Affinage

CD200R1

Cell surface glycoprotein CD200 receptor 1 · UniProt Q8TD46

Round 2 corrected
Length
348 aa
Mass
39.0 kDa
Annotated
2026-04-28
130 papers in source corpus 26 papers cited in narrative 25 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CD200R1 is an inhibitory immunoreceptor on myeloid and lymphoid cells that restrains inflammatory activation upon engagement by CD200 or its homologues. Ligation triggers Src-family-kinase-dependent phosphorylation of cytoplasmic tyrosines Y286 and Y297 (the latter within an NPxY motif), directly recruiting the adaptor Dok2, which in turn recruits RasGAP to suppress Ras/MAPK and NF-κB signaling, thereby inhibiting macrophage TNF-α secretion, mast cell degranulation, ILC2 cytokine production, and microglial priming (PMID:19786546, PMID:16330532, PMID:33953190, PMID:15661892). CD200R1 expression is transcriptionally repressed by a C/EBPβ/HDAC1 complex under inflammatory conditions and post-transcriptionally by miR-129-5p, while type I interferon-induced cleavage of p120-RasGAP can switch CD200R1 signaling from inhibitory to pro-inflammatory, as observed in systemic lupus erythematosus (PMID:22776069, PMID:34952004, PMID:34637328). Beyond classical inhibition, CD200R1 is required for neutrophil ROS production limiting intracellular bacterial proliferation and for TLR2-dependent inflammasome assembly during herpesvirus infection, revealing context-dependent pro-host-defense functions (PMID:31073183, PMID:23082204).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2000 High

    Identification of CD200R as the myeloid-restricted receptor for CD200 resolved how CD200 delivers its immunosuppressive signal, establishing binding affinity (~2.5 µM), tyrosine-phosphorylation potential, and in vivo inhibitory function in EAE.

    Evidence Surface plasmon resonance, pervanadate phosphorylation, and antibody blockade in murine EAE model

    PMID:10981966

    Open questions at the time
    • Downstream signaling intermediates unknown
    • Cytoplasmic phosphorylation sites not mapped
    • Expression on non-myeloid lineages not fully characterized
  2. 2003 High

    Characterization of the CD200R gene family in human and mouse distinguished the inhibitory CD200R1 (which binds CD200) from activating CD200R-like receptors (which pair with DAP12 and do not bind CD200), clarifying receptor–ligand specificity within the family.

    Evidence DAP12 co-precipitation, quantitative RT-PCR, flow cytometry across human and mouse

    PMID:12960329

    Open questions at the time
    • Signaling pathway downstream of CD200R1 still unresolved
    • Human CD200R family members less characterized than mouse
  3. 2004 High

    Demonstration that the viral CD200 homologue HHV-8 K14 engages CD200R with near-native affinity to suppress macrophage TNF-α established that pathogens exploit this checkpoint and confirmed the contact-dependent inhibitory mechanism.

    Evidence Surface plasmon resonance for K14–CD200R binding, TNF-α secretion assay with anti-CD200R blocking antibody

    PMID:15220441

    Open questions at the time
    • Signaling events downstream of viral ligand engagement not compared to endogenous CD200
    • Scope of viral mimicry across herpesviruses not defined
  4. 2005 High

    Systematic mutagenesis of the three cytoplasmic tyrosines identified Y286 and Y297 (NPxY motif) as the critical phosphorylation sites for CD200R-mediated mast cell inhibition, and showed Src-family kinases mediate this phosphorylation, defining the proximal signaling code.

    Evidence Site-directed mutagenesis of Y286/Y289/Y297, phosphorylation and mast cell degranulation assays

    PMID:15661892 PMID:16330532

    Open questions at the time
    • Identity of the adaptor recruited to phospho-NPxY not yet determined
    • Relative contribution of each tyrosine in non-mast-cell lineages unknown
  5. 2007 High

    Generation of CD200R1-knockout mice proved CD200R1 is the essential receptor for CD200-mediated immunosuppression in vivo, as CD200Fc failed to suppress allograft rejection or modulate alloreactivity in CD200R1−/− animals, while a separate study revealed an unexpected positive role for CD200–CD200R in osteoclast fusion and RANK signaling.

    Evidence CD200R1−/− mouse model with skin graft rejection, MLR, LPS-TNF assay; CD200−/− mice with osteoclast differentiation/bone histology and recombinant protein rescue

    PMID:17667818 PMID:17726108

    Open questions at the time
    • Mechanism by which CD200R1 promotes RANK signaling in osteoclasts is unclear
    • Possible CD200R1-independent effects of CD200 not fully excluded
  6. 2009 High

    Identification of Dok2 as the primary adaptor directly binding the phosphorylated NPxY motif, with ~10-fold higher affinity than Dok1, and its downstream recruitment of RasGAP, established the core inhibitory signaling cascade (CD200R1→Dok2→RasGAP) in human myeloid cells.

    Evidence Direct binding affinity measurements, RNAi knockdown of Dok2/RasGAP vs Dok1/SHIP, co-immunoprecipitation in U937 cells

    PMID:19786546

    Open questions at the time
    • Structural basis of Dok2 selectivity over Dok1 for the NPxY motif unknown
    • Whether RasGAP enzymatic activity is the sole effector not tested
  7. 2010 High

    Discovery that Dok1/CrkL negatively regulates CD200R1 signaling by competing with Dok2 for receptor access revealed an internal rheostat that tunes the inhibitory output, explaining why Dok1 knockdown paradoxically enhances inhibition.

    Evidence RNAi knockdown of Dok1/CrkL, phosphorylation time-course, co-immunoprecipitation

    PMID:21078907

    Open questions at the time
    • Stoichiometric model of Dok1 vs. Dok2 competition not quantified
    • Role of Nck recruitment by Dok2 functionally undefined
  8. 2012 High

    Two parallel discoveries reshaped understanding: (1) C/EBPβ and HDAC1 were shown to co-occupy the CD200R1 promoter upon LPS stimulation, defining the transcriptional repression mechanism that silences CD200R1 during inflammation; (2) CD200R1−/− macrophages failed to upregulate TLR2 or assemble inflammasomes upon HSV-1 infection, revealing an unexpected pro-inflammatory licensing role.

