Affinage

CD226

CD226 antigen · UniProt Q15762

Length
336 aa
Mass
38.6 kDa
Annotated
2026-04-28
100 papers in source corpus 29 papers cited in narrative 29 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CD226 (DNAM-1) is an immunoglobulin superfamily costimulatory receptor that promotes NK cell and T cell cytotoxicity, cytokine production, and tumor immunosurveillance by competing with the inhibitory receptors TIGIT and CD96 for shared ligands CD155 and CD112 (PMID:12847109, PMID:22427644, PMID:24658051, PMID:19029379). Its crystal structure reveals a unique side-by-side two-IgV-domain ectodomain in which D1 forms the conserved CD155-binding interface and D2 stabilizes the architecture; intracellularly, ligand engagement triggers Src kinase phosphorylation of a conserved ITT-like motif that recruits Grb2 and activates Vav-1/PI3K/PLCγ1/Erk/Akt signaling, driving actin polymerization, granule polarization, and FOXO1 inactivation (PMID:30591568, PMID:26552706, PMID:30504141). Tumor-derived CD155 exploits CD226 signaling by promoting Src-dependent Y319 phosphorylation, enabling CBL-B-mediated ubiquitination and proteasomal degradation of CD226, which limits antitumor immunity and reduces responsiveness to checkpoint blockade (PMID:33053330, PMID:33053331). On regulatory T cells, CD226 competes with TIGIT for CD155 binding and thereby modulates TIGIT-dependent PI3K-mTORC1 suppression and Foxp3 stability, positioning the CD226–TIGIT balance as a determinant of Treg function and inflammatory disease outcomes (PMID:34011606, PMID:25994968).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1985 Medium

    Before molecular identity was known, antibody blockade established that CD226 (TLiSA1) is an activation antigen required for CTL differentiation but not proliferation, defining its functional niche as a costimulatory molecule.

    Evidence Monoclonal antibody blocking in mixed lymphocyte culture with limiting dilution CTL assays

    PMID:2580933

    Open questions at the time
    • Molecular identity and ligand unknown
    • Mechanism of differentiation versus proliferation selectivity unexplained
  2. 1997 High

    Cloning revealed CD226 as a two-IgV-domain immunoglobulin superfamily member expressed on T cells and platelets, unifying the previously separate TLiSA1 and PTA1 identities and establishing its molecular architecture.

    Evidence cDNA cloning from Jurkat cells, protein sequencing from platelets, RT-PCR

    PMID:9268302

    Open questions at the time
    • Ligand identity unknown
    • Signaling mechanism unresolved
  3. 2003 High

    Demonstration that thrombin-induced tyrosine phosphorylation of CD226 (specifically Y322) is required for platelet-endothelial adhesion established CD226 as a phosphorylation-regulated adhesion receptor beyond the lymphocyte lineage.

    Evidence Y322 mutagenesis, immunoprecipitation, platelet/endothelial adhesion assays

    PMID:12847109

    Open questions at the time
    • Kinase responsible for Y322 phosphorylation not identified
    • Role of CD226 in endothelial contexts only partially explored (PMID:12941439)
  4. 2005 High

    Identification of S329 phosphorylation as the trigger for lipid raft recruitment and subsequent tyrosine phosphorylation established a two-step activation model linking CD226 membrane partitioning to LFA-1 costimulatory signaling for T cell priming, and selective Th1 expression positioned CD226 in adaptive immune polarization.

    Evidence S329 mutant transfectants, lipid raft fractionation, confocal microscopy, in vivo anti-CD226 in EAE model

    PMID:15684041 PMID:16034094

    Open questions at the time
    • Kinase for S329 not identified
    • Whether Th1 selectivity is transcriptionally controlled was unknown
  5. 2008 High

    DNAM-1 knockout mice revealed that CD226 is essential for tumor immunosurveillance and extends the range of targets activating NK cells and CD8+ T cells, particularly when other activating ligands are scarce.

    Evidence Cd226−/− mice challenged with CD155-expressing tumors, carcinogen models, in vitro cytotoxicity assays (two independent labs)

    PMID:19029379 PMID:19029380

    Open questions at the time
    • Downstream signaling pathway not yet defined at this point
    • Role of CD226 in memory lymphocyte responses unexplored
  6. 2012 High

    Epistasis experiments established that TIGIT competes with CD226 for CD155, creating a costimulatory–coinhibitory axis analogous to CD28–CTLA-4, and that CD96 also opposes CD226 in NK cell regulation.

    Evidence TIGIT shRNA knockdown with anti-CD226 blockade, IFN-γ readouts; Cd96−/− mice with tumor and LPS challenge

    PMID:22427644 PMID:24658051

    Open questions at the time
    • Relative binding affinities of CD226, TIGIT, and CD96 for CD155 not quantitatively resolved
    • Cis versus trans competition not distinguished
  7. 2014 High

    Studies in MCMV infection showed that DNAM-1 is required for memory NK cell differentiation via Fyn and PKCη, extending CD226's role beyond acute effector function to long-lived immunological memory.

