Affinage

KLRK1

NKG2-D type II integral membrane protein · UniProt P26718

Length
216 aa
Mass
25.3 kDa
Annotated
2026-06-10
100 papers in source corpus 22 papers cited in narrative 22 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KLRK1/NKG2D is a homodimeric C-type lectin-like activating receptor of NK cells and CD8+ T cells that couples recognition of stress-induced MHC class I-like ligands to cytotoxicity, cytokine production, and tumor immunosurveillance (PMID:11557981, PMID:15500864, PMID:11973127). Structurally, it binds asymmetric monomeric ligands (MICA, MICB, ULBPs in humans; Rae-1, H60, Mult1 in mice) in 2:1 complexes, each monomer using an equivalent surface to engage divergent ligands by 'rigid adaptation' rather than induced fit, which explains its recognition degeneracy (PMID:15500864); ligand discrimination is further refined by mechanical force, which selectively prolongs interaction lifetimes with MICA/MICB through force-induced rotational conformational changes that strengthen the interface, while ULBP binding is force-insensitive (PMID:34913508). Signaling proceeds through the DAP10 adapter (DAP10 or DAP12 in mouse splice isoforms), coupling to PI3K-AKT-mTOR and to JNK/ERK MAP kinase cascades to drive perforin-dependent cytotoxicity (PMID:26041808, PMID:20082299, PMID:17109473). Functionally NKG2D operates as a primary activation receptor on NK cells and as a costimulatory receptor on T cells, augmenting TCR/CD3 signaling and proliferation and engaging β-catenin/PPARγ programs distinct from CD28 costimulation (PMID:21518928, PMID:17109473, PMID:11973127). Its activity is tuned by epistatic crosstalk with inhibitory Ly49 receptors, by ligand-induced endocytosis and degradation of the receptor triggered by soluble shed MIC, and by IDO1-driven miR-18a that directly represses NKG2D and its ligand Mult-1 (PMID:12384702, PMID:15328154, PMID:30268986). NKG2D ligand abundance is itself a tightly regulated checkpoint: ligands are induced through the DNA damage response and ERK signaling and by CBP/p300 acetyltransferases, and repressed by PARP1 and by β-catenin/TCF4, defining the tumor and senescent-cell contexts in which NKG2D enables killing (PMID:26878797, PMID:31316209, PMID:27477692, PMID:33484773). Beyond surveillance of tumors and senescent cells, NKG2D engagement drives pathology in allergic pulmonary inflammation and ischemia-reperfusion lung injury and underlies costimulation in autoimmune vasculitis (PMID:24290277, PMID:33290276, PMID:23417963).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2001 High

    Established that NKG2D ligand expression on a target cell is sufficient to trigger immune rejection in vivo, linking the receptor directly to tumor elimination.

    Evidence Ectopic Rae1β/H60 expression on syngeneic tumor lines with NK depletion and adoptive transfer in mice

    PMID:11557981

    Open questions at the time
    • Did not resolve the receptor's signaling subunit
    • Relative NK vs CD8+ T cell contribution not fully partitioned
  2. 2002 High

    Revealed a tumor immune-evasion mechanism: soluble shed ligand engages NKG2D to drive its endocytosis and degradation, downregulating receptor surface levels and impairing effector responsiveness.

    Evidence Flow cytometry of patient samples correlated with in vitro endocytosis/degradation assays

    PMID:12384702

    Open questions at the time
    • Endocytic trafficking machinery not defined
    • Whether shedding kinetics differ across ligands not addressed
  3. 2004 High

    Explained how a single receptor recognizes structurally divergent ligands by showing 2:1 homodimeric binding via rigid adaptation rather than induced fit.

    Evidence Crystal structures with thermodynamic and kinetic analyses across multiple NKG2D-ligand pairs

    PMID:15500864

    Open questions at the time
    • Static structures did not capture force-dependent behavior
    • Did not link affinity differences to functional discrimination
  4. 2004 Medium

    Demonstrated that activating NKG2D output is constrained by inhibitory Ly49 receptors and target MHC class I, establishing integration of opposing NK signals.