    Evidence Quantitative ChIP, co-IP of C/EBPβ/HDAC1, HDAC inhibitor rescue in microglia; CD200R1−/− macrophage cytokine/TLR2/inflammasome assays and in vivo HSV-1 infection

    PMID:22776069 PMID:23082204

    Open questions at the time
    • Direct chromatin remodeling mechanism by HDAC1 at CD200R1 locus not resolved
    • How CD200R1 licenses TLR2 expression mechanistically is unknown
  9. 2016 Medium

    Identification of gastrointestinal epithelial CD200 homologues iSEC1/iSEC2 as additional CD200R ligands expanded the ligand repertoire beyond CD200, with functional suppression of intraepithelial lymphocytes demonstrating mucosal immune regulation.

    Evidence Binding assays across CD200R family, IEL cytokine and cytolytic activity assays

    PMID:27819346

    Open questions at the time
    • Structural basis of iSEC1–CD200R interaction vs. CD200–CD200R not compared
    • In vivo role of iSEC ligands in gut homeostasis not tested with genetic models
  10. 2017 Medium

    Acute stress was shown to downregulate CD200R1 in brain regions via glucocorticoid-induced C/EBPβ, and soluble CD200Fc delivery blocked stress-induced microglial priming, linking neuroendocrine regulation to the CD200–CD200R1 checkpoint in the CNS.

    Evidence In vivo stressor model, microglia isolation, RU486 blockade, adrenalectomy with corticosterone replacement, intracisterna magna CD200Fc injection

    PMID:29104062 PMID:31078691

    Open questions at the time
    • Whether glucocorticoid receptor acts directly on CD200R1 promoter or indirectly through C/EBPβ not distinguished
    • Translational relevance to human stress responses not established
  11. 2018 Medium

    N-glycosylation at Asn44 was shown to be required for CD200 binding; its mutation abolished the interaction and de-repressed microglial pro-inflammatory markers, pinpointing a post-translational determinant of receptor competence.

    Evidence Site-directed mutagenesis of N44 glycosylation site, neuronal-microglia co-culture functional assay

    PMID:30574022

    Open questions at the time
    • Other glycosylation sites not systematically tested
    • Crystal structure of glycosylated CD200R–CD200 complex unavailable
  12. 2019 High

    CD200R-deficient neutrophils displayed reduced ROS production and increased intracellular bacterial burden in Francisella infection, and neutrophil depletion rescued the phenotype, establishing a non-classical pro-defense role for CD200R in innate antimicrobial killing.

    Evidence CD200R−/− mouse model, ROS assay, in vivo Francisella tularensis infection, neutrophil depletion rescue

    PMID:31073183

    Open questions at the time
    • Mechanism linking CD200R signaling to NADPH oxidase activation unknown
    • Whether this extends to other intracellular pathogens not tested
  13. 2021 High

    Three key advances emerged: (a) type I IFN-induced cleavage of p120-RasGAP switches CD200R from inhibitory to pro-inflammatory, explaining the paradoxical IFN-γ potentiation seen in SLE patients; (b) miR-129-5p was identified as a post-transcriptional repressor targeting CD200R1 3′-UTR, silenceable by anti-miR in vivo; (c) CD200R engagement inhibits both canonical and non-canonical NF-κB in ILC2s, expanding the receptor's scope to innate lymphoid regulation of type-2 immunity.

    Evidence Human PBMC signaling assays with p120-RasGAP cleavage analysis and SLE patient samples; primary microglia miR-129-5p/anti-miR experiments with methylation analysis; mouse and human ILC2 NF-κB pathway analysis with in vivo AHR models

    PMID:33953190 PMID:34637328 PMID:34952004

    Open questions at the time
    • Protease responsible for p120-RasGAP cleavage during IFN signaling not identified
    • Whether miR-129-5p regulation operates in non-CNS tissues not determined
    • Structural basis of CD200R non-canonical NF-κB inhibition unknown
  14. 2023 Medium

    A therapeutic anti-CD200R1 blocking antibody confirmed the CD200–CD200R1–DOK2 axis as an immune checkpoint in cancer: antibody blockade prevented DOK2 recruitment, enhanced T cell cytotoxicity, and suppressed tumor growth, linking GWAS-identified pathway genes to a druggable target.

    Evidence Humanized antibody binding/DOK2 recruitment assays, T cell killing assays, S91 melanoma syngeneic model, GWAS data

    PMID:37288324

    Open questions at the time
    • Efficacy across diverse tumor types not shown
    • Biomarkers for patient selection not defined
    • Whether combination with other checkpoint inhibitors is synergistic not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of Dok2 selectivity for the CD200R1 NPxY motif, the protease mediating IFN-induced p120-RasGAP cleavage that switches CD200R1 output, the mechanism linking CD200R1 to neutrophil NADPH oxidase activation, and whether the inhibitory-to-activating switch operates in tissue-resident macrophage subsets beyond PBMCs.
  • No crystal structure of CD200R1 cytoplasmic domain with Dok2
  • Protease identity for p120-RasGAP cleavage unknown
  • CD200R1 signaling in tissue-specific macrophage subsets incompletely mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 5 GO:0098772 molecular function regulator activity 4
Localization
GO:0005886 plasma membrane 4
Pathway
R-HSA-168256 Immune System 6 R-HSA-162582 Signal Transduction 5
Partners
CD200CRKLDOK1DOK2NCK1RASA1

