| killer cell lectin-like receptor subfamily C, member 1 | |||||||
|---|---|---|---|---|---|---|---|
| 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. 12p13 | ||||||
| |||||||
NKG2 also known asCD159 (Cluster ofDifferentiation159) is a receptor family fornatural killer cells (NK cells). There are 7 NKG2 members: A, B, C, D, E, F and H.NKG2D is an activating receptor on the NK cell surface. NKG2A dimerizes withCD94 to make an inhibitory receptor (CD94/NKG2A).
IPH2201 is amonoclonal antibody targeted atNKG2A.[1]
In both humans and mice,genes encoding theNKG2 family are clustered – in humangenome onchromosome 12, in mouse on chromosome 6.[2] They are generally expressed onNK cells and a subset ofCD8+ T cells, although the expression ofNKG2D was also confirmed onγδ T cells,NKT cells, and even on some subsets ofCD4+ T cells or myeloid cells.NKG2D expression can also be present on cancer cells and is proven to stimulate oncogenic bioenergeticmetabolism, proliferation andmetastases generation.[3]
On NK cells,NKG2genes are expressed through theontogeny as well as inadulthood. As about 90% offetal NK cells expressNKG2 genes, one of the proposed functions of the gene family is contribution toself-tolerance.[4] The level of expression ofNKG2 genes is not constant, rather it is affected bycytokine environment (mainlyinterleukin-2 (IL-2),IL-7 andIL-15).[5]
ForCD8+ T lymphocytes,NKG2 family expression is believed to be a marker of activated ormemory T cells. The expression is triggered namely byIL-15,IL-12,IL-10 andTGF-β.CD94/NKG2 expression is shown to significantly increase the survival ofT cells.[4]
NKG2 are members of theC-type lectin-like receptor superfamily. NKG2A, -B, -C, -E and -H formheterodimers withCD94, linked bydisulfide bonds, whereas NKG2D formshomodimers.[6]
Inhibitory moleculesNKG2A and its splice variantNKG2B contain immunoreceptor tyrosine-based inhibition motifs (ITIMs) in the intracellular part of themolecule. Activatory moleculesNKG2C,NKG2E and its splice variantNKG2H do not have an activating immunoreceptor tyrosine-based activation motifs (ITAMs) in their molecule. Rather, they contain a positively charged residue in theirtransmembrane regions by which they interact withadaptor molecules containingITAMs, mainly DNAX-activating protein of 12 kDa (DAP-12).[4]
NKG2D pairs with eitherDAP-12 orDAP-10, depending on theisoform. 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 withCD94, rather it associates withDAP-12. It is only expressed onmembranes ofintracellular compartments.[2]
Inhibitory NKG2molecules containingITIMs recruite the Src homology 2 domain containing phosphatasesSHP-1 andSHP-2, which leads to the inhibition ofcytotoxicity.ITAMs, included inDAP-12, on the other hand, recruite the Src homology domain containing kinasesSyk (spleen tyrosine kinase) orZap70 (Zeta-chain-associated protein kinase 70). Kinase activation is followed by NK celldegranulation and transcription ofcytokine andchemokine genes.[6]
DAP-10 connects toGRB2 orp85, leading to signalling through phosphoinositide 3-kinase (PI3K) and other molecules, leading tocytotoxicity.[6]
Ligands ofCD94/NKG2 heterodimeric molecules are nonclassicalMHC class I molecules –Qa1b molecules in mice andHLA-E in humans. These molecules both present sequences from the digestedleading peptides of classicalMHC class I molecules. This enables the monitoring of classicalMHC class I expression on target cells.[6]
NKG2D recognizes mostly stress-induced proteins, namely human MHC class-I-chain related protein (MIC-A) andMIC-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]
NKG2A was documented to promote survival inT cells. Along with its splice variantNKG2B, these molecules are inhibitory and lead to a decrease incytotoxicity.NKG2C andNKG2E (and its splice variantNKG2H) recognize the same ligand with different (usually lower in physiological conditions) affinity. However, the affinity forHLA-E (orQa1b) 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 includeviral andbacterialinfections byHCMV,HIV-1 and Hepatitis virus type C (HCV) in humans, orLCMV,HSV-1,Influenza andListeria monocytogenes infections in mice. In cancers, a role ofCD94/NKG2 was demonstrated formelanoma,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 solubleNKG2D ligands or secretingTGF-β, leading to thedownregulation of theNKG2D expression.NKG2D ligands are alsoupregulated by cells infected withviral pathogens. Certainviruses can produceproteins that block the expression ofNKG2D ligands on the cell surface to decrease the recognition by NK cells, increasingviruspathogenicity.[3]