    Evidence Cd226−/− mice, MCMV infection model, adoptive transfer, signaling inhibitor studies

    PMID:24440149

    Open questions at the time
    • How Fyn versus PKCη pathways diverge downstream of CD226 incompletely characterized
    • Whether memory CD8+ T cells similarly depend on CD226 not tested
  8. 2015 High

    Comprehensive mutagenesis defined the ITT-like motif as the hub for Src-dependent Grb2 recruitment activating Vav-1/PI3K/PLCγ1/Erk/Akt, calcium flux, and actin-driven granule polarization, providing the full intracellular signaling cascade for CD226-mediated cytotoxicity.

    Evidence Mutant DNAM-1 transfectants, Co-IP (DNAM-1/Grb2), in vitro kinase assays, multiple downstream pathway readouts

    PMID:26552706

    Open questions at the time
    • Whether Grb2 is the sole adaptor or others are recruited
    • Structural basis of the ITT-like motif interaction unresolved
  9. 2015 Medium

    CD226 expression on Tregs was shown to reduce suppressive capacity and Foxp3 stability, while an MS-associated CD226 variant (rs763361) altered surface expression and Treg function, linking CD226 to autoimmune disease susceptibility.

    Evidence Treg sorting and suppression assays, human variant analysis, Cd226−/− Treg functional assays, EAE model

    PMID:25994968 PMID:26359290

    Open questions at the time
    • Mechanism by which CD226 destabilizes Foxp3 not defined at this stage
    • Whether the rs763361 variant directly alters signaling or only expression levels unclear
  10. 2018 High

    Structural determination of the CD226 ectodomain revealed its unique side-by-side IgV arrangement and the D1-mediated CD155 binding interface, while functional studies showed CD226 engagement drives FOXO1 phosphorylation as a key effector mechanism for antitumor NK cell responses.

    Evidence X-ray crystallography with domain deletion binding assays; Cd226−/− mice with FOXO1 phosphorylation analysis and inhibitor studies

    PMID:30504141 PMID:30591568

    Open questions at the time
    • Full-length CD226–CD155 complex structure at the immune synapse not available
    • FOXO1 target genes mediating antitumor effect incompletely catalogued
  11. 2020 High

    Discovery that tumor-derived CD155 triggers Src-dependent Y319 phosphorylation, enabling CBL-B-mediated ubiquitination and proteasomal degradation of CD226, explained how tumors actively downregulate this activating receptor; Eomes-driven transcriptional loss of CD226 on CD8+ T cells was shown to impair checkpoint blockade efficacy.

    Evidence Y319 mutagenesis, CBL-B Co-IP and ubiquitination assays, in vivo tumor models; Eomes genetic models with anti-PD-1/anti-CD137 therapy

    PMID:33053330 PMID:33053331

    Open questions at the time
    • Whether CBL-B-dependent degradation operates in all lymphocyte subsets unclear
    • Therapeutic strategies to block Y319 phosphorylation not developed
  12. 2021 High

    On Tregs, DNAM-1 was found to regulate TIGIT signaling by competitive ligand sequestration rather than by delivering its own intracellular signal, with DNAM-1 absence augmenting TIGIT-mediated PI3K-mTORC1 inhibition and stabilizing Foxp3 under inflammatory conditions.

    Evidence DNAM-1-deficient Treg transfer in GVHD model, competitive binding and PI3K-mTORC1 pathway analysis

    PMID:34011606

    Open questions at the time
    • Whether this non-signaling competitive mechanism applies to effector T cells
    • Stoichiometric requirements of CD226–TIGIT competition on single cells unknown
  13. 2023 High

    Super-resolution imaging revealed that TIGIT can inhibit T cells through nanocluster reorganization independently of CD226, and that TIGIT–CD226 co-expression is rare on tumor-infiltrating lymphocytes, challenging the simple competition model.

    Evidence Super-resolution microscopy, TIGIT ITT-like motif mutants, matched tumor/blood flow cytometry

    PMID:37596248

    Open questions at the time
    • Whether CD226-independent TIGIT inhibition dominates in all tumor types
    • Spatial relationship between CD226 and TIGIT nanoclusters at the synapse unresolved
  14. 2024 Medium

    CD226 function was extended to innate lymphoid cells (ILC2s), where it enhances PI3K/AKT and MAPK signaling and drives airway hyperreactivity, broadening CD226 biology beyond classical lymphocytes.

