Affinage

CD200

OX-2 membrane glycoprotein · UniProt P41217

Length
278 aa
Mass
31.3 kDa
Annotated
2026-06-09
100 papers in source corpus 25 papers cited in narrative 26 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

CD200 (OX-2) is a cell-surface immunoglobulin-superfamily glycoprotein that functions as the ligand for the inhibitory receptor CD200R, delivering a tonic immunosuppressive signal that restrains myeloid and lymphoid effector activity (PMID:12960329, PMID:16081818). CD200 engages CD200R through their N-terminal Ig-like domains in an immunological synapse-like cell-cell contact, a binding mode resolved at atomic resolution; the structurally related activating receptors (CD200RLa and family members that pair with DAP12) fail to bind CD200, defining a paired inhibitory/activatory receptor architecture in which CD200 is the exclusive CD200R ligand (PMID:15162439, PMID:16081818, PMID:23602662, PMID:15471863). Receptor engagement triggers tyrosine phosphorylation of the CD200R cytoplasmic NPLY motif, which recruits the PTB-domain adaptor Dok2 (with higher affinity than Dok1), and Dok2 in turn recruits RasGAP to suppress Ras/MAPK (ERK, JNK, p38) signaling—a mechanism distinct from ITIM/SHP-based inhibition; Dok1 acting through CrkL negatively tunes this Dok2-RasGAP output (PMID:15557172, PMID:19786546, PMID:21078907). The downstream consequence is suppression of mast cell degranulation and cytokine production, dampening of NK, ILC2, and macrophage activation, and inhibition of macrophage phagocytosis of tumor cells, the latter mediated by the kinase Csk rather than SHP-1/SHP-2 (PMID:15557172, PMID:33953190, PMID:40461553). Beyond classical receptor signaling, CD200 generates a biologically active soluble ectodomain via metalloproteinase shedding (ADAM28, MMP3, MMP11) that binds and phosphorylates CD200R at a distance, and γ-secretase cleavage liberates the CD200 cytoplasmic tail, which translocates to the nucleus, binds DNA, and alters expression of proliferation-associated transcription factors (PMID:27111430, PMID:36074574, PMID:29698858). CD200 also acts developmentally to promote macrophage fusion and osteoclastogenesis through RANK-downstream NF-κB/MAPK signaling, and in the CNS its neuronal expression restrains microglial activation (PMID:17726108, PMID:6147390). This inhibitory axis is co-opted in disease: tumors exploit it to suppress NK killing, expand MDSCs, and impair T-cell metabolism and cytokine output (PMID:36074574, PMID:32581043, PMID:34326171).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2003 High

    Establishing the receptor and its expression pattern was the prerequisite for any mechanism: it defined CD200R as the myeloid-restricted partner of CD200 and revealed a paired inhibitory/activatory receptor family.

    Evidence qRT-PCR, novel monoclonal antibodies, and protein binding assays across human and mouse

    PMID:12960329

    Open questions at the time
    • Did not resolve the molecular signaling cascade downstream of CD200R
    • Function of DAP12-pairing CD200R-like receptors left undefined
  2. 2004 High

    Mapping the binding determinants showed the interaction occurs via the N-terminal Ig domains, establishing the structural basis and an evolutionary origin from a homotypic interaction.

    Evidence Site-directed mutagenesis with recombinant protein binding assays

    PMID:15162439

    Open questions at the time
    • Atomic-resolution interface not yet determined
    • Affinity not quantified
  3. 2004 High

    Dissecting CD200R signaling answered how an Ig-domain ligand inhibits effector cells: it works through Dok adaptors and RasGAP to suppress Ras/MAPK, a non-ITIM mechanism, with a functional readout in mast cells.

    Evidence Co-IP, phosphorylation assays, and mast cell degranulation/cytokine assays in mouse BMMCs

    PMID:15557172

    Open questions at the time
    • Relative contributions of Dok1 vs Dok2 not yet resolved
    • Demonstrated in mouse mast cells only
  4. 2005 High

    Quantifying binding established CD200 as the exclusive ligand of inhibitory CD200R with micromolar affinity and no binding to the activating CD200R-related receptors, ruling out ligand promiscuity.

    Evidence Direct binding assays with monomeric/dimeric fusion proteins and cell-surface binding

    PMID:16081818

    Open questions at the time
    • Endogenous ligand(s) of the activating receptors not identified
    • Physiological consequence of low (~4 µM) affinity unaddressed
  5. 2009 High

    Defining the human cytoplasmic motif resolved adaptor hierarchy: the NPLY motif recruits Dok2 (not Dok1 or SHIP) as the essential effector linking to RasGAP, confirmed by loss-of-function.

    Evidence NPLY mutational analysis, affinity measurements, and RNAi knockdown with functional inhibition readouts in U937 cells

    PMID:19786546

    Open questions at the time
    • Identity of the kinase phosphorylating NPLY unspecified
    • Did not address signaling in primary human myeloid cells
  6. 2010 High

    Refining the adaptor network showed Dok1 acts as a negative regulator of Dok2-mediated signaling via CrkL, explaining how inhibitory output is tuned.

