Affinage

KLRK1

NKG2-D type II integral membrane protein · UniProt P26718

Length
216 aa
Mass
25.3 kDa
Annotated
2026-04-28
100 papers in source corpus 21 papers cited in narrative 22 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KLRK1 (NKG2D) is a homodimeric C-type lectin-like activating receptor on NK cells and CD8+ T cells that detects stress-induced ligands (MICA/B, ULBPs, Rae-1, H60) on transformed, infected, or damaged cells to trigger cytotoxicity, cytokine production, and tumor rejection (PMID:11557981, PMID:12426564). NKG2D requires the adapter DAP10 for surface expression and signals through a YINM motif that recruits PI3K, Vav1, Rho GTPases, and PLCγ independently of Syk kinases; in murine NK cells it can alternatively associate with DAP12 to recruit protein tyrosine kinases, functioning as a primary activating receptor rather than a costimulator (PMID:12426564, PMID:12740575). Surface NKG2D expression is dynamically regulated by ligand-induced internalization and lysosomal degradation, by soluble ligand shedding (facilitated by ERp5-dependent disulfide isomerization of MICA), and by transcriptional control of its ligands through CBP/p300–CREB, PARP1 repression, STING-dependent DNA sensing, and EGFR–AUF1-mediated mRNA stabilization (PMID:19329438, PMID:17495932, PMID:27477692, PMID:31316209, PMID:24590060, PMID:24718859). Chronic in vivo engagement of NKG2D by constitutive RAE-1ε on endothelial cells desensitizes NK cells globally, establishing NKG2D as a peripheral tolerance checkpoint (PMID:29231815).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2001 High

    Establishing that NKG2D ligand expression on tumor cells is sufficient to drive immune rejection resolved the question of whether NKG2D engagement has functional antitumor consequences in vivo.

    Evidence Ectopic Rae1β/H60 expression on syngeneic tumors with NK/CD8 depletion controls in mice

    PMID:11557981

    Open questions at the time
    • Whether endogenous ligand levels on spontaneous tumors suffice for rejection
    • Relative contributions of NK vs CD8+ T cells in different tumor contexts
  2. 2001 Medium

    Demonstrating that NKG2D requires DAP10 for surface expression established an obligate adapter dependency conserved across species.

    Evidence Pig NKG2D/DAP10 co-transfection in COS-7 cells with surface expression by flow cytometry

    PMID:11398969

    Open questions at the time
    • Mechanism by which DAP10 retains NKG2D intracellularly in its absence
    • Whether other adapters can substitute in any context
  3. 2002 High

    Identifying that NKG2D pairs with DAP10 in CD8+ T cells versus DAP12 in NK cells explained cell-type-specific signaling and resolved why NKG2D functions as a costimulator in T cells but a primary activating receptor in NK cells.

    Evidence DAP10-knockout mice with cell-type-specific functional assays showing selective loss of NKG2D on CD8+ T cells but retention on NK cells via DAP12

    PMID:12426564

    Open questions at the time
    • Whether adapter switching occurs under activation conditions
    • The stoichiometry of NKG2D–DAP10 vs NKG2D–DAP12 complexes
  4. 2003 High

    Mapping the DAP10 YINM motif to PI3K, Vav1, Rho GTPases, and PLCγ recruitment — independent of Syk — defined the intracellular signaling cascade linking NKG2D engagement to cytotoxicity.

    Evidence In vitro kinase assays, pharmacological inhibitors, and dominant-negative constructs in NK cells

    PMID:12740575

    Open questions at the time
    • How Vav1/Rho signaling connects to granule polarization
    • Whether DAP12-associated signaling engages distinct downstream effectors in human NK cells
  5. 2004 Medium

    Showing that inhibitory Ly49 receptors can override NKG2D activation in a receptor-specific manner established the hierarchical integration of activating and inhibitory signals at the NK cell level.

    Evidence NK cell cytotoxicity and cytokine assays with antibody crosslinking of NKG2D and individual Ly49 receptors

    PMID:15328154

    Open questions at the time
    • Molecular basis for differential dominance among Ly49 family members
    • Whether human KIR receptors show analogous hierarchies over NKG2D
  6. 2006 Medium

    Discovery that soluble ULBPs and soluble MICA shed from tumors downregulate NKG2D surface expression on NK cells identified a major immune evasion mechanism and linked ligand shedding to receptor internalization.

