The DOI matches its Crossref record; 74 of the 78 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“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
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA.
Bauer, S., Groh, V., Wu, J., Steinle, A., Phillips, J., Lanier, L., & Spies, T. (1999) · Science · doi:10.1126/science.285.5428.727 · Cited by 3,272 · cited 2×
“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 (…”
BackgroundSelf-citationTumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation
Groh, V., Wu, J. D., Yee, C., & Spies, T. (2002) · Nature · doi:10.1038/nature01112 · Cited by 1,674 · cited 1×
“These include systemic release of NKG2D ligands by tumors in cancer patients (65, 66).”
BackgroundCosman, D., Müllberg, J., Sutherland, C. L., Chin, W. A., Armitage, R., Fanslow, W., Kubin, M., & Chalupny, N. (2001) · Immunity · doi:10.1016/s1074-7613(01)00095-4 · Cited by 1,394 · cited 11×
“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…”
BackgroundInfluentialThe DNA damage pathway regulates innate immune system ligands of the NKG2D receptor
Gasser, S., Orsulic, S., Brown, E. J., & Raulet, D. H. (2005) · Nature · doi:10.1038/nature03884 · Cited by 1,308 · cited 1×
“In some cases, ligands may be induced due to the genomic instability of the transformed cells, resulting in activation of the ATM and ATR DNA repair pathways (61).”
BackgroundAn activating immunoreceptor complex formed by NKG2D and DAP10.
Wu, J., Song, Y., Bakker, A. B., Bauer, S., Spies, T., Lanier, L., & Phillips, J. (1999) · Science · doi:10.1126/science.285.5428.730 · Cited by 1,168 · cited 6×
“org Cancer Immunol Res; 3(6) June 2015 579”
BackgroundInfluentialSelf-citationRae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity
Diefenbach, A., Jensen, E. R., Jamieson, A. M., & Raulet, D. H. (2001) · Nature · doi:10.1038/35093109 · Cited by 1,083 · cited 1×
“Studies using transplantable mouse tumors have demonstrated that expression of an NKG2D ligand is sufficient to cause rejection of the tumor (62, 63).”
BackgroundImmunoreceptor DAP12 bearing a tyrosine-based activation motif is involved in activating NK cells
Lanier, L. L., Corliss, B. C., Wu, J., Leong, C. C., & Phillips, J. H. (1998) · Nature · doi:10.1038/35642 · Cited by 907 · cited 1×
“Association of NKG2D with DAP12 versus DAP10 has significant consequences for signal transduction in that DAP12 possesses a canonical immunotyrosine-based activation motif (ITAM), which recruits Syk and ZAP70 tyrosine kinases (7), whereas DAP10 has a YINM motif, which recruits a p85 PI3 kinase and Vav-1 signaling comp…”
BackgroundSelf-citationMeresse, B., Chen, Z., Ciszewski, C., Tretiakova, M., Bhagat, G., Krausz, T., Raulet, D., Lanier, L., Groh, V., Spies, T., et al. (2004) · Immunity · doi:10.1016/j.immuni.2004.06.020 · Cited by 901 · cited 1×
“NKG2D-dependent, TCR-independent cytolytic activity has also been observed in intraepithelial intestinal CD8þ T cells isolated from patients with celiac disease, possibly due to exposure to excess IL15 in the inflamed tissue (43).”
BackgroundSelf-citationBryceson, Y., March, M., Ljunggren, H., & Long, E. O. (2006) · Blood · doi:10.1182/blood-2005-04-1351 · Cited by 885 · cited 1×
“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 (…”
BackgroundDiefenbach, A., Jamieson, A. M., Liu, S. D., Shastri, N., & Raulet, D. H. (2000) · Nature Immunology · doi:10.1038/77793 · Cited by 878
Research works printed but not linked: 2
- Castriconi, 2003, Transforming growth factor beta 1 inhibits expression of NKp30 and NKG2D receptors: consequences for the NK-mediated killing of dendritic cells, Proc Natl Acad Sci U S A, 100, 4120, 10.1073/pnas.0730640100 · DOI
- Spear, 2013, NKG2D ligands as therapeutic targets, Cancer Immun, 13, 8
Cited by
Sorted by citations
Items 201–300 of 516
Natural killer cell engagers for cancer immunotherapy
Nikkhoi, S. K., Li, G., & Hatefi, A. (2025) · Frontiers in Oncology · doi:10.3389/fonc.2024.1483884 · Cited by 23
Cantoni, C., Falco, M., Vitale, M., Pietra, G., Munari, E., Pende, D., Mingari, M. C., Sivori, S., & Moretta, L. (2024) · OncoImmunology · doi:10.1080/2162402x.2024.2378520 · Cited by 36
“104,118,119 Their expression can be diminished following the release of soluble ligands in exosomes, as a result of proteolytic shedding or translation of alternatively spliced transcripts.”