    Evidence Reciprocal Co-IP and RNAi knockdown with phosphorylation readouts in U937 cells

    PMID:21078907

    Open questions at the time
    • Physiological setting where Dok1 tuning matters not established
    • Single cell-line system
  7. 2013 High

    Crystal structures gave the definitive interface and explained, at the residue level, why the activating receptor cannot bind CD200 and how herpesviruses mimic the host ligand.

    Evidence X-ray crystallography of CD200R, CD200RLa, and the CD200R-CD200 complex

    PMID:23602662

    Open questions at the time
    • Does not address signaling dynamics or receptor clustering in cells
    • Viral mimic functional consequences not tested here
  8. 2007 High

    A genetic KO revealed a developmental, non-immunosuppressive role: CD200 promotes macrophage fusion and osteoclastogenesis through RANK-downstream signaling, broadening CD200 function beyond inhibition.

    Evidence CD200-/- mice, recombinant protein rescue, shRNA knockdown, and bone histomorphometry with NF-κB/MAPK analysis

    PMID:17726108

    Open questions at the time
    • How a normally inhibitory ligand drives a positive fusion signal mechanistically unresolved
    • Direct CD200R-to-RANK signaling crosstalk not defined
  9. 1984 Medium

    Early localization established neuronal-specific surface expression of CD200 in the CNS, later providing the anatomical basis for its role restraining microglia.

    Evidence Immunoperoxidase and double-immunofluorescence of rat brain and cerebellar cultures with cell-type markers

    PMID:6147390

    Open questions at the time
    • No receptor or mechanism identified at the time
    • Functional consequence of neuronal expression not tested
  10. 1997 Medium

    An early functional study placed CD200 in T-cell costimulation through a non-B7/CD28, non-cytokine-inducing pathway, distinguishing it from classical costimulatory ligands.

    Evidence CHO transfectants, T-cell proliferation and cytokine assays, CTLA4-Ig blocking

    PMID:9144466

    Open questions at the time
    • Receptor mediating this costimulation not identified
    • Apparent costimulation contrasts with later inhibitory model and was not reconciled
  11. 2004 Medium

    Characterization of an activating CD200R-like receptor (CD200RL3) that pairs with DAP12 fleshed out the paired-receptor family but showed it does not bind CD200.

    Evidence Microarray screen, splice variant and DAP12-association analysis

    PMID:15471863

    Open questions at the time
    • Endogenous ligand of the activating receptor unidentified
    • In vivo function not established
  12. 2015 Medium

    A mechanism for CNS immunosuppression was identified: CD200-Fc downregulates macrophage TLR4 to restrain phagocytosis and improve myelination after ischemia.

    Evidence Primary phagocytosis assays and an in vivo white matter ischemia model with TLR4 and myelination readouts

    PMID:26661156

    Open questions at the time
    • Link between CD200R signaling and TLR4 downregulation mechanistically incomplete
    • CD200-Fc may not recapitulate membrane-bound ligand
  13. 2016 Medium

    Demonstrating that shed soluble CD200 is functionally active established a paracrine mode: the ectodomain alone binds and phosphorylates CD200R, with ADAM28 implicated as a sheddase.

    Evidence Domain-specific Western blot, flow cytometry, ADAM28 silencing, and CD200R1-HEK293 functional assay with PMA stimulation

    PMID:27111430

    Open questions at the time
    • Full set of sheddases not defined
    • Physiological abundance and reach of soluble CD200 in vivo unquantified
  14. 2018 Medium

    An intracellular signaling role was uncovered: γ-secretase releases the CD200 cytoplasmic tail, which enters the nucleus, binds DNA, and reprograms proliferation-associated transcription factors.

    Evidence γ-secretase inhibitor experiments, ChIP-seq, nuclear translocation assays, and CD200C-tail transfection in HEK293

    PMID:29698858

    Open questions at the time
    • Direct DNA-binding mode of a non-canonical tail fragment not structurally defined
    • Physiological relevance versus overexpression artifact in HEK293 untested
  15. 2014 Medium

    Pathway epistasis positioned PPAR-γ upstream of CD200-CD200R1, explaining how an anti-inflammatory lipid ligand maintains the axis to protect neurons.

    Evidence Neuron-microglia cocultures with 15d-PGJ2 treatment, LPS/IFN-γ stimulation, and CD200-CD200R1 blocking antibodies

    PMID:24639050

    Open questions at the time
    • Direct transcriptional regulation of CD200/CD200R by PPAR-γ not demonstrated
    • In vivo confirmation lacking
  16. 2021 Medium

    ILC2 work extended the inhibitory axis to type 2 immunity, showing CD200R engagement suppresses ILC2 activation via canonical and non-canonical NF-κB, with therapeutic effect on airway hyperreactivity.

    Evidence In vitro ILC2 activation assays, NF-κB analysis, and humanized mouse asthma models

    PMID:33953190

    Open questions at the time
    • How CD200R-Dok2-RasGAP signaling intersects NF-κB not reconciled
    • Single-lab models
  17. 2022 Medium

    A tumor-immune-evasion mechanism was dissected: MMP3/MMP11-shed soluble CD200 binds NK-cell CD200R, suppressing MAPK and, via PPARγ-Fas/FADD/FasL, driving activation-induced NK apoptosis.