    Evidence NK cell co-culture with tumor supernatants, recombinant ULBP-Fc treatment, flow cytometry, and cytotoxicity assays

    PMID:16630603 PMID:16732291

    Open questions at the time
    • Quantitative threshold of soluble ligand needed for functional NKG2D loss
    • Whether soluble and membrane-bound ligands trigger qualitatively different signaling
  7. 2007 High

    Identifying ERp5 as the disulfide isomerase that enables proteolytic shedding of MICA from tumor cells provided a specific molecular mechanism for soluble MICA generation and a potential therapeutic target.

    Evidence Co-IP, ERp5 knockdown, pharmacological thioreductase inhibition, and disulfide bond analysis on tumor cells

    PMID:17495932

    Open questions at the time
    • Identity of the protease that cleaves MICA after ERp5 action
    • Whether ERp5 similarly promotes shedding of ULBP ligands
  8. 2009 Medium

    Tracking NKG2D/DAP10 to secretory lysosomes after ligand engagement and showing ~50% receptor degradation with partial recycling established the intracellular trafficking pathway governing NKG2D surface dynamics.

    Evidence Confocal and live imaging of NKL and primary NK cells with lysosomal inhibitors and subcellular fractionation

    PMID:19329438

    Open questions at the time
    • Molecular machinery directing NKG2D to lysosomes vs recycling endosomes
    • Whether DAP12-associated NKG2D follows the same degradation pathway
  9. 2010 Medium

    Demonstrating NKG2D requirement for NK cell activation during adenoviral infection — through ligand upregulation on dendritic cells and macrophages — extended NKG2D's role beyond tumor surveillance to antiviral immunity.

    Evidence NKG2D antibody blockade and NK cell depletion in adenoviral infection model in vivo

    PMID:21076062

    Open questions at the time
    • Which viral factors trigger NKG2D ligand induction on accessory cells
    • Whether NKG2D-dependent antiviral function extends to non-adenoviral infections in the same tissue
  10. 2011 Medium

    Identification of β-catenin activation as a unique downstream output of NKG2D costimulation in CD8+ T cells — suppressing anti-inflammatory cytokines via PPARγ — revealed a signaling branch distinct from TCR/CD28 pathways.

    Evidence Chimeric NKG2D receptor signaling, β-catenin pathway analysis, and pharmacological inhibition

    PMID:21518928

    Open questions at the time
    • How DAP10 couples to β-catenin stabilization mechanistically
    • In vivo relevance of β-catenin-dependent cytokine suppression
  11. 2013 High

    Demonstrating that NKG2D and granzyme B are required for allergen-induced pulmonary inflammation expanded NKG2D's physiological roles to non-tumor, non-infection tissue injury.

    Evidence NKG2D-deficient mice, adoptive transfer of WT vs granzyme B-deficient NK cells in HDM allergen model

    PMID:24290277

    Open questions at the time
    • Identity of the NKG2D ligand induced on airway cells by HDM
    • Whether NKG2D-dependent allergic inflammation is granzyme B-mediated in human asthma
  12. 2014 High

    Placing NKG2D ligand induction downstream of the STING–TBK1–IRF3 cytosolic DNA sensing pathway connected the DNA damage response to innate immune recognition via NKG2D.

    Evidence STING pathway genetic knockout in Eμ-Myc mice, DNA transfection into ligand-negative cells inducing RAE-1

    PMID:24590060

    Open questions at the time
    • Whether STING-dependent induction applies to human NKG2D ligands (MICA/B, ULBPs)
    • Whether other pattern-recognition pathways converge on NKG2D ligand promoters
  13. 2014 High

    Discovering that EGFR activation stabilizes NKG2D ligand mRNAs by relocalizing the destabilizing factor AUF1 away from AU-rich 3′ UTR elements defined a post-transcriptional regulatory axis for NKG2D ligand expression in epithelial cells.

    Evidence EGFR activation/inhibition, AUF1 relocalization, mRNA stability assays, validated with clinical EGFR inhibitors and patient carcinoma samples

    PMID:24718859

    Open questions at the time
    • Which kinase downstream of EGFR phosphorylates AUF1 to trigger relocalization
    • Whether other RNA-binding proteins cooperate with AUF1 in NKG2D ligand mRNA regulation
  14. 2015 High

    Characterizing the MICA-129 dimorphism showed that higher-affinity NKG2D binding (Met variant) paradoxically limits NKG2D function through faster receptor downregulation and greater MICA shedding, resolving how ligand affinity inversely correlates with sustained signaling.

