NKG2 also known as CD159 (Cluster of Differentiation 159) is a receptor for natural killer cells (NK 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).
killer cell lectin-like receptor subfamily C, member 1 | |||||||
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Identifiers | |||||||
Symbol | KLRC1 | ||||||
Alt. symbols | NKG2, NKG2-A, NKG2-B, CD159a | ||||||
NCBI gene | 3821 | ||||||
HGNC | 6374 | ||||||
OMIM | 161555 | ||||||
RefSeq | NM_007328 | ||||||
UniProt | P26715 | ||||||
Other data | |||||||
Locus | Chr. 12 p13 | ||||||
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IPH2201 is a monoclonal antibody targeted at NKG2A.[1]
Gene expression
editIn both humans and mice, genes encoding the NKG2 family are clustered – in human genome on chromosome 12, in mouse on chromosome 6.[2] They are generally expressed on NK cells and a subset of CD8+ T cells, although the expression of NKG2D was also confirmed on
On NK cells, NKG2 genes are expressed through the ontogeny as well as in adulthood. As about 90% of fetal NK cells express NKG2 genes, one of the proposed functions of the gene family is contribution to self-tolerance.[4] The level of expression of NKG2 genes is not constant, rather it is affected by cytokine environment (mainly interleukin-2 (IL-2), IL-7 and IL-15).[5]
For CD8+ T lymphocytes, NKG2 family expression is believed to be a marker of activated or memory T cells. The expression is triggered namely by IL-15, IL-12, IL-10 and TGF-
Structure
editNKG2 are members of the C-type lectin-like receptor superfamily. NKG2A, -B, -C, -E and -H form heterodimers with CD94, linked by disulfide bonds, whereas NKG2D forms homodimers.[6]
Inhibitory molecules NKG2A and its splice variant NKG2B contain immunoreceptor tyrosine-based inhibition motifs (ITIMs) in the intracellular part of the molecule. Activatory molecules NKG2C, NKG2E and its splice variant NKG2H do not have an activating immunoreceptor tyrosine-based activation motifs (ITAMs) in their molecule. Rather, they contain a positively charged residue in their transmembrane regions by which they interact with adaptor molecules containing ITAMs, mainly DNAX-activating protein of 12 kDa (DAP-12).[4]
NKG2D pairs with either DAP-12 or DAP-10, depending on the isoform. There are two isoforms in mice – the long isoform (NKG2D-L) pairs only with DAP-10, whereas the short isoform (NKG2-S) can also pair with DAP-12. Only long isoform is present in humans.[6]
NKG2F also does not dimerize with CD94, rather it associates with DAP-12. It is only expressed on membranes of intracellular compartments.[2]
Signalling
editInhibitory NKG2 molecules containing ITIMs recruite the Src homology 2 domain containing phosphatases SHP-1 and SHP-2, which leads to the inhibition of cytotoxicity. ITAMs, included in DAP-12, on the other hand, recruite the Src homology domain containing kinases Syk (spleen tyrosine kinase) or Zap70 (Zeta-chain-associated protein kinase 70). Kinase activation is followed by NK cell degranulation and transcription of cytokine and chemokine genes.[6]
DAP-10 connects to GRB2 or p85, leading to signalling through phosphoinositide 3-kinase (PI3K) and other molecules, leading to cytotoxicity.[6]
Ligands
editLigands of CD94/NKG2 heterodimeric molecules are nonclassical MHC class I molecules – Qa1b molecules in mice and HLA-E in humans. These molecules both present sequences from the digested leading peptides of classical MHC class I molecules. This enables the monitoring of classical MHC class I expression on target cells.[6]
NKG2D recognizes mostly stress-induced proteins, namely human MHC class-I-chain related protein (MIC-A) and MIC-B, and also other stress-induced proteins common to humans and mice – retinoic acid early transcript 1 (Rae1) and RAET1 in humans, H60 and UL16-binding protein-like transcript 1 (Mult1) in mice, and the UL16-binding proteins (ULBPs) in humans.[3]
Function
editNKG2A was documented to promote survival in T cells. Along with its splice variant NKG2B, these molecules are inhibitory and lead to a decrease in cytotoxicity. NKG2C and NKG2E (and its splice variant NKG2H) recognize the same ligand with different (usually lower in physiological conditions) affinity. However, the affinity for HLA-E (or Qa1b) can drastically change after a small change in the presented peptide, which can lead to NK cell activation.[4]
CD94/NKG2 and their ligands can also play a role in certain diseases, where their expression can be modified on different cell types. These include viral and bacterial infections by HCMV, HIV-1 and Hepatitis virus type C (HCV) in humans, or LCMV, HSV-1, Influenza and Listeria monocytogenes infections in mice. In cancers, a role of CD94/NKG2 was demonstrated for melanoma, cervical cancer, lymphoma/leukemia and more. NKG2 match can also prevent graft versus leukemia effect (GvL) as well as the graft versus host disease (GvHD).[2]
NKG2D is an activating receptor playing a role in the cell-mediated control of some cancers. Many tumors avoid the cytotoxicity by excreting soluble NKG2D ligands or secreting TGF-
See also
editReferences
edit- ^ AstraZeneca Inks $1.8B in Immuno-Oncology Deals as Q1 Profit Dips
- ^ a b c Borrego F, Masilamani M, Marusina AI, Tang X, Coligan JE (2006). "The CD94/NKG2 family of receptors: from molecules and cells to clinical relevance". Immunologic Research. 35 (3): 263–78. doi:10.1385/IR:35:3:263. PMID 17172651. S2CID 8949036.
- ^ a b c Raulet DH (October 2003). "Roles of the NKG2D immunoreceptor and its ligands". Nature Reviews. Immunology. 3 (10): 781–90. doi:10.1038/nri1199. PMID 14523385. S2CID 18234848.
- ^ a b c d Gunturi A, Berg RE, Forman J (2004). "The role of CD94/NKG2 in innate and adaptive immunity". Immunologic Research. 30 (1): 29–34. doi:10.1385/IR:30:1:029. PMID 15258309. S2CID 8693028.
- ^ López-Soto A, Huergo-Zapico L, Acebes-Huerta A, Villa-Alvarez M, Gonzalez S (April 2015). "NKG2D signaling in cancer immunosurveillance". International Journal of Cancer. 136 (8): 1741–50. doi:10.1002/ijc.28775. PMID 24615398. S2CID 30489883.
- ^ a b c d e Pegram HJ, Andrews DM, Smyth MJ, Darcy PK, Kershaw MH (February 2011). "Activating and inhibitory receptors of natural killer cells". Immunology and Cell Biology. 89 (2): 216–24. doi:10.1038/icb.2010.78. PMID 20567250. S2CID 205150594.
External links
edit- NKG2+protein at the U.S. National Library of Medicine Medical Subject Headings (MeSH)