NKG2D is a transmembrane protein belonging to the CD94/NKG2 family of C-type lectin-like receptors. NKG2D is encoded by KLRK1 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.
Human NKG2D receptor complex assembles into a hexameric structure. NKG2D itself forms a homodimer whose ectodomains serve for ligand binding. Each NKG2D monomer is associated with DAP10 dimer. This association is maintained by ionic interaction of a positively charged arginine present in a transmembrane segment of NKG2D and negatively charged aspartic acids within both transmembrane regions of DAP10 dimer. DAP10 functions as an adaptor protein and transduces the signal after the ligand binding by recruiting the p85 subunit of PI3K and Grb2-Vav1 complex which are responsible for subsequent downstream events.
In mice, alternative splicing generates two distinct NKG2D isoforms: the long one (NKG2D-L) and the short one (NKG2D-S). NKG2D-L binds DAP10 similarly to human NKG2D. By contrast, NKG2D-S associates with two adaptor proteins: DAP10 and DAP12. DAP10 recruits the p85 subunit of PI3K and a complex of Grb2 and Vav1. DAP12 bears ITAM motif and activates protein tyrosine kinases Syk and Zap70 signalling.
NKG2D ligands are induced-self proteins which are completely absent or present only at low levels on surface of normal cells, but they are overexpressed by infected, transformed, senescent and stressed cells. Their expression is regulated at different stages (transcription, mRNA and protein stabilization, cleavage from the cell surface) by various stress pathways. Among them, one of the most prominent stress pathways is DNA damage response. Genotoxic stress, stalled DNA replication, poorly regulated cell proliferation in tumorigenesis, viral replication or some viral products activate the ATM and ATR kinases. These kinases initiate the DNA damage response pathway which participates in NKG2D ligand upregulation. DNA damage response thus participate in alerting the immune system to the presence of potentially dangerous cells.
All NKG2D ligands are homologous to MHC class I molecules and are divided into two families: MIC and RAET1/ULBP.
Among ten known human RAET1/ULBP genes, six encode functional proteins: RAET1E/ULBP4, RAET1G/ULBP5, RAET1H/ULBP2, RAET1/ULBP1, RAET1L/ULBP6, RAET1N/ULBP3. In mice, proteins from orthologous RAET1/ULBP family fall into three subfamiles: Rae-1, H60, and MULT-1.
NKG2D is a major recognition receptor for the detection and elimination of transformed and infected cells as its ligands are induced during cellular stress, either as a result of infection or genomic stress such as in cancer. In NK cells, NKG2D serves as an activating receptor, which itself is able to trigger cytotoxicity. 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.
Role in senescent cell removal
As part of the DNA damage response during induction of cellular senescence, cells upregulate the expression of NKG2D ligands that enable NK-mediated killing of senescent cells via the granule exocytosis pathway. 
- 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. doi:10.1084/jem.173.4.1017. PMC 2190798. PMID 2007850.
- Brown MG, Fulmek S, Matsumoto K, Cho R, Lyons PA, Levy ER, Scalzo AA, Yokoyama MW (1997). "A 2-Mb YAC contig and physical map of the natural killer gene complex on mouse chromosome 6". Genomics. 42 (1): 16–25. doi:10.1006/geno.1997.4721. PMID 9177771.
- Yabe T, McSherry C, Bach FH, Fisch P, Schall RP, Sondel PM, Houchins JP (1993). "A multigene family on human chromosome 12 encodes natural killer-cell lectins". Immunogenetics. 37 (6): 455–460. doi:10.1007/BF00222470. PMID 8436421.
- Jamieson AM, Diefenbach A, McMahon CW, Xiong N, Carlyle JR, Raulet DH (2002). "The role of the NKG2D immunoreceptor in immune cell activation and natural killing". Immunity. 17 (1): 19–29. doi:10.1016/S1074-7613(02)00333-3. PMID 12150888.
- Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL, Spies T (Jul 1999). "Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA". Science. 285 (5428): 727–9. doi:10.1126/science.285.5428.727. PMID 10426993.
- Raulet DH (Oct 2003). "Roles of the NKG2D immunoreceptor and its ligands". Nature Reviews. Immunology. 3 (10): 781–90. doi:10.1038/nri1199. PMID 14523385.