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 CD200R (OX2R) is a novel cell-surface receptor restricted to myeloid lineage cells that binds CD200 (OX2) with a dissociation constant of ~2.5 μM and koff 0.8 s⁻¹; pervanadate treatment showed CD200R can be tyrosine-phosphorylated; antibody blockade of OX2-OX2R interaction exacerbated experimental allergic encephalomyelitis, indicating an inhibitory function in myeloid cell regulation. Surface plasmon resonance (binding kinetics), pervanadate phosphorylation assay, antibody blockade in EAE model Immunity High 10981966
2003 Human CD200R (hCD200R) was characterized and shown to bind hCD200; a closely related gene hCD200RLa was identified. Mouse CD200R-related genes (mCD200RLa–d) were identified; mCD200RLa and mCD200RLb pair with the activatory adaptor DAP12 and do not bind CD200, distinguishing them functionally from the inhibitory CD200R. CD200R is most strongly expressed on macrophages and neutrophils but also on monocytes, mast cells, and T lymphocytes. Quantitative RT-PCR, novel monoclonal antibodies, DAP12 co-precipitation, flow cytometry Journal of Immunology High 12960329
2004 Human herpesvirus 8 K14 protein binds human CD200R with an affinity nearly identical to CD200 (KD ≈ 0.5 μM) and, when expressed on cell surfaces, inhibits TNF-α secretion by activated macrophages—an effect relieved by anti-CD200R mAb or soluble CD200. This demonstrates that CD200R-mediated macrophage suppression occurs via direct cell–cell contact and is mimicked by a viral CD200 homologue. Surface plasmon resonance, cell-surface expression assay, TNF-α secretion assay with blocking antibodies Journal of Virology High 15220441
2005 CD200R is expressed on mouse and human mast cells; engagement by agonist antibodies or CD200 ligand potently inhibits mast cell degranulation and cytokine secretion in vitro and in vivo without requiring coligation to FcεRI. CD200R does not contain an ITIM, establishing it as a novel inhibitory receptor class on mast cells. Flow cytometry, in vitro degranulation and cytokine secretion assays, in vivo mast cell activation model Journal of Immunology High 15661892
2005 Site-directed mutagenesis of the three cytoplasmic tyrosines of CD200R (Y286, Y289, Y297) in mouse mast cells showed Y286 and Y297 are the major phosphorylation sites critical for CD200R-mediated inhibition of mast cell activation; Y289 is dispensable. Y297 resides in an NPxY motif. Src family kinases mediate CD200R and Dok phosphorylation. Site-directed mutagenesis, tyrosine phosphorylation assays, mast cell activation assays Journal of Leukocyte Biology High 16330532
2009 In human myeloid (U937) cells, CD200R inhibitory signaling is mediated through the NPLY (NPxY) motif in its cytoplasmic tail. The adaptor Dok2 binds directly to the phosphorylated NPLY motif with ~10-fold higher affinity (KD ~1 μM at 37°C) than Dok1. Dok2 is phosphorylated upon CD200R engagement and recruits RasGAP. RNAi knockdown of Dok2 and RasGAP abolished CD200R-mediated inhibition, while knockdown of Dok1 and SHIP did not, establishing a Dok2→RasGAP pathway as the primary human CD200R signaling mechanism. Cytoplasmic tail mutants, direct binding affinity measurement, RNAi knockdown, co-immunoprecipitation Journal of Immunology High 19786546
2010 CD200R-induced phosphorylation of Dok2 precedes Dok1 phosphorylation. Dok2 recruits RasGAP and the adaptor Nck; Dok1 recruits CrkL (and constitutively binds Crk). Knockdown of Dok1 or CrkL increases Dok2 phosphorylation and RasGAP recruitment, indicating that Dok1 negatively regulates Dok2-mediated CD200R inhibitory signaling via CrkL. RNAi knockdown, co-immunoprecipitation, phosphorylation time-course assays Journal of Immunology High 21078907
2007 CD200 (not normally expressed in myeloid lineage) is strongly upregulated in macrophages at the onset of fusion; CD200R is expressed on osteoclasts and CD4+ T cells. In CD200-knockout mice, osteoclast differentiation is reduced and NF-κB and MAPK signaling downstream of RANK is depressed. A soluble CD200 extracellular domain protein rescued fusion and RANK signaling in CD200-/- macrophages; soluble CD200R extracellular domain or shRNA silencing of CD200R prevented fusion. CD200-/- mice have fewer osteoclasts and accumulate more bone. CD200-/- mouse model, shRNA silencing, recombinant protein rescue, NF-κB/MAPK signaling assays, bone histology PNAS High 17726108
2007 Mice lacking CD200R1 (CD200R1-/- generated by deletion of exons encoding extracellular domain) showed loss of FACS staining with anti-CD200R1 mAb on myeloid cells/splenocytes, enhanced LPS-stimulated splenic TNF-α production that was not suppressible by CD200Fc, loss of CD200Fc-mediated modulation of alloreactivity dependent on CD200R1+ stimulatory and T responder cells, and failure of CD200Fc to suppress graft rejection. This defines CD200R1 as the essential receptor mediating CD200-induced immunosuppression in vivo. CD200R1-/- mouse generation (ES cell targeting), FACS, LPS-TNF assay, mixed leukocyte culture, skin graft rejection model Transplantation High 17667818
