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NKG2D Receptor and Its Ligands in Host Defense
Open accessAbstract
NKG2D is an activating receptor expressed on the surface of natural killer (NK) cells, CD8+ T cells, and subsets of CD4+ T cells, invariant NKT cells (iNKT), and γδ T cells. In humans, NKG2D transmits signals by its association with the DAP10 adapter subunit, and in mice alternatively spliced isoforms transmit signals either using DAP10 or DAP12 adapter subunits. Although NKG2D is encoded by a highly conserved gene (KLRK1) with limited polymorphism, the receptor recognizes an extensive repertoire of ligands, encoded by at least eight genes in humans (MICA, MICB, RAET1E, RAET1G, RAET1H, RAET1I, RAET1L, and RAET1N), some with extensive allelic polymorphism. Expression of the NKG2D ligands is tightly regulated at the level of transcription, translation, and posttranslation. In general, healthy adult tissues do not express NKG2D glycoproteins on the cell surface, but these ligands can be induced by hyperproliferation and transformation, as well as when cells are infected by pathogens. Thus, the NKG2D pathway serves as a mechanism for the immune system to detect and eliminate cells that have undergone “stress.” Viruses and tumor cells have devised numerous strategies to evade detection by the NKG2D surveillance system, and diversification of the NKG2D ligand genes likely has been driven by selective pressures imposed by pathogens. NKG2D provides an attractive target for therapeutics in the treatment of infectious diseases, cancer, and autoimmune diseases. Cancer Immunol Res; 3(6); 575–82. ©2015 AACR.
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The candidate signature gene RAET1G is one of the few genes that could encode a ligand recognized by NKG2D proteins in response to stress and infections.
“Remarkably, the candidate signature gene RAET1G is one of the few genes that could encode a ligand recognized by NKG2D proteins in response to stress and infections (Eagle and Trowsdale, 2007; Tomasec et al., 2007; Lanier, 2015).”
From Identification of Candidate Signature Genes and Key Regulators Associated With Trypanotolerance in the Sheko Breed (2019) · cites this paper as Lanier, 2015
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Radosavljevic, M., Cuillerier, B., Wilson, M. J., Clément, O., Wicker, S., Gilfillan, S., Beck, S., Trowsdale, J., & Bahram, S. (2002) · Genomics · doi:10.1006/geno.2001.6673 · Cited by 178
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BackgroundInfluentialNKG2D Ligand MICA Is Retained in the cis-Golgi Apparatus by Human Cytomegalovirus Protein UL142
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“Induction of ligands might also be caused by hyperproliferation of the transformed cell that results in activation of E2F transcription factors (38).”
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“Similarly, adenovirus E3/19k (56), U21 of human herpesvirus 7 (57), and the K5 ubiquitin ligase encoded by human herpesvirus 8 (58) cause the degradation of MICA and MICB.”
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“Although NKG2D is expressed constitutively on essentially all resting human NK cells and CD8þ T cells (14), engagement of NKG2D alone is insufficient to trigger cell-mediated cytotoxicity or cytokine production (12, 40), although the simultaneous engagement of NKG2D and other "costimulatory" receptors, such as CD335 (…”
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The herpesviral Fc receptor fcr-1 down-regulates the NKG2D ligands MULT-1 and H60
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“Although the mouse Raet1 genes were originally identified as being constitutively expressed in the developing embryo (36), in general, the NKG2D ligands are not expressed on the surface of healthy cells and tissues in adults.”
BackgroundCytosolic PLA2 is required for CTL-mediated immunopathology of celiac disease via NKG2D and IL-15
Tang, F., Chen, Z., Ciszewski, C., Setty, M., Solus, J., Tretiakova, M., Ebert, E., Han, J., Lin, A., Guandalini, S., et al. (2009) · Journal of Experimental Medicine · doi:10.1084/jem.20071887 · Cited by 89 · cited 1×
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BackgroundSecretory pathways generating immunosuppressive NKG2D ligands
Raneros, A. B., Suárez-Álvarez, B., & López-Larrea, C. (2014) · Oncoimmunology · doi:10.4161/onci.28497 · Cited by 82
Intracellular Sequestration of the NKG2D Ligand ULBP3 by Human Cytomegalovirus
Bennett, N. J., Ashiru, O., Morgan, F. J. E., Pang, Y., Okecha, G., Eagle, R. A., Trowsdale, J., Sissons, J. G. P., & Wills, M. R. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.1000789 · Cited by 82
Structural Basis for Recognition of Cellular and Viral Ligands by NK Cell Receptors
Li, Y., & Mariuzza, R. A. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00123 · Cited by 68
Muntasell, A., Magri, G., Pende, D., Angulo, A., & López‐Botet, M. (2010) · Blood · doi:10.1182/blood-2009-11-256479 · Cited by 64 · cited 1×
“In humans, IL2, IL7, IL12, and IL15 upregulate NKG2D expression (18–21), whereas TGFb (22–24), IFNb1 (25), and IL21 (26) downmodulate NKG2D.”
Schneider, C. L., & Hudson, A. W. (2011) · PLoS Pathogens · doi:10.1371/journal.ppat.1002362 · Cited by 51 · cited 1×
“Similarly, adenovirus E3/19k (56), U21 of human herpesvirus 7 (57), and the K5 ubiquitin ligase encoded by human herpesvirus 8 (58) cause the degradation of MICA and MICB.”