    Evidence NK cytotoxicity and cytokine assays titrating H60 against defined Ly49/MHC contexts

    PMID:15328154

    Open questions at the time
    • Molecular basis of signal integration not resolved
    • Single-lab functional assays
  5. 2005 Medium

    Showed NKG2D ligands have receptor-independent effects, suppressing T cell proliferation via IL-10 through a non-NKG2D receptor.

    Evidence T cell proliferation assays with IL-10 neutralization and NKG2D-blocking antibodies

    PMID:16091471

    Open questions at the time
    • The alternative receptor was not identified
    • Physiological relevance in vivo unclear
  6. 2006 Medium

    Defined the proximal signaling logic: NKG2D couples through DAP10 to PI3K and synergizes with TCR signals as a costimulatory receptor on antigen-specific CD4+ T cells.

    Evidence mAb crosslinking with CFSE proliferation and intracellular cytokine staining on HCMV-specific T cells

    PMID:17109473

    Open questions at the time
    • Did not map downstream effector branching
    • Single-lab functional readouts
  7. 2011 High

    Mapped the activation pathway downstream of NKG2D-DAP10 to PI3K-AKT-mTOR (S6K1/4E-BP1) and JNK/ERK, and unexpectedly showed cancer cells can express functional NKG2D that drives oncogenic metabolism.

    Evidence Reciprocal Co-IP, phosphorylation and bioenergetics assays with siRNA/overexpression in tumor lines

    PMID:21321202

    Open questions at the time
    • Generality of tumor-intrinsic NKG2D across cancer types not established
    • Ligand source driving autocrine signaling unclear
  8. 2011 Medium

    Distinguished NKG2D costimulation from CD28, showing CD3+NKG2D engagement activates β-catenin/PPARγ and suppresses anti-inflammatory cytokines.

    Evidence Chimeric NKG2D-CD3ζ receptor with β-catenin reporters, cytokine ELISA, siRNA and inhibitors

    PMID:21518928

    Open questions at the time
    • Link between DAP10 signaling and β-catenin not mechanistically traced
    • Chimeric construct may not fully mimic native receptor
  9. 2013 Medium

    Connected NKG2D to surveillance of senescent cells and established dual transcriptional control of ligands by the DNA damage response (induction) and ERK (maintenance).

    Evidence In vitro senescence models, NK cytotoxicity, DDR/ERK inhibitors, and NKG2D-knockout mice with liver fibrosis readout

    PMID:26878797

    Open questions at the time
    • Transcription factors downstream of DDR/ERK not identified
    • Single-lab in vivo model
  10. 2013 High

    Extended NKG2D function beyond surveillance to pathology, showing it is required for allergic pulmonary inflammation via NK-cell granzyme B.

    Evidence NKG2D-knockout mice with NK adoptive transfer epistasis in an HDM allergy model

    PMID:24290277

    Open questions at the time
    • Ligand identity driving lung response not defined
    • How NK NKG2D engagement promotes allergic priming unclear
  11. 2013 Medium

    Documented NKG2D as a costimulatory receptor on senescent T cells in autoimmune vasculitis, linking it to GCA/PMR pathology.

    Evidence Ex vivo proliferation/cytokine assays and temporal artery immunohistology from patients

    PMID:23417963

    Open questions at the time
    • Causal contribution to disease not tested by intervention
    • Ligand source in arterial tissue not defined
  12. 2013 Medium

    Identified a druggable axis to boost ligand expression, with spironolactone inducing NKG2D ligands via RXRγ-driven ATM-Chk2 DDR signaling.

    Evidence Nuclear receptor siRNA screen with ATM-Chk2 inhibitors and NK cytotoxicity assays on colon cancer cells

    PMID:24190430

    Open questions at the time
    • RXRγ-to-DDR mechanistic link not fully resolved
    • Single-lab finding
  13. 2016 Medium

    Identified CBP/p300 acetyltransferases as epigenetic regulators of basal and stress-induced NKG2D ligand transcription.