2012 CD200R1-/- macrophages showed 70–75% reduction in IL-6 and CCL5 production in response to TLR2 agonist Pam2CSK4 and to HSV-1. CD200R1-/- macrophages could not upregulate TLR2 expression or assemble a functional inflammasome in response to HSV-1. CD200R1-/- mice were protected from HSV-1 infection and showed dysfunctional TLR2 signaling and markedly reduced ability to support HSV-1 replication. This reveals an unanticipated requirement for CD200R1 in 'licensing' pro-inflammatory TLR2 functions. CD200R1-/- mouse model, cytokine assays, TLR2 expression analysis, inflammasome assembly assay, viral replication assay PLoS One High 23082204
2012 LPS treatment of microglial cells decreases CD200R1 mRNA and protein expression in a C/EBPβ-dependent manner: C/EBPβ binds the CD200R1 promoter in LPS-treated (but not control) glial cells, and C/EBPβ overexpression alone reduces basal CD200R1 expression. HDAC1 co-immunoprecipitates with C/EBPβ and binds the C/EBPβ consensus sequence in the CD200R1 promoter in LPS-treated cells; HDAC1 inhibitors reverse LPS-induced CD200R1 downregulation. This defines a C/EBPβ/HDAC1 transcriptional repression axis for CD200R1. Primary microglial cultures from wild-type and C/EBPβ-KO mice, BV2 overexpression, quantitative ChIP, co-immunoprecipitation, HDAC inhibitor treatment Journal of Neuroinflammation High 22776069
2014 PPAR-γ agonist 15d-PGJ2 inhibits the pro-inflammatory response in reactive glial cells and prevents LPS/IFN-γ-induced downregulation of CD200R1 and upregulation of CD200. In neuron-microglia co-cultures, 15d-PGJ2 abrogates reactive-microglia-induced neurotoxicity through a CD200-CD200R1-dependent mechanism, placing PPAR-γ upstream of CD200R1 expression regulation. Primary neuronal and glial cultures, neuron-microglia co-cultures, LPS/IFN-γ stimulation, PPAR-γ agonist treatment, Western blot/qPCR, functional neurotoxicity assay Glia Medium 24639050
2017 Exposure to acute stressor reduces CD200R1 expression across hippocampal sub-regions, amygdala, and isolated microglia. The transcriptional suppressor C/EBPβ is induced by stress and inversely correlated with CD200R1 expression. Intracisterna magna administration of soluble CD200 (mCD200Fc) prior to stress blocked stress-induced microglial priming and hippocampal HMGB1 increase; soluble CD200R1Fc recapitulated microglial priming. Glucocorticoids (GCs) mediate stress-induced CD200R1 reduction, as shown by GC receptor blockade (RU486) and adrenalectomy experiments. In vivo stressor exposure, microglia isolation and ex vivo cytokine assay, pharmacological blockade (RU486), adrenalectomy with CORT replacement, intracisterna magna injection Brain, Behavior, and Immunity Medium 29104062 31078691
2014 DNA aptamers that bind murine CD200R1 act as agonists in the absence of exogenous CD200, inducing rapid phosphorylation of the CD200R1 cytoplasmic tail and suppressing CTL induction in allogeneic mixed leukocyte cultures. PEGylated aptamers show in vivo immunosuppression and enhance allogeneic skin graft survival comparably to CD200Fc. Suppression is absent in CD200R1-/- responder cells, confirming direct CD200R1 engagement as the mechanism. SELEX aptamer selection, cytoplasmic tail phosphorylation assay, allogeneic MLC suppression, CD200R1-/- control, in vivo skin graft model Molecular Therapy. Nucleic Acids Medium 25158092
2021 In the presence of cleaved p120-RasGAP (generated during mild cellular stress or IFN-α treatment), CD200R loses its capacity to inhibit rpS6 phosphorylation (mTORC1 activity). Furthermore, upon IFN-α pretreatment of human PBMCs, CD200R switches from inhibiting to potentiating TLR7/8-induced IFN-γ gene expression. SLE patients with elevated cleaved p120-RasGAP show similar CD200R signaling reversal. This demonstrates that type I IFN rewires CD200R from inhibitory to pro-inflammatory by altering the availability of the downstream effector p120-RasGAP. Human PBMC stimulation assays, p120-RasGAP cleavage analysis, rpS6 phosphorylation (mTORC1 readout), IFN-γ mRNA measurement, SLE patient samples Science Signaling High 34637328
2018 N-glycosylation of CD200R1 at asparagine 44 (Asn44/N44) is required for CD200-CD200R1 interaction; mutation of N44 disrupts CD200 binding and upregulates pro-inflammatory markers iNOS, CD86, IL-1β, and TNF-α in a neuronal-microglia co-culture system. Site-directed mutagenesis of glycosylation site, neuronal-microglia co-culture, cytokine/marker expression assays Journal of Inflammation Medium 30574022
2021 miR-129-5p is a posttranscriptional repressor of CD200R1: arsenic exposure demethylates the miR-129-5p promoter, increasing its expression, which represses CD200R1 by binding its 3'-UTR and shuttling CD200R1 mRNA to cytoplasmic processing bodies in microglia. Anti-miR-129 injection in mice restores CD200R1 expression and reduces IL-6 and TNF-α. CD200R1 siRNA loss-of-function confirmed an miR-129-5p → CD200R1 → IL-6/TNF-α axis. Findings were replicated in a human cell line and validated in human samples. In silico miRNA target prediction, primary neonatal microglia and BV2 assays, methylation analysis, stereotaxic anti-miR injection in mice, CD200R1 siRNA, human cell line validation Journal of Biological Chemistry High 34952004