BackgroundDysregulation of DNAM-1-Mediated NK Cell Anti-Cancer Responses in the Tumor Microenvironment
Paolini, R., & Molfetta, R. (2023) · Cancers · doi:10.3390/cancers15184616 · Cited by 23
“…than one ligand: NKG2D ligands include MHC-I related proteins, MICA/B and ULBP1-6 proteins in humans, and Rae-1 α - ε , MULT1 and H60a-c in mice [5,6]; DNAM-1 ligands consist of two adhesion molecules, CD155 (PVR/Necl5) and CD112 (PVRL2/Nectin-2) [7,8]; NCR ligands include transmembrane, nuclear…”
BackgroundSARS-CoV-2 peptides bind to NKG2D and increase NK cell activity
Kim, H., Byun, J.-E., Yoon, S., Koohy, H., Jung, H., & Choi, I. (2021) · Cellular Immunology · doi:10.1016/j.cellimm.2021.104454 · Cited by 23
Any closer to successful therapy of multiple myeloma? CAR-T cell is a good reason for optimism
Marofi, F., Tahmasebi, S., Rahman, H. S., Kaigorodov, D., Markov, A. A., Yumashev, A. V., Shomali, N., Chartrand, M. S., Pathak, Y. V., Mohammed, R. N., et al. (2021) · Stem Cell Research & Therapy · doi:10.1186/s13287-021-02283-z · Cited by 28
Tozatto-Maio, K., Girot, R., Ly, I. D., Silva-Pinto, A. C., Rocha, V., Fernandes, F., Diagne, I., Benzerara, Y., Dinardo, C., Soler, J., et al. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.02041 · Cited by 23
“NKG2D is a transmembrane receptor expressed on the surface of NK cells, iNKT cells, T CD8+ and some subsets of TCD4+ lymphocytes (27).”
BackgroundNovel immune-related genes in the tumor microenvironment with prognostic value in breast cancer
Tan, W., Liu, M., Wang, L., Guo, Y., Wei, C., Zhang, S., Luo, C., & Liu, N. (2021) · BMC Cancer · doi:10.1186/s12885-021-07837-1 · Cited by 27
Zekri, A., Deeb, S. E., Bahnassy, A., Badr, A., Abdellateif, M. S., Esmat, G., Salama, H., Mohanad, M., Eldien, A., Rabah, S., et al. (2018) · World Journal of Gastroenterology · doi:10.3748/wjg.v24.i11.1228 · Cited by 23
NKG2D ligand expression in Crohn’s disease and NKG2D-dependent stimulation of CD8+ T cell migration
Vadstrup, K., Galsgaard, E., Jensen, H., Lanier, L., Ryan, J., Chen, S.-Y., Nolan, G., Vester-Andersen, M., Pedersen, J., Gerwien, J., et al. (2017) · Experimental and molecular pathology (Print) · doi:10.1016/j.yexmp.2017.06.010 · Cited by 23
“NKG2D is an activating receptor constitutively expressed in on human NK, γδ T, MAIT, CD56 T, and CD8 T cells (Carapito and Bahram, 2015; Lanier, 2015), which can participate in the recognition of inducible “stressed-self” ligands on the surface of target cells (Champsaur and Lanier, 2010).”
BackgroundMethodSelf-citationγδT cells, a key subset of T cell for cancer immunotherapy
Lv, J., Liu, Z., Ren, X., Song, S., Zhang, Y., & Wang, Y. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1562188 · Cited by 25
Li, S., Zhao, R., Zheng, D., Qin, L., Cui, Y., Li, Y.-H., Jiang, Z.-W., Zhong, M., Shi, J., Li, M., et al. (2022) · Molecular Therapy: Oncolytics · doi:10.1016/j.omto.2022.06.003 · Cited by 22
Epstein–Barr Virus in Inborn Immunodeficiency—More Than Infection
Lino, C. N. R., & Ghosh, S. (2021) · Cancers · doi:10.3390/cancers13194752 · Cited by 28
Current strategies exploiting NK‐cell therapy to treat haematologic malignancies
Johnson, J. K., & Miller, J. S. (2018) · International Journal of Immunogenetics · doi:10.1111/iji.12387 · Cited by 22
“Great reviews have been published on these activating receptors, and they will not be discussed further (Lanier, 2015; Raulet, Gasser, Gowen, Deng, & Jung, 2013).”
BackgroundCutting an NKG2D Ligand Short: Cellular Processing of the Peculiar Human NKG2D Ligand ULBP4
Zöller, T., Wittenbrink, M., Hoffmeister, M., & Steinle, A. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00620 · Cited by 21
“NKG2D-mediated “induced-self ” recognition is facilitated by various MHC class I-related cell surface glycoproteins, which usually are not or barely expressed on “healthy” cells but are strongly upregulated at the cell surface upon cellular stress, exposure to PAMPs, viral infection, or malignant transformation, there…”
BackgroundLee, Y.-S., Heo, W., Nam, J., Jeung, Y.-T., & Bae, J. (2018) · Journal of Radiation Research · doi:10.1093/jrr/rry005 · Cited by 22
CAR-NK cell therapy: a potential antiviral platform.
Lin, M.-H., Hu, L.-J., Miller, J. S., Huang, X.-J., & Zhao, X.-Y. (2025) · Science Bulletin · doi:10.1016/j.scib.2025.01.002 · Cited by 21
Cigarette smoke stimulates clonal expansion of Jak2V617F and Tet2-/- cells
Ramanathan, G., Chen, J. H., Mehrotra, N., Trieu, T., Huang, A., Mas, E., Mena, J. M., Bliss, B., Herman, D. A., Kleinman, M. T., et al. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1210528 · Cited by 24
“Raet1 is a ligand for the cytotoxic lymphocyte activating receptor (NGKD) and plays a major role in NK cell function, and is expressed only under cellular stress conditions such as oxidative stress, DNA damage and hyperproliferation (39).”