    Evidence Anti-CD226 blockade, RNA-seq, PI3K/AKT and MAPK analysis in ILC2s, Rag2−/− mouse asthma model

    PMID:38244725

    Open questions at the time
    • ILC2-specific signaling partners downstream of CD226 not identified
    • Whether CD226 on ILC2s competes with TIGIT as it does on NK and T cells untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full-length CD226–CD155 complex structure at the immune synapse, the identity of the S329 kinase, whether therapeutic stabilization of CD226 surface expression (e.g., Y319 mutation) can be exploited clinically, and how CD226 intrinsic signaling versus competitive ligand sequestration is balanced across different lymphocyte subsets.
  • No full-length synaptic complex structure
  • S329 kinase identity unknown
  • In vivo therapeutic targeting of CD226 degradation pathway untested
  • Cell-type-specific balance of signaling versus competition model unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0098631 cell adhesion mediator activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 4 GO:0005576 extracellular region 3
Pathway
R-HSA-168256 Immune System 7 R-HSA-162582 Signal Transduction 6 R-HSA-1643685 Disease 4
Partners
CBLBCD96FYNGRB2LFA1NECTIN2PVRTIGIT

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1985 CD226 (TLiSA1) is a T lineage-specific activation antigen expressed on activated T cells that, when blocked by antibody, inhibits the differentiation of cytotoxic T lymphocytes (CTL) and anomalous killer (AK) cells from their precursors without affecting proliferation, establishing a role in lymphocyte differentiation. Monoclonal antibody blocking in mixed lymphocyte culture, limiting dilution assay, immunoprecipitation, Scatchard analysis The Journal of experimental medicine Medium 2580933
1997 CD226 (TLiSA1/PTA1) is a novel member of the immunoglobulin superfamily with two V domains only; identity between the T cell antigen TLiSA1 and platelet PTA1 was established by immunological criteria, internal peptide sequencing from purified platelet glycoprotein, and RT-PCR sequencing of the platelet transcript. cDNA cloning from Jurkat cells, protein sequencing, RT-PCR, flow cytometry The Journal of biological chemistry High 9268302
2003 CD226 mediates adhesion of thrombin-activated platelets and megakaryocytic cell lines to vascular endothelial cells; thrombin activation induces tyrosine phosphorylation of CD226, and mutation of tyrosine 322 impairs its adhesive function. Anti-CD226 mAb blocking, mutant transfectant experiments, immunoprecipitation, cell adhesion assay The Journal of biological chemistry High 12847109
2003 CD226 is expressed on activated endothelial cells and mediates adhesion between endothelial cells and leukocytes or tumor cells, as shown by CD226/Ig fusion protein blockade. Western blot, RT-PCR, CD226/Ig fusion protein blockade, cell adhesion assay Life sciences Medium 12941439
2005 Serine phosphorylation at residue 329 (S329) of CD226 is required for its recruitment into lipid rafts at the peripheral supra-molecular activation clusters of the immunological synapse; lipid raft association of CD226 is necessary for its tyrosine phosphorylation, which is essential for LFA-1-mediated co-stimulatory signaling for naive T cell proliferation and differentiation. Mutant transfectants (S329 mutant), lipid raft fractionation, confocal microscopy, T cell proliferation assay International immunology High 15684041
2005 CD226 is specifically expressed on Th1 but not Th2 or Th0 cells; in vivo anti-CD226 treatment reduces Th1 cell expansion, induces APCs that inhibit T cell activation, and delays onset of experimental autoimmune encephalomyelitis, establishing CD226 as a costimulatory molecule for Th1 cells. Flow cytometry, in vivo antibody treatment, EAE mouse model, APC functional assays Journal of immunology Medium 16034094
2006 The CD226 gene contains two promoters (P1 at -810 to -287 bp and P2 at +33 to +213 bp) with a negative regulatory element between them; transcription factor AP-1 upregulates both promoters, and Ets-1 differentially modulates them — promoting AP-1-induced P2 activity while inhibiting AP-1-induced P1 activity via a 10-bp AP-1/Ets-1 composite site. Promoter-reporter luciferase assays, bioinformatics, transcription factor overexpression The Journal of biological chemistry Medium 16887814
2008 DNAM-1 (CD226)-deficient CD8+ T cells require DNAM-1 for co-stimulation when antigen is presented by nonprofessional APCs but not by dendritic cells; DNAM-1-deficient NK cells fail to eliminate tumor cells with few other activating ligands, establishing DNAM-1 as extending the range of target cells that activate lymphocytes. DNAM-1 knockout mice, in vitro cytotoxicity assays, in vivo tumor challenge The Journal of experimental medicine High 19029380