2017 CD200R engagement activates STAT6 phosphorylation as a downstream effector; STAT6 activation modulates Foxp3 transcription in microglia. CD200R suppression prevents anti-inflammatory microglial phenotype, while Foxp3 overexpression enhances it. CD200R/Foxp3-mediated signaling enhances hippocampal neuronal viability and confers neuroprotection by counteracting iNOS. Excitotoxicity hippocampal neuroinflammation model, CD200R suppression, Foxp3 overexpression, STAT6 phosphorylation assay Scientific Reports Medium 27731341
2017 Anti-inflammatory stimulation of CD200R1 after germinal matrix hemorrhage (GMH) in rat pups activates Dok1 downstream: CD200Fc increases Dok1 expression and decreases IL-1β and TNF-α, whereas CD200R1 siRNA or Dok1 siRNA abolishes these effects. This places Dok1 as a downstream mediator of CD200R1 anti-inflammatory signaling in the neonatal brain. Neonatal rat GMH model, intracerebroventricular CD200Fc, siRNA knockdown of CD200R1 and Dok1, Western blot for Dok1/cytokines, neurobehavioral assessment Journal of Cerebral Blood Flow and Metabolism Medium 28792282
2021 CD200R expressed on ILC2s inhibits their activation, proliferation, and type 2 cytokine production upon engagement; mechanistically, CD200R engagement inhibits both canonical and non-canonical NF-κB signaling pathways in activated ILC2s. CD200R is also expressed on human ILC2s, and its engagement in humanized mouse models ameliorates airway hyperreactivity. Mouse and human ILC2 flow cytometry, CD200R engagement assays, NF-κB signaling pathway analysis, in vivo AHR models (preventative and therapeutic) Nature Communications High 33953190
2023 A humanized anti-CD200R1 antibody (23ME-00610) blocks CD200 binding to CD200R1 and inhibits recruitment of the downstream adaptor protein DOK2, inducing T-cell cytokine production and enhancing T cell-mediated tumor cell killing in vitro; it inhibits tumor growth in an S91 melanoma model in vivo. Genome-wide association data identified CD200, CD200R1, and DOK2 as a linked immune checkpoint pathway. High-affinity antibody binding assay (KD <0.1 nM), DOK2 recruitment inhibition assay, T cell cytokine/killing assays, syngeneic tumor model Oncoimmunology Medium 37288324
2015 CD200Fc (CD200R1 agonist) in human renal proximal tubular epithelial cells inhibits LPS-induced TLR4 expression and its adapter interactions (MyD88 and phospho-TAK1), abolishes TLR4-MyD88 and TLR4-TAK1 co-immunoprecipitation, and attenuates downstream IκB phosphorylation, NF-κB-p65 nuclear translocation, and ERK1/2/p38/JNK phosphorylation, as well as pro-inflammatory mediator release. Co-immunoprecipitation, NF-κB nuclear translocation assay, Western blot for phosphorylated signaling intermediates, ELISA for cytokines Biochemical and Biophysical Research Communications Medium 25791482
2016 Novel CD200 homologues iSEC1 and iSEC2, expressed exclusively by secretory cells of the gastrointestinal epithelium, bind CD200R but not other CD200R family members. Binding of iSEC1 to CD200R on intraepithelial lymphocytes suppresses their cytokine production and cytolytic activity, identifying iSEC1 as a previously unrecognized CD200R ligand in gastrointestinal mucosal immunity. Binding assays across CD200R family members, IEL cytokine and cytolytic activity assays Scientific Reports Medium 27819346
2019 CD200R-deficient neutrophils display significantly reduced reactive oxygen species (ROS) production; in vivo, CD200R deficiency increases bacterial burden in neutrophils and enhances colonization by Francisella tularensis. Depletion of the neutrophil niche in CD200R-/- mice restores bacterial burden to wild-type levels. This establishes that CD200R promotes antimicrobial ROS production in neutrophils to limit intracellular bacterial proliferation. CD200R-/- mouse model, ROS production assay, in vitro and in vivo infection assays, neutrophil depletion Nature Communications High 31073183
2021 CD200R1 knockout in CAR T cells is detrimental to their metabolic fitness and activity, while a CD200R-CD28 switch receptor (replacing CD200R cytoplasmic tail with CD28 signaling domain) potently enhances CAR T-cell polyfunctionality, cytotoxicity, proliferation, and metabolic fitness in response to CD200+ multiple myeloma cells in vitro and in xenograft models. CD200R dominant-negative provided modest benefit. This demonstrates that the CD200R cytoplasmic signaling domain determines functional outcome and can be rewired to deliver costimulation. CRISPR-Cas9 knockout, switch receptor engineering, in vitro co-culture killing assays, metabolic assays, murine xenograft models of plasmacytoma and disseminated disease Blood High 37616575