    Evidence siRNA knockdown, ChIP for CREB binding and histone acetylation, HDAC inhibitors, and Eμ-Myc lymphoma model

    PMID:27477692

    Open questions at the time
    • Upstream signals recruiting CBP/p300 to ligand promoters unclear
    • Single-lab study
  14. 2017 Medium

    Established that the antitumor efficacy of DNA-damaging chemoradiotherapy in glioblastoma operates through DDR-induced NKG2D ligands, and is limited by MGMT.

    Evidence NKG2D-knockout mice and blocking antibodies in syngeneic orthotopic glioblastoma with TMZ/IR

    PMID:29162646

    Open questions at the time
    • Which ligands and effector cells dominate not fully partitioned
    • Single-lab models
  15. 2018 Medium

    Revealed a post-transcriptional immune-evasion circuit in which IDO1 drives miR-18a to simultaneously repress NKG2D translation and degrade the ligand Mult-1.

    Evidence AGO2 Co-IP, 3'UTR luciferase reporters, miR-18a gain/loss, and IDO1 inhibitor rescue

    PMID:30268986

    Open questions at the time
    • In vivo contribution not established
    • Whether human ligand 3'UTRs are equivalently targeted unclear
  16. 2019 High

    Identified PARP1 as a repressor of NKG2D ligands selectively on leukemic stem cells, defining a therapeutic vulnerability via PARP1 inhibition.

    Evidence PARP1 genetic deletion and inhibitors in patient-derived xenotransplants with NK cytotoxicity readouts

    PMID:31316209

    Open questions at the time
    • Mechanism of LSC-selective derepression not fully defined
    • Durability of NK control in vivo not established
  17. 2021 High

    Resolved the biophysical basis of ligand discrimination, showing mechanical force selectively stabilizes NKG2D-MICA/MICB via rotational conformational change to set activation thresholds.

    Evidence Live-cell single-molecule force assay, steered molecular dynamics, and mutagenesis

    PMID:34913508

    Open questions at the time
    • How force-tuned lifetimes convert into intracellular signal strength not traced
    • ULBP force-insensitivity functional consequence not fully explored
  18. 2021 High

    Extended NKG2D pathology to sterile injury, showing IRI-induced ligands on lung endothelium/epithelium drive NK NKG2D-mediated acute lung injury.

    Evidence NK-deficient mouse rescue, adoptive transfer, and antibody blockade across IRI models

    PMID:33290276

    Open questions at the time
    • Trigger inducing ligands after IRI not defined
    • Translational blockade window not established
  19. 2021 Medium

    Defined β-catenin/TCF4 as a transcriptional repressor of NKG2D ligands (ULBP1/2, Rae-1) in hepatocellular carcinoma, linking oncogenic Wnt to immune escape.

    Evidence RNA-seq, expression profiling, TCF4 ChIP, and β-catenin-activated mouse HCC models

    PMID:33484773

    Open questions at the time
    • Direct vs indirect TCF4 repression not fully separated
    • Whether reversing β-catenin restores NK killing in vivo untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How force-tuned receptor binding kinetics are mechanistically transduced through DAP10 into graded PI3K and MAPK signaling, and how the many opposing transcriptional/post-transcriptional ligand controls are integrated in a given tissue context, remains unresolved.
  • No unified model linking ligand affinity/force to quantitative signal output
  • Tissue-specific dominance among CBP/p300, PARP1, β-catenin, DDR, and miR-18a regulation unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 4
Partners
DAP10DAP12MICAMICBPIK3ULBP
Complex memberships
NKG2D-DAP10 receptor complex