    Evidence Sheddase identification in basal cell carcinoma, NK ERK/PPARγ/Fas pathway analysis, and CD200 blockade rescue

    PMID:36074574

    Open questions at the time
    • Relative contributions of distinct sheddases across tissues unresolved
    • Generalizability beyond BCC NK cells untested
  18. 2025 High

    Comparing inhibitory phagocytosis checkpoints showed CD200R1 uses the kinase Csk rather than SHP-1/SHP-2, making CD200-CD200R1 a mechanistically distinct, additive target alongside SIRPα-CD47.

    Evidence CRISPR/genetic KO of CD200R1 and CD200, macrophage phagocytosis assays, Csk vs SHP signaling analysis, and combined-blockade tumor models

    PMID:40461553

    Open questions at the time
    • How Csk integrates with the Dok2-RasGAP module not delineated
    • Clinical translatability of combined blockade unestablished
  19. 2021 Medium

    Cancer-context studies established CD200 as an immunosuppressive driver across tumor types—expanding MDSCs, impairing T-cell metabolism/cytokine output, and inducing cathepsin K in myeloid cells to promote metastasis—and validated CD200R-CD28 switch receptors as a therapeutic conversion strategy.

    Evidence Recombinant CD200 and isogenic models, scRNA-seq/spatial transcriptomics, T-cell metabolic and CAR-T switch-receptor assays, and in vivo blockade/xenograft models

    PMID:32581043 PMID:34183355 PMID:34326171 PMID:37616575 PMID:37903272 PMID:38396288

    Open questions at the time
    • Cell-type-specific downstream effectors (e.g., Ctsk induction) mechanistically incomplete
    • Many findings are single-lab disease-context observations not cross-validated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple modes of CD200 action—membrane CD200R-Dok2-RasGAP signaling, Csk-dependent phagocytosis control, soluble-ectodomain paracrine signaling, and γ-secretase-released nuclear tail—are integrated within a single cell, and how context dictates which mode dominates, remains unresolved.
  • No unified model linking forward CD200R signaling and reverse intracellular CD200 signaling
  • Stoichiometry and in vivo relevance of soluble vs membrane CD200 unquantified
  • Effector divergence (RasGAP vs Csk vs NF-κB) across cell types not mechanistically reconciled

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0098772 molecular function regulator activity 3 GO:0003677 DNA binding 1
Localization
GO:0005886 plasma membrane 3 GO:0005576 extracellular region 2 GO:0005634 nucleus 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 4 R-HSA-1643685 Disease 3
Partners
CD200R1CRKLCSKDOK1DOK2RASA1