BackgroundA selective role of NKG2D in inflammatory and autoimmune diseases
Guerra, N., Pestal, K., Juarez, T., Beck, J., Tkach, K. E., Wang, L., & Raulet, D. H. (2013) · Clinical Immunology · doi:10.1016/j.clim.2013.09.003 · Cited by 49
Differential Susceptibility of RAE-1 Isoforms to Mouse Cytomegalovirus
Arapović, J., Lenac, T., Antulov, R., Polić, B., Ruzsics, Z., Carayannopoulos, L., Koszinowski, U., Krmpotić, A., & Jonjić, S. (2009) · Journal of Virology · doi:10.1128/jvi.02549-08 · Cited by 49 · cited 1×
“Mouse CMV m152 protein blocks surface expression of Raet1 proteins (50, 51); m155 blocks H60 (52), m145 blocks MULT1 (53), and m138 blocks expression of MULT1 and H60 (54).”
BackgroundFernández-Messina, L., Ashiru, O., Agüera-González, S., Reyburn, H., & Valés-Gómez, M. (2011) · Journal of Cell Science · doi:10.1242/jcs.076042 · Cited by 42 · cited 1×
“MICA, MICB, RAET1E (ULBP4), and RAET1G (ULBP5) are transmembrane-anchored glycoproteins, whereas RAET1I (ULBP1), RAET1H (ULBP2), RAET1N (ULBP3), and RAET1L (ULBP6) are glycophosphatidylinositol (GPI)-anchored, although RAET1H (ULBP2) may be expressed in both transmembraneanchored and GPI-anchored forms (28), and RAET1…”
BackgroundTrsan, T., Busche, A., Abram, M., Wensveen, F. M., Lemmermann, N., Arapović, M., Babić, M., Tomic, A., Golemac, M., Brinkmann, M., et al. (2013) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.1310215110 · Cited by 28
Ohashi, M., Eagle, R. A., & Trowsdale, J. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.077636 · Cited by 18 · cited 2×
“The mouse ligands include Rae1a, Rae1b, Rae1g , Rae1d, and Rae1e, MULT1, and H60a, H60b, and H60c, with MULT1, H60a, and H60b being transmembraneanchored and the others GPI-anchored (30–33).”
BackgroundA truncated human NKG2D splice isoform negatively regulates NKG2D-mediated function
Karimi, M., Aguilar, O., Zou, B., Bachmann, M. H., Carlyle, J., Baldwin, C., & Kambayashi, T. (2014) · Journal of Immunology · doi:10.4049/jimmunol.1400920 · Cited by 17
Buhtoiarov, I., Rakhmilevich, A., Lanier, L., Ranheim, E., & Sondel, P. (2009) · Journal of Immunology · doi:10.4049/jimmunol.0800443 · Cited by 13 · cited 1×
“org) and express NKG2D on the cell surface (11, 13).”
BackgroundSelf-citation
Flagged first, then by citations
4 of the 78 references couldn’t be matched to a known paper.
Research works printed but not linked: 2
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NK cells and cancer: you can teach innate cells new tricks
Morvan, M. G., & Lanier, L. L. (2015) · Nature reviews. Cancer · doi:10.1038/nrc.2015.5 · Cited by 1,190
Self-citationTargeting natural killer cells in cancer immunotherapy
Guillerey, C., Huntington, N. D., & Smyth, M. J. (2016) · Nature Immunology · doi:10.1038/ni.3518 · Cited by 1,081
Metastatic Latency and Immune Evasion through Autocrine Inhibition of WNT
Malladi, S., Macalinao, D. G., Jin, X., He, L., Basnet, H., Zou, Y., de Stanchina, E., & Massagué, J. (2016) · Cell · doi:10.1016/j.cell.2016.02.025 · Cited by 791
C-type lectins in immunity and homeostasis
Brown, G. D., Willment, J. A., & Whitehead, L. (2018) · Nature reviews. Immunology · doi:10.1038/s41577-018-0004-8 · Cited by 609
Human NK cells: surface receptors, inhibitory checkpoints, and translational applications
Sivori, S., Vacca, P., Zotto, G. D., Munari, E., Mingari, M., & Moretta, L. (2019) · Cellular & Molecular Immunology · doi:10.1038/s41423-019-0206-4 · Cited by 493
Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell–driven tumor immunity
de Andrade, L. F., Tay, R.-E., Pan, D., Luoma, A. M., Ito, Y., Badrinath, S., Tsoucas, D. M., Franz, B., May, K. F., Harvey, C. J., et al. (2018) · Science · doi:10.1126/science.aao0505 · Cited by 427
NKG2D ligands mediate immunosurveillance of senescent cells
Sagiv, A., Burton, D. G. A., Moshayev, Z., Vadai, E., Wensveen, F., Ben-Dor, S., Golani, O., Polic, B., & Krizhanovsky, V. (2016) · Aging · doi:10.18632/aging.100897 · Cited by 345
“NKG2D receptor recognizes ligands MICA/B and ULBP1-6 on the surface of stressed cells leading to direct cytotoxicity [24, 28, 29].”
BackgroundInfluentialProtein Glycosylation and Tumor Microenvironment Alterations Driving Cancer Hallmarks
Peixoto, A., Relvas‐Santos, M., Azevedo, R., Santos, L. L., & Ferreira, J. A. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.00380 · Cited by 337
Baumeister, S. H. C., Murad, J., Werner, L. L., Daley, H., Trebeden‐Negre, H., Gicobi, J. K., Schmucker, A. C., Reder, J., Sentman, C. L., Gilham, D. E., et al. (2018) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-18-0307 · Cited by 334
NK cell-based immunotherapy for cancer.