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 Binding of soluble MIC (shed from tumors) to NKG2D induces endocytosis and degradation of NKG2D on T cells, causing systemic downregulation of NKG2D expression on tumor-infiltrating and peripheral blood T cells and impairing effector T cell responsiveness. Flow cytometry of patient samples, in vitro endocytosis/degradation assays, correlation of circulating soluble MICA with NKG2D levels Nature High 12384702
2001 Ectopic expression of murine NKG2D ligands Rae1β or H60 on tumor cell lines causes potent rejection by syngeneic mice mediated by NK cells and/or CD8+ T cells, directly linking NKG2D ligand expression to tumor rejection and priming of cytotoxic T cells and NK cell sensitization in vivo. In vivo syngeneic tumor rejection assays, adoptive transfer, NK cell depletion experiments Nature High 11557981
2005 NKG2D (human) transmits signals via its association with the DAP10 adapter subunit, coupling to phosphoinositide 3-kinase (PI3K); in mice, alternatively spliced isoforms signal through either DAP10 or DAP12. Biochemical co-immunoprecipitation, signaling assays, splice-isoform analysis Cancer immunology research High 26041808
2011 Cancer cells themselves express NKG2D in complex with DAP10; triggering NKG2D on these cancer cells activates the PI3K–AKT–mTOR oncogenic signaling axis and downstream effectors S6K1 and 4E-BP1, as well as JNK and ERK MAP kinase cascades, increasing bioenergetic metabolism and proliferation of tumor cells. Immunoprecipitation, phosphorylation assays, siRNA knockdown, overexpression in tumor lines, bioenergetics measurements Proceedings of the National Academy of Sciences of the United States of America High 21321202
2021 NKG2D discriminates between its ligands through selective mechanical force-induced conformational changes: force application selectively prolongs NKG2D interaction lifetimes with MICA and MICB (but not ULBPs), with MICA undergoing force-induced rotational conformational changes that form additional hydrogen bonds at the NKG2D interface, impeding dissociation under force and determining downstream NK cell activation. Live-cell single-molecule biomechanical assay, steered molecular dynamics simulations, mutagenesis, in situ binding kinetics The EMBO journal High 34913508
2004 NKG2D-mediated cytotoxicity and cytokine secretion are regulated by inhibitory Ly49 receptors (Ly49A/G and Ly49C/I) in a manner dependent on both H60 expression level and MHC class I identity on target cells; even high H60 expression cannot overcome Ly49A/G inhibition, establishing epistatic crosstalk between activating NKG2D and inhibitory receptors. NK cell cytotoxicity assays with antibody crosslinking, IFN-γ/GM-CSF secretion assays, titration of H60 expression on target cells Blood Medium 15328154
2010 Resveratrol enhances NK cell cytotoxicity through NKG2D-dependent JNK and ERK-1/2 MAP kinase pathways, leading to increased perforin expression; siRNA knockdown of JNK-1 or ERK-2 abolishes the resveratrol-enhanced cytotoxicity. NK92 cell culture, siRNA knockdown of JNK-1/ERK-2, kinase inhibitor treatments, cytotoxicity assays, perforin western blot Journal of cellular physiology Medium 20082299