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 CD200 (OX-2) interacts with CD200R through their N-terminal immunoglobulin-like domains; both human and mouse CD200R were characterized, showing expression restricted predominantly to myeloid cells (macrophages, neutrophils, monocytes, mast cells) and some T lymphocytes. CD200R-related genes (CD200RLa, CD200RLb) pair with the activatory adaptor DAP12 but do not bind CD200, indicating a paired inhibitory/activatory receptor family architecture. Quantitative RT-PCR, novel monoclonal antibodies, protein binding assays, flow cytometry Journal of immunology High 12960329
2004 CD200 and CD200R interact through their N-terminal Ig-like domains (GFCC' face), spanning four Ig superfamily domains across the cell-cell interface. Site-directed mutagenesis of CD200R confirmed that binding involves its N-terminal domain, mirroring CD200's binding mode, suggesting the interaction evolved from a homotypic interaction. Site-directed mutagenesis, recombinant protein binding assays European journal of immunology High 15162439
2004 Engagement of CD200R by CD200 on mouse bone marrow-derived mast cells leads to tyrosine phosphorylation of CD200R, recruitment of adaptor proteins Dok1 and Dok2, subsequent binding of SHIP to phosphorylated Dok1, and recruitment of RasGAP by both Dok1 and Dok2, resulting in inhibition of the Ras/MAPK pathway (ERK, JNK, p38) and suppression of mast cell degranulation and cytokine production. Co-immunoprecipitation, phosphorylation assays, mast cell degranulation assays, cytokine production assays Journal of immunology High 15557172
2005 Recombinant mouse CD200 binds the inhibitory receptor CD200R with a Kd of ~4 µM but gives negligible binding to activating receptors CD200RLa, CD200RLb, CD200RLc, and CD200RLe, whether assessed as monomeric or dimeric fusion proteins or at the cell surface. This establishes that CD200 is the exclusive ligand for CD200R but not for the activating CD200R-related receptors. Direct protein binding assays using monomeric and dimeric recombinant fusion proteins, cell surface binding assays Journal of immunology High 16081818
2009 In human myeloid cells (U937), CD200R inhibitory signaling is mediated via the PTB domain-binding NPLY motif in the cytoplasmic region. Dok2 binds directly to the phosphorylated NPLY motif with ~10-fold higher affinity (Kd ~1 µM) than Dok1, is phosphorylated upon CD200R engagement, and recruits RasGAP. Knockdown of Dok2 and RasGAP by RNAi abolished CD200R-mediated inhibition, while knockdown of Dok1 and SHIP did not affect inhibition. Mutational analysis of NPLY motif, direct binding affinity measurements, RNA interference knockdown, functional inhibition assays Journal of immunology High 19786546
2010 CD200R-induced phosphorylation of Dok2 precedes that of Dok1; Dok2 recruits RasGAP and the adaptor Nck, while Dok1 recruits CrkL (but not CrkL's relative Crk, which binds Dok1 constitutively). Knockdown of Dok1 or CrkL increases Dok2 phosphorylation and RasGAP recruitment to Dok2, indicating that Dok1 negatively regulates Dok2-mediated CD200R signaling through CrkL recruitment. Co-immunoprecipitation, RNAi knockdown, phosphorylation assays in U937 cells Journal of immunology High 21078907
2013 X-ray crystallography structures of CD200R, the activating receptor CD200RLa, and a CD200R-CD200 complex were solved. Both proteins interact through their NH2-terminal Ig domains, consistent with immunological synapse-like cell-cell interactions. The failure of the activating receptor CD200RLa to bind CD200 was mapped to subtle changes around the binding interface. CD200 has been acquired by herpesviruses as a mimic of this host interaction. X-ray crystallography, structural analysis of CD200-CD200R complex Structure High 23602662
2007 CD200 is strongly expressed in macrophages at the onset of fusion (not in non-fusing myeloid cells), while CD200R is expressed on osteoclasts and CD4+ T cells. CD200-/- mice have fewer osteoclasts and accumulate more bone. Soluble recombinant CD200 extracellular domain rescued fusion of CD200-/- macrophages and restored downstream RANK signaling (NF-κB and MAP kinase). Conversely, soluble CD200R extracellular domain or shRNA silencing of CD200R prevented macrophage fusion and osteoclastogenesis. CD200-/- mouse model, recombinant protein rescue experiments, shRNA knockdown, signaling pathway analysis (NF-κB, MAPK), bone histomorphometry Proceedings of the National Academy of Sciences High 17726108
1984 OX-2 (CD200) antigen is localized to the surfaces of neurons in rat brain (all tetanus toxin-positive cells are OX-2-positive) and is absent from GFAP-positive astrocytes, establishing neuronal-specific surface expression in the CNS. Indirect immunoperoxidase staining, double-immunofluorescence of cerebellar interneuron cultures with OX-2 antibody and tetanus toxin Journal of neurochemistry Medium 6147390