2008 DNAM-1-deficient CTL and NK cells show significantly reduced cytotoxic activity against DNAM-1 ligand-expressing tumors; DNAM-1-deficient mice display accelerated tumor development after transplantation of CD155-expressing tumor cells and after chemical carcinogen treatment, establishing DNAM-1 as required for tumor immunosurveillance in vivo. DNAM-1 knockout mice, in vitro cytotoxicity assays, MCA/DMBA carcinogen models, tumor transplantation The Journal of experimental medicine High 19029379
2009 CD226 (DNAM-1) on Vγ9Vδ2 T cells mediates cytotoxicity against hepatocellular carcinoma cells expressing Nectin-like-5 (CD155); antibody-mediated masking of DNAM-1 reduces both cytotoxicity and IFN-γ production, and DNAM-1 cooperates with NKG2D in tumor cell lysis. mAb-mediated blocking, cytotoxicity assays, IFN-γ production assays European journal of immunology Medium 19404979
2009 CD226 is expressed on mouse thymocytes and antagonizes apoptosis; shRNA knockdown of CD226 in fetal thymus organ culture reduces cellularity with enhanced apoptosis, while CD226-transgenic mice show enlarged thymus due to increased cellularity; CD226 regulates survivin expression as part of its anti-apoptotic mechanism. shRNA knockdown, fetal thymus organ culture, transgenic mice, flow cytometry, Western blot for survivin Journal of immunology Medium 19380793
2009 Soluble CD226 (sCD226) is shed from cell membranes by proteases (protease inhibitors increase membrane CD226 and decrease sCD226 in supernatants); sCD226-Fc fusion protein dose-dependently inhibits NK cell cytotoxicity against K562 cells. ELISA, flow cytometry, protease inhibitor treatment, NK cytotoxicity assay with CD226-Fc fusion protein BMC immunology Medium 19490613
2012 TIGIT exerts immunosuppressive effects on T cells by competing with CD226 for the same CD155 ligand; increases in IFN-γ following TIGIT knockdown could be overcome by blocking CD226 signaling, placing CD226 and TIGIT as competing receptors for CD155 on T cells. agonistic anti-TIGIT mAb, shRNA TIGIT knockdown, anti-CD226 blocking, IFN-γ/cytokine measurement Journal of immunology High 22427644
2014 CD96 competes with CD226 for binding to CD155 and limits NK cell function by direct inhibition; Cd96-/- mice display hyperinflammatory responses to LPS and resistance to carcinogenesis and experimental lung metastases, establishing CD96 as opposing CD226 in NK cell regulation. Cd96-/- mice, NK cell functional assays, tumor metastasis models, LPS challenge, binding competition assay Nature immunology High 24658051
2014 DNAM-1 is a costimulatory molecule required for optimal expansion and differentiation of MCMV-specific memory NK cells; Src-family kinase Fyn and PKCη signaling through DNAM-1 play distinct roles in generating effector versus memory NK cells during MCMV infection. Cd226-/- mice, antibody blockade, MCMV infection model, adoptive transfer, signaling inhibitor studies Immunity High 24440149
2015 DNAM-1 (CD226) controls NK cell-mediated cytotoxicity and cytokine production via a conserved tyrosine- and asparagine-based ITT-like motif in its cytoplasmic domain; upon phosphorylation by Src kinases, this motif enables binding to adaptor Grb2, leading to activation of Vav-1, PI3K, PLCγ1, Erk, Akt, and calcium fluxes, as well as increased actin polymerization and granule polarization. Mutant DNAM-1 transfectants, Co-IP (DNAM-1/Grb2), in vitro kinase assays, cytotoxicity assays, calcium flux measurement, actin polymerization assay, granule polarization imaging The Journal of experimental medicine High 26552706
2015 CD226 expression on Treg cells is associated with reduced suppressive capacity and lineage stability; TIGIT+ Tregs have higher suppressive function, while CD226+TIGIT- Tregs show reduced purity and suppressive capacity after expansion with increased effector cytokine production. Flow cytometry, in vitro Treg expansion, suppression assays, transcriptional profiling Journal of immunology Medium 25994968
2015 CD226 on donor immune cells (specifically CD4+ T cells and FoxP3+ Tregs) promotes graft-versus-host disease after bone marrow transplantation; absence of DNAM-1 promotes expansion and suppressive function of Treg cells post-BMT while sparing graft-versus-leukemia effects. DNAM-1-/- donor grafts in MHC-mismatched and MHC-matched BMT models, in vivo Treg expansion assays, GVHD scoring Blood Medium 23430112
2018 CD226 regulates NK cell antitumor cytotoxicity through inactivation (phosphorylation) of FOXO1; CD226 engagement by CD155 results in FOXO1 phosphorylation, and FOXO1 phosphorylation inhibitors abrogate CD226-mediated effector responses; CD226 deficiency leads to dysregulated FOXO1-regulated gene expression in tumor-infiltrating NK cells. Cd226-/- mice, gene expression analysis, in vitro cytotoxicity assays, FOXO1 phosphorylation analysis, FOXO1 inhibitor treatment Proceedings of the National Academy of Sciences High 30504141