2011 Simultaneous stimulation of CD8+ T cells through CD3 and NKG2D (or a chimeric NKG2D-CD3ζ receptor) activates β-catenin signaling and suppresses production of anti-inflammatory cytokines (IL-10, IL-9, IL-13, VEGF-α) in a β-catenin- and PPARγ-dependent manner, distinct from TCR+CD28 costimulation. Chimeric receptor expression, β-catenin reporter assays, cytokine ELISA, siRNA, pharmacological inhibition Blood Medium 21518928
2006 Human NKG2D is coupled by the DAP10 adapter to phosphoinositide 3-kinase (PI3K) and specifically interacts with stress-inducible ligands (MICA, MICB, ULBP); on CD4+ T cells specific for human cytomegalovirus, NKG2D engagement synergizes with TCR-dependent activation, triggering proliferation and cytokine production (IFN-γ, TNF-α), functioning as a costimulatory receptor. Flow cytometry, CFSE proliferation assay, intracellular cytokine staining, mAb crosslinking of NKG2D European journal of immunology Medium 17109473
2013 NKG2D ligand expression on senescent cells (MICA and ULBP2) is necessary for efficient NK-mediated cytotoxicity toward senescent fibroblasts; initial NKG2D ligand expression in senescence depends on the DNA damage response, while continuous expression is regulated by the ERK signaling pathway. In mice lacking NKG2D, senescent liver stellate cells accumulate and liver fibrosis is increased. In vitro senescence models, NK cytotoxicity assays, NKG2D-knockout mice, liver fibrosis histology, ERK/DDR pathway inhibitors Aging Medium 26878797
2019 PARP1 represses expression of NKG2D ligands on leukemic stem cells (LSCs); genetic or pharmacological inhibition of PARP1 induces NKG2DL on the LSC surface (but not on healthy or pre-leukemic cells), rendering LSCs susceptible to NK cell killing and suppressing leukemogenesis in patient-derived xenotransplant models. PARP1 genetic deletion, PARP1 inhibitor treatment, patient-derived xenotransplant models, NK cell cytotoxicity assays, flow cytometry Nature High 31316209
2013 NK cell NKG2D and granzyme B are both required for HDM-induced allergic pulmonary inflammation; NKG2D-deficient mice are resistant to allergic inflammation, and adoptive transfer of wild-type NK cells (but not CD3+ T cells) restores the response only if the NK cells express granzyme B. NKG2D-knockout mouse model, adoptive transfer of NK cells, HDM-induced allergy model, lung histology, IgE measurement The Journal of allergy and clinical immunology High 24290277
2021 NKG2D ligands are induced on lung endothelial and epithelial cells following ischemia-reperfusion injury; NK cell NKG2D receptor ligation mediates acute lung injury, as antibody-mediated NKG2D blockade or NK cell depletion abrogates injury in mouse models. NK cell-deficient mouse strain, adoptive transfer, antibody blockade, IRI mouse models, NK cell trafficking/maturation analysis The Journal of clinical investigation High 33290276
2016 CBP/p300 acetyltransferases regulate basal and stress-induced expression of NKG2D ligands (MICA/B, ULBP2, RAE-1) on tumor cells; loss of CBP/p300 reduces surface NKG2D ligand expression and NK cell-mediated killing; CREB binding and histone acetylation at NKG2D ligand promoters are increased during upregulation. siRNA knockdown of CBP/p300, ChIP assay, HDAC inhibitor treatment, NK cytotoxicity assays, Eμ-Myc mouse lymphoma model Oncogene Medium 27477692