- Li P, Morris DL, Willcox BE, Steinle A, Spies T, Strong RK (May 2001). "Complex structure of the activating immunoreceptor NKG2D and its MHC class I-like ligand MICA". Nature Immunology. 2 (5): 443–51. doi:10.1038/87757. PMID 11323699.
- Garrity D, Call ME, Feng J, Wucherpfennig KW (May 2005). "The activating NKG2D receptor assembles in the membrane with two signaling dimers into a hexameric structure". Proceedings of the National Academy of Sciences of the United States of America. 102 (21): 7641–6. doi:10.1073/pnas.0502439102. PMC 1140444. PMID 15894612.
- Upshaw JL, Arneson LN, Schoon RA, Dick CJ, Billadeau DD, Leibson PJ (May 2006). "NKG2D-mediated signaling requires a DAP10-bound Grb2-Vav1 intermediate and phosphatidylinositol-3-kinase in human natural killer cells". Nature Immunology. 7 (5): 524–32. doi:10.1038/ni1325. PMID 16582911.
- Diefenbach A, Tomasello E, Lucas M, Jamieson AM, Hsia JK, Vivier E, Raulet DH (Dec 2002). "Selective associations with signaling proteins determine stimulatory versus costimulatory activity of NKG2D". Nature Immunology. 3 (12): 1142–9. doi:10.1038/ni858. PMID 12426565.
- Gilfillan S, Ho EL, Cella M, Yokoyama WM, Colonna M (Dec 2002). "NKG2D recruits two distinct adapters to trigger NK cell activation and costimulation". Nature Immunology. 3 (12): 1150–5. doi:10.1038/ni857. PMID 12426564.
- Raulet DH, Gasser S, Gowen BG, Deng W, Jung H (2013-01-01). "Regulation of ligands for the NKG2D activating receptor". Annual Review of Immunology. 31 (1): 413–41. doi:10.1146/annurev-immunol-032712-095951. PMC 4244079. PMID 23298206.
- Gasser S, Orsulic S, Brown EJ, Raulet DH (Aug 2005). "The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor". Nature. 436 (7054): 1186–90. doi:10.1038/nature03884. PMC 1352168. PMID 15995699.
- Carapito R, Bahram S (Sep 2015). "Genetics, genomics, and evolutionary biology of NKG2D ligands". Immunological Reviews. 267 (1): 88–116. doi:10.1111/imr.12328. PMID 26284473.
- 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. doi:10.1016/j.it.2008.04.007. PMID 18602338.
- Jamieson AM, Diefenbach A, McMahon CW, Xiong N, Carlyle JR, Raulet DH (Jul 2002). "The role of the NKG2D immunoreceptor in immune cell activation and natural killing". Immunity. 17 (1): 19–29. doi:10.1016/S1074-7613(02)00333-3. PMID 12150888.
- 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. doi:10.1007/s00018-011-0797-0. PMC 3192283. PMID 21898152.
- Welte SA, Sinzger C, Lutz SZ, Singh-Jasuja H, Sampaio KL, Eknigk U, Rammensee HG, Steinle A (Jan 2003). "Selective intracellular retention of virally induced NKG2D ligands by the human cytomegalovirus UL16 glycoprotein". European Journal of Immunology. 33 (1): 194–203. doi:10.1002/immu.200390022. PMID 12594848.
- Serrano AE, Menares-Castillo E, Garrido-Tapia M, Ribeiro CH, Hernández CJ, Mendoza-Naranjo A, Gatica-Andrades M, Valenzuela-Diaz R, Zúñiga R, López MN, Salazar-Onfray F, Aguillón JC, Molina MC (Mar 2011). "Interleukin 10 decreases MICA expression on melanoma cell surface". Immunology and Cell Biology. 89 (3): 447–57. doi:10.1038/icb.2010.100. PMID 20714339.
- Sagiv, A., Burton, D.G.A,. Moshayev, Z., Vadai, E., Wensveen, F., Ben-Dor, S., Golani, O., Polic, B. and Krizhanovsky, V. (2016). NKG2D ligands mediate immunosurveillance of senescent cells Aging
- Sagiv A, Biran A, Yon M, Simon J, Lowe SW, Krizhanovsky V. (2013). Granule exocytosis mediates immune surveillance of senescent cells Oncogene, 32, 1971–197, doi:10.1038/onc.2012.206