    Evidence Allele-specific MICA expression in melanoma cells, NK functional assays, soluble MICA ELISA, intracellular MICA quantification

    PMID:26483398 PMID:26585323

    Open questions at the time
    • Whether MICA-129 dimorphism affects ERp5-dependent shedding specifically
    • Structural basis for affinity difference at the NKG2D–MICA interface
  15. 2016 High

    Identifying CBP/p300 acetyltransferases and CREB as direct transcriptional activators of NKG2D ligand promoters established the epigenetic control layer governing basal and stress-induced ligand expression.

    Evidence ChIP for CREB and CBP/p300 at NKG2D ligand promoters, histone acetylation assays, CBP/p300 knockdown reducing NK killing, Eμ-Myc mouse validation

    PMID:27477692

    Open questions at the time
    • Whether CBP/p300 activity at these promoters is regulated by specific stress kinases
    • Interplay between CREB/CBP regulation and STING or EGFR pathways
  16. 2017 High

    Showing that constitutive RAE-1ε on lymph node and tumor endothelium chronically engages NKG2D in vivo, causing internalization and global NK cell desensitization, established NKG2D as a peripheral tolerance/education receptor beyond its activating function.

    Evidence In vivo NKG2D engagement studies, NKG2D internalization, NK cell functional assays, and tumor challenge in WT mice

    PMID:29231815

    Open questions at the time
    • Molecular basis of global desensitization downstream of chronic NKG2D engagement
    • Whether human endothelium expresses NKG2D ligands constitutively
  17. 2019 High

    Demonstrating that PARP1 represses NKG2D ligand expression specifically on leukemic stem cells — and that PARP inhibition restores ligand expression and NK killing — identified a targetable epigenetic barrier to NKG2D-mediated immunosurveillance in AML.

    Evidence PARP1 knockout and pharmacological inhibition, NKG2D ligand surface expression, patient-derived xenotransplant NK killing assays

    PMID:31316209

    Open questions at the time
    • Whether PARP1 repression is direct (at ligand promoters) or indirect
    • Whether PARP inhibitor-induced NKG2D ligand expression persists long-term in patients

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for NKG2D adapter switching between DAP10 and DAP12, the protease responsible for MICA cleavage after ERp5 processing, and whether chronic NKG2D engagement on human endothelium contributes to NK cell tolerance in patients.
  • Structural basis of DAP10 vs DAP12 selectivity in the NKG2D transmembrane domain
  • Identity of the MICA-cleaving protease downstream of ERp5
  • In vivo relevance of NKG2D-mediated NK tolerance in human tumor microenvironments

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 5 GO:0005764 lysosome 1
Pathway
R-HSA-168256 Immune System 6 R-HSA-1643685 Disease 3 R-HSA-162582 Signal Transduction 2
Partners
H60HCSTMICAMICBRAET1ETYROBPULBP1
Complex memberships
NKG2D–DAP10 complexNKG2D–DAP12 complex