BackgroundLeem, G., Jeon, M., Kim, K. W., Jeong, S., Choi, S. J., Lee, Y. J., Kim, E.-S., Lee, J.-I., Ha, S. Y., Park, S., et al. (2021) · Thorax · doi:10.1136/thoraxjnl-2021-217001 · Cited by 35
Evasion of the Host Immune Response by Betaherpesviruses
Sausen, D. G., Reed, K. M., Bhutta, M., Gallo, E. S., & Borenstein, R. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22147503 · Cited by 22
“are not typically expressed by healthy cells; instead, they are induced by cellular stresses such as hyperproliferation, transformation, and infection [100].”
BackgroundTay, J. C., Wang, J.-J., Du, Z., Ng, Y., Li, Z.-D., Ren, Y.-F., Zhang, C.-K., Zhu, J., Xu, X.-H., & Wang, S. (2021) · Molecular Therapy: Methods & Clinical Development · doi:10.1016/j.omtm.2021.02.023 · Cited by 21
“Within the MIC family, allelic polymorphism results in a wide panel of 105 protein variants encoded by the MICA and MICB genetic loci found on human chromosome 6, all of which are recognized by the cognate NKG2D receptor.1 Members of the ULBP family are glycoproteins encoded by the RAET1 genes found similarly on chrom…”
BackgroundInfluentialNatural killer cells involved in tumour immune escape of hepatocellular carcinomar
Chen, H., Jiang, Y., Wang, Z., & Wang, H. (2019) · International Immunopharmacology · doi:10.1016/j.intimp.2019.04.057 · Cited by 25
Gorska, M. (2017) · Current Opinion in Allergy and Clinical Immunology · doi:10.1097/aci.0000000000000327 · Cited by 21
Guan, Y., Li, W.-Q., Hou, Z.-H., Han, Q.-J., Lan, P., Zhang, J., Tian, Z., & Zhang, C. (2016) · OncoTarget · doi:10.18632/oncotarget.11271 · Cited by 21
“As a potent activating receptor, the NKG2D receptor plays an important role in the control of viral infections and tumorigenesis through recognizing its ligands, including MICA, MICB and ULBP1-4 in humans and Rae-1, H60 and MULT1 in mice [4].”
BackgroundMaking a case for using γδ T cells against SARS-CoV-2
Yazdanifar, M., Mashkour, N., & Bertaina, A. (2020) · Critical reviews in microbiology · doi:10.1080/1040841x.2020.1822279 · Cited by 20
Li, Q., Chi, Z., Ang, W. X., Chen, C., Tay, J. C., Ng, Y. Y., Xu, X., Wang, J., Zhu, J., & Wang, S. (2020) · Immunotherapy · doi:10.2217/imt-2019-0137 · Cited by 21
Godbersen, C., Coupet, T. A., Huehls, A., Zhang, T., Battles, M., Fisher, J., Ernstoff, M., & Sentman, C. (2017) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-16-0846 · Cited by 20
“NKG2D functions in the recognition of carcinogenic transformation of cells (18).”
BackgroundCbx3/HP1γ deficiency confers enhanced tumor-killing capacity on CD8+ T cells
Sun, M. T., Ha, N., Pham, D.-H., Frederick, M. A., Sharma, B., Naruse, C., Asano, M., Pipkin, M. E., George, R. E., & Thai, T. (2017) · Scientific Reports · doi:10.1038/srep42888 · Cited by 19
Human Immune Responses to Epstein-Barr Virus Highlighted by Immunodeficiencies
Latour, S. (2025) · Annual Review of Immunology · doi:10.1146/annurev-immunol-082323-035455 · Cited by 19
Covino, D., Desimio, M., & Doria, M. (2022) · Scientific Reports · doi:10.1038/s41598-022-23010-5 · Cited by 19
Kim, K. H., Yu, H. T., Hwang, I., Park, S., Park, S., Kim, S., & Shin, E. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02865 · Cited by 28
“NKG2D receptor, which mediates the cytolytic activity of NK cells against target cells expressing NKG2D ligands (20), was most highly expressed in FcεRIγNKG2C NK cells, and expressed at significantly lower levels in FcεRIγNKG2C and FcεRIγNKG2C NK cells compared to FcεRIγNKG2C NK cells (Figure 5F).”
BackgroundModular Activating Receptors in Innate and Adaptive Immunity
Berry, R., & Call, M. E. (2017) · Biochemistry · doi:10.1021/acs.biochem.6b01291 · Cited by 17
NKp30 and its ligands: emerging players in tumor immune evasion from natural killer cells.
von Strandmann, E. P., Shatnyeva, O., & Hansen, H. (2015) · Annals of Translational Medicine · doi:10.3978/j.issn.2305-5839.2015.09.08 · Cited by 19
“NK cells are terminally activated by ligation of the activating NK receptors NKG2D, NKp30 or NKp46 through their corresponding ligands, which are up-regulated on the cell surface of dangerous cells (1-5).”
BackgroundThe role of NK cells in regulating tumorimmunity: current state, challenges and future strategies
Zhu, W., Fan, C., Zhao, Y., Li, W., Niu, J., Dong, S., Yang, Z., & Zhou, W. (2025) · Cancer Cell International · doi:10.1186/s12935-025-03980-y · Cited by 17
“Understanding the intricacies of these immune cell populations and their interplay will provide valuable insights for the development of novel therapeutic strategies against tumors cells, CD8 T cells, and intrinsic T cells, such as NKT cells and γδ T cells [187, 188].”
