{"gene":"CD200","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":1986,"finding":"CD200 (MRC OX-2) is a member of the immunoglobulin superfamily with a structure resembling an Ig light chain, containing a V-like domain and a C-like domain followed by transmembrane and cytoplasmic sections, encoded by 248 amino acids.","method":"cDNA cloning and sequence analysis","journal":"Biochemical Society symposium","confidence":"High","confidence_rationale":"Tier 1 — direct sequence determination establishing domain architecture","pmids":["2880589"],"is_preprint":false},{"year":1984,"finding":"CD200 (OX-2 antigen) is localized on the surfaces of neurons (all tetanus toxin-positive cells in cerebellar interneurone cultures) but not on GFAP-positive astrocytes, establishing its neuronal membrane localization.","method":"Indirect immunoperoxidase staining and double-immunofluorescence of cerebellar cultures with OX-2 antibody and tetanus toxin","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 2 — direct localization by immunofluorescence with functional cellular context","pmids":["6147390"],"is_preprint":false},{"year":2002,"finding":"CD200 functions as a ligand for a myeloid-restricted receptor (CD200R) and delivers inhibitory signals to myeloid cells; CD200-deficient mice show increased myeloid cell activation upon immunological stimulation.","method":"CD200 knockout mouse model with functional immunological readouts","journal":"Trends in immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic loss-of-function with defined cellular phenotype, widely replicated","pmids":["12072366"],"is_preprint":false},{"year":2004,"finding":"Upon CD200 binding, CD200R is phosphorylated on tyrosine and recruits adaptor proteins Dok1 and Dok2; Dok1 then binds SHIP and both Dok1 and Dok2 recruit RasGAP, which inhibits Ras/MAPK pathways (ERK, JNK, p38), resulting in inhibition of mast cell degranulation and cytokine production.","method":"Biochemical phosphorylation assays, co-immunoprecipitation of Dok1/Dok2/SHIP/RasGAP, functional assays in mouse bone marrow-derived mast cells","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal biochemical methods establishing signaling cascade","pmids":["15557172"],"is_preprint":false},{"year":2009,"finding":"In human myeloid cells, CD200R inhibition is mediated via its NPLY motif; Dok2 binds directly to the phosphorylated NPLY motif with ~10-fold higher affinity than Dok1 (Kd ~1 µM at 37°C), is phosphorylated upon CD200R engagement, and recruits RasGAP. Knockdown of Dok2 and RasGAP (but not Dok1 or SHIP) abolishes CD200R-mediated inhibition.","method":"Mutant receptor expression in U937 cells, direct binding affinity measurements, RNA interference knockdown, functional inhibition assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding measurements, mutagenesis, and RNAi with quantitative functional readouts","pmids":["19786546"],"is_preprint":false},{"year":2002,"finding":"CD200 expressed constitutively on retinal neurons and vascular endothelium regulates retinal microglial activation; CD200-deficient mice show increased microglial numbers and inducible NOS2 expression in microglia at baseline, demonstrating that CD200:CD200R axis controls tonic microglial suppression.","method":"CD200 knockout mouse model, immunohistochemistry for NOS2, microglial counting","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with defined cellular phenotype (NOS2 expression, cell numbers)","pmids":["12414514"],"is_preprint":false},{"year":2003,"finding":"CD200 is a p53-target gene; its expression increases on dendritic cells undergoing apoptosis through both p53-dependent and caspase-dependent pathways, and CD200 expression on apoptotic DCs suppresses proinflammatory cytokine responses to self-antigens and is required for UVB-mediated tolerance.","method":"p53 pathway analysis, caspase inhibitor experiments, in vitro cytokine assays, in vivo UVB tolerance model","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 — genetic/pharmacological pathway dissection with functional readouts in single study","pmids":["14644999"],"is_preprint":false},{"year":2007,"finding":"CD200 engagement of CD200R at the initiation of macrophage fusion regulates further differentiation to osteoclasts; CD200-deficient mice have fewer osteoclasts and more bone, and a soluble CD200 extracellular domain rescues