Natural cytotoxicity triggering receptor 3 is a protein that in humans is encoded by the NCR3 gene. [3] [4] [5] NCR3 has also been designated as CD337 (cluster of differentiation 337) and as NKp30. NCR3 belongs to the family of NCR membrane receptors together with NCR1 (NKp46) and NCR2 (NKp44). [6]
NKp30 receptor was first identified in 1999. According to Western blot analysis specific monoclonal antibodies reacted with 30kDa molecule, therefore was the protein named NKp30. [7]
Gene for NKp30 is located in the MHC class III region of the human MHC locus and encodes 190 amino acid long type I transmembrane receptor which belongs to immunoglobulin super family (IgSF). [7] [8] NKp30 has a mass of 30 kDa and includes one Ig-like extracellular domain which is 138 amino acids long, a 19 amino acid transmembrane (TM) domain and a 33 amino acid cytoplasmic tail. [7] [6] [9] The Ig-like domain consists of 2 antiparallel beta-sheets linked by a disulphide bond. [9] [10] The extracellular domain contains two potential sites for N-linked glycosylation involved in ligand binding. [7] The TM domain contains a positivelly charged arginine residue, which associates with negatively charged aspartate in TM domain of ITAM adaptor molecules CD3ζ and FCεRIγ. 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 on cytoplasmic membrane of mature NK cells and functions as an activating receptor of NK cells. However it is also expressed on surface of CD8+ T cells, γδ T cells with Vδ1 TCR and ILC2. [6] [11] The presence of IL-15 stimulates the expression of NKp30+ CD8+ T cells with anti-tumor activity. [6] [13] Expression of NKp30 in γδ T cells is induced by IL-2 or IL-15. [6] [14] After progesteron stimulation NKp30 can be found on the cytoplasmic membrane of endometrial epithelial cells as well. [8]
NKp30 plays a major role in NK anti-tumor response and immunosurveillance, mainly by activating NK cell cytotoxicity and cytokine secretion. [6] [15] Direct killing happens similarly to other natural cytotoxicity receptors (NCRs) such as NKp44 and NKp46. [7] [16] NCR3 has a wide range of non-MHC ligands secreted or expressed by cancer or virus-infected cells, e.g. to heparan sulfate glycosaminoglycans (HS GAGs) and B7-H6. [6] [9] [17] [15]
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]
Ligation of NKp30 and intracellular protein HLA-B-associated transcript 3 (BAT3) released by tumour cells to extracellular matrix results in NK and dendritic cell cross-talk. [6] [17] [10]
Human cytomegalovirus protein pp65 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 primary Sjögren'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 with acute 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 produce TNFα which is capable of inducing dendritic cell maturation. [16]
Uterine NK cells (uNK) are the most abundant lymphocyte population in uterus during pregnancy on the maternal-fetal interface. These cells are responsible for angiogenesis and vascular remodelling in trophoblast. [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]
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 (LGL), and belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represent 5–20% of all circulating lymphocytes in humans. The role of NK cells is analogous to that of cytotoxic T cells in the vertebrate adaptive immune response. NK cells provide rapid responses to virus-infected cells, stressed cells, tumor cells, and other intracellular pathogens based on signals from several activating and inhibitory receptors. Most immune cells detect the antigen presented on 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. 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.
CD155, also known as the poliovirus receptor, is a protein that in humans is encoded by the PVR gene. It is a transmembrane protein that is involved in forming junctions between neighboring cells. It is also the molecule that poliovirus uses to enter cells. The gene is specific to the primates.
Killer-cell immunoglobulin-like receptors (KIRs), are a family of type I transmembrane glycoproteins expressed on the plasma membrane of natural killer (NK) cells and a minority of T cells. In humans, they are encoded in the leukocyte receptor complex (LRC) on chromosome 19q13.4; the KIR region is approximately 150 kilobases and contains 14 loci, including 7 protein-coding genes and 2 pseudogenes.
CD16, also known as FcγRIII, is a cluster of differentiation molecule found on the surface of natural killer cells, neutrophils, monocytes, macrophages, and certain T cells. CD16 has been identified as Fc receptors FcγRIIIa (CD16a) and FcγRIIIb (CD16b), which participate in signal transduction. The most well-researched membrane receptor implicated in triggering lysis by NK cells, CD16 is a molecule of the immunoglobulin superfamily (IgSF) involved in antibody-dependent cellular cytotoxicity (ADCC). It can be used to isolate populations of specific immune cells through fluorescent-activated cell sorting (FACS) or magnetic-activated cell sorting, using antibodies directed towards CD16.
Ly49 is a family of membrane C-type lectin-like receptors expressed mainly on NK cells but also on other immune cells. Their primary role is to bind MHC-I molecules to distinguish between self healthy cells and infected or altered cells. Ly49 family is coded by Klra gene cluster and include genes for both inhibitory and activating paired receptors, but most of them are inhibitory. Inhibitory Ly49 receptors play a role in the recognition of self cells and thus maintain self-tolerance and prevent autoimmunity by suppressing NK cell activation. On the other hand, activating receptors recognise ligands from cancer or viral infected cells and are used when cells lack or have abnormal expression of MHC-I molecules, which activate cytokine production and cytotoxic activity of NK and immune cells.
NKG2 also known as CD159 is a receptor for natural killer cells. There are 7 NKG2 types: A, B, C, D, E, F and H. NKG2D is an activating receptor on the NK cell surface. NKG2A dimerizes with CD94 to make an inhibitory receptor (CD94/NKG2).