Designs of NKG2D-based immunotherapeutics for cancer
Han, J., Wang, Y.-W., Chan, G. C., & Chan, W. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1557644 · Cited by 18
Huang, S., Qin, Z.-H., Wang, F.-Y., Kang, Y.-X., & Ren, B. (2024) · Oncology Report · doi:10.3892/or.2024.8796 · Cited by 18
“MHC class I molecules are often underex‑ pressed or not expressed in tumor cells, making it impossible to activate the cytotoxic functions of CD8 + T cells (8,9).”
BackgroundMaking a Killer: Selecting the Optimal Natural Killer Cells for Improved Immunotherapies
Barnes, S. A., Trew, I., de Jong, E., & Foley, B. A. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.765705 · Cited by 18
“Other activating receptors include: the natural cytotoxicity receptors (NCRs) NKp30, NKp44 and NKp46, which directly bind to a wide variety tumor-associated ligands (10); NKG2D, which recognizes the cell-stress induced major histocompatibility complex class I-related molecules MICA and MICB and the UL16-binding protei…”
BackgroundJacobs, B., Gebel, V., Heger, L., Grèze, V., Schild, H., Dudziak, D., & Ullrich, E. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.670540 · Cited by 18
“Those encoded proteins belong to a group of at least 100 different ligands which are selectively expressed on non-healthy cells for the induction of NK cell activation (14).”
BackgroundSeidel, E., Dassa, L., Schuler, C., Oiknine-Djian, E., Wolf, D., Le-Trilling, V., & Mandelboim, O. (2020) · bioRxiv · doi:10.1371/journal.ppat.1008807 · Cited by 18
“A major activating receptor expressed on all NK cells is NKG2D, a c-type lectin that binds a family of eight stress induced ligands: MHC class I polypeptide-related sequences (MIC) A and B, and UL16 binding proteins (ULBP) 1–6 [17].”
BackgroundDynamic urinary proteomic analysis in a Walker 256 intracerebral tumor model
Zhang, L., Li, Y., Meng, W., Ni, Y., & Gao, Y.-H. (2018) · bioRxiv · doi:10.1101/481697 · Cited by 18
“Furthermore, NKG2D acts as an activating receptor for killer cells (NK), which can be induced by hyperproliferation and transformation and by pathogen infection, providing therapeutic targets for the treatment of infectious diseases, cancer and autoimmune diseases[34].”
BackgroundPossible role of circulating endothelial cells in patients after acute myocardial infarction.
Rakić, M., Peršić, V., Kehler, T., Bastiančić, A. L., Rosovic, I., Laškarin, G., & Tokmadzic, V. S. (2018) · Medical Hypotheses · doi:10.1016/j.mehy.2018.06.005 · Cited by 18
Intragenic transcriptional interference regulates the human immune ligand MICA
Lin, D., Hiron, T. K., & O'Callaghan, C. A. (2018) · EMBO Journal · doi:10.15252/embj.201797138 · Cited by 18
“Engagement of NKG2D on NK cells by MICA expressed on target cells promotes cytokine release and killing of the target cells and is implicated in cancer immunity, antiviral immunity and autoimmunity (Bauer et al , 1999; Ullrich et al , 2013; Lanier, 2015).”
Martinović, K. M., Vuletić, A., Babović, N. L., Dzodic, R., Konjević, G., & Jurišić, V. (2017) · Cytokine · doi:10.1016/j.cyto.2017.02.024 · Cited by 18
“This receptor upon binding to its ligands, the MHC class I chain-related (MIC) proteins A and B, and the UL-16 binding proteins (ULBPs), upregulated on transformed cells, in association with DAP10 adaptor molecule induces NK cell and CTL-mediated cytotoxicity against cancer [3].”
BackgroundNKG2D signaling between human NK cells enhances TACE-mediated TNF-α release
Sharma, N., Trinidad, C., Trembath, A. P., & Markiewicz, M. (2017) · Journal of Immunology · doi:10.4049/jimmunol.1700647 · Cited by 18
“NKG2D ligands are not expressed by most healthy tissue, but rather are induced upon cellular stress, such as microbial infection, cellular transformation, or DNA damage (4).”
BackgroundRole of Immune Cells and Immunotherapy in Multiple Myeloma
Radhakrishnan, V., Golla, U., & Kudva, A. K. (2024) · Life · doi:10.3390/life14040461 · Cited by 18
“Both primary and metastatic cancer cells frequently upregulate stress-induced ligands closely related to MHC class I [177].”
BackgroundKiefer, A., Prüfer, M., Röder, J., Serrahima, J. P., Bodden, M., Kühnel, I., Oberoi, P., & Wels, W. (2024) · Cells · doi:10.3390/cells13030246 · Cited by 17
“Natural Killer Group 2D (NKG2D) is a C-type lectin-like type II transmembrane protein that serves as an activating receptor for natural killer (NK) cells, CD8 + T cells, NKT cells, and subpopulations of CD4 + and γδ T cells [1–3].”