2018 The crystal structure of CD226 ectodomain reveals a unique side-by-side arrangement of two tandem IgV domains (distinct from conventional head-to-tail arrangements); the hybrid complex structure of mouse CD226 ectodomain bound to human CD155-D1 shows that D1 of CD226 forms the conserved binding interface while D2 both stabilizes the architecture and forms direct contacts with CD155; deletion of D2 substantially reduces CD226 binding to CD155. Crystal structure (X-ray crystallography), surface plasmon resonance binding assay, domain deletion constructs Proceedings of the National Academy of Sciences High 30591568
2018 DNAM-1 is selectively expressed on small peritoneal macrophages (SPMs) but not large peritoneal macrophages (LPMs); DNAM-1 on SPMs mediates CD4+ T cell costimulation during antigen presentation, and DNAM-1 deficiency or blockade impairs CD4+ T cell priming by SPMs. Flow cytometry, macrophage subset isolation, OVA-specific CD4+ T cell priming assay, DNAM-1 KO mice, antibody blockade Scientific reports Medium 30315271
2020 Tumor-derived CD155 initiates phosphorylation of CD226 at tyrosine 319 (Y319) by Src kinases, enabling ubiquitination of CD226 by CBL-B, internalization, and proteasomal degradation; mutation of Y319 leads to increased CD226 surface expression and enhanced anti-tumor immunity and improved efficacy of immune checkpoint blockade. Y319 mutant CD226, Src kinase inhibitor studies, Co-IP (CD226/CBL-B), ubiquitination assays, in vivo tumor models, flow cytometry Immunity High 33053330
2020 CD226 loss on CD8+ T cells is driven by an antigen-specific mechanism involving the transcription factor Eomesodermin (Eomes); CD226neg CD8+ T cells exhibit reduced LFA-1 activation, altered TCR signaling, and a distinct transcriptomic program; loss of CD226 impairs response to anti-PD-1 and anti-CD137 immunotherapy. Cd226-/- mice, Eomes genetic models, transcriptomics, TCR signaling assays, immune checkpoint blockade in vivo Immunity High 33053331
2020 Soluble CD155 (sCD155) secreted by tumor cells preferentially binds DNAM-1 over TIGIT and CD96 and interferes with DNAM-1-mediated NK cell degranulation; in vivo experiments with DNAM-1 KO but not TIGIT KO or CD96 KO mice show loss of sCD155's tumor-promoting effect, establishing DNAM-1 as the primary target of sCD155. Cd226 KO, TIGIT KO, CD96 KO mice, in vivo tumor colony assays, NK depletion, in vitro degranulation assays, binding affinity comparison The Journal of experimental medicine High 32040157
2020 NK cell-derived exosomes carry surface DNAM-1; DNAM-1 on exosomes mediates cytotoxicity against tumor cells, as shown by blocking antibodies to DNAM-1 or its ligands reducing exosome-mediated killing and delaying target cell apoptosis. Exosome characterization (Western blot, flow cytometry), blocking antibody experiments, cytotoxicity assays Cancers Medium 32178479
2021 DNAM-1 competes with TIGIT on Treg cells for binding to CD155, thereby regulating TIGIT signaling without delivering its own intracellular signal; DNAM-1 deficiency augments TIGIT signaling, which inhibits the PI3K-mTORC1 pathway, resulting in maintenance of Foxp3 expression and Treg function under inflammatory conditions. DNAM-1-deficient Treg transfer, GVHD model, Co-IP/competitive binding assays, PI3K-mTORC1 pathway analysis, Foxp3 stability assay Proceedings of the National Academy of Sciences High 34011606
2024 CD226 expressed on ILC2s enhances cytokine secretion and effector functions; mechanistically, CD226 alters intracellular metabolism and enhances PI3K/AKT and MAPK signaling pathways in ILC2s; blocking CD226 ameliorates ILC2-dependent airway hyperreactivity in mouse models. Anti-CD226 antibody blockade, RNA sequencing, flow cytometry, PI3K/AKT and MAPK pathway analysis, Rag2-/- mouse model The Journal of allergy and clinical immunology Medium 38244725
2015 The MS-associated CD226 genetic variant (rs763361) reduces surface CD226 expression on memory T cells and impairs its induction after stimulation; Foxp3+ Tregs from protective variant carriers show superior suppressive capacity; Cd226-/- mouse Tregs show reduced inhibitory activity with exacerbated EAE, establishing that CD226 regulates Treg function. Human genetic variant analysis, flow cytometry, Cd226-/- mouse Treg functional assays, EAE model Brain Medium 26359290
2023 TIGIT inhibits T cell activation via ligation-induced reorganization into dense nanoclusters at TCR-rich immune synapse clusters, independently of CD226; this inhibitory effect requires TIGIT's intracellular ITT-like signaling motif and reduces cytokine secretion; TIGIT and CD226 co-expression is rare on tumor-infiltrating lymphocytes, indicating CD226-independent TIGIT inhibition is dominant in the tumor microenvironment. Super-resolution microscopy, flow cytometry of matched tumor/blood samples, TIGIT ITT-like motif mutants, cytokine secretion assays Nature communications High 37596248