Fang, F., Xiao, W.-H., & Tian, Z. (2017) · Seminars in Immunology · doi:10.1016/j.smim.2017.07.009 · Cited by 281
The Role of Natural Killer Cells in Autoimmune Diseases
Küçüksezer, U. C., Çetin, E. A., Esen, F., Tahralı, İ., Akdeniz, N., Gelmez, M. Y., & Deniz, G. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.622306 · Cited by 300
“Tumors could escape from the host immune system by shedding of NKG2D ligands from tumor cells (62, 63).”
BackgroundNK cells and ILCs in tumor immunotherapy
Sivori, S., Pende, D., Quatrini, L., Pietra, G., Chiesa, M. D., Vacca, P., Tumino, N., Moretta, F., Mingari, M. C., Locatelli, F., et al. (2020) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2020.100870 · Cited by 279
“The presence of a positively-charged aminoacid in the NCR transmembrane domain allows NCR association with ITAM-bearing adaptor proteins, in particular CD3-ζ and/or FcεRI-γ (for NKp30 and NKp46) and KARAP/DAP12 (for NKp44), that are essential for the transduction of positive signals inside NK cells.”
BackgroundNKG2D and Its Ligands: “One for All, All for One”
Zingoni, A., Molfetta, R., Fionda, C., Soriani, A., Paolini, R., Cippitelli, M., Cerboni, C., & Santoni, A. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00476 · Cited by 267
“Its ligands belong to the H60 (a–c), RAE (α–ε), and MULT1 families in mice, and to the MIC (MICA and MICB) and ULBP (ULBP1–ULBP6) families in humans, where their repertoire is more complex than in other species (1, 2).”
Sestrins induce natural killer function in senescent-like CD8+ T cells
Pereira, B. I., Maeyer, R. P. H. D., Covre, L. P., Nehar-Belaid, D., Lanna, A., Ward, S., Marcheş, R., Chambers, E. S., Gomes, D. C. O., Riddell, N. E., et al. (2020) · Nature Immunology · doi:10.1038/s41590-020-0643-3 · Cited by 255
NKG2D and its ligands in cancer
Dhar, P., & Wu, J. D. (2018) · Current Opinion in Immunology · doi:10.1016/j.coi.2018.02.004 · Cited by 251
NK Cells in Cancer Immunotherapy
Addou-Klouche, L. (2017) · InTech eBooks · doi:10.5772/intechopen.71217 · Cited by 206
“Activating KIR receptor recognizes classical MHC-I molecules [45], whereas NKG2D recognizes the nonclassical MHC-I molecules, MICA/MICB, retinoic acid early transcript 1E protein (RAET1E), RAET1G, RAET1H, RAET1I, RAET1L, and RAET1N (also known as ULBP1–ULBP6) [46, 47].”
BackgroundTetramethylpyrazine: A review on its mechanisms and functions
Lin, J., Wang, Q., Zhou, S., Xu, S., & Yao, K. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.113005 · Cited by 219
NKG2D-CAR T cells eliminate senescent cells in aged mice and nonhuman primates
Yang, D., Sun, B., Li, S., Wei, W., Liu, X., Cui, X., Zhang, X., Liu, N., Yan, L., Deng, Y., et al. (2023) · Science Translational Medicine · doi:10.1126/scitranslmed.add1951 · Cited by 217
“Unfortunately, the limited clinical efficacy may be due to the shedding of NKG2DLs by cancer cells or limited function of CAR T cells under the complex tumor microenvironment (48, 49).”
BackgroundNatural killer cell cytotoxicity and its regulation by inhibitory receptors
Kumar, S. (2018) · Immunology · doi:10.1111/imm.12921 · Cited by 230
Therapeutic interventions for aging: the case of cellular senescence
Soto-Gamez, A., & Demaria, M. (2017) · Drug Discovery Today · doi:10.1016/j.drudis.2017.01.004 · Cited by 192
“91 Lanier, L.L. (2015) NKG2D receptor and its ligands in host defense.”
BackgroundThe activation of bystander CD8+ T cells and their roles in viral infection
Kim, T.-S., & Shin, E. (2019) · Experimental and Molecular Medicine · doi:10.1038/s12276-019-0316-1 · Cited by 190
Hong, C., Sharma, P., Yerneni, S. S., Simms, P. E., Jackson, E. K., Whiteside, T. L., & Boyiadzis, M. M. (2017) · Scientific Reports · doi:10.1038/s41598-017-14661-w · Cited by 198
Origin and Consequences of Necroinflammation
Sarhan, M., Land, W. G., Tonnus, W., Hugo, C., & Linkermann, A. (2018) · Physiological Reviews · doi:10.1152/physrev.00041.2016 · Cited by 217
Chester, C., Fritsch, K., & Kohrt, H. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00601 · Cited by 174
“Ligands of the human NKG2D receptor are the MHC I-related molecules MICA/MICB, and the UL16binding proteins (ULBP-1 to ULBP-6) (57).”
BackgroundBreakthrough of solid tumor treatment: CAR-NK immunotherapy
Wang, W., Liu, Y., He, Z., Li, L., Liu, S., Jiang, M., Zhao, B., Deng, M., Wang, W., Ge, X., et al. (2024) · Cell Death Discovery · doi:10.1038/s41420-024-01815-9 · Cited by 190
“MICA/B, mainly MICA, MICB, and ULBP1-6 in humans [53], is found in gastro-intestinal epithelial tumors, as well as lung, breast, kidney, ovary, and prostate tumors [54].”
BackgroundHuman NK cells, their receptors and function
Quatrini, L., Chiesa, M. D., Sivori, S., Mingari, M. C., Pende, D., & Moretta, L. (2021) · European Journal of Immunology · doi:10.1002/eji.202049028 · Cited by 202
Human immunity against EBV—lessons from the clinic
Tangye, S., Palendira, U., & Edwards, E. (2017) · Journal of Experimental Medicine · doi:10.1084/jem.20161846 · Cited by 166
“, 2016), a C-type lectin that potently activates effector function of cytotoxic lymphocytes (Lanier, 2015).”