BackgroundLutz, S., Klausz, K., Albici, A.-M., Ebinger, L., Sellmer, L., Teipel, H., Frenzel, A., Langner, A., Winterberg, D., Krohn, S., et al. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1227572 · Cited by 19
“One candidate in this aspect is the activating receptor natural killer group 2 member D (NKG2D; CD314), a C-type lectin-like receptor, that plays a key role in immunosurveillance of tumors and pathogens (17, 18).”
BackgroundDesimio, M., Covino, D., Rivalta, B., Cancrini, C., & Doria, M. (2023) · Cancers · doi:10.3390/cancers15061914 · Cited by 17
“NKG2D is expressed by NK and CD8 T cells as well as by subsets of iNKT, γδ T, and CD4 T cells, and recognizes eight cell surface proteins (MICA, MICB, and ULBP1-6 proteins, referred to overall as NKG2D ligands or NKG2DLs) whose expression is highly restricted in normal cells but can be induced via stress pathways on t…”
BackgroundIL-1R8: A molecular brake of anti-tumor and anti-viral activity of NK cells and ILC.
Mariotti, F., Supino, D., Landolina, N., Garlanda, C., Mantovani, A., Moretta, L., & Maggi, E. (2023) · Seminars in Immunology · doi:10.1016/j.smim.2023.101712 · Cited by 17
Wang, W., Xi, Y., Li, S.-L., Liu, X., Wang, G.-X., Wang, H., Pei, M.-M., Zhang, J., Gui, J.-G., & Ni, X. (2022) · Journal of Virology · doi:10.1128/jvi.00946-22 · Cited by 17
Dhar, P., Basher, F., Ji, Z., Huang, L., Qin, S.-S., Wainwright, D., Robinson, J., Hagler, S., Zhou, J., Mackay, S., et al. (2021) · Communications Biology · doi:10.1038/s42003-021-02440-3 · Cited by 17
Induction of T Cell Senescence by Cytokine Induced Bystander Activation
Abbas, A. A., & Akbar, A. N. (2021) · Frontiers in Aging · doi:10.3389/fragi.2021.714239 · Cited by 23
CD3-CD56+ NK cells display an inflammatory profile in RR-MS patients
Tahralı, İ., Küçüksezer, U. C., Akdeniz, N., Altıntaş, A., Uygunoğlu, U., Aktaş-Çetin, E., & Deniz, G. (2019) · Immunology Letters · doi:10.1016/j.imlet.2019.10.006 · Cited by 16
Luu, T. T., Ganesan, S., Wagner, A., Sarhan, D., Meinke, S., Garbi, N., Hämmerling, G., Alici, E., Kärre, K., Chambers, B., et al. (2016) · Scientific Reports · doi:10.1038/srep37996 · Cited by 17
Djelloul, M., Popa, N., Pelletier, F., Raguénez, G., & Boucraut, J. (2016) · Brain, behavior, and immunity · doi:10.1016/j.bbi.2016.07.147 · Cited by 17
“NK cells, invariant NKT cells, cd T cells, CD8+ T cells and subsets of CD4+ T cells (reviewed in (Lanier, 2015)) is complex and should take into account the other NKG2D ligands, i.”
Evasion of NKG2D-mediated cytotoxic immunity by sarbecoviruses
Hartmann, J., Cardoso, M., Talarico, M. C. R., Kenney, D., Leone, M. R., Reese, D. C., Turcinovic, J., O'Connell, A., Gertje, H., Marino, C., et al. (2024) · Cell · doi:10.1016/j.cell.2024.03.026 · Cited by 16
Sadrolvaezin, A., Pezhman, A., Zare, I., Nasab, S. Z., Chamani, S., Naghizadeh, A., & Mostafavi, E. (2023) · MedComm · doi:10.1002/mco2.386 · Cited by 18
“36,75,76 Likewise, NKG2D receptors were neutralized by the administration of anti-NKG2D mAb, resulting in significantly reduced ear swelling by Pd 36 (Figure 4).”
BackgroundUstiuzhanina, M. O., Vavilova, J. D., Boyko, A. A., Streltsova, M. A., Kust, S. A., Kanevskiy, L. M., Sapozhnikov, A. M., Iskhakov, R. N., Gubernatorova, E. O., Drutskaya, M. S., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24031996 · Cited by 20
“It was previously shown that an increased proportion of highly differentiated NK cells with a reduced FcεRγ expression level distinguished lethal patients from those who recovered [26].”
BackgroundWang, J., Liu, K., Xiao, T.-X., Liu, P.-G., Prinz, R., & Xu, X. (2022) · Oncoimmunology · doi:10.1080/2162402x.2021.2016159 · Cited by 16
“NKG2D ligands bind to their receptor expressed on natural killer cells, γδ T cells, and CD8 T cells and play an important role in activating immune cells and antitumor immunity.(1,7) Genotoxic drugs such as 5-fluorouracil (5-FU) or gemcitabine are thought to exert their tumoricidal effects by inhibiting DNA replicatio…”
BackgroundLe, D. T., Huynh, T. R., Burt, B. M., Buren, G. V., Abeynaike, S. A., Zalfa, C., Nikzad, R., Kheradmand, F., Tyner, J. J., & Paust, S. (2021) · JCI Insight · doi:10.1172/jci.insight.140116 · Cited by 23
“NKG2D-expressing NK cells were also seen at higher proportions in TIL-PDX-LUAD mouse spleens (Figure 8, A and B), while their proportions remained unchanged in the tumor (Figure 8C).”