MHC class I polypeptide–related sequence A (MICA) is a highly polymorphic cell surface glycoprotein encoded by the MICA gene located within MHC locus. MICA is related to MHC class I and it has similar domain structure, however, it is not associated with β2-microglobulin nor binds peptides as conventional MHC class I molecules do. MICA rather functions as a stress-induced ligand (as a danger signal) for integral membrane protein receptor NKG2D ("natural-killer group 2, member D"). MICA is broadly recognized by NK cells, γδ T cells, and CD8+ αβ T cells which carry NKG2D receptor on their cell surface and which are activated via this interaction.
CD244 also known as 2B4 or SLAMF4 is a protein that in humans is encoded by the CD244 gene.
Natural cytotoxicity triggering receptor 1 is a protein that in humans is encoded by the NCR1 gene. NCR1 has also been designated as CD335 (cluster of differentiation, NKP46, NKp46, NK-p46, and LY94.
CD226, PTA1 or DNAM-1 is a ~65 kDa immunoglobulin-like transmembrane glycoprotein expressed on the surface of natural killer cells, NK T cell, B cells, dendritic cells, hematopoietic precursor cells, platelets, monocytes and T cells.
Leukocyte-specific transcript 1 protein is a protein that in humans is encoded by the LST1 gene.
Macrophage receptor with collagenous structure (MARCO) is a protein that in humans is encoded by the MARCO gene. MARCO is a class A scavenger receptor that is found on particular subsets of macrophages. Scavenger receptors are pattern recognition receptors (PRRs) found most commonly on immune cells. Their defining feature is that they bind to polyanions and modified forms of a type of cholesterol called low-density lipoprotein (LDL). MARCO is able to bind and phagocytose these ligands and pathogen-associated molecular patterns (PAMPs), leading to the clearance of pathogens and cell signaling events that lead to inflammation. As part of the innate immune system, MARCO clears, or scavenges, pathogens, which leads to inflammatory responses. The scavenger receptor cysteine-rich (SRCR) domain at the end of the extracellular side of MARCO binds ligands to activate the subsequent immune responses. MARCO expression on macrophages has been associated with tumor development and also with Alzheimer's disease, via decreased responses of cells when ligands bind to MARCO.
Natural cytotoxicity triggering receptor 2 is a protein that in humans is encoded by the NCR2 gene. NCR2 has also been designated as CD336, NKp44, NKP44; NK-p44, LY95, and dJ149M18.1.
UL16 binding protein 2 (ULBP2) is a cell surface glycoprotein encoded by ULBP2 gene located on the chromosome 6. ULBP2 is related to MHC class I molecules, but its gene maps outside the MHC locus. The domain structure of ULBP2 differs significantly from those of conventional MHC class I molecules. It does not contain the α3 domain and the transmembrane segment. ULBP2 is thus composed of only the α1α2 domain which is linked to the cell membrane by the GPI anchor.
CD160 antigen is a protein that in humans is encoded by the CD160 gene.
Interleukin-28 receptor is a type II cytokine receptor found largely in epithelial cells. It binds type 3 interferons, interleukin-28 A, Interleukin-28B, interleukin 29 and interferon lambda 4. It consists of an α chain and shares a common β subunit with the interleukin-10 receptor. Binding to the interleukin-28 receptor, which is restricted to select cell types, is important for fighting infection. Binding of the type 3 interferons to the receptor results in activation of the JAK/STAT signaling pathway.
NKG2D is an activating receptor (transmembrane protein) belonging to the NKG2 family of C-type lectin-like receptors. NKG2D is encoded by KLRK1 (killer cell lectin like receptor K1) gene which is located in the NK-gene complex (NKC) situated on chromosome 6 in mice and chromosome 12 in humans. In mice, it is expressed by NK cells, NK1.1+ T cells, γδ T cells, activated CD8+ αβ T cells and activated macrophages. In humans, it is expressed by NK cells, γδ T cells and CD8+ αβ T cells. NKG2D recognizes induced-self proteins from MIC and RAET1/ULBP families which appear on the surface of stressed, malignant transformed, and infected cells.
Cytokine-induced killer cells (CIK) cells are a group of immune effector cells featuring a mixed T- and natural killer (NK) cell-like phenotype. They are generated by ex vivo incubation of human peripheral blood mononuclear cells (PBMC) or cord blood mononuclear cells with interferon-gamma (IFN-γ), anti-CD3 antibody, recombinant human interleukin (IL)-1 and recombinant human interleukin (IL)-2.
An adaptive natural killer (NK) cell or memory-like NK cell is a specialized natural killer cell that has the potential to form immunological memory. They can be distinguished from cytotoxic NK (cNK) cells by their receptor expression profile and epigenome. Adaptive NK cells are so named for properties which they share with the adaptive immune system. Though adaptive NK cells do not possess antigen specificity, they exhibit dynamic expansions of defined cell subsets, increased proliferation and long-term persistence for up to 3 months in vivo, high IFN-γ production, potent cytotoxic activity upon ex vivo restimulation, and protective memory responses.
Paired receptors are pairs or clusters of receptor proteins that bind to extracellular ligands but have opposing activating and inhibitory signaling effects. Traditionally, paired receptors are defined as homologous pairs with similar extracellular domains and different cytoplasmic regions, whose genes are located together in the genome as part of the same gene cluster and which evolved through gene duplication. Homologous paired receptors often, but not always, have a shared ligand in common. More broadly, pairs of receptors have been identified that exhibit paired functional behavior - responding to a shared ligand with opposing intracellular signals - but are not closely homologous or co-located in the genome. Paired receptors are highly expressed in the cells of the immune system, especially natural killer (NK) and myeloid cells, and are involved in immune regulation.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