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2003 Characterization of the CD200 receptor family in mice and humans and their interactions with CD200. Journal of immunology (Baltimore, Md. : 1950) 367 12960329
2002 CD200 and membrane protein interactions in the control of myeloid cells. Trends in immunology 336 12072366
2000 Lymphoid/neuronal cell surface OX2 glycoprotein recognizes a novel receptor on macrophages implicated in the control of their function. Immunity 327 10981966
2003 The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment. Genome research 285 12975309
2007 hORFeome v3.1: a resource of human open reading frames representing over 10,000 human genes. Genomics 222 17207965
2001 The unusual distribution of the neuronal/lymphoid cell surface CD200 (OX2) glycoprotein is conserved in humans. Immunology 184 11260322
2009 Distribution of the immune inhibitory molecules CD200 and CD200R in the normal central nervous system and multiple sclerosis lesions suggests neuron-glia and glia-glia interactions. Journal of neuropathology and experimental neurology 159 19151626
2009 Essential roles for Dok2 and RasGAP in CD200 receptor-mediated regulation of human myeloid cells. Journal of immunology (Baltimore, Md. : 1950) 124 19786546
2013 Structural basis for endosomal trafficking of diverse transmembrane cargos by PX-FERM proteins. Proceedings of the National Academy of Sciences of the United States of America 121 23382219
2012 The genetic architecture of economic and political preferences. Proceedings of the National Academy of Sciences of the United States of America 121 22566634
2011 CD200-CD200R dysfunction exacerbates microglial activation and dopaminergic neurodegeneration in a rat model of Parkinson's disease. Journal of neuroinflammation 114 22053982
2004 CD200 is a ligand for all members of the CD200R family of immunoregulatory molecules. Journal of immunology (Baltimore, Md. : 1950) 111 15187158
2007 The inhibitory CD200R is differentially expressed on human and mouse T and B lymphocytes. Molecular immunology 110 17714785
2018 Role of the CD200-CD200R Axis During Homeostasis and Neuroinflammation. Neuroscience 95 30367946
2005 The CD200 receptor is a novel and potent regulator of murine and human mast cell function. Journal of immunology (Baltimore, Md. : 1950) 94 15661892
2004 Human herpesvirus 8 K14 protein mimics CD200 in down-regulating macrophage activation through CD200 receptor. Journal of virology 93 15220441
2022 A physical wiring diagram for the human immune system. Nature 92 35922511
2004 Signal peptide prediction based on analysis of experimentally verified cleavage sites. Protein science : a publication of the Protein Society 92 15340161
2021 CD200:CD200R Interactions and Their Importance in Immunoregulation. International journal of molecular sciences 90 33562512
2005 Down-regulation of basophil function by human CD200 and human herpesvirus-8 CD200. Journal of immunology (Baltimore, Md. : 1950) 88 16177086
2004 Expression of human prepro-orexin and signaling characteristics of orexin receptors in the male reproductive system. The Journal of clinical endocrinology and metabolism 87 15070969
2011 Impaired CD200-CD200R-mediated microglia silencing enhances midbrain dopaminergic neurodegeneration: roles of aging, superoxide, NADPH oxidase, and p38 MAPK. Free radical biology & medicine 83 21295135
2020 A Human IgSF Cell-Surface Interactome Reveals a Complex Network of Protein-Protein Interactions. Cell 81 32822567
2012 CD200R signaling in tumor tolerance and inflammation: A tricky balance. Current opinion in immunology 75 22264927
2008 CNS inflammation and neuronal degeneration is aggravated by impaired CD200-CD200R-mediated macrophage silencing. Journal of neuroimmunology 75 18164423
2014 The CD200-CD200R1 inhibitory signaling pathway: immune regulation and host-pathogen interactions. Advances in immunology 73 24388216
2010 CD200R1 agonist attenuates mechanisms of chronic disease in a murine model of multiple sclerosis. The Journal of neuroscience : the official journal of the Society for Neuroscience 71 20147531
2007 Mice lacking CD200R1 show absence of suppression of lipopolysaccharide-induced tumor necrosis factor-alpha and mixed leukocyte culture responses by CD200. Transplantation 68 17667818
2001 Distribution of OX2 antigen and OX2 receptor within retina. Investigative ophthalmology & visual science 66 11133863
2006 A genome-wide scan and HCRTR2 candidate gene analysis in a European cluster headache cohort. Neurology 65 16801656
2017 Stress disinhibits microglia via down-regulation of CD200R: A mechanism of neuroinflammatory priming. Brain, behavior, and immunity 63 29104062
2014 Brain innate immunity in the regulation of neuroinflammation: therapeutic strategies by modulating CD200-CD200R interaction involve the cannabinoid system. Current pharmaceutical design 63 24588829
2012 Characterization and functionality of the CD200-CD200R system during mesenchymal stromal cell interactions with T-lymphocytes. Immunology letters 63 22575528
2011 CD200-CD200R signaling suppresses anti-tumor responses independently of CD200 expression on the tumor. Oncogene 63 22020332
2007 CD200 and its receptor, CD200R, modulate bone mass via the differentiation of osteoclasts. Proceedings of the National Academy of Sciences of the United States of America 62 17726108
2006 Detection of autoantibodies against hypocretin, hcrtrl, and hcrtr2 in narcolepsy: anti-Hcrt system antibody in narcolepsy. Sleep 61 16774153
2020 The CD200/CD200R signaling pathway contributes to spontaneous functional recovery by enhancing synaptic plasticity after stroke. Journal of neuroinflammation 58 32473633
2010 Downstream of tyrosine kinase 1 and 2 play opposing roles in CD200 receptor signaling. Journal of immunology (Baltimore, Md. : 1950) 58 21078907
2005 Augmented Induction of CD4+CD25+ Treg using monoclonal antibodies to CD200R. Transplantation 57 15880066
2020 CD200-CD200R Pathway in the Regulation of Tumor Immune Microenvironment and Immunotherapy. Advances in experimental medicine and biology 56 32030689
2012 CD200/CD200R paired potent inhibitory molecules regulating immune and inflammatory responses; Part I: CD200/CD200R structure, activation, and function. Acta medica (Hradec Kralove) 56 22696929
2012 CD200 positive human mesenchymal stem cells suppress TNF-alpha secretion from CD200 receptor positive macrophage-like cells. PloS one 54 22363701
2011 A secreted protein microarray platform for extracellular protein interaction discovery. Analytical biochemistry 53 21982860