InfluentialZheng, P., Huang, C., Leng, D., Sun, B., & Zhang, X. D. (2020) · BMC Medical Genomics · doi:10.1186/s12920-020-00785-y · Cited by 24
Arming cytotoxic lymphocytes for cancer immunotherapy by means of the NKG2D/NKG2D-ligand system
Lazarova, M., Wels, W., & Steinle, A. (2020) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2020.1803273 · Cited by 16
Inhibitory checkpoints in human natural killer cells: IUPHAR Review 28
Mariotti, F. R., Quatrini, L., Munari, E., Vacca, P., Tumino, N., Pietra, G., Mingari, M. C., & Moretta, L. (2020) · British Journal of Pharmacology · doi:10.1111/bph.15081 · Cited by 17
“Also, its ligands, namely, ULBPs and MICA/B, are overexpressed in infected and tumour cells (Lanier, 2015).”
BackgroundNatural Killer Cell Receptor Genes in Camels: Another Mammalian Model
Futas, J., Oppelt, J., Jelinek, A. L., Elbers, J. P., Wijacki, J., Knoll, A., Burger, P., & Horin, P. (2019) · Frontiers in Genetics · doi:10.3389/fgene.2019.00620 · Cited by 16
“The low polymorphism of camelid KLRK is comparable to the limited polymorphism of this gene in humans and mice encoding an activating receptor NKG2D for diverse ligands (reviewed in Lanier, 2015).”
BackgroundNKG2D and Its Ligand MULT1 Contribute to Disease Progression in a Mouse Model of Multiple Sclerosis
Legroux, L., Moratalla, A. C., Laurent, C., Deblois, G., Verstraeten, S. L., & Arbour, N. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00154 · Cited by 16
“their surface as well as a small subpopulation of activated CD4T lymphocytes in both species (3).”
BackgroundBonacini, M., Soriano, A., Zerbini, A., Calò, E., Cimino, L., Muratore, F., Fontana, L., Braglia, L., Parmeggiani, M., Salvarani, C., et al. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02157 · Cited by 16
“NKG2D acts as a sensor for recognition of induced-self antigens in cells infected by pathogens, transformed or stressed cells (17).”
BackgroundHarnessing innate lung anti-cancer effector functions with a novel bacterial-derived immunotherapy
Bazett, M., Costa, A. M., Bosiljcic, M., Anderson, R. M., Alexander, M. P., Wong, S. W. Y., Dhanji, S., Chen, J. M. H., Pankovich, J., Lam, S., et al. (2017) · Oncoimmunology · doi:10.1080/2162402x.2017.1398875 · Cited by 16
“NKG2D recognizes stress-associated molecules (collectively called NKG2D ligands) that are upregulated on cells upon infection and/or malignant transformation.(26) It was hypothesized that QBKPN administration may induce or enhance NK cell-mediated anti-tumor efficacy through the NKG2D pathway.”
BackgroundResultInfluentialProteome-wide Mendelian randomization identifies causal plasma proteins in lung cancer
Li, H., Du, S., Dai, J., Jiang, Y., Li, Z., Fan, Q., Zhang, Y., You, D., Zhang, R., Zhao, Y., et al. (2024) · iScience · doi:10.1016/j.isci.2024.108985 · Cited by 16
Milito, N. D., Zingoni, A., Stabile, H., Soriani, A., Capuano, C., Cippitelli, M., Gismondi, A., Santoni, A., Paolini, R., & Molfetta, R. (2022) · European Journal of Immunology · doi:10.1002/eji.202250198 · Cited by 15
Zhao, N.-H., Qian, Y., Wu, C.-S., Wang, J.-W., Fang, Y., Fan, X.-P., Gao, S., Fan, Y.-C., & Wang, K. (2019) · Biomarkers in Medicine · doi:10.2217/bmm-2019-0102 · Cited by 15
Gao, L.-C., Jiang, Y.-F., Wang, Y.-C., Qu, X., Li, L., Lou, X., Wang, Y., Guo, H., & Liu, Y. (2018) · Medicine · doi:10.1097/md.0000000000013668 · Cited by 15
“NKG2D is a highly evolutionary and conservative activating receptor on the surface of NK cells, and it recognizes an array of diverse ligands (NKG2DLs) encoded by numerous genes, such as MICA, MICB, and RAET1.”
Advances in adoptive cellular therapy for colorectal cancer: A narrative review
Yi, X., & Hu, W. (2022) · Annals of Translational Medicine · doi:10.21037/atm-22-6196 · Cited by 14
“Generally, these ligands are highly expressed in response to stressors (e.g., infection and oncogenic transformation) but are at low levels in normal tissues (57,58,60).”
Wu, Y., Yin, M., Xia, W., Dou, B., Liu, X., & Sun, R. (2025) · Phytotherapy Research · doi:10.1002/ptr.8456 · Cited by 14
“NKG2D, a C-type lectin-like receptor, is one of the best-characterized activating NK cell receptors implicated in immune responses against cancer (Lanier 2015).”
Wu, Q., Li, X., Yang, Y., Huang, J., Yao, M., Li, J., Huang, Y., Cai, X., Geller, D. A., & Yan, Y. (2024) · Cancers · doi:10.3390/cancers16020269 · Cited by 14
“…therapy upregulated the expression of major histocompatibility complex (MHC) class I associated chains A (MICA) in HCC cells through IRF1 mediation [9], and increased the number of natural killer (NK) cells and CD8+ T cells through the activation of natural killer group 2D (NKG2D) receptors [10].”