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 The receptors CD96 and CD226 oppose each other in the regulation of natural killer cell functions. Nature immunology 389 24658051
2012 The TIGIT/CD226 axis regulates human T cell function. Journal of immunology (Baltimore, Md. : 1950) 388 22427644
2008 DNAM-1 promotes activation of cytotoxic lymphocytes by nonprofessional antigen-presenting cells and tumors. The Journal of experimental medicine 281 19029380
2009 Primary human tumor cells expressing CD155 impair tumor targeting by down-regulating DNAM-1 on NK cells. Journal of immunology (Baltimore, Md. : 1950) 234 19801517
2008 Accelerated tumor growth in mice deficient in DNAM-1 receptor. The Journal of experimental medicine 221 19029379
2015 Divergent Phenotypes of Human Regulatory T Cells Expressing the Receptors TIGIT and CD226. Journal of immunology (Baltimore, Md. : 1950) 215 25994968
2011 Decreased expression of DNAM-1 on NK cells from acute myeloid leukemia patients. Immunology and cell biology 183 21383766
2014 Costimulatory molecule DNAM-1 is essential for optimal differentiation of memory natural killer cells during mouse cytomegalovirus infection. Immunity 151 24440149
2020 Characterization of Human NK Cell-Derived Exosomes: Role of DNAM1 Receptor In Exosome-Mediated Cytotoxicity Against Tumor. Cancers 139 32178479
2020 CD155 on Tumor Cells Drives Resistance to Immunotherapy by Inducing the Degradation of the Activating Receptor CD226 in CD8+ T Cells. Immunity 129 33053330
2020 Eomes-Dependent Loss of the Co-activating Receptor CD226 Restrains CD8+ T Cell Anti-tumor Functions and Limits the Efficacy of Cancer Immunotherapy. Immunity 121 33053331
2005 CD226 is specifically expressed on the surface of Th1 cells and regulates their expansion and effector functions. Journal of immunology (Baltimore, Md. : 1950) 118 16034094
2015 DNAM-1 controls NK cell activation via an ITT-like motif. The Journal of experimental medicine 117 26552706
2013 DNAM-1 control of natural killer cells functions through nectin and nectin-like proteins. Immunology and cell biology 117 24343663
2015 Immunosurveillance and therapy of multiple myeloma are CD226 dependent. The Journal of clinical investigation 109 25893601
1985 TLiSA1, a human T lineage-specific activation antigen involved in the differentiation of cytotoxic T lymphocytes and anomalous killer cells from their precursors. The Journal of experimental medicine 109 2580933
2009 DNAX accessory molecule-1 (CD226) promotes human hepatocellular carcinoma cell lysis by Vgamma9Vdelta2 T cells. European journal of immunology 108 19404979
2021 TIGIT/CD226 Axis Regulates Anti-Tumor Immunity. Pharmaceuticals (Basel, Switzerland) 100 33670993
2010 Reduced DNAM-1 expression on bone marrow NK cells associated with impaired killing of CD34+ blasts in myelodysplastic syndrome. Leukemia 94 20613786
2014 TIGIT and CD226: tipping the balance between costimulatory and coinhibitory molecules to augment the cancer immunotherapy toolkit. Cancer cell 89 25490444
2003 CD226 mediates platelet and megakaryocytic cell adhesion to vascular endothelial cells. The Journal of biological chemistry 89 12847109
1999 Pta1, a component of yeast CF II, is required for both cleavage and poly(A) addition of mRNA precursor. Molecular and cellular biology 81 10523662
2010 The autoimmune disease-associated KIF5A, CD226 and SH2B3 gene variants confer susceptibility for multiple sclerosis. Genes and immunity 78 20508602
2020 Tumor-derived soluble CD155 inhibits DNAM-1-mediated antitumor activity of natural killer cells. The Journal of experimental medicine 76 32040157
2017 CD8+T cells expressing both PD-1 and TIGIT but not CD226 are dysfunctional in acute myeloid leukemia (AML) patients. Clinical immunology (Orlando, Fla.) 71 28893624
2020 DNAM1 and 2B4 Costimulatory Domains Enhance the Cytotoxicity of Anti-GPC3 Chimeric Antigen Receptor-Modified Natural Killer Cells Against Hepatocellular Cancer Cells in vitro. Cancer management and research 68 32440221
2019 Suppression of Natural Killer cell NKG2D and CD226 anti-tumour cascades by platelet cloaked cancer cells: Implications for the metastatic cascade. PloS one 67 30908480
2017 Perturbed CD8+ T cell TIGIT/CD226/PVR axis despite early initiation of antiretroviral treatment in HIV infected individuals. Scientific reports 65 28084312
2020 TIGIT blockade enhances functionality of peritoneal NK cells with altered expression of DNAM-1/TIGIT/CD96 checkpoint molecules in ovarian cancer. Oncoimmunology 60 33224630
2010 Non-synonymous variant (Gly307Ser) in CD226 is associated with susceptibility to multiple autoimmune diseases. Rheumatology (Oxford, England) 59 20338887
2015 NKG2D and DNAM-1 Ligands: Molecular Targets for NK Cell-Mediated Immunotherapeutic Intervention in Multiple Myeloma. BioMed research international 58 26161387
2016 Altered expression of CD226 and CD96 on natural killer cells in patients with pancreatic cancer. Oncotarget 57 27626490
2018 CD226 regulates natural killer cell antitumor responses via phosphorylation-mediated inactivation of transcription factor FOXO1. Proceedings of the National Academy of Sciences of the United States of America 55 30504141