1997 OX-2 (CD200) expressed on CHO transfectants costimulates murine CD4+ T cell proliferation in both antigen-independent (anti-CD3) and antigen-dependent (peptide) fashions through a non-B7/CD28 pathway. Unlike B7-1, OX-2-mediated costimulation does not induce IL-2, IL-4, or IFN-γ and is not inhibited by CTLA4-Ig, but is blocked by anti-OX-2 mAb. CHO cell transfection expressing OX-2, T cell proliferation assays, cytokine measurement (IL-2, IL-4, IFN-γ), CTLA4-Ig blocking experiments Journal of immunology Medium 9144466
2004 CD200 receptor-like family member CD200RL3 (identified by microarray during helminth infection) is highly expressed on basophils and mast cells, pairs with DAP12 for cell surface expression and signaling (requiring the second Ig-like domain encoded by exon 4 and specific cytoplasmic domain splice variants for efficient DAP12 pairing), and functions as an activating receptor, in contrast to inhibitory CD200R. Microarray screen, splice variant characterization, DAP12 association assay, cell surface expression analysis Journal of Biological Chemistry Medium 15471863
2016 Shed soluble CD200 (sCD200) retains a biologically active extracellular domain capable of binding to and phosphorylating CD200R1 on CD200R1-expressing HEK293 cells, but lacks the cytoplasmic domain of CD200. CD200 ectodomain shedding is enhanced by PMA stimulation and partially mediated by ADAM28 (and additional metalloproteinases), generating a functionally active immunosuppressive species. Western blot with domain-specific antibodies, flow cytometry, ADAM28 silencing, CD200R1-expressing HEK293 functional assay, PMA stimulation PloS one Medium 27111430
2022 In basal cell carcinoma, CD200 undergoes ectodomain shedding by metalloproteinases MMP3 and MMP11, releasing biologically active soluble CD200 into the tumor microenvironment. Soluble CD200 binds CD200R on NK cells to suppress MAPK pathway signaling, blocking IFN-γ release and direct tumor cell killing. Reduced ERK phosphorylation relieves negative regulation of PPARγ-regulated transcription, leading to membrane accumulation of Fas/FADD and FasL, causing activation-induced NK cell apoptosis. MMP3/MMP11 identification in situ, NK cell signaling assays (ERK phosphorylation), PPARγ pathway analysis, Fas/FADD/FasL expression analysis, CD200 blockade rescue experiments Journal of Clinical Investigation Medium 36074574
2018 Cell membrane-bound CD200 signals not only extracellularly via CD200R but also intracellularly: γ-secretase cleavage releases the CD200 cytoplasmic tail (CD200C-tail) which translocates to the nucleus, binds DNA (identified by ChIP-seq), and alters expression of transcription factors associated with cell proliferation regulation. CD200C-tail transfection in CD200-negative HEK293 cells reproduced these gene expression changes. γ-secretase inhibitor experiments, chromatin immunoprecipitation followed by sequencing (ChIP-seq), nuclear translocation assays, CD200C-tail transfection in HEK293 cells, siRNA knockdown of POTEA Leukemia research Medium 29698858
2021 Mouse ILC2s express CD200R, and CD200R engagement inhibits ILC2 activation, proliferation, and type 2 cytokine production. Mechanistically, CD200R engagement inhibits both canonical and non-canonical NF-κB signaling pathways in activated ILC2s. Human ILC2s also express CD200R, and CD200R engagement ameliorated airway hyperreactivity in humanized mouse models. Flow cytometry, in vitro ILC2 activation assays, NF-κB pathway analysis, in vivo asthma models (preventative and therapeutic), humanized mouse models Nature communications Medium 33953190
2015 CD200-Fc treatment downregulates toll-like receptor 4 (TLR4) expression in macrophages, restraining macrophage phagocytosis of oligodendrocyte precursor cells. In vivo, CD200-Fc treatment after white matter ischemia suppressed TLR4 expression in peripherally circulating macrophages and improved myelination. Primary cell culture phagocytosis assays, in vivo white matter ischemia model with endothelin-1, TLR4 expression analysis, myelination assessment Journal of cerebral blood flow and metabolism Medium 26661156
2025 CD200R1 inhibits macrophage phagocytosis of tumor cells in a mechanistically distinct manner from SIRPα: unlike SIRPα which uses phosphatases SHP-1 and SHP-2, CD200R1 mediates its inhibitory effect via the kinase Csk. Blocking or removing CD200R1 from macrophages, or CD200 from tumor cells, increases phagocytosis and suppresses tumor growth. Combined CD200R1-CD200 and SIRPα-CD47 blockade further boosts phagocytosis compared to either blockade alone. CRISPR/genetic KO of CD200R1 and CD200, macrophage phagocytosis assays, signaling pathway analysis (Csk vs SHP-1/SHP-2), tumor growth models, combined blockade experiments Nature communications High 40461553