fusion and RANK-downstream NF-κB and MAP kinase signaling in CD200-/- macrophages.","method":"CD200 knockout mouse model, recombinant soluble CD200/CD200R proteins, shRNA silencing of CD200R, NF-κB and MAPK pathway analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — reconstitution with recombinant protein, genetic KO, shRNA, and signaling pathway analysis","pmids":["17726108"],"is_preprint":false},{"year":2004,"finding":"CD200 receptor-like 3 (a CD200R family member) associates with the activating adaptor DAP12 at the cell surface; the second Ig-like domain (exon 4) is required for cell surface expression and DAP12 recruitment, and splice variants generate unique cytoplasmic domains contributing to DAP12 pairing.","method":"Microarray screen, splice variant characterization, functional surface expression assays in basophils and mast cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — domain mapping with functional surface expression readouts","pmids":["15471863"],"is_preprint":false},{"year":2009,"finding":"Endothelial CD200 mediates T-cell adhesion to endothelium through physical CD200-CD200R binding; a synthetic CD200 agonist peptide can trigger CD200R signaling in macrophages to suppress their adhesion to endothelium. Endothelial CD200 expression is differentially regulated by LPS in different vascular beds.","method":"Functional adhesion assays, antibody blocking, synthetic peptide agonist treatment, in vivo and in vitro LPS stimulation","journal":"Journal of anatomy","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional adhesion assay with antibody blocking and peptide agonist","pmids":["19166481"],"is_preprint":false},{"year":2011,"finding":"Rat cytomegalovirus encodes a CD200 orthologue (e127) that is expressed at the cell surface on infected cells and binds the host CD200R with the same affinity as the host CD200 protein, acting as a viral mimic to potentially downregulate immune responses.","method":"Cell surface expression assays, binding affinity measurements of e127 vs. host CD200 for CD200R","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 — direct binding affinity comparison with functional implication","pmids":["21471432"],"is_preprint":false},{"year":2014,"finding":"CD200 can interact with and activate the fibroblast growth factor receptor (FGFR), inducing neuritogenesis and promoting neuronal survival; CD200R abrogates CD200-induced FGFR phosphorylation, and a minimal FGFR-binding motif was identified in the first Ig-like module of CD200 that overlaps with the CD200R binding site.","method":"FGFR phosphorylation assays, neuritogenesis assays in primary neurons, competitive binding with CD200R, motif identification","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 — direct phosphorylation assay and functional neuritogenesis readout, single lab","pmids":["25502296"],"is_preprint":false},{"year":2016,"finding":"CD200 expression is regulated by PPAR-γ in glial cells; the PPAR-γ agonist 15d-PGJ2 prevents CD200 upregulation and CD200R1 downregulation in reactive glia, and CD200-CD200R1 interaction mediates the anti-inflammatory and neuroprotective effects of PPAR-γ agonists in neuron-microglia cocultures.","method":"Primary neuronal and glial cultures, LPS/IFN-γ activation, PPAR-γ agonist treatment, neurotoxicity assays","journal":"Glia","confidence":"Medium","confidence_rationale":"Tier 2-3 — pathway dependence shown by CD200-CD200R1 blocking in functional neuroprotection assay","pmids":["24639050"],"is_preprint":false},{"year":2016,"finding":"CD200 deficiency in microglia leads to increased phagocytic activity associated with increased lysosomal activity and decreased mTOR signaling; inhibiting mTOR with rapamycin increases phagocytosis similarly, indicating that CD200-CD200R signaling regulates lysosomal/mTOR-dependent phagocytosis in microglia.","method":"CD200-deficient mouse microglia isolation, phagocytosis assays, lysosomal activity measurement, mTOR inhibition with rapamycin","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with mechanistic follow-up using pharmacological inhibitor","pmids":["27830533"],"is_preprint":false},{"year":2016,"finding":"CD200-Fc (soluble CD200 fusion protein) downregulates toll-like receptor 4 (TLR4) expression in macrophages, thereby inhibiting macrophage phagocytosis of oligodendrocyte precursor cells; in vivo treatment with