2007 CD200-CD200R regulation of microglia activation in the pathogenesis of Parkinson's disease. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 53 18040859
2017 A CD200R-CD28 fusion protein appropriates an inhibitory signal to enhance T-cell function and therapy of murine leukemia. Blood 52 29042364
2017 Monocytes, microglia, and CD200-CD200R1 signaling are essential in the transmission of inflammation from the periphery to the central nervous system. Journal of neurochemistry 51 28164283
2005 Identification of tyrosine residues crucial for CD200R-mediated inhibition of mast cell activation. Journal of leukocyte biology 49 16330532
2012 The immune inhibitory complex CD200/CD200R is developmentally regulated in the mouse brain. The Journal of comparative neurology 48 22323214
2012 OX2R activation induces PKC-mediated ERK and CREB phosphorylation. Experimental cell research 48 22652455
2014 CD200R1 and CD200 expression are regulated by PPAR-γ in activated glial cells. Glia 47 24639050
2020 The prenatal challenge with lipopolysaccharide and polyinosinic:polycytidylic acid disrupts CX3CL1-CX3CR1 and CD200-CD200R signalling in the brains of male rat offspring: a link to schizophrenia-like behaviours. Journal of neuroinflammation 46 32829711
2016 CD200R1 agonist attenuates glial activation, inflammatory reactions, and hypersensitivity immediately after its intrathecal application in a rat neuropathic pain model. Journal of neuroinflammation 46 26891688
2010 Expression of orexin receptors 1 (OX1R) and 2 (OX2R) in the porcine ovary during the oestrous cycle. Regulatory peptides 45 20688107
2005 Augmented induction of CD4+CD25+ Treg using monoclonal antibodies to CD200R. Transplantation 44 15729177
2012 Inhibition of CD200R1 expression by C/EBP β in reactive microglial cells. Journal of neuroinflammation 42 22776069
2021 CD200-CD200R immune checkpoint engagement regulates ILC2 effector function and ameliorates lung inflammation in asthma. Nature communications 41 33953190
2020 Disease Progression-Dependent Expression of CD200R1 and CX3CR1 in Mouse Models of Parkinson's Disease. Aging and disease 41 32257540
2019 CD200-CD200R1 inhibitory signaling prevents spontaneous bacterial infection and promotes resolution of neuroinflammation and recovery after stroke. Journal of neuroinflammation 41 30777093
2008 Haplotype analysis confirms the association between the HCRTR2 gene and cluster headache. Headache 40 18399985
2023 Dysregulated CD200-CD200R signaling in early diabetes modulates microglia-mediated retinopathy. Proceedings of the National Academy of Sciences of the United States of America 38 37903272
2012 Suppression of antigen-specific T cell responses by the Kaposi's sarcoma-associated herpesvirus viral OX2 protein and its cellular orthologue, CD200. Journal of virology 38 22491458
2012 The differential effects of OX1R and OX2R selective antagonists on morphine conditioned place preference in naïve versus morphine-dependent mice. Behavioural brain research 38 22995645
2012 Chronic infection drives expression of the inhibitory receptor CD200R, and its ligand CD200, by mouse and human CD4 T cells. PloS one 36 22496920
2018 CD200 modulates spinal cord injury neuroinflammation and outcome through CD200R1. Brain, behavior, and immunity 35 29870752
2012 Aberrant CD200/CD200R1 expression and function in systemic lupus erythematosus contributes to abnormal T-cell responsiveness and dendritic cell activity. Arthritis research & therapy 34 22621248
2018 Genetic association of HCRTR2, ADH4 and CLOCK genes with cluster headache: a Chinese population-based case-control study. The journal of headache and pain 33 29318394
2015 CD200R1 agonist attenuates LPS-induced inflammatory response in human renal proximal tubular epithelial cells by regulating TLR4-MyD88-TAK1-mediated NF-κB and MAPK pathway. Biochemical and biophysical research communications 33 25791482
2014 Decreased CD200R expression on monocyte-derived macrophages correlates with Th17/Treg imbalance and disease activity in rheumatoid arthritis patients. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 33 24496593
2017 The immunoglobulin superfamily member CD200R identifies cells involved in type 2 immune responses. Allergy 32 28106273
2016 A Critical Role for CD200R Signaling in Limiting the Growth and Metastasis of CD200+ Melanoma. Journal of immunology (Baltimore, Md. : 1950) 31 27385779
2015 Reduced Dendritic Cells Expressing CD200R1 in Children with Inflammatory Bowel Disease: Correlation with Th17 and Regulatory T Cells. International journal of molecular sciences 31 26690123
2013 Kinetic properties of "dual" orexin receptor antagonists at OX1R and OX2R orexin receptors. Frontiers in neuroscience 31 24376396
2010 Expression of orexin receptors 1 (OX1R) and 2 (OX2R) in the porcine hypothalamus during the oestrous cycle. Journal of physiology and pharmacology : an official journal of the Polish Physiological Society 31 20610868
2017 Gingival Tissue Inflammation Promotes Increased Matrix Metalloproteinase-12 Production by CD200Rlow Monocyte-Derived Cells in Periodontitis. Journal of immunology (Baltimore, Md. : 1950) 30 29101312
2009 Expression of orexin receptors 1 (OX1R) and 2 (OX2R) in the porcine pituitary during the oestrous cycle. Animal reproduction science 30 19394166
2018 CD200-CD200R imbalance correlates with microglia and pro-inflammatory activation in rat spinal cords exposed to amniotic fluid in retinoic acid-induced spina bifida. Scientific reports 29 30006626
2020 Maternal Immune Activation Sensitizes Male Offspring Rats to Lipopolysaccharide-Induced Microglial Deficits Involving the Dysfunction of CD200-CD200R and CX3CL1-CX3CR1 Systems. Cells 28 32664639
2019 Neurogenesis promoted by the CD200/CD200R signaling pathway following treadmill exercise enhances post-stroke functional recovery in rats. Brain, behavior, and immunity 28 31513876
2021 The CD200R1 microglial inhibitory receptor as a therapeutic target in the MPTP model of Parkinson's disease. Journal of neuroinflammation 27 33823877
2013 The role of CD200-CD200R in tumor immune evasion. Journal of theoretical biology 27 23541619
2021 The CD200-CD200R Axis Promotes Squamous Cell Carcinoma Metastasis via Regulation of Cathepsin K. Cancer research 26 34183355
2014 Both Ox1r and Ox2r orexin receptors contribute to the cardiovascular and locomotor components of the novelty stress response in the rat. Neuropharmacology 26 25239810