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 NKG2D recruits two distinct adapter molecules depending on cell type: DAP10 (which recruits PI3K) in CD8+ T cells, and DAP12 (which recruits protein tyrosine kinases) in NK cells. In DAP10-deficient mice, CD8+ T cells lack NKG2D expression and cannot mount tumor-specific responses, while NK cells retain functional NKG2D via DAP12 association. DAP10-deficient mouse model, functional immune assays, receptor-adapter association studies Nature immunology High 12426564
2003 NKG2D-DAP10 signaling triggers NK cell killing independently of Syk family kinases. A YINM motif in the DAP10 cytoplasmic tail couples receptor stimulation to PI3K, Vav1, Rho family GTPases, and phospholipase C activation. In vitro kinase assays, signaling pathway dissection with pharmacological inhibitors and dominant-negative constructs Nature immunology High 12740575
2001 Ectopic expression of murine NKG2D ligands Rae1β or H60 on tumor cells causes potent rejection mediated by NK cells and/or CD8+ T cells in syngeneic mice, directly linking NKG2D ligand expression to tumor cell rejection in vivo. Tumor transplantation in syngeneic mice, NK/CD8 T cell depletion, in vivo rejection assays Nature High 11557981
2007 On tumor cell surfaces, MICA associates with ERp5 (PDIA6/P5), a disulfide isomerase. ERp5 forms transitory mixed disulfide complexes with MICA's membrane-proximal alpha3 domain, enabling proteolytic cleavage and shedding of soluble MICA, which promotes tumor immune evasion by inducing NKG2D internalization and degradation. Co-IP, ERp5 gene silencing, pharmacological inhibition of thioreductase activity, disulfide bond analysis Nature High 17495932
2006 NKG2D costimulation of NKG2D+CD4+ T cells in late-stage tumor settings drives Fas ligand (FasL) production; these NKG2D-costimulated cells are protected from Fas-mediated growth arrest while FasL suppresses proliferation of T cells lacking NKG2D costimulation, revealing a paracrine immunosuppressive mechanism. In vitro T cell stimulation assays, FasL blocking, peripheral blood NKG2D+CD8+ T cell studies Nature immunology Medium 16732291
2006 Soluble ULBP (sULBP) released by tumor cells downregulates surface NKG2D expression on NK cells, reducing NK cell cytotoxicity in an NKG2D-dependent manner; GPI-anchored ULBPs on tumor cells are shed via phospholipase C activity. NK cell co-culture with tumor supernatants, recombinant ULBP-Fc treatment, PI-PLC inhibition, flow cytometry for NKG2D surface expression, cytotoxicity assays Cellular immunology Medium 16630603
2009 Upon interaction with MICB-expressing target cells, NKG2D and its adapter DAP10 are trafficked to secretory lysosomes; approximately 50% of total NKG2D protein is degraded via lysosomal pathway, while an intracellular pool recycles to the plasma membrane in activated NK cells. DAP10 polarizes to the cytotoxic immune synapse before degradation. Confocal microscopy, subcellular fractionation, live imaging of NKL cells and primary NK cells, lysosomal inhibitors The Journal of biological chemistry Medium 19329438
2004 NKG2D-mediated cytotoxicity and cytokine secretion (IFN-γ, GM-CSF) are counter-regulated by inhibitory Ly49 receptors; Ly49A/G inhibition cannot be overcome even by high H60 expression, whereas Ly49C/I inhibition can be overridden depending on H60 expression levels on target cells. NK cell cytotoxicity assays, antibody-mediated crosslinking of NKG2D and Ly49 receptors, cytokine ELISA Blood Medium 15328154
2011 HMBOX1, a homeobox protein highly expressed in primary human NK cells, negatively regulates NKG2D surface expression and suppresses the NKG2D/DAP10 signaling pathway, reducing NK cell cytotoxicity, CD107a degranulation, and cytolytic protein production. HMBOX1 overexpression and knockdown in NK cells, flow cytometry for NKG2D expression, cytotoxicity assays, CD107a degranulation assay Cellular & molecular immunology Medium 21706044
2011 Co-stimulation of CD8+ T cells through CD3 and NKG2D simultaneously activates β-catenin and induces β-catenin target gene expression, preventing production of anti-inflammatory cytokines (IL-10, IL-9, IL-13, VEGF-α) in a β-catenin- and PPARγ-dependent manner, a signaling outcome not observed with TCR or TCR+CD28 stimulation alone. Chimeric NKG2D receptor signaling, β-catenin pathway analysis, cytokine measurement, pharmacological inhibition of PPARγ and β-catenin Blood Medium 21518928
2001 Pig NKG2D requires DAP10 for cell surface expression; when transiently transfected into COS-7 cells, pig NKG2D only reaches the cell surface in the presence of DAP10, demonstrating a conserved obligate adapter requirement for receptor surface expression. Transient transfection of COS-7 cells, flow cytometry for surface expression Immunogenetics Medium 11398969