2014 PPAR-γ activation by its endogenous ligand 15d-PGJ2 prevents CD200R1 downregulation and CD200 upregulation in reactive (LPS/IFN-γ stimulated) glial cells. The neuroprotective and anti-inflammatory effects of 15d-PGJ2 in neuron-microglia cocultures depend on the CD200-CD200R1 interaction, placing PPAR-γ upstream of CD200-CD200R1 in the anti-inflammatory pathway. Mouse primary neuronal and glial cultures, neuron-microglia cocultures, 15d-PGJ2 treatment, LPS/IFN-γ stimulation, CD200-CD200R1 blocking antibodies Glia Medium 24639050
2020 In vitro cytokine-driven expansion and suppressive activity of human MDSCs was enhanced when cocultured with recombinant CD200 protein, and CD200R expression was elevated on CD11b+CD33+HLA-DRlo/- MDSC populations from PDAC patients. In vivo antibody blockade of CD200 reduced intratumoral MDSC percentage and enhanced efficacy of PD-1 checkpoint antibodies. Recombinant CD200 MDSC expansion assays, flow cytometry, in vivo antibody blockade in subcutaneous and KPC-Brca2 mouse models, single-cell RNA sequencing Journal for immunotherapy of cancer Medium 32581043
2021 CD200 expression on AML cells significantly impairs OXPHOS metabolic activity in T cells from healthy donors, representing a mechanism of T cell suppression. CD200+ leukemia in PBMC-humanized mice showed T cells with an abundance of metabolically quiescent CD8+ central and effector memory cells. A CD200R-CD28 switch receptor on CAR T-cells converted CD200-mediated inhibitory signaling into CD28 costimulation, potently enhancing CAR T-cell polyfunctionality, proliferation, cytotoxicity, and metabolism. CyTOF, RNA-sequencing, T cell metabolic assays (OXPHOS), PBMC-humanized mouse models, CD200R-CD28 switch receptor engineering, patient-derived xenograft models Journal for immunotherapy of cancer Medium 34326171
2021 CD200 expression on AML cells impairs cytokine secretion in both innate and adaptive immune cell subsets. Engineered CD200R-CD28 switch receptors on CAR T-cells leverage CD200-CD200R engagement to provide CD28 costimulation, improving CAR T-cell performance, while CD200R knockout was detrimental to CAR T-cell metabolic activity. Isogenic cell line models, in vitro co-culture with immune cells, CAR T-cell engineering, PBMC-humanized xenograft models, metabolic assays Blood Medium 37616575
2021 CD200 expression on AML cells impairs cytokine secretion in both innate and adaptive immune cell subsets. Engineered CD200R-CD28 switch receptors on CAR T-cells leverage CD200-CD200R engagement to provide CD28 costimulation, improving CAR T-cell performance, while CD200R knockout was detrimental to CAR T-cell metabolic activity. Isogenic cell line models, in vitro co-culture with immune cells, CAR T-cell engineering, PBMC-humanized xenograft models, metabolic assays Blood Medium 37616575
2023 CD200-CD200R signaling between amacrine cells and microglia is dysregulated in early diabetic retinopathy (DR). Targeting CD200R attenuates high glucose-induced inflammation and phagocytosis in cultured microglia. In vivo CD200R targeting prevents visual dysfunction, microglia activation, and retinal inflammation in the diabetic mouse. Type I diabetes mouse model, retinal microglial ablation, flow cytometry (engulfment assays), in vitro high glucose microglial culture with CD200R targeting, in vivo CD200R targeting Proceedings of the National Academy of Sciences Medium 37903272
2021 The CD200-CD200R axis promotes squamous cell carcinoma (cSCC) metastasis via induction of cathepsin K (Ctsk) in CD200R+ infiltrating myeloid cells. CD200-CD200R engagement in a coculture system induced Ctsk expression in CD11b+Cd200R+ myeloid cells. Ctsk inhibition, but not MMP inhibition, blocked cSCC cell migration in vitro, and targeted CD200 disruption plus Ctsk pharmacologic inhibition reduced metastasis in vivo. RNA sequencing of sorted infiltrating myeloid cells, CD200-CD200R coculture system, Ctsk inhibition assays, in vitro migration assay, in vivo metastasis model with CD200 tumor cell disruption Cancer research Medium 34183355
2024 CD200+DKK3+ pro-resolving fibroblasts stabilize type 2 innate lymphoid cell (ILC2) phenotype and induce resolution of arthritis via CD200-CD200R1 signaling. Single-cell RNA-sequencing and spatial transcriptomics revealed that pro-resolving CD200+DKK3+ fibroblasts cluster with ILC2s in resolution niches, distinct from pro-inflammatory MMP3+/IL6+ fibroblast clusters. Biopsy-based single-cell RNA-sequencing, spatial transcriptomics, PET imaging of FAP, functional coculture assays, in vivo experimental arthritis models Nature immunology Medium 38396288
2009 In rat vascular endothelium, CD200 expression is heterogeneous across vascular beds and regulated by LPS (decreased during endotoxemia). Physical binding between CD200 and CD200R is involved in T-cell adhesion to endothelium, but not in macrophage-endothelium interaction. A CD200 agonist peptide can trigger CD200R signaling in macrophages to suppress their adhesion to endothelium. Immunoelectron microscopy, in vivo LPS model, T-cell and macrophage adhesion assays, CD200 agonist peptide treatment Journal of anatomy Low 19166481