2013 Spironolactone upregulates NKG2D ligand expression on colon cancer cells through the ATM-Chk2-mediated DNA damage checkpoint pathway via RXRγ activation (not the mineralocorticoid receptor), enhancing NK cell-mediated tumor elimination. siRNA library screen of nuclear hormone receptors, ATM-Chk2 pathway inhibitors, NKG2DL expression assays, NK cytotoxicity assays The Journal of experimental medicine Medium 24190430
2021 β-catenin signaling (via CTNNB1 mutation) downregulates expression of ULBP1 and ULBP2 NKG2D ligands in hepatocellular carcinoma; in mouse HCC models, β-catenin signaling reduces Rae-1 expression through TCF4 binding at ligand promoters. RNA-seq, TaqMan expression profiling, ChIP (TCF4 binding), mouse HCC models with β-catenin activation Journal of hepatology Medium 33484773
2005 H60 and MICA can suppress T cell proliferation through a receptor other than NKG2D in an IL-10-dependent manner, demonstrating that NKG2D ligands can mediate inhibitory effects on T cells independent of the NKG2D receptor itself. T cell proliferation assays with IL-10 neutralization, NKG2D-blocking antibodies, loss-of-function experiments Proceedings of the National Academy of Sciences of the United States of America Medium 16091471
2004 NKG2D is a homodimeric C-type lectin-like receptor that interacts with asymmetric monomeric ligands in 2:1 complexes; each NKG2D monomer uses an equivalent surface to bind structurally divergent ligand surfaces through 'rigid adaptation' rather than induced-fit, explaining recognition degeneracy. Crystal structure analysis, thermodynamic and kinetic analyses of multiple NKG2D-ligand pairs Advances in protein chemistry High 15500864
2018 IDO1 promotes expression of miR-18a, which directly downregulates NKG2D (via its 3'UTR) and the NKG2D ligand Mult-1 (via its 3'UTR); IDO1 promotes binding of miR-18a to AGO2, leading to degradation of Mult-1 mRNA and inhibition of NKG2D translation, thereby impairing NK cell cytotoxicity. Co-immunoprecipitation of AGO2, 3'UTR luciferase reporter assays, miR-18a overexpression/inhibition, INCB024360 treatment, IDO1 overexpression Molecular immunology Medium 30268986
2017 NKG2D-dependent antitumor effects of temozolomide (TMZ) and irradiation (IR) in glioblastoma require an intact DNA damage response and are attenuated by MGMT; blocking NKG2D pathway or using NKG2D-knockout mice reduces the survival benefit of TMZ or IR in syngeneic orthotopic glioblastoma models. NKG2D-knockout mouse model, NKG2D-blocking antibodies, syngeneic orthotopic glioblastoma model, in vitro DDR pathway analysis Clinical cancer research Medium 29162646
2013 NKG2D signaling in human CD8+ T cells co-stimulates TCR activation; on NK cells, NKG2D can act as a primary activation receptor sufficient to trigger cytotoxicity. Antibody crosslinking, cytotoxicity assays, cytokine secretion assays comparing NK vs. T cell responses Current opinion in immunology Medium 11973127
2013 NKG2D in T cells (NKG2D cross-linkage) augments anti-CD3-triggered proliferation and IFN-γ/TNF-α production in CD8 T cells; in GCA and PMR patients, NKG2D is preferentially expressed on senescent CD4+CD28- and CD8+ T cells and NKG2D ligands are present in temporal arteries, supporting a costimulatory role in autoimmune vasculitis. Flow cytometry, CFSE proliferation assay, intracellular cytokine staining, immunofluorescence and immunohistology of temporal artery biopsies Annals of the rheumatic diseases Medium 23417963