2015 The MICA-129Met isoform binds NKG2D with higher affinity than MICA-129Val, triggers stronger NKG2D signaling (more degranulation and IFN-γ production in NK cells, faster CD8+ T cell costimulation), but also induces faster and stronger NKG2D downregulation from the cell surface, limiting NKG2D-mediated functions at high expression levels. Allele-specific MICA expression in melanoma cells, NK cell functional assays (degranulation, IFN-γ ELISA), NKG2D surface expression by flow cytometry, patient transplantation outcome data EMBO molecular medicine High 26483398
2015 The MICA-129Met variant shows higher susceptibility to shedding (more soluble MICA released) and more intracellular retention compared to MICA-129Val, linking the polymorphism to differential plasma membrane expression and proteolytic shedding. MICA isoform expression in MICA-negative melanoma cells, soluble MICA ELISA, intracellular vs. surface MICA quantification by flow cytometry Immunogenetics Medium 26585323
2014 Induction of NKG2D ligand RAE-1 expression by the DNA damage response requires a STING-dependent DNA sensor pathway involving TBK1 and IRF3; cytosolic DNA is detected in RAE-1-expressing lymphoma cell lines, and transfection of DNA into ligand-negative cells is sufficient to induce RAE-1. STING pathway genetic knockout (Irf3+/- Eμ-Myc mice), DNA transfection into ligand-negative cells, cytosolic DNA detection Cancer research High 24590060
2014 Surface upregulation of NKG2D ligands (MICA/B and ULBP families) in human epithelial cells in response to UV irradiation, osmotic shock, oxidative stress, and EGF is mediated by EGFR activation, which causes intracellular relocalization of AUF1 proteins that ordinarily destabilize NKG2D ligand mRNAs by targeting a conserved AU-rich element in the 3' UTR of most human NKG2D ligand genes. EGFR activation/inhibition, AUF1 relocalization studies, mRNA stability assays, clinical EGFR inhibitor treatment, primary human carcinoma analysis Science translational medicine High 24718859
2016 CBP and p300 acetyltransferases regulate basal and stress-induced NKG2D ligand expression (MICA/B, ULBP2, and mouse RAE-1) on tumor cells; CBP/p300 loss decreases NKG2D ligand surface expression and abrogates NK cell-mediated killing. Mechanistically, CREB is activated and binds NKG2D ligand promoters together with CBP/p300, increasing histone acetylation at these loci. CBP/p300 knockdown, ChIP for CREB and CBP/p300 at NKG2D-L promoters, histone acetylation assays, NK cell killing assays, Eμ-Myc mouse model Oncogene High 27477692
2017 In healthy mice, NKG2D is engaged in vivo by RAE-1ε constitutively expressed on lymph node endothelial cells and highly induced on tumor-associated endothelium; this engagement causes NKG2D internalization from NK cell surface and desensitizes NK cell responses globally to acute stimulation, impairing antitumor NK responses in vivo. In vivo NKG2D engagement studies, NKG2D internalization assays, NK cell functional assays in WT mice, tumor challenge models eLife High 29231815
2019 PARP1 represses expression of NKG2D ligands on leukemic stem cells (LSCs); genetic or pharmacologic inhibition of PARP1 induces NKG2DL surface expression on LSCs but not on healthy or pre-leukemic cells, rendering LSCs susceptible to NK cell-mediated killing. PARP1 genetic knockout and pharmacological inhibition, NKG2DL surface expression by flow cytometry, patient-derived xenotransplant NK cell killing assays Nature High 31316209
2013 NK cell NKG2D engagement by RAE-1ε expressed on murine endothelial cells in vivo causes NKG2D internalization and transmits an NK-intrinsic signal that globally desensitizes NK cells to acute stimulation. Chronic NKG2D engagement leads to reduced responsiveness, demonstrating NKG2D's role in NK cell peripheral tolerance/education. In vivo receptor engagement, NK cell desensitization assays, NKG2D internalization measurement eLife Medium 29231815
2013 NKG2D-mediated NK cell activation plays a required role in pulmonary ischemia-reperfusion injury; NKG2D ligands are induced on lung endothelial and epithelial cells following IRI, and antibody-mediated NKG2D blockade or NK cell depletion abrogates acute lung injury in mouse models. NK cell-deficient mice, adoptive NK cell transfer, NKG2D antibody blockade, two IRI mouse models The Journal of clinical investigation Medium 33290276
2013 NKG2D and granzyme B in NK cells are required for HDM-induced allergic pulmonary inflammation; NKG2D-deficient mice resist allergic induction, and adoptive transfer of wild-type NK cells (but not CD3+ cells or granzyme B-deficient NK cells) restores allergic inflammation. NKG2D-deficient mouse model, adoptive NK cell transfer, granzyme B-deficient NK cells, HDM allergen challenge model The Journal of allergy and clinical immunology High 24290277
2010 NKG2D is required for NK cell activation and cytolytic function in response to adenoviral infection; NKG2D ligands are upregulated on accessory cells (dendritic cells, macrophages) upon adenoviral infection, and NKG2D blockade inhibits NK cell activation and delays adenoviral clearance in vivo. NKG2D antibody blockade, adenoviral infection model in vivo and in vitro, NK cell depletion, NKG2D ligand upregulation analysis Journal of immunology Medium 21076062

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Roles of the NKG2D immunoreceptor and its ligands. Nature reviews. Immunology 1038 14523385
2001 Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity. Nature 753 11557981
2013 Regulation of ligands for the NKG2D activating receptor. Annual review of immunology 680 23298206
2003 Functional expression and release of ligands for the activating immunoreceptor NKG2D in leukemia. Blood 430 12714493
2010 Effect of NKG2D ligand expression on host immune responses. Immunological reviews 401 20536569
2002 NKG2D recruits two distinct adapters to trigger NK cell activation and costimulation. Nature immunology 322 12426564
2007 Disulphide-isomerase-enabled shedding of tumour-associated NKG2D ligands. Nature 302 17495932
2019 Absence of NKG2D ligands defines leukaemia stem cells and mediates their immune evasion. Nature 300 31316209
2007 Promiscuity and the single receptor: NKG2D. Nature reviews. Immunology 297 17673918
2003 NKG2D-DAP10 triggers human NK cell-mediated killing via a Syk-independent regulatory pathway. Nature immunology 278 12740575
2018 NKG2D: A Master Regulator of Immune Cell Responsiveness. Frontiers in immunology 220 29568297
2004 Downregulation and/or release of NKG2D ligands as immune evasion strategy of human neuroblastoma. Neoplasia (New York, N.Y.) 212 15548365
2018 NKG2D and Its Ligands: "One for All, All for One". Frontiers in immunology 204 29662484
2018 NKG2D and its ligands in cancer. Current opinion in immunology 185 29525346
2006 Immunobiology of human NKG2D and its ligands. Current topics in microbiology and immunology 166 16329186
2013 Generation of soluble NKG2D ligands: proteolytic cleavage, exosome secretion and functional implications. Scandinavian journal of immunology 156 23679194
2002 Lymphocyte activation via NKG2D: towards a new paradigm in immune recognition? Current opinion in immunology 149 11973127
2014 RAE1 ligands for the NKG2D receptor are regulated by STING-dependent DNA sensor pathways in lymphoma. Cancer research 145 24590060
2023 NKG2D-CAR T cells eliminate senescent cells in aged mice and nonhuman primates. Science translational medicine 143 37585504
2019 Role of NKG2D and its ligands in cancer immunotherapy. American journal of cancer research 140 31720075
2018 NKG2D Ligands-Critical Targets for Cancer Immune Escape and Therapy. Frontiers in immunology 138 30254634
2006 Fas-ligand-mediated paracrine T cell regulation by the receptor NKG2D in tumor immunity. Nature immunology 132 16732291
2019 Impairment of NKG2D-Mediated Tumor Immunity by TGF-β. Frontiers in immunology 123 31803194
2019 Eradication of Hepatocellular Carcinoma by NKG2D-Based CAR-T Cells. Cancer immunology research 122 31484657
2018 Functions of NKG2D in CD8+ T cells: an opportunity for immunotherapy. Cellular & molecular immunology 121 29400704
2007 Regulation of ligands for the activating receptor NKG2D. Immunology 120 17614877
2005 Exosomes and the MICA-NKG2D system in cancer. Blood cells, molecules & diseases 120 15885603
2021 Leveraging NKG2D Ligands in Immuno-Oncology. Frontiers in immunology 116 34394116
2020 NKG2D and MICA/B shedding: a 'tag game' between NK cells and malignant cells. Clinical & translational immunology 113 33363734
2006 The role of the NKG2D receptor for tumor immunity. Seminars in cancer biology 107 16914326
2008 Soluble NKG2D ligands: prevalence, release, and functional impact. Frontiers in bioscience : a journal and virtual library 104 18508446
2017 NKG2D-Dependent Antitumor Effects of Chemotherapy and Radiotherapy against Glioblastoma. Clinical cancer research : an official journal of the American Association for Cancer Research 102 29162646
2013 New prospects on the NKG2D/NKG2DL system for oncology. Oncoimmunology 102 24353908
2018 A CS1-NKG2D Bispecific Antibody Collectively Activates Cytolytic Immune Cells against Multiple Myeloma. Cancer immunology research 101 29769244
2006 Soluble ULBP suppresses natural killer cell activity via down-regulating NKG2D expression. Cellular immunology 99 16630603
2005 NKG2D in NK and T cell-mediated immunity. Journal of clinical immunology 93 16380817
2015 Genetics, genomics, and evolutionary biology of NKG2D ligands. Immunological reviews 92 26284473
2017 Memory T Cells Expressing an NKG2D-CAR Efficiently Target Osteosarcoma Cells. Clinical cancer research : an official journal of the American Association for Cancer Research 91 28659311
2006 Expression and function of NKG2D in CD4+ T cells specific for human cytomegalovirus. European journal of immunology 90 17109473
2014 NKG2D CARs as cell therapy for cancer. Cancer journal (Sudbury, Mass.) 89 24667963
2008 The NKG2D receptor: immunobiology and clinical implications. Immunologic research 88 18193361
2008 The NKG2D receptor: sensing stressed cells. Trends in molecular medicine 86 18353724
2008 Selective induction of expression of a ligand for the NKG2D receptor by proteasome inhibitors. Cancer research 85 18316620
2005 MIC and other NKG2D ligands: from none to too many. Current opinion in immunology 83 16087327
2014 MicroRNA-mediated down-regulation of NKG2D ligands contributes to glioma immune escape. Oncotarget 82 25277195
2007 Chimeric NKG2D receptor-bearing T cells as immunotherapy for ovarian cancer. Cancer research 82 17510432
2019 NKG2D/NKG2-Ligand Pathway Offers New Opportunities in Cancer Treatment. Frontiers in immunology 75 30984204
2017 Endothelial cells express NKG2D ligands and desensitize antitumor NK responses. eLife 73 29231815
2015 The MICA-129 dimorphism affects NKG2D signaling and outcome of hematopoietic stem cell transplantation. EMBO molecular medicine 69 26483398
2009 Potential role of NKG2D and its ligands in organ transplantation: new target for immunointervention. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 69 19178412
2014 Secretory pathways generating immunosuppressive NKG2D ligands: New targets for therapeutic intervention. Oncoimmunology 67 25050215
2021 A summary of current NKG2D-based CAR clinical trials. Immunotherapy advances 66 34604863
2010 Recombinant mouse cytomegalovirus expressing a ligand for the NKG2D receptor is attenuated and has improved vaccine properties. The Journal of clinical investigation 66 21099111
2008 Chimeric NKG2D receptor-expressing T cells as an immunotherapy for multiple myeloma. Experimental hematology 63 18599182
2003 The NKG2D receptor and its ligands-recognition beyond the "missing self"? Microbes and infection 63 12593971
2013 NKG2D CAR T-cell therapy inhibits the growth of NKG2D ligand heterogeneous tumors. Immunology and cell biology 62 23628805
2021 NKG2D Natural Killer Cell Receptor-A Short Description and Potential Clinical Applications. Cells 61 34200375
2021 Natural killer cells activated through NKG2D mediate lung ischemia-reperfusion injury. The Journal of clinical investigation 60 33290276
2018 The Paradoxical Role of NKG2D in Cancer Immunity. Frontiers in immunology 55 30150983
2014 Advances in NKG2D ligand recognition and responses by NK cells. Immunology and cell biology 55 24445601
2021 Expression of NKG2D ligands is downregulated by β-catenin signalling and associates with HCC aggressiveness. Journal of hepatology 54 33484773
2013 Modulation of NKG2D ligand expression and metastasis in tumors by spironolactone via RXRγ activation. The Journal of experimental medicine 53 24190430
2009 The role of the activating receptor NKG2D in autoimmunity. Molecular immunology 50 19286259
2014 Molecular Bases for the Regulation of NKG2D Ligands in Cancer. Frontiers in immunology 49 24711808
2014 Immunological visibility: posttranscriptional regulation of human NKG2D ligands by the EGF receptor pathway. Science translational medicine 49 24718859
2024 Targeting senescent cells with NKG2D-CAR T cells. Cell death discovery 48 38704364
2020 Boosting Natural Killer Cell-Mediated Targeting of Sarcoma Through DNAM-1 and NKG2D. Frontiers in immunology 48 32082316
2012 Gut microbiota regulates NKG2D ligand expression on intestinal epithelial cells. European journal of immunology 48 23136011
2016 Regulation of NKG2D Expression and Signaling by Endocytosis. Trends in immunology 47 27667711
2015 The MICA-129Met/Val dimorphism affects plasma membrane expression and shedding of the NKG2D ligand MICA. Immunogenetics 47 26585323
2022 Regulation of NKG2D Stress Ligands and Its Relevance in Cancer Progression. Cancers 46 35565467
2013 Natural killer cell NKG2D and granzyme B are critical for allergic pulmonary inflammation. The Journal of allergy and clinical immunology 45 24290277
2008 TNK cells (NKG2D+ CD8+ or CD4+ T lymphocytes) in the control of human tumors. Cancer immunology, immunotherapy : CII 44 19089424
2018 IDO1 impairs NK cell cytotoxicity by decreasing NKG2D/NKG2DLs via promoting miR-18a. Molecular immunology 43 30268986
2016 Impact of the MICA-129Met/Val Dimorphism on NKG2D-Mediated Biological Functions and Disease Risks. Frontiers in immunology 43 28018354
2014 MICA SNPs and the NKG2D system in virus-induced HCC. Journal of gastroenterology 43 25270965
2004 NKG2D receptor-mediated NK cell function is regulated by inhibitory Ly49 receptors. Blood 43 15328154
2023 The Role and Regulation of the NKG2D/NKG2D Ligand System in Cancer. Biology 38 37626965
2009 The traffic of the NKG2D/Dap10 receptor complex during natural killer (NK) cell activation. The Journal of biological chemistry 38 19329438
2011 NKG2D receptor regulates human effector T-cell cytokine production. Blood 37 21518928
2008 Murine NKG2D ligands: "double, double toil and trouble". Molecular immunology 37 19081632
2012 Cancer immunotherapy using NKG2D and DNAM-1 systems. Anticancer research 36 22641658
2020 BCMA-targeting Bispecific Antibody That Simultaneously Stimulates NKG2D-enhanced Efficacy Against Multiple Myeloma. Journal of immunotherapy (Hagerstown, Md. : 1997) 35 32349046
2008 Cancer immunosurveillance: NKG2D breaks cover. Immunity 34 18400193
2021 Targeting the NKG2D/NKG2D-L axis in acute myeloid leukemia. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 33 33508619
2008 Murine cytomegalovirus regulation of NKG2D ligands. Medical microbiology and immunology 33 18259774
2011 HMBOX1 negatively regulates NK cell functions by suppressing the NKG2D/DAP10 signaling pathway. Cellular & molecular immunology 32 21706044
2017 Disarming Cellular Alarm Systems-Manipulation of Stress-Induced NKG2D Ligands by Human Herpesviruses. Frontiers in immunology 31 28443092
2005 NKG2D-independent suppression of T cell proliferation by H60 and MICA. Proceedings of the National Academy of Sciences of the United States of America 29 16091471
2020 Recent Advances in Molecular Mechanisms of the NKG2D Pathway in Hepatocellular Carcinoma. Biomolecules 28 32075046
2008 Viral inhibitors of NKG2D ligands: friends or foes of immune surveillance? European journal of immunology 28 18979514
2018 Fusion Proteins of NKG2D/NKG2DL in Cancer Immunotherapy. International journal of molecular sciences 26 29316666
2016 Association of NKG2D gene variants with susceptibility and severity of rheumatoid arthritis. Clinical and experimental immunology 26 27783394
2012 Immunogenetics of the NKG2D ligand gene family. Immunogenetics 26 22843249
2001 Molecular cloning and characterization of pig immunoreceptor DAP10 and NKG2D. Immunogenetics 26 11398969
2023 Engaging natural killer cells for cancer therapy via NKG2D, CD16A and other receptors. mAbs 25 37165468
2016 CBP/p300 acetyltransferases regulate the expression of NKG2D ligands on tumor cells. Oncogene 25 27477692
2010 NKG2D is required for NK cell activation and function in response to E1-deleted adenovirus. Journal of immunology (Baltimore, Md. : 1950) 25 21076062
2017 How Mucosal Epithelia Deal with Stress: Role of NKG2D/NKG2D Ligands during Inflammation. Frontiers in immunology 23 29209320
2005 Imbalance of NKG2D and its inhibitory counterparts: how does tumor escape from innate immunity? International immunopharmacology 23 15914316