2009 The essential N terminus of the Pta1 scaffold protein is required for snoRNA transcription termination and Ssu72 function but is dispensable for pre-mRNA 3'-end processing. Molecular and cellular biology 50 19188448
2019 DNAM-1 Activating Receptor and Its Ligands: How Do Viruses Affect the NK Cell-Mediated Immune Surveillance during the Various Phases of Infection? International journal of molecular sciences 49 31366013
2017 Expression of CD226 is associated to but not required for NK cell education. Nature communications 49 28561023
2021 DNAM-1 versus TIGIT: competitive roles in tumor immunity and inflammatory responses. International immunology 48 34694361
2005 Requirement of the serine at residue 329 for lipid raft recruitment of DNAM-1 (CD226). International immunology 46 15684041
2023 TIGIT can inhibit T cell activation via ligation-induced nanoclusters, independent of CD226 co-stimulation. Nature communications 45 37596248
2021 Hitting the complexity of the TIGIT-CD96-CD112R-CD226 axis for next-generation cancer immunotherapy. BMB reports 44 33298247
2016 Inflammatory monocytes and NK cells play a crucial role in DNAM-1-dependent control of cytomegalovirus infection. The Journal of experimental medicine 42 27503073
2018 Binding mode of the side-by-side two-IgV molecule CD226/DNAM-1 to its ligand CD155/Necl-5. Proceedings of the National Academy of Sciences of the United States of America 41 30591568
2013 Chemotherapy-elicited upregulation of NKG2D and DNAM-1 ligands as a therapeutic target in multiple myeloma. Oncoimmunology 39 24498552
2013 Promoting regulation via the inhibition of DNAM-1 after transplantation. Blood 37 23430112
2021 DNAM-1 regulates Foxp3 expression in regulatory T cells by interfering with TIGIT under inflammatory conditions. Proceedings of the National Academy of Sciences of the United States of America 36 34011606
2018 Interaction of PVR/PVRL2 with TIGIT/DNAM-1 as a novel immune checkpoint axis and therapeutic target in cancer. Mammalian genome : official journal of the International Mammalian Genome Society 36 30132062
2012 Cancer immunotherapy using NKG2D and DNAM-1 systems. Anticancer research 36 22641658
2020 Higher TIGIT+CD226- γδ T cells in Patients with Acute Myeloid Leukemia. Immunological investigations 35 32819181
1992 PTA1, an essential gene of Saccharomyces cerevisiae affecting pre-tRNA processing. Molecular and cellular biology 35 1508188
2021 BCL9 regulates CD226 and CD96 checkpoints in CD8+ T cells to improve PD-1 response in cancer. Signal transduction and targeted therapy 33 34417435
2015 Expression of DNAM-1 (CD226) on inflammatory monocytes. Molecular immunology 32 26675069
2022 Emergence of the CD226 Axis in Cancer Immunotherapy. Frontiers in immunology 31 35812451
1997 TLiSA1 (PTA1) activation antigen implicated in T cell differentiation and platelet activation is a member of the immunoglobulin superfamily exhibiting distinctive regulation of expression. The Journal of biological chemistry 31 9268302
2020 Characteristic of TIGIT and DNAM-1 Expression on Foxp3+ γδ T Cells in AML Patients. BioMed research international 29 32802845
2019 CD226 attenuates Treg suppressive capacity via CTLA-4 and TIGIT during EAE. Immunologic research 29 31919790
2012 Influence of MIF, CD40, and CD226 polymorphisms on risk of rheumatoid arthritis. Molecular biology reports 29 22302395
2018 Identification of ST3AGL4, MFHAS1, CSNK2A2 and CD226 as loci associated with systemic lupus erythematosus (SLE) and evaluation of SLE genetics in drug repositioning. Annals of the rheumatic diseases 28 29625966
2014 CD226 (DNAM-1) is associated with susceptibility to juvenile idiopathic arthritis. Annals of the rheumatic diseases 28 25057181
2022 DNAM-1-chimeric receptor-engineered NK cells, combined with Nutlin-3a, more effectively fight neuroblastoma cells in vitro: a proof-of-concept study. Frontiers in immunology 27 35967339
2003 The expression, regulation and adhesion function of a novel CD molecule, CD226, on human endothelial cells. Life sciences 27 12941439
2022 CD226 and TIGIT Cooperate in the Differentiation and Maturation of Human Tfh Cells. Frontiers in immunology 26 35273617
2020 Alteration of CD226/TIGIT immune checkpoint on T cells in the pathogenesis of primary Sjögren's syndrome. Journal of autoimmunity 26 32466852
2019 Human peripheral blood DNAM-1neg NK cells are a terminally differentiated subset with limited effector functions. Blood advances 25 31167820
2015 Multiple sclerosis associated genetic variants of CD226 impair regulatory T cell function. Brain : a journal of neurology 24 26359290
2015 'Emergency exit' of bone-marrow-resident CD34(+)DNAM-1(bright)CXCR4(+)-committed lymphoid precursors during chronic infection and inflammation. Nature communications 24 26436997
2024 Blocking CD226 regulates type 2 innate lymphoid cell effector function and alleviates airway hyperreactivity. The Journal of allergy and clinical immunology 23 38244725
2020 CD226 Attenuates Treg Proliferation via Akt and Erk Signaling in an EAE Model. Frontiers in immunology 23 32983109
