|Symbols||; CD314; D12S2489E; KLR; NKG2-D; NKG2D|
NKG2D is an activating receptor found on NK cells and CD8 T cells (both αβ and γδ) which was first identified in 1991 and is encoded by the KLRK1 gene. Its function as an activating receptor was first described in 1999, and its ligands are stress-induced proteins such as MICA, MICB, ULBP1, ULBP2, ULBP3, and ULBP4-6 for human NKG2D, and Rae-1, Mult1, and H-60 for murine NKG2D.
The structure of NKG2D consists of two disulphide-linked type II transmembrane proteins with short intracellular domains incapable of transducing signals. They therefore require adaptor proteins in order to transduce signals, and this receptor uses two adapter proteins, DAP10 and DAP12, which associate as homodimers to the receptor - therefore the entire receptor complex appears as a hexamer.
The ligands for NKG2D are induced during times of cellular stress, either as a result of infection or genomic stress such as in cancer, which renders the cell susceptible to NK cell mediated lysis. The function of NKG2D on CD8 T cells is to send co-stimulatory signals to activate them.
Viruses, as intracellular pathogens, can induce the expression of stress ligands for NKG2D. NKG2D is thought to be important in viral control as viruses have adapted mechanisms by which to evade NKG2D responses. For example, cytomegalovirus (CMV) encodes a protein, UL16, which binds to NKG2D ligands ULBP1 and 2 (thus their name "UL16-binding protein") and MICB, which prevents their surface expression.
Role in tumour control
As cancerous cells are "stressed", NKG2D ligands become upregulated, rendering the cell susceptible to NK cell-mediated lysis. Tumor cells that can evade NKG2D responses are thus more likely to propagate.
- Houchins JP, Yabe T, McSherry C, Bach FH (Apr 1991). "DNA sequence analysis of NKG2, a family of related cDNA clones encoding type II integral membrane proteins on human natural killer cells". The Journal of Experimental Medicine 173 (4): 1017–20. PMC 2190798. PMID 2007850. doi:10.1084/jem.173.4.1017.
- Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL et al. (Jul 1999). "Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA". Science 285 (5428): 727–9. PMID 10426993. doi:10.1126/science.285.5428.727.
- Raulet DH (Oct 2003). "Roles of the NKG2D immunoreceptor and its ligands". Nature Reviews. Immunology 3 (10): 781–90. PMID 14523385. doi:10.1038/nri1199.
- Zafirova B, Wensveen FM, Gulin M, Polić B (Nov 2011). "Regulation of immune cell function and differentiation by the NKG2D receptor". Cellular and Molecular Life Sciences 68 (21): 3519–29. PMC 3192283. PMID 21898152. doi:10.1007/s00018-011-0797-0.
- González S, López-Soto A, Suarez-Alvarez B, López-Vázquez A, López-Larrea C (Aug 2008). "NKG2D ligands: key targets of the immune response". Trends in Immunology 29 (8): 397–403. PMID 18602338. doi:10.1016/j.it.2008.04.007.
- Welte SA, Sinzger C, Lutz SZ, Singh-Jasuja H, Sampaio KL, Eknigk U et al. (Jan 2003). "Selective intracellular retention of virally induced NKG2D ligands by the human cytomegalovirus UL16 glycoprotein". European Journal of Immunology 33 (1): 194–203. PMID 12594848. doi:10.1002/immu.200390022.
- Serrano AE, Menares-Castillo E, Garrido-Tapia M, Ribeiro CH, Hernández CJ, Mendoza-Naranjo A et al. (Mar 2011). "Interleukin 10 decreases MICA expression on melanoma cell surface". Immunology and Cell Biology 89 (3): 447–57. PMID 20714339. doi:10.1038/icb.2010.100.