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature 1266 12384702
2003 Roles of the NKG2D immunoreceptor and its ligands. Nature reviews. Immunology 1042 14523385
2001 Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity. Nature 756 11557981
2013 Regulation of ligands for the NKG2D activating receptor. Annual review of immunology 689 23298206
2015 NKG2D Receptor and Its Ligands in Host Defense. Cancer immunology research 495 26041808
2010 Effect of NKG2D ligand expression on host immune responses. Immunological reviews 401 20536569
2008 NKG2D ligands in tumor immunity. Oncogene 317 18836475
2019 Absence of NKG2D ligands defines leukaemia stem cells and mediates their immune evasion. Nature 305 31316209
2007 Promiscuity and the single receptor: NKG2D. Nature reviews. Immunology 297 17673918
2016 NKG2D ligands mediate immunosurveillance of senescent cells. Aging 278 26878797
2018 NKG2D: A Master Regulator of Immune Cell Responsiveness. Frontiers in immunology 224 29568297
2013 NKG2D ligands as therapeutic targets. Cancer immunity 221 23833565
2004 Downregulation and/or release of NKG2D ligands as immune evasion strategy of human neuroblastoma. Neoplasia (New York, N.Y.) 213 15548365
2018 NKG2D and Its Ligands: "One for All, All for One". Frontiers in immunology 205 29662484
2008 NKG2D ligands: key targets of the immune response. Trends in immunology 204 18602338
2018 NKG2D and its ligands in cancer. Current opinion in immunology 191 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 158 23679194
2023 NKG2D-CAR T cells eliminate senescent cells in aged mice and nonhuman primates. Science translational medicine 154 37585504
2002 Lymphocyte activation via NKG2D: towards a new paradigm in immune recognition? Current opinion in immunology 149 11973127
2019 Role of NKG2D and its ligands in cancer immunotherapy. American journal of cancer research 145 31720075
2018 NKG2D Ligands-Critical Targets for Cancer Immune Escape and Therapy. Frontiers in immunology 140 30254634
2015 NKG2D Ligands in Tumor Immunity: Two Sides of a Coin. Frontiers in immunology 129 25788898
2019 Impairment of NKG2D-Mediated Tumor Immunity by TGF-β. Frontiers in immunology 128 31803194
2014 Cancer exosomes and NKG2D receptor-ligand interactions: impairing NKG2D-mediated cytotoxicity and anti-tumour immune surveillance. Seminars in cancer biology 125 24602822
2019 Eradication of Hepatocellular Carcinoma by NKG2D-Based CAR-T Cells. Cancer immunology research 123 31484657
2018 Functions of NKG2D in CD8+ T cells: an opportunity for immunotherapy. Cellular & molecular immunology 123 29400704
2007 Regulation of ligands for the activating receptor NKG2D. Immunology 122 17614877
2020 NKG2D and MICA/B shedding: a 'tag game' between NK cells and malignant cells. Clinical & translational immunology 121 33363734
2021 Leveraging NKG2D Ligands in Immuno-Oncology. Frontiers in immunology 120 34394116
2005 Exosomes and the MICA-NKG2D system in cancer. Blood cells, molecules & diseases 120 15885603
2014 NKG2D signaling in cancer immunosurveillance. International journal of cancer 115 24615398
2006 The role of the NKG2D receptor for tumor immunity. Seminars in cancer biology 107 16914326
2017 NKG2D-Dependent Antitumor Effects of Chemotherapy and Radiotherapy against Glioblastoma. Clinical cancer research : an official journal of the American Association for Cancer Research 104 29162646
2008 Soluble NKG2D ligands: prevalence, release, and functional impact. Frontiers in bioscience : a journal and virtual library 104 18508446
2013 New prospects on the NKG2D/NKG2DL system for oncology. Oncoimmunology 102 24353908
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
2011 Regulation of immune cell function and differentiation by the NKG2D receptor. Cellular and molecular life sciences : CMLS 90 21898152
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 89 18193361
2008 The NKG2D receptor: sensing stressed cells. Trends in molecular medicine 87 18353724
2005 MIC and other NKG2D ligands: from none to too many. Current opinion in immunology 83 16087327
2019 NKG2D/NKG2-Ligand Pathway Offers New Opportunities in Cancer Treatment. Frontiers in immunology 75 30984204
2017 Regulation of NKG2D-Dependent NK Cell Functions: The Yin and the Yang of Receptor Endocytosis. International journal of molecular sciences 74 28767057
2006 NKG2D and cytotoxic effector function in tumor immune surveillance. Seminars in immunology 73 16675266
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 70 19178412
2021 A summary of current NKG2D-based CAR clinical trials. Immunotherapy advances 67 34604863
2010 Resveratrol enhances perforin expression and NK cell cytotoxicity through NKG2D-dependent pathways. Journal of cellular physiology 66 20082299
2021 NKG2D Natural Killer Cell Receptor-A Short Description and Potential Clinical Applications. Cells 65 34200375
2013 Immunobiology and conflicting roles of the human NKG2D lymphocyte receptor and its ligands in cancer. Journal of immunology (Baltimore, Md. : 1950) 65 23913973