BackgroundInfluentialProgress of exosomes in the diagnosis and treatment of lung cancer
Xu, K., Zhang, C., Du, T., Gabriel, A. N. A., Wang, X., Li, X., Sun, L. J., Wang, N., Jiang, X., & Zhang, Y. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.111111 · Cited by 183
Function of γδ T cells in tumor immunology and their application to cancer therapy
Park, J., & Lee, H. (2021) · Experimental and Molecular Medicine · doi:10.1038/s12276-021-00576-0 · Cited by 156
Transplantation and Damage-Associated Molecular Patterns (DAMPs)
Land, W. G., Agostinis, P., Gasser, S., Garg, A. D., & Linkermann, A. (2016) · American Journal of Transplantation · doi:10.1111/ajt.13963 · Cited by 171
Overcoming Resistance to Natural Killer Cell Based Immunotherapies for Solid Tumors
Nayyar, G., Chu, Y., & Cairo, M. S. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.00051 · Cited by 180
Impairment of NKG2D-Mediated Tumor Immunity by TGF-β
Lazarova, M., & Steinle, A. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02689 · Cited by 149
“ULBP1 through ULBP3 and ULBP6 are GPI-anchored, whereas ULBP4 and ULBP5 are inserted into the membrane with a single transmembrane domain (67, 70, 71).”
BackgroundExercise and cancer: from “healthy” to “therapeutic”?
Idorn, M., & Straten, P. T. (2017) · Cancer Immunology and Immunotherapy · doi:10.1007/s00262-017-1985-z · Cited by 147
“, NKG2D recognizing ligands expressed on cancer cells [17].”
BackgroundNKG2D-CAR-transduced natural killer cells efficiently target multiple myeloma
Leivas, A., Valeri, A., Córdoba, L., García-Ortiz, A., Ortiz, A., Sánchez-Vega, L., Graña-Castro, O., Fernández, L., Carreño-Tarragona, G., Pérez, M., et al. (2021) · Blood Cancer Journal · doi:10.1038/s41408-021-00537-w · Cited by 139
“NKG2D recognizes and kills infected cells and cancer cells by targeting up to eight stressinduced ligands (NKG2DL), namely MICA, MICB, and ULBP [1–6] that are overexpressed on viral infected, DNA-damaged or transformed cells, and not usually expressed in healthy tissues [12, 13].”
BackgroundLeveraging NKG2D Ligands in Immuno-Oncology
Fuertes, M. B., Domaica, C. I., & Zwirner, N. W. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.713158 · Cited by 152
“In humans, 8 different NKG2DL have been described (51, 55).”
BackgroundA vaccine targeting resistant tumours by dual T cell plus NK cell attack
Badrinath, S., Dellacherie, M. O., Li, A. W., Zheng, S.-W., Zhang, X., Sobral, M. C., Pyrdol, J. W., Smith, K. L., Lu, Y., Haag, S., et al. (2022) · Nature · doi:10.1038/s41586-022-04772-4 · Cited by 137
Innate immune mediators in cancer: between defense and resistance
Berraondo, P., Minute, L., Ajona, D., Corrales, L. P., Melero, I., & Pı́o, R. (2016) · Immunological Reviews · doi:10.1111/imr.12464 · Cited by 134
Colorectal cancer immunotherapy-Recent progress and future directions
Zhao, W., Jin, L., Chen, P., Li, D., Gao, W., & Dong, G. (2022) · Cancer Letters · doi:10.1016/j.canlet.2022.215816 · Cited by 157
Research Progress on NK Cell Receptors and Their Signaling Pathways
Chen, Y.-Y., Lu, D., Churov, A., & Fu, R. (2020) · Mediators of Inflammation · doi:10.1155/2020/6437057 · Cited by 125
“It is a major activating receptor expressed on NK cells and CD8 T cells in a dimer form [67].”
BackgroundRegulation of nucleotide metabolism in cancers and immune disorders
Ali, E. S., & Ben‐Sahra, I. (2023) · Trends in Cell Biology · doi:10.1016/j.tcb.2023.03.003 · Cited by 137
Novel CAR T therapy is a ray of hope in the treatment of seriously ill AML patients
Marofi, F., Rahman, H. S., Al-Obaidi, Z. M. J., Jalil, A. T., Abdelbasset, W. K., Suksatan, W., Dorofeev, A. E., Shomali, N., Chartrand, M. S., Pathak, Y. V., et al. (2021) · Stem Cell Research & Therapy · doi:10.1186/s13287-021-02420-8 · Cited by 138
“NKG2D has a wide spectrum of ligands that overexpressed encountering DNA damage, infections, and malignant transformation [140, 141].”
BackgroundModulation of innate and adaptive immunity by cytomegaloviruses
Berry, R., Watson, G. M., Jonjić, S., Degli-Esposti, M., & Rossjohn, J. (2019) · Nature reviews. Immunology · doi:10.1038/s41577-019-0225-5 · Cited by 113
Tangye, S., & Latour, S. (2020) · Blood · doi:10.1182/blood.2019000928 · Cited by 104
Pathogenesis of ocular toxoplasmosis
Smith, J. R., Ashander, L. M., Arruda, S., Cordeiro, C. A., Lie, S., Rochet, E., Belfort, R., & Furtado, J. M. (2020) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2020.100882 · Cited by 112
Cellular senescence as a potential mediator of COVID‐19 severity in the elderly
Nehme, J., Borghesan, M., Mackedenski, S., Bird, T. G., & Demaria, M. (2020) · Aging Cell · doi:10.1111/acel.13237 · Cited by 94
Regulation of Natural Killer Cell Function by STAT3
Cacalano, N. A. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00128 · Cited by 88
Extracellular Vesicles and Immunity: At the Crossroads of Cell Communication
Aloi, N., Drago, G., Ruggieri, S., Cibella, F., Colombo, P., & Longo, V. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25021205 · Cited by 101
“The expression of NKG2D ligands (NKG2DLs) serves as a “danger signal”, marking cells for immune cell attack [120].”
