (April 2001). "Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis".Annual Review of Immunology.19 (1):197–223.doi:10.1146/annurev.immunol.19.1.197.PMID11244035.
^Hanna J, Goldman-Wohl D, Hamani Y, Avraham I, Greenfield C, Natanson-Yaron S, et al. (September 2006). "Decidual NK cells regulate key developmental processes at the human fetal-maternal interface".Nature Medicine.12 (9):1065–74.doi:10.1038/nm1452.PMID16892062.S2CID19158471.
Djeu JY, Jiang K, Wei S (March 2002). "A view to a kill: signals triggering cytotoxicity".Clinical Cancer Research.8 (3):636–40.PMID11895890.
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