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Characterization of the CD200 receptor family in mice and humans and their interactions with CD200. Journal of immunology (Baltimore, Md. : 1950) 368 12960329
2002 CD200 and membrane protein interactions in the control of myeloid cells. Trends in immunology 337 12072366
2008 Decreased expression of CD200 and CD200 receptor in Alzheimer's disease: a potential mechanism leading to chronic inflammation. Experimental neurology 214 18938162
2004 Molecular mechanisms of CD200 inhibition of mast cell activation. Journal of immunology (Baltimore, Md. : 1950) 204 15557172
2006 Regulation of myeloid cell function through the CD200 receptor. Journal of immunology (Baltimore, Md. : 1950) 190 16365410
2000 Protein oxidation and degradation during proliferative senescence of human MRC-5 fibroblasts. Free radical biology & medicine 127 10754265
2009 Essential roles for Dok2 and RasGAP in CD200 receptor-mediated regulation of human myeloid cells. Journal of immunology (Baltimore, Md. : 1950) 125 19786546
2007 Monoclonal antibody-mediated CD200 receptor signaling suppresses macrophage activation and tissue damage in experimental autoimmune uveoretinitis. The American journal of pathology 110 17600119
2009 Expression of the inhibitory CD200 receptor is associated with alternative macrophage activation. Journal of innate immunity 101 20375636
2007 CD200: a putative therapeutic target in cancer. Biochemical and biophysical research communications 100 18060862
1984 Localisation of the MRC OX-2 glycoprotein on the surfaces of neurones. Journal of neurochemistry 99 6147390
2018 Role of the CD200-CD200R Axis During Homeostasis and Neuroinflammation. Neuroscience 95 30367946
2021 CD200:CD200R Interactions and Their Importance in Immunoregulation. International journal of molecular sciences 94 33562512
2006 Is the CD200/CD200 receptor interaction more than just a myeloid cell inhibitory signal? Critical reviews in immunology 91 16928187
2005 CD200 and its receptors as targets for immunoregulation. Current opinion in investigational drugs (London, England : 2000) 90 15912961
2009 Biochemical and behavioural characterization of EMPA, a novel high-affinity, selective antagonist for the OX(2) receptor. British journal of pharmacology 76 19751316
2020 CD200 promotes immunosuppression in the pancreatic tumor microenvironment. Journal for immunotherapy of cancer 73 32581043
2014 The CD200-CD200R1 inhibitory signaling pathway: immune regulation and host-pathogen interactions. Advances in immunology 73 24388216
2011 CD200-CD200R signaling suppresses anti-tumor responses independently of CD200 expression on the tumor. Oncogene 64 22020332
2014 CD200 in CNS tumor-induced immunosuppression: the role for CD200 pathway blockade in targeted immunotherapy. Journal for immunotherapy of cancer 63 25598973
2012 Characterization and functionality of the CD200-CD200R system during mesenchymal stromal cell interactions with T-lymphocytes. Immunology letters 63 22575528
2004 The CD200 and CD200 receptor cell surface proteins interact through their N-terminal immunoglobulin-like domains. European journal of immunology 63 15162439
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 CD200, a "no danger" signal for hair follicles. Journal of dermatological science 60 16386879
2010 Downstream of tyrosine kinase 1 and 2 play opposing roles in CD200 receptor signaling. Journal of immunology (Baltimore, Md. : 1950) 59 21078907
2020 CD200-CD200R Pathway in the Regulation of Tumor Immune Microenvironment and Immunotherapy. Advances in experimental medicine and biology 56 32030689
2013 Structures of CD200/CD200 receptor family and implications for topology, regulation, and evolution. Structure (London, England : 1993) 56 23602662
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
2005 Recombinant CD200 protein does not bind activating proteins closely related to CD200 receptor. Journal of immunology (Baltimore, Md. : 1950) 55 16081818
2024 CD200+ fibroblasts form a pro-resolving mesenchymal network in arthritis. Nature immunology 54 38396288
2010 CD200 (OX-2 membrane glycoprotein) expression in b cell-derived neoplasms. American journal of clinical pathology 54 20959655
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
2004 CD200 receptor family members represent novel DAP12-associated activating receptors on basophils and mast cells. The Journal of biological chemistry 51 15471863
2020 CD200 expression marks leukemia stem cells in human AML. Blood advances 49 33147339
2010 The role of CD200 in immunity to B cell lymphoma. Journal of leukocyte biology 48 20442224
2014 CD200R1 and CD200 expression are regulated by PPAR-γ in activated glial cells. Glia 47 24639050
2021 CD200-CD200R immune checkpoint engagement regulates ILC2 effector function and ameliorates lung inflammation in asthma. Nature communications 46 33953190
2009 Endothelial CD200 is heterogeneously distributed, regulated and involved in immune cell-endothelium interactions. Journal of anatomy 45 19166481
2019 CD200-CD200R1 inhibitory signaling prevents spontaneous bacterial infection and promotes resolution of neuroinflammation and recovery after stroke. Journal of neuroinflammation 41 30777093
2015 CD200 restrains macrophage attack on oligodendrocyte precursors via toll-like receptor 4 downregulation. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 41 26661156
2018 CD200-, CX3CL1-, and TREM2-mediated neuron-microglia interactions and their involvements in Alzheimer's disease. Reviews in the neurosciences 40 29729150
2015 Upregulation of CD200 is associated with regulatory T cell expansion and disease progression in multiple myeloma. Hematological oncology 40 26033514
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
2022 CD200 ectodomain shedding into the tumor microenvironment leads to NK cell dysfunction and apoptosis. The Journal of clinical investigation 38 36074574
2017 Reduced CD200 expression is associated with altered Th1/Th2 cytokine production in placental trophoblasts from preeclampsia. American journal of reproductive immunology (New York, N.Y. : 1989) 38 28940677
2016 Analysis of the Impact of CD200 on Phagocytosis. Molecular neurobiology 38 27830533
2011 CD200 (OX-2 membrane glycoprotein) is expressed by follicular T helper cells and in angioimmunoblastic T-cell lymphoma. The American journal of surgical pathology 38 21164290
2002 Binding and invasion of HeLa and MRC-5 cells by Streptococcus agalactiae. Microbiology (Reading, England) 36 12480896
2018 CD200 modulates spinal cord injury neuroinflammation and outcome through CD200R1. Brain, behavior, and immunity 35 29870752
2013 CD200-expressing human basal cell carcinoma cells initiate tumor growth. Proceedings of the National Academy of Sciences of the United States of America 34 23292936