BackgroundDalessandri, T., Crawford, G., Hayes, M. D., Seoane, R. C., & Strid, J. (2016) · Nature Communications · doi:10.1038/ncomms12080 · Cited by 92
NK cells in pancreatic cancer demonstrate impaired cytotoxicity and a regulatory IL-10 phenotype
Marcon, F., Zuo, J., Pearce, H., Nicol, S. M., Margielewska-Davies, S., Farhat, M., Mahon, B., Middleton, G., Brown, R. M., Roberts, K., et al. (2020) · Oncoimmunology · doi:10.1080/2162402x.2020.1845424 · Cited by 87
IL-15 Overcomes Hepatocellular Carcinoma-Induced NK Cell Dysfunction
Easom, N. J. W., Stegmann, K. A., Swadling, L., Pallett, L., Burton, A. R., Odera, D., Schmidt, N., Huang, W.-C., Fusai, G., Davidson, B., et al. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01009 · Cited by 87
“However, the NKG2D pathway plays a complex role in tumor immunity, with some evidence it can also mediate the opposing effect of downmodulating NK cell tumor immunity or even promoting HCC progression (8, 9).”
BackgroundEndothelial cells express NKG2D ligands and desensitize antitumor NK responses
Thompson, T. W., Kim, A. B., Li, P. J., Wang, J.-X., Jackson, B. T., Huang, K. T., Zhang, L., & Raulet, D. (2017) · eLife · doi:10.7554/elife.30881 · Cited by 86
The Function of NK Cells in Tumor Metastasis and NK Cell-Based Immunotherapy
Yu, Y. (2023) · Cancers · doi:10.3390/cancers15082323 · Cited by 95
“NKG2D can bind to the ligands of NKG2D (NKG2D), such as MICA/B [44] and UL16binding proteins (ULBPs) [45,46], extending the signals via the adaptor protein DAP10, thereby activating the PI3K singling pathway to trigger cytotoxicity [47].”
BackgroundNK Cells as Potential Targets for Immunotherapy in Endometriosis
Ścieżyńska, A., Komorowski, M., Soszyńska, M., & Malejczyk, J. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8091468 · Cited by 83
“Endometriosis was also reported to be associated with a decreased expression of stimulatory NKG2D molecule [114] recognizing the non-classical MHC class I ligands belonging to the MIC and ULBP family [62,115].”
BackgroundRegulation of NKG2D-Dependent NK Cell Functions: The Yin and the Yang of Receptor Endocytosis
Molfetta, R., Quatrini, L., Santoni, A., & Paolini, R. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18081677 · Cited by 94
“Moreover, several cytokines including IL-2, IL-7, IL-12, and IL-15, increase NKG2D/DAP10 expression acting at transcriptional and post-transcriptional level [5,66].”
Backgroundvan Dijk, S. J., Zhou, J., Peters, T. J., Buckley, M. J., Sutcliffe, B., Oytam, Y., Gibson, R. A., McPhee, A. J., Yelland, L. N., Makrides, M., et al. (2016) · Clinical Epigenetics · doi:10.1186/s13148-016-0281-7 · Cited by 94
“The DMRs identified at birth were located in genes with a variety of functions, including lipid exchange between membranes (ESYT3 [32]), plasma membrane function (SLC12A6 [33]), appetite regulation (CCK [34]), immune function (RAET1L and LTB [35, 36]) and neurodevelopment/brain function (SLC12A6, TRAK1, LPHN3 and RFPL…”
BackgroundTietze, J., Angelova, D., Heppt, M., Reinholz, M., Murphy, W., Spannagl, M., Ruzicka, T., & Berking, C. (2017) · European Journal of Cancer · doi:10.1016/j.ejca.2016.12.031 · Cited by 79
Wang, T.-T., Li, P.-L., Qi, Q.-C., Zhang, S., Xie, Y., Wang, J., Liu, S.-B., Ma, S., Li, S.-J., Gong, T., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-40389-5 · Cited by 78
“These genes are related to immune receptors 58 .”
BackgroundZalfa, C., & Paust, S. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.633205 · Cited by 100
“NK cells do not express a TCR but instead have many activating receptors and also inhibitory receptors, which bind major histocompatibility complex class I (MHC-I) (19, 20).”
BackgroundInfluentialThe Ambiguous Role of γδ T Lymphocytes in Antitumor Immunity
Chitadze, G., Oberg, H., Wesch, D., & Kabelitz, D. (2017) · Trends in Immunology · doi:10.1016/j.it.2017.06.004 · Cited by 92
Timmers, M., Roex, G., Wang, Y., Campillo-Davó, D., Tendeloo, V. F. V., Chu, Y., Berneman, Z. N., Luo, F., Acker, H. H. V., & Anguille, S. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01613 · Cited by 86
“Its ligands include major histocompatibility complex class I polypeptide-related sequence A/B and UL16 binding protein 1–6 (50).”