BackgroundThe MICA-NKG2D axis in clear cell renal cell carcinoma bolsters MICA as target in immuno-oncology
Secchiari, F., Nuñez, S. Y., Sierra, J., Ziblat, A., Regge, M. V., Raffo-Iraolagoitia, X., Rovegno, A., Ameri, C., Secin, F., Richards, N., et al. (2022) · Oncoimmunology · doi:10.1080/2162402x.2022.2104991 · Cited by 14
“protein (ULBP) family, also known as Retinoic Acid Early Transcripts (RAET) 1, ULBP1 (RAET1I), ULBP2 (RAET1H), ULBP3 (RAET1N), ULBP4 (RAET1E), ULBP5 (RAET1G) and ULBP6 (RAET1L).(21,27) Although MICA and MICB transcripts could be detected in many normal tissues,(28) the expression of the proteins is highly restricted t…”
BackgroundJacquelot, N., Seillet, C., Souza-Fonseca-Guimarães, F., Sacher, A. G., Belz, G. T., & Ohashi, P. S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22169044 · Cited by 16
MG132 selectively upregulates MICB through the DNA damage response pathway in A549 cells
Luo, D., Dong, X.-W., Yan, B., Liu, M., Xue, T., Liu, H., You, J., Li, F., Wang, Z.-L., & Chen, Z.-N. (2018) · Molecular Medicine Reports · doi:10.3892/mmr.2018.9676 · Cited by 14
“Previous studies have revealed that numerous factors, including cell stress, heat shock, infection, DNA damage and transformation, can upregulate the expression of MICs (13-18).”
CD1-Restricted T Cells During Persistent Virus Infections: “Sympathy for the Devil”
Schönrich, G., & Raftery, M. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00545 · Cited by 14
“Activation of CD1d-Restricted T Cells Persistent viruses such as HHVs also interfere with NKG2D ligand upregulation on virus-infected cells thereby reducing the likelihood of NKG2D-mediated activation of antiviral iNKT and type 2 NKT cells (280, 281).”
BackgroundCharacterization of circulating gamma-delta T cells in relapsing vs remission multiple sclerosis
Monteiro, A., Cruto, C., Rosado, P., Martinho, A., Rosado, L. E. P., Fonseca, A. M., & Paiva, A. A. (2018) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2018.02.009 · Cited by 14
Morvan, M. G., Champsaur, M., Reizis, B., & Lanier, L. (2017) · ImmunoHorizons · doi:10.4049/immunohorizons.1700004 · Cited by 14
“The ligands of NKG2D are frequently expressed by tumors of many cell types in humans and mice, by infected cells during viral infections, and by certain tissues in the context of autoimmune diseases (1, 2).”
BackgroundSelf-citationInhibition of Sophocarpine on Poly I: C/D-GalN-Induced Immunological Liver Injury in Mice
Huang, Y.-Q., Li, P., Wang, J.-B., Zhou, H.-Q., Yang, Z.-R., Yang, R.-C., Bai, Z.-F., Wang, L.-F., Li, J.-Y., Liu, H.-H., et al. (2016) · Frontiers in Pharmacology · doi:10.3389/fphar.2016.00256 · Cited by 14
“The expression of the NKG2D protein on the surface of NK cells requires interactions with its adapter protein to stabilize the receptor complex (Lanier, 2015).”
BackgroundZhao, X.-M., Xi, M., Wu, J.-Y., Zhu, X.-J., & Xiao, Y. (2026) · Annals of Hematology · doi:10.1007/s00277-026-06742-6 · Cited by 13
“Additional engineering strategies, including stress-induced ligands, including MICA, MICB, and mem - bers of the ULBP family [70–72 ].”
The cell stress and immunity cycle in cancer: Toward next generation of cancer immunotherapy
Laureano, R. S., Vanmeerbeek, I., Sprooten, J., Govaerts, J., Naulaerts, S., & Garg, A. D. (2023) · Immunological Reviews · doi:10.1111/imr.13287 · Cited by 13
“30,31 Another example of how the immune system contributes to restoring homeostasis after cellular stress is in situations of mechanical disruption (e.g., a skin wound).”
BackgroundIdentification of small-molecule protein–protein interaction inhibitors for NKG2D
Thompson, A., Harbut, M., Kung, P.-P., Karpowich, N., Branson, J., Grant, J. C., Hagan, D. L., Pascual, H., Bai, G.-Y., Zavareh, R. B., et al. (2023) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.2216342120 · Cited by 13
Ferretti, E., Carlomagno, S., Pesce, S., Muccio, L., Obino, V., Greppi, M., Solari, A., Setti, C., Marcenaro, E., Chiesa, M. D., et al. (2020) · Cancers · doi:10.3390/cancers12123705 · Cited by 13
Overview of Strategies to Improve Therapy against Tumors Using Natural Killer Cell
Yang, C.-P., Li, Y., Yang, Y.-Z., & Chen, Z. (2020) · Journal of Immunological Research · doi:10.1155/2020/8459496 · Cited by 13
“The NK cells with NKG2D expression can detect and eliminate cells that have undergone “ stress ” , showing its promising application in the treatment of infectious disease, cancer, and autoimmune disease [26].”