2014 CD226 rs763361 is associated with the susceptibility to type 1 diabetes and greater frequency of GAD65 autoantibody in a Brazilian cohort. Mediators of inflammation 23 24891767
2023 DNAM-1 chimeric receptor-engineered NK cells: a new frontier for CAR-NK cell-based immunotherapy. Frontiers in immunology 22 37359555
2023 Treg-Specific CD226 Deletion Reduces Diabetes Incidence in NOD Mice by Improving Regulatory T-Cell Stability. Diabetes 22 37625150
2018 Selective DNAM-1 expression on small peritoneal macrophages contributes to CD4+ T cell costimulation. Scientific reports 22 30315271
2009 Increased levels of soluble CD226 in sera accompanied by decreased membrane CD226 expression on peripheral blood mononuclear cells from cancer patients. BMC immunology 22 19490613
2019 Diminished cytolytic activity of γδ T cells with reduced DNAM-1 expression in neuroblastoma patients. Clinical immunology (Orlando, Fla.) 21 30999035
2022 Human allogenic γδ T cells kill patient-derived glioblastoma cells expressing high levels of DNAM-1 ligands. Oncoimmunology 20 36338147
2018 Human NK Cells Lyse Th2-Polarizing Dendritic Cells via NKp30 and DNAM-1. Journal of immunology (Baltimore, Md. : 1950) 20 30120122
2024 Revisiting T-cell adhesion molecules as potential targets for cancer immunotherapy: CD226 and CD2. Experimental & molecular medicine 19 39349829
2024 TGF-β-mediated crosstalk between TIGIT+ Tregs and CD226+CD8+ T cells in the progression and remission of type 1 diabetes. Nature communications 19 39406740
2021 Expansion of circulating peripheral TIGIT+CD226+ CD4 T cells with enhanced effector functions in dermatomyositis. Arthritis research & therapy 19 33413573
2014 XLP1 inhibitory effect by 2B4 does not affect DNAM-1 and NKG2D activating pathways in NK cells. European journal of immunology 19 24496997
2012 Association between the CD226 rs763361 polymorphism and susceptibility to autoimmune diseases: a meta-analysis. Lupus 19 22941566
2011 DNAM-1 mediates epithelial cell-specific cytotoxicity of aberrant intraepithelial lymphocyte lines from refractory celiac disease type II patients. Journal of immunology (Baltimore, Md. : 1950) 19 21525383
2009 Identification and characterization of a matrix metalloproteinase (Pta1-MMP) expressed during Loblolly pine (Pinus taeda) seed development, germination completion, and early seedling establishment. Planta 19 19466448
2023 CD226 identifies functional CD8+T cells in the tumor microenvironment and predicts a better outcome for human gastric cancer. Frontiers in immunology 18 37056782
2016 MiR-892a Promotes Hepatocellular Carcinoma Cells Proliferation and Invasion Through Targeting CD226. Journal of cellular biochemistry 18 27883251
2022 Human CD4+CD25+CD226- Tregs Demonstrate Increased Purity, Lineage Stability, and Suppressive Capacity Versus CD4+CD25+CD127lo/- Tregs for Adoptive Cell Therapy. Frontiers in immunology 17 35693814
2019 Early Cytomegalovirus Reactivation and Expansion of CD56brightCD16dim/-DNAM1+ Natural Killer Cells Are Associated with Antileukemia Effect after Haploidentical Stem Cell Transplantation in Acute Leukemia. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 17 31212079
2015 Association between the CTLA-4, CD226, FAS polymorphisms and rheumatoid arthritis susceptibility: a meta-analysis. Human immunology 17 25645050
2019 Recovery of CD226-TIGIT+FoxP3+ and CD226-TIGIT-FoxP3+ regulatory T cells contributes to clinical remission from active stage in ulcerative colitis patients. Immunology letters 16 31883787
2011 The CD226 gene in susceptibility of rheumatoid arthritis in the Chinese Han population. Rheumatology international 16 21286723
2006 Identification and characterization of the CD226 gene promoter. The Journal of biological chemistry 15 16887814
2000 Preparation and characterization of mabs against different epitopes of CD226 (PTA1). Hybridoma 15 11152401
2024 Immune checkpoint molecule DNAM-1/CD112 axis is a novel target for natural killer-cell therapy in acute myeloid leukemia. Haematologica 14 37731380
2022 NKG2D engagement on human NK cells leads to DNAM-1 hypo-responsiveness through different converging mechanisms. European journal of immunology 14 36440686
2016 Soluble DNAM-1, as a Predictive Biomarker for Acute Graft-Versus-Host Disease. PloS one 14 27257974
2009 Expression of CD226 antagonizes apoptotic cell death in murine thymocytes. Journal of immunology (Baltimore, Md. : 1950) 14 19380793
2009 The CD226 gene in susceptibility of type 1 diabetes. Tissue antigens 14 19624611
1989 Expression of TLiSA1 on T cells from patients with rheumatoid arthritis and systemic lupus erythematosus. Clinical immunology and immunopathology 14 2788052
2023 Dysregulation of DNAM-1-Mediated NK Cell Anti-Cancer Responses in the Tumor Microenvironment. Cancers 13 37760586
2018 Association between CD226 polymorphism and soluble levels in rheumatoid arthritis: Relationship with clinical activity. Immunological investigations 13 29319370
2014 Recombinant soluble CD226 protein directly inhibits cancer cell proliferation in vitro. International immunopharmacology 12 24468679