BackgroundLai, H., Zeng, D., Liu, C., Zhang, Q., Wang, X., & Chen, T. (2019) · Biomaterials · doi:10.1016/j.biomaterials.2019.119377 · Cited by 75
The NKG2D/NKG2DL Axis in the Crosstalk Between Lymphoid and Myeloid Cells in Health and Disease
Stojanovic, A., Correia, M. P., & Cerwenka, A. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00827 · Cited by 92
“Cancer Immunol Res (2017) 5(9):778–89.”
BackgroundA summary of current NKG2D-based CAR clinical trials
Curio, S., Jonsson, G., & Marinović, S. (2021) · Immunotherapy Advances · doi:10.1093/immadv/ltab018 · Cited by 77
“The interaction between the NKG2D ligand (NKG2DL) and the NKG2D receptor triggers the activation, expansion, and production of proinflammatory cytokines of effector immune cells, typically leading to target cell elimination [7] (Fig.”
BackgroundNK Cell Therapy: A Rising Star in Cancer Treatment
Du, N., Guo, F.-F., Wang, Y.-F., & Cui, J. (2021) · Cancers · doi:10.3390/cancers13164129 · Cited by 72
“The ligands of NKG2D include MHC class I homologues MICA/B and ULBP (cytomegalovirus UL16-binding protein) in humans and RAE1 (retinoic acid early transcript 1), MULT1 (murine UL16-binding protein-1), and H60 in mice [15].”
BackgroundNKG2D Natural Killer Cell Receptor—A Short Description and Potential Clinical Applications
Siemaszko, J., Marzec-Przyszlak, A., & Bogunia‐Kubik, K. (2021) · Cells · doi:10.3390/cells10061420 · Cited by 92
The Sweet Side of Immune Evasion: Role of Glycans in the Mechanisms of Cancer Progression
Nardy, A. F. F. R., Freire-de-Lima, L., Freire-de-Lima, C., & Morrot, A. (2016) · Frontiers in Oncology · doi:10.3389/fonc.2016.00054 · Cited by 71
“1+ T cells, γδ T cells, and activated CD8+αβ T cells and macrophages (86).”
Chung, B. K., Karlsen, T. H., & Folseraas, T. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2017.08.020 · Cited by 76
“natural killer T (NKT) cells, CD8+ T cells and subsets of CD4+ T cells [110].”
BackgroundJensen, H., Potempa, M., Gotthardt, D., & Lanier, L. (2017) · Journal of Immunology · doi:10.4049/jimmunol.1700497 · Cited by 70
“diabetes, celiac disease, and Crohn’s disease (1).”
InfluentialSelf-citationGonzalez, V. D., Huang, Y.-W., Delgado‐González, A., Chen, S.-Y., Donoso, K., Sachs, K., Gentles, A. J., Allard, G. M., Kolahi, K. S., Howitt, B. E., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109632 · Cited by 84
“…tumor cells onto NK-92 cells could reactivate ADAM17 to cleave NK activating receptor ligand substrates thereby indirectly facilitating immune escape by ligand and/or receptor shedding (Boutet et al., 2009; Ferrari de Andrade et al., 2018; Lanier, 2015; Okumura et al., 2020; Raulet et al., 2013).”
BackgroundDriouk, L., Gicobi, J. K., Kamihara, Y., Rutherford, K. D., Dranoff, G., Ritz, J., & Baumeister, S. H. C. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.580328 · Cited by 73
“Nevertheless, reports of low level NKG2D-ligand expression in gut epithelium (35, 36), the possibility of NKG2D-ligandupregulation in healthy tissues under conditions of cell stress and infection (19) and dose-dependent toxicity observed in mouse models (37, 38) were of potential concern for the translation of this ap…”
BackgroundSheehan, C. S., & D’Souza‐Schorey, C. (2019) · Journal of Cell Science · doi:10.1242/jcs.235085 · Cited by 79
“While expressed at low levels in normal cell types, NKG2D ligands are upregulated in response to cell stress, marking the cell for destruction by the innate immune response (Lanier, 2015).”
BackgroundParodi, M., Favoreel, H., Candiano, G., Gaggero, S., Sivori, S., Mingari, M., Moretta, L., Vitale, M., & Cantoni, C. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00719 · Cited by 67
Impact of exercise on the immune system and outcomes in hematologic malignancies
Sitlinger, A. P., Brander, D. M., & Bartlett, D. B. (2020) · Blood Advances · doi:10.1182/bloodadvances.2019001317 · Cited by 73
“MICA and MICB are ligands for the natural cytotoxicity receptor NKG2D, leading to tumor cell destruction.(60) Conversely, cytotoxicity is downregulated by engagement of human leukocyte antigen (HLA)–specific inhibitory receptors such as killer immunoglobulinlike receptors, protecting normal host tissue.”
BackgroundMantovani, S., Oliviero, B., Varchetta, S., Mele, D., & Mondelli, M. U. (2020) · Cancers · doi:10.3390/cancers12040926 · Cited by 70
“NKG2D expression can be modulated by up- or down-regulating cytokine-mediated stimuli [16].”
BackgroundThe immunoreceptor NKG2D promotes tumour growth in a model of hepatocellular carcinoma
Sheppard, S., Guedes, J., Mróz, A., Zavitsanou, A., Kudo, H., ROTHERY, S. M., Angelopoulos, P., Goldin, R. D., & Guerra, N. (2017) · Nature Communications · doi:10.1038/ncomms13930 · Cited by 64
Mechanisms of activation of innate-like intraepithelial T lymphocytes
Vandereyken, M., James, O. J., & Swamy, M. (2020) · Mucosal Immunology · doi:10.1038/s41385-020-0294-6 · Cited by 65
“In humans, NKG2D is found at the surface of both resting and activated CD8 T cells while murine T cells only express NKG2D when activated.(56) Consistent with this, NKG2D is found at the surface of all murine DETC(57) and human intestinal T-IEL, albeit at low levels.”