2019 CD200R deletion promotes a neutrophil niche for Francisella tularensis and increases infectious burden and mortality. Nature communications 25 31073183
2019 CD200-CD200R signaling and diseases: a potential therapeutic target? International journal of physiology, pathophysiology and pharmacology 25 31993106
2017 Anti-inflammation conferred by stimulation of CD200R1 via Dok1 pathway in rat microglia after germinal matrix hemorrhage. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 24 28792282
2013 Elevated serum soluble CD200 and CD200R as surrogate markers of bone loss under bed rest conditions. Bone 24 24333170
2019 Glucocorticoids mediate stress induction of the alarmin HMGB1 and reduction of the microglia checkpoint receptor CD200R1 in limbic brain structures. Brain, behavior, and immunity 23 31078691
2018 Antitumor Activity of TLR7 Is Potentiated by CD200R Antibody Leading to Changes in the Tumor Microenvironment. Cancer immunology research 23 30021725
2013 Cure of metastatic growth of EMT6 tumor cells in mice following manipulation of CD200:CD200R signaling. Breast cancer research and treatment 23 24166280
2023 Activation of the CD200/CD200R1 axis attenuates neuroinflammation and improves postoperative cognitive dysfunction via the PI3K/Akt/NF-κB signaling pathway in aged mice. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 22 37902837
2017 Alterations in CD200-CD200R1 System during EAE Already Manifest at Presymptomatic Stages. Frontiers in cellular neuroscience 22 28522962
2016 Reduced expression of monocyte CD200R is associated with enhanced proinflammatory cytokine production in sarcoidosis. Scientific reports 22 27929051
2014 Aberrant CD200/CD200R1 expression and its potential role in Th17 cell differentiation, chemotaxis and osteoclastogenesis in rheumatoid arthritis. Rheumatology (Oxford, England) 22 25261692
2012 CD200R1 supports HSV-1 viral replication and licenses pro-inflammatory signaling functions of TLR2. PloS one 22 23082204
2023 Cancel cancer: The immunotherapeutic potential of CD200/CD200R blockade. Frontiers in oncology 21 36756156
2019 Interaction of CD200 Overexpression on Tumor Cells with CD200R1 Overexpression on Stromal Cells: An Escape from the Host Immune Response in Rectal Cancer Patients. Journal of oncology 21 30800162
2022 Orexin 2 receptor (OX2R) protein distribution measured by autoradiography using radiolabeled OX2R-selective antagonist EMPA in rodent brain and peripheral tissues. Scientific reports 20 35589803
2019 Analysis of HCRTR2 Gene Variants and Cluster Headache in Sweden. Headache 20 30652302
2016 CD200R/Foxp3-mediated signalling regulates microglial activation. Scientific reports 20 27731341
2010 CD200R1 regulates the severity of arthritis but has minimal impact on the adaptive immune response. Clinical and experimental immunology 20 20735439
2023 CD200/CD200R: Bidirectional Role in Cancer Progression and Immunotherapy. Biomedicines 19 38137547
2024 Exploiting the CD200-CD200R immune checkpoint axis in multiple myeloma to enhance CAR T-cell therapy. Blood 18 37616575
2012 CD200/CD200R paired potent inhibitory molecules regulating immune and inflammatory responses; Part II: CD200/CD200R potential clinical applications. Acta medica (Hradec Kralove) 18 23101267
2006 A role for the immunomodulatory molecules CD200 and CD200R in regulating bone formation. Immunology letters 18 16530849
2014 Agonistic CD200R1 DNA Aptamers Are Potent Immunosuppressants That Prolong Allogeneic Skin Graft Survival. Molecular therapy. Nucleic acids 17 25158092
2009 Heterogeneity in the CD200R paired receptor family. Immunogenetics 17 19967353
2017 CD200Fc Attenuates Retinal Glial Responses and RGCs Apoptosis After Optic Nerve Crush by Modulating CD200/CD200R1 Interaction. Journal of molecular neuroscience : MN 16 29280053
2015 Absence of mutations in HCRT, HCRTR1 and HCRTR2 in patients with ROHHAD. Respiratory physiology & neurobiology 16 26555080
2014 Is HCRTR2 a genetic risk factor for Alzheimer's disease? Dementia and geriatric cognitive disorders 16 24969517
2010 Elevated expression of orexin receptor 2 (HCRTR2) in benign prostatic hyperplasia is accompanied by lowered serum orexin A concentrations. International journal of molecular medicine 16 21186399
2023 23ME-00610, a genetically informed, first-in-class antibody targeting CD200R1 to enhance antitumor T cell function. Oncoimmunology 14 37288324
2018 The role of N-glycosylation of CD200-CD200R1 interaction in classical microglial activation. Journal of inflammation (London, England) 14 30574022
2016 Constitutively expressed Siglec-9 inhibits LPS-induced CCR7, but enhances IL-4-induced CD200R expression in human macrophages. Bioscience, biotechnology, and biochemistry 14 26923638
2012 Effect of CD200 and CD200R1 expression within tissue grafts on increased graft survival in allogeneic recipients. Immunology letters 14 23178470
2010 Potent immunosuppression by a bivalent molecule binding to CD200R and TGF-betaR. Transplantation 14 20548263
2019 Analysis of HCRTR2, GNB3, and ADH4 Gene Polymorphisms in a Southeastern European Caucasian Cluster Headache Population. Journal of molecular neuroscience : MN 13 31768945
2016 Novel CD200 homologues iSEC1 and iSEC2 are gastrointestinal secretory cell-specific ligands of inhibitory receptor CD200R. Scientific reports 13 27819346
2007 The 1246G-->A polymorphism of the HCRTR2 gene is not associated with migraine. Cephalalgia : an international journal of headache 13 17645762
2023 Jingfang Granule alleviates bleomycin-induced acute lung injury via CD200-CD200R immunoregulatory pathway. Journal of ethnopharmacology 12 37011735
2022 Altered expression of the immunoregulatory ligand-receptor pair CD200-CD200R1 in the brain of Parkinson's disease patients. NPJ Parkinson's disease 12 35296683
2021 The CD200/CD200R mechanism in mesenchymal stem cells' regulation of dendritic cells. American journal of translational research 12 34540085
2021 Signaling by the inhibitory receptor CD200R is rewired by type I interferon. Science signaling 12 34637328
2021 MicroRNA-129-5p-regulated microglial expression of the surface receptor CD200R1 controls neuroinflammation. The Journal of biological chemistry 12 34952004
2020 Parkinsonian neurotoxicants impair the anti-inflammatory response induced by IL4 in glial cells: involvement of the CD200-CD200R1 ligand-receptor pair. Scientific reports 12 32606391
2018 A Synthetic Cross-Species CD200R1 Agonist Suppresses Inflammatory Immune Responses In Vivo. Molecular therapy. Nucleic acids 12 30195773