2003 The NKG2D receptor and its ligands-recognition beyond the "missing self"? Microbes and infection 63 12593971
2021 Natural killer cells activated through NKG2D mediate lung ischemia-reperfusion injury. The Journal of clinical investigation 62 33290276
2013 NKG2D CAR T-cell therapy inhibits the growth of NKG2D ligand heterogeneous tumors. Immunology and cell biology 62 23628805
2018 The Paradoxical Role of NKG2D in Cancer Immunity. Frontiers in immunology 57 30150983
2021 Expression of NKG2D ligands is downregulated by β-catenin signalling and associates with HCC aggressiveness. Journal of hepatology 56 33484773
2014 Advances in NKG2D ligand recognition and responses by NK cells. Immunology and cell biology 55 24445601
2013 Modulation of NKG2D ligand expression and metastasis in tumors by spironolactone via RXRγ activation. The Journal of experimental medicine 53 24190430
2024 Targeting senescent cells with NKG2D-CAR T cells. Cell death discovery 52 38704364
2020 NKG2D Ligand Shedding in Response to Stress: Role of ADAM10. Frontiers in immunology 52 32269567
2006 How NKG2D ligands trigger autoimmunity? Human immunology 52 16698443
2009 NKG2D and its ligands. The international journal of biochemistry & cell biology 50 19631280
2022 Regulation of NKG2D Stress Ligands and Its Relevance in Cancer Progression. Cancers 49 35565467
2014 Molecular Bases for the Regulation of NKG2D Ligands in Cancer. Frontiers in immunology 49 24711808
2021 NKG2D discriminates diverse ligands through selectively mechano-regulated ligand conformational changes. The EMBO journal 48 34913508
2020 Boosting Natural Killer Cell-Mediated Targeting of Sarcoma Through DNAM-1 and NKG2D. Frontiers in immunology 48 32082316
2016 Regulation of NKG2D Expression and Signaling by Endocytosis. Trends in immunology 47 27667711
2013 Natural killer cell NKG2D and granzyme B are critical for allergic pulmonary inflammation. The Journal of allergy and clinical immunology 45 24290277
2018 IDO1 impairs NK cell cytotoxicity by decreasing NKG2D/NKG2DLs via promoting miR-18a. Molecular immunology 44 30268986
2014 MICA SNPs and the NKG2D system in virus-induced HCC. Journal of gastroenterology 44 25270965
2013 NKG2D stimulated T-cell autoreactivity in giant cell arteritis and polymyalgia rheumatica. Annals of the rheumatic diseases 44 23417963
2008 TNK cells (NKG2D+ CD8+ or CD4+ T lymphocytes) in the control of human tumors. Cancer immunology, immunotherapy : CII 44 19089424
2017 NKG2D: A versatile player in the immune system. Immunology letters 43 28414183
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 41 37626965
2011 Expression, signaling proficiency, and stimulatory function of the NKG2D lymphocyte receptor in human cancer cells. Proceedings of the National Academy of Sciences of the United States of America 41 21321202
2019 The NKG2D axis: an emerging target in cancer immunotherapy. Expert opinion on therapeutic targets 40 30732494
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
2021 Targeting the NKG2D/NKG2D-L axis in acute myeloid leukemia. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 34 33508619
2008 Murine cytomegalovirus regulation of NKG2D ligands. Medical microbiology and immunology 33 18259774
2008 Tumor cell recognition by the NK cell activating receptor NKG2D. European journal of immunology 31 18979516
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
2016 CBP/p300 acetyltransferases regulate the expression of NKG2D ligands on tumor cells. Oncogene 27 27477692
2016 NKG2D ligand expression in pediatric brain tumors. Cancer biology & therapy 27 27834580
2004 NKG2D and Related Immunoreceptors. Advances in protein chemistry 27 15500864
2023 Engaging natural killer cells for cancer therapy via NKG2D, CD16A and other receptors. mAbs 26 37165468
2018 Fusion Proteins of NKG2D/NKG2DL in Cancer Immunotherapy. International journal of molecular sciences 26 29316666
2017 Anti-NKG2D mAb: A New Treatment for Crohn's Disease? International journal of molecular sciences 26 28926962
2016 Association of NKG2D gene variants with susceptibility and severity of rheumatoid arthritis. Clinical and experimental immunology 26 27783394
2013 Endothelial cell activation and proliferation modulate NKG2D activity by regulating MICA expression and shedding. Journal of innate immunity 26 23860405
2012 Immunogenetics of the NKG2D ligand gene family. Immunogenetics 26 22843249
2023 The Role of NKG2D and Its Ligands in Autoimmune Diseases: New Targets for Immunotherapy. International journal of molecular sciences 25 38139373
2019 Expressions of natural cytotoxicity receptor, NKG2D and NKG2D ligands in endometriosis. Journal of reproductive immunology 25 31655348
2017 How Mucosal Epithelia Deal with Stress: Role of NKG2D/NKG2D Ligands during Inflammation. Frontiers in immunology 24 29209320

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