BackgroundZumwalde, N. A., Sharma, A., Xu, X., Ma, S.-D., Schneider, C. L., Romero-Masters, J. C., Hudson, A., Gendron‐Fitzpatrick, A., Kenney, S., & Gumperz, J. (2017) · JCI Insight · doi:10.1172/jci.insight.93179 · Cited by 65
“, microbial infection, hyperproliferation, and neoplastic transformation), and many tumors express elevated levels of these ligands at the cell surface (20).”
BackgroundCAR-NK cells for cancer immunotherapy: recent advances and future directions
Li, T., Niu, M., Zhang, W., Qin, S., Zhou, J., & Yi, M. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1361194 · Cited by 61
“Activating receptors, such as NK gene 2D (NKG2D) and natural cytotoxicity receptors (NCRs), play crucial roles in NK cell responses against cancer cells (23, 24).”
BackgroundCell Therapy for Colorectal Cancer: The Promise of Chimeric Antigen Receptor (CAR)-T Cells
Aparicio, C., Belver, M., Enríquez, L., Espeso, F., Núñez, L., Sánchez, A., de la Fuente, M. Á., & González‐Vallinas, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222111781 · Cited by 118
“These ligands are expressed in response to external signals such as stress or pathogens and during neoplastic cell transformation but they are rarely present in healthy tissue [49,50].”
BackgroundCytotoxic Immunity in Peripheral Nerve Injury and Pain
Davies, A. J., Rinaldi, S., Costigan, M., & Oh, S. B. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00142 · Cited by 73
“…T cells) express the receptor NKG2D and engagement with ligands such as RAE1 augments CD8+ T cell function, but only after prior stimulation by antigenspecific T cell receptors (TCRs) (Lanier, 2015), suggesting that NK cells are an important responder to ‘stressed-self ’ in the non-immunized state.”
BackgroundThe Paradoxical Role of NKG2D in Cancer Immunity
Sheppard, S., Ferry, A., Guedes, J., & Guerra, N. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01808 · Cited by 62
“Gastroenterology (2007) 132(7): 2346–58.”
BackgroundNidogen-1 is a novel extracellular ligand for the NKp44 activating receptor
Gaggero, S., Bruschi, M., Petretto, A., Parodi, M., Zotto, G. D., Lavarello, C., Prato, C., Santucci, L., Barbuto, A., Bottino, C., et al. (2018) · Oncoimmunology · doi:10.1080/2162402x.2018.1470730 · Cited by 62
“Ligands specific for these receptors have been extensively characterized: MICA/B and ULBPs molecules are recognized by NKG2D, while PVR and Nectin-2 (belonging to the Nectin family), are ligands for DNAM-1.(32,33,35,36)”
BackgroundInfluentialHosomi, S., Grootjans, J., Tschurtschenthaler, M., Krupka, N., Matute, J. D., Flak, M. B., Martı́nez-Naves, E., del Moral, M. G., Glickman, J. N., Ohira, M., et al. (2017) · The Journal of Experimental Medicine · doi:10.1084/jem.20162041 · Cited by 63
Self-citationWu, C., Spector, S. A., Theodoropoulos, G., Nguyen, D. J. M., Kim, E., Garcia, A., Savaraj, N., Lim, D. C., Paul, A., Feun, L. G., et al. (2023) · Cancer & Metabolism · doi:10.1186/s40170-023-00307-1 · Cited by 69
“NKG2D is a type II transmembrane receptor that is important for the induction of NK-mediated elimination of target cells [22].”
BackgroundRegulation of NKG2D Stress Ligands and Its Relevance in Cancer Progression
Jones, A. B., Rocco, A., Lamb, L. S., Friedman, G. K., & Hjelmeland, A. B. (2022) · Cancers · doi:10.3390/cancers14092339 · Cited by 66
“Distinct polymorphisms of the NKG2D receptor have been described and have varying roles within disease etiology [25,35].”
BackgroundNKG2D Ligand Shedding in Response to Stress: Role of ADAM10
Zingoni, A., Vulpis, E., Loconte, L., & Santoni, A. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00447 · Cited by 59
“NKG2D ligands are absent or expressed at low levels on healthy cells, and their expression dramatically increases in virus-infected or tumor cells, as well as in response to a number of stress stimuli (2).”
BackgroundEmerging roles of nucleotide metabolism in cancer development: progress and prospect
Ma, J., Zhong, M., Xiong, Y., Gao, Z., Wu, Z., Liu, Y., & Hong, X. (2021) · Aging · doi:10.18632/aging.202962 · Cited by 65
“Cancer cells, virusinfected cells, cells that undergo rapid proliferation and other abnormal cell types express the cell-surface glycoprotein MHC class I polypeptide-related sequence A (MICA), which can be identified by Natural killer group 2D (NKG2D), allowing immune identification and the removal of potential pathol…”
BackgroundSeliger, B. (2016) · HLA · doi:10.1111/tan.12898 · Cited by 56
Recent updates on allogeneic CAR-T cells in hematological malignancies
Mansoori, S., Noei, A., Maali, A., Seyed-Motahari, S. S., & Sharifzadeh, Z. (2024) · Cancer Cell International · doi:10.1186/s12935-024-03479-y · Cited by 57
The Role and Regulation of the NKG2D/NKG2D Ligand System in Cancer
Tan, G., Spillane, K. M., & Maher, J. F. (2023) · Biology · doi:10.3390/biology12081079 · Cited by 56
“It participates in both innate and adaptive immune responses and immune surveillance and is expressed on natural killer (NK) cells, invariant natural killer T (iNKT) cells, γδ T cells and CD8+ T cells [1].”