Chakladar, J., Li, W.-T., Bouvet, M., Chang, E. Y., Wang-Rodriguez, J., & Ongkeko, W. (2019) · Cancers · doi:10.3390/cancers11081179 · Cited by 13
“The retinoic acid early transcript (RAET) proteins are stress-induced ligands for the immune cell activating receptor NKG2D [29].”
BackgroundAssociation of MICA and MICB polymorphisms with the susceptibility of leukemia in Korean patients
Baek, I.-C., Shin, D.-H., Choi, E.-J., Kim, H.-J., Yoon, J.-H., Cho, B., Kim, Y.-J., Lee, S., Min, W., Kim, H., et al. (2018) · Blood Cancer Journal · doi:10.1038/s41408-018-0092-5 · Cited by 13
Qian, L., Liu, Y., Wang, S., Gong, W.-J., Jia, X.-Q., Liu, L., Ye, F., Ding, J., Xu, Y., Fu, Y., et al. (2017) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.13124 · Cited by 13
“Ligand activation of NKG2D is critical for antitumour immune response through activating NK cells and CD8 T cells [2].”
BackgroundMcQueen, B., Trace, K., Whitman, E., Bedsworth, T., & Barber, A. (2015) · Immunology · doi:10.1111/imm.12563 · Cited by 20
Mechanical communication and function regulation of immune cells
Chen, Y., Xie, R., Cao, T., Zhang, Y., Wang, X., Xu, Y., Fan, Q., & Ye, F. (2024) · Fundamental Research · doi:10.1016/j.fmre.2024.04.008 · Cited by 14
“Stimulatory immune receptors, such as natural killer group 2 member D (NKG2D), can recognize various ligands to trigger a distinct immune response [ 127 , 128 ].”
Sacramento, L. A., Amorim, C. F., Campos, T. M., Saldanha, M. G., Arruda, S. M., Carvalho, L. P., Beiting, D. P., Carvalho, E. M., Novais, F. O., & Scott, P. (2023) · PLoS neglected tropical diseases · doi:10.1371/journal.pntd.0011552 · Cited by 18
“The ligands for NKG2D in humans belong to the MHC class I chainrelated protein A and B (MICA and MICB) and UL16 binding protein (ULBP1-ULBP6) families [18,19] and are induced in sites of inflammation [15,20–24].”
BackgroundMolfetta, R., Petillo, S., Cippitelli, M., & Paolini, R. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1213114 · Cited by 12
“NKG2D is expressed on NK cells but also on CD8+αβ T cells, γδ T cells, and activated CD4+αβ T cells (Ullrich et al., 2013; Marcus et al., 2014; Lanier, 2015).”
BackgroundInfluentialmiR-4299 inhibits tumor progression in pancreatic cancer through targeting ADAM17
Liu, J., Ye, L., Lin, K., Zhong, T., Luo, J., Wang, T., Suo, L., Mo, Q., Li, S., Chen, Q., et al. (2022) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-022-04617-8 · Cited by 12
“It has been evidenced that the immunity effects of NK cells depend on natural killer group 2D (NKG2D)-mediated killing of tumor cells, and the efficiency of NKG2D-mediated cytotoxicity is linked to NKG2D ligand (NKG2DL) expression upon the target cells [26].”
BackgroundLiu, R., Luo, Q., Luo, W., Wan, L., Zhu, Q., Yin, X., Lu, X., Song, Z.-X., Wei, L.-Y., Xiang, Z., et al. (2022) · Aging and Disease · doi:10.14336/ad.2022.0415 · Cited by 12
“The natural killer group 2, member D (NKG2D)– NKG2D ligand (NKG2DL) axis is the major pathway through which human NK cells are activated to kill tumor cells and virus-infected cells [18-20].”
BackgroundThe Oncoprotein SKI Acts as A Suppressor of NK Cell-Mediated Immunosurveillance in PDAC
Ponath, V., Frech, M., Bittermann, M., Khayer, R. A., Neubauer, A., Brendel, C., & von Strandmann, E. P. (2020) · Cancers · doi:10.3390/cancers12102857 · Cited by 12
“Their expression is regulated by transcriptional, translational and posttranslational mechanisms [16], although the transcription factors involved are not yet entirely defined.”
BackgroundGuo, W., Wang, X., Li, Y., & Bai, O. (2020) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2020.103071 · Cited by 13
Prinz, D., Klein, K. R., List, J., Knab, V. M., Menzl, I., Leidenfrost, N., Heller, G., Polić, B., Putz, E., Witalisz-Siepracka, A., et al. (2019) · European Journal of Immunology · doi:10.1002/eji.201948222 · Cited by 12
Characterization of human natural killer cells for therapeutic use.
Wagner, A., Alici, E., & Lowdell, M. (2019) · Cytotherapy · doi:10.1016/j.jcyt.2018.11.001 · Cited by 12
Wang, L., Shi, M., Sung, A. Y., Yin, C. C., Bai, Y., & Chen, M. (2025) · Seminars in Diagnostic Pathology · doi:10.1016/j.semdp.2025.150916 · Cited by 14
Zheng, E., Włodarczyk, M., Węgiel, A., Osielczak, A., Możdżan, M., Biskup, L., Grochowska, A., Wołyniak, M., Gajewski, D., Porc, M., et al. (2024) · Frontiers in Surgery · doi:10.3389/fsurg.2024.1398289 · Cited by 10
“This mechanism was used in adoptive cell therapy (166, 167).”
Method
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