2011 CD200 receptor and macrophage function in the intestine. Immunobiology 34 22204814
2021 Overexpression of CD200 is a Stem Cell-Specific Mechanism of Immune Evasion in AML. Journal for immunotherapy of cancer 33 34326171
2019 CD200 dysfunction in neuron contributes to synaptic deficits and cognitive impairment. Biochemical and biophysical research communications 31 31277944
2019 CD200 Checkpoint Reversal: A Novel Approach to Immunotherapy. Clinical cancer research : an official journal of the American Association for Cancer Research 30 31624103
2013 CD200 upregulation in vascular endothelium surrounding cutaneous squamous cell carcinoma. JAMA dermatology 30 23560298
2003 Characterization of human cd200 glycoprotein receptor gene located on chromosome 3q12-13. Gene 30 12853143
2017 CD200 Expression in Neuroendocrine Neoplasms. American journal of clinical pathology 29 28821198
1997 MRC OX-2 defines a novel T cell costimulatory pathway. Journal of immunology (Baltimore, Md. : 1950) 29 9144466
2019 Circular RNA ANKRD36 attends to lipopolysaccharide-aroused MRC-5 cell injury via regulating microRNA-31-3p. BioFactors (Oxford, England) 28 31793082
2023 CD200+ cytotoxic T lymphocytes in the tumor microenvironment are crucial for efficacious anti-PD-1/PD-L1 therapy. Science translational medicine 27 36652534
2018 CD200 is a useful marker in the diagnosis of chronic lymphocytic leukemia. Cytometry. Part B, Clinical cytometry 27 30328261
2010 Distribution and expression of CD200 in the rat respiratory system under normal and endotoxin-induced pathological conditions. Journal of anatomy 27 20070425
2021 The CD200-CD200R Axis Promotes Squamous Cell Carcinoma Metastasis via Regulation of Cathepsin K. Cancer research 26 34183355
2020 CD200 and Chronic Lymphocytic Leukemia: Biological and Clinical Relevance. Frontiers in oncology 26 33324560
2019 CD200-CD200R signaling and diseases: a potential therapeutic target? International journal of physiology, pathophysiology and pharmacology 26 31993106
2017 Orexin OX2 Receptor Antagonists as Sleep Aids. Current topics in behavioral neurosciences 25 27909987
2019 Differential Expression of CD43, CD81, and CD200 in Classic Versus Variant Hairy Cell Leukemia. Cytometry. Part B, Clinical cytometry 24 31077558
2012 CD200 expression in B-cell chronic lymphoproliferative disorders. Journal of investigative medicine : the official publication of the American Federation for Clinical Research 23 22064604
2023 Cancel cancer: The immunotherapeutic potential of CD200/CD200R blockade. Frontiers in oncology 22 36756156
2020 Estrogen-regulated CD200 inhibits macrophage phagocytosis in endometriosis. Journal of reproductive immunology 22 32014721
2020 CD200 is overexpressed in neuroblastoma and regulates tumor immune microenvironment. Cancer immunology, immunotherapy : CII 22 32514618
2016 Over-Expression of CD200 Protects Mice from Dextran Sodium Sulfate Induced Colitis. PloS one 22 26841120
2016 Characterization of CD200 Ectodomain Shedding. PloS one 22 27111430
2014 Aberrant CD200/CD200R1 expression and its potential role in Th17 cell differentiation, chemotaxis and osteoclastogenesis in rheumatoid arthritis. Rheumatology (Oxford, England) 22 25261692
2013 Dissection of agonistic and blocking effects of CD200 receptor antibodies. PloS one 21 23691022
2023 The immunoregulatory protein CD200 as a potentially lucrative yet elusive target for cancer therapy. Oncotarget 20 36738455
2023 CD200/CD200R: Bidirectional Role in Cancer Progression and Immunotherapy. Biomedicines 20 38137547
2020 Determination of CD43 and CD200 surface expression improves accuracy of B-cell lymphoma immunophenotyping. Cytometry. Part B, Clinical cytometry 20 32716606
2021 Neuronal CD200 Signaling Is Protective in the Acute Phase of Ischemic Stroke. Stroke 19 34353112
2016 Low expression of CD200 predicts shorter time-to-treatment in chronic lymphocytic leukemia. Oncotarget 19 26910908
2015 Lung CD200 Receptor Activation Abrogates Airway Hyperresponsiveness in Experimental Asthma. American journal of respiratory cell and molecular biology 19 25569356
2024 Exploiting the CD200-CD200R immune checkpoint axis in multiple myeloma to enhance CAR T-cell therapy. Blood 18 37616575
2017 Checkpoint blockade in solid tumors and B-cell malignancies, with special consideration of the role of CD200. Cancer management and research 18 29180896
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
2022 Knockdown of FBLN2 suppresses TGF-β1-induced MRC-5 cell migration and fibrosis by downregulating VTN. Tissue & cell 17 36608640
2018 Forced expression of CD200 improves the differentiation capability and immunoregulatory functions of mesenchymal stromal cells. Biotechnology letters 17 29740779
2018 CD200 Expression Marks a Population of Quiescent Limbal Epithelial Stem Cells with Holoclone Forming Ability. Stem cells (Dayton, Ohio) 17 30157305
2017 Th1/Th2 PB balance and CD200 expression of patients with active severe alopecia areata. Experimental and therapeutic medicine 17 28587354
2015 Adhesion of MRC-5 and A549 cells on poly(dimethylsiloxane) surface modified by proteins. Electrophoresis 17 26311334
2023 GAS6 From CD200+ Adipose-Derived Stem Cells Mitigates Colonic Inflammation in a Macrophage-Dependent Manner. Journal of Crohn's & colitis 16 36006655
2015 CD200 receptor restriction of myeloid cell responses antagonizes antiviral immunity and facilitates cytomegalovirus persistence within mucosal tissue. PLoS pathogens 16 25654642
2020 CD200 maintains the region-specific phenotype of microglia in the midbrain and its role in Parkinson's disease. Glia 15 32112601
2018 Cell membrane-bound CD200 signals both via an extracellular domain and following nuclear translocation of a cytoplasmic fragment. Leukemia research 15 29698858
2013 CD200 expression in patients with Multiple Myeloma: another piece of the puzzle. Leukemia research 15 24183830
2017 Role of CD200 in differential diagnosis of mature B-cell neoplasm. International journal of laboratory hematology 14 28422443
2016 Protein crystallization screens developed at the MRC Laboratory of Molecular Biology. Drug discovery today 14 27032894
2012 Effect of CD200 and CD200R1 expression within tissue grafts on increased graft survival in allogeneic recipients. Immunology letters 14 23178470
2025 CD200R1-CD200 checkpoint inhibits phagocytosis differently from SIRPα-CD47 to suppress tumor growth. Nature communications 13 40461553
2023 Emerging Immune Checkpoint Molecules on Cancer Cells: CD24 and CD200. International journal of molecular sciences 13 37894750
2022 Altered expression of the immunoregulatory ligand-receptor pair CD200-CD200R1 in the brain of Parkinson's disease patients. NPJ Parkinson's disease 13 35296683

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