BackgroundFive decades of natural killer cell discovery
Lanier, L. L. (2024) · Journal of Experimental Medicine · doi:10.1084/jem.20231222 · Cited by 54
“NKG2D is broadly expressed on essentially all NK cells and subsets of T cells and is the focus of development of agonist and antagonist therapeutics in cancer and autoimmune diseases (Lanier, 2015).”
BackgroundSelf-citationZhang, C., Röder, J., Scherer, A., Bodden, M., Serrahima, J. P., Bhatti, A., Waldmann, A., Müller, N., Oberoi, P., & Wels, W. (2021) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2021-002980 · Cited by 54
Extracellular vesicles: important collaborators in cancer progression
Sato, S., & Weaver, A. M. (2018) · Essays in Biochemistry · doi:10.1042/ebc20170080 · Cited by 57
Mucosa-associated invariant T cells in malignancies: a faithful friend or formidable foe?
Haeryfar, S. M. M., Shaler, C. R., & Rudak, P. T. (2018) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-018-2132-1 · Cited by 58
“It binds to proteins encoded by the MHC class I polypeptide-related sequence (MIC) A and B loci and members of the UL16-binding protein/ retinoic acid early transcript 1 (ULBP/RAET1) family [66, 67].”
Regulation of NKG2D Expression and Signaling by Endocytosis
Molfetta, R., Quatrini, L., Zitti, B., Capuano, C., Galandrini, R., Santoni, A., & Paolini, R. (2016) · Trends in Immunology · doi:10.1016/j.it.2016.08.015 · Cited by 59
“Regulation of NKG2D Expression and Functional Consequences NKG2D expression is positively or negatively regulated by different cytokines, including IL-2, IL-7, IL-12, IL-15, and type I interferons (IFNs) [14_TD$DIFF], which have been shown to increase NKG2D surface expression, whereas IL-21, IFN-g, and TGF-b have the…”
BackgroundVulpis, E., Loconte, L., Peri, A., Molfetta, R., Caracciolo, G., Masuelli, L., Tomaipitinca, L., Peruzzi, G., Petillo, S., Petrucci, M., et al. (2022) · Journal of Extracellular Vesicles · doi:10.1002/jev2.12176 · Cited by 53
“NKG2D is a C-type lectin-like activating receptor expressed on NK cells, γδ T cells, CD8 + T cells and some autoreactive or immunosuppressive CD4 + T cells and represents a major recognition receptor for the detection and elimination of virus-infected, and cancer cells (Lanier, 2015).”
Weil, S., Memmer, S., Lechner, A., Huppert, V., Giannattasio, A., Becker, T., Müller-Runte, A., Lampe, K., Beutner, D., Quaas, A., et al. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00387 · Cited by 53
“In this respect, it was shown that NKG2D expression can be increased by different cytokines including IL-2, IL-12, IL-15, and type I interferons (66).”
BackgroundPaired single-cell multi-omics data integration with Mowgli
Huizing, G.-J., Deutschmann, I. M., Gabriel Peyré, A., & Cantini, L. (2023) · Nature Communications · doi:10.1038/s41467-023-43019-2 · Cited by 59
“…CD8 T-cells (CD8 TEM cells), corresponding to factor 49, Mowgli could extract two top genes ( CRTAM and KLRK1 ), known to be essential for CD8+T-cell-mediated cytotoxicity 53,54 , two top proteins (CD45RO, TCR-a/b) that are a known memory T cell marker and a T cell receptor, respectively 55,56 .”
Xie, X., Ma, L.-M., Zhou, Y., Shen, W., Xu, D., Dou, J., Shen, B.-Y., & Zhou, C.-L. (2019) · Carbohydrate Polymers · doi:10.1016/j.carbpol.2019.115223 · Cited by 52
Impact of the MICA-129Met/Val Dimorphism on NKG2D-Mediated Biological Functions and Disease Risks
Isernhagen, A., Malzahn, D., Bickeböller, H., & Dressel, R. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00588 · Cited by 52
“NKG2D is expressed on most human NK cells, CD8+ αβ T cells, γδ T cells, iNKT cells, and subsets of effector or memory CD4+ T cells (8, 9).”
Metadata
- Authors
- Lanier, L. L.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Lanier, Lewis L.
- ORCID
- Lanier, Lewis L.
- Venue
- Cancer Immunology Research
- Published
- 2015-06-01
- Volume
- 3
- Issue
- 6
- Pages
- 575-582
- ISSN
- 2326-6066 (ISSN-L)
- 2326-6074
- PMC
- PMC4457299
- OpenAlex
- W2142548447
- Cited by
- 599
- References
- 78
- Citations by year
- 2026: 27 · 2025: 53 · 2024: 56 · 2023: 73 · 2022: 56 · 2021: 66 · 2020: 63 · 2019: 51 · 2018: 65 · 2017: 47 · 2016: 37 · 2015: 4
- FWCI
- 4.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Immunology Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Cancer Institute (R01CA089189)
- National Institute of Allergy and Infectious Diseases (AI-068129, R01AI068129, R37AI066897, AI066897)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
- Keywords
- NKG2D, NKG2D ligands, mica, MICB, natural killer cells, DAP10, DAP12, immune evasion, viral evasion, tumor immune evasion, host defense, NK cell activation
- MeSH terms
- Animals, Communicable Diseases, Humans, Killer Cells, Natural, Ligands, Lymphocyte Activation, Neoplasms, Lymphocyte Subsets, NK Cell Lectin-Like Receptor Subfamily K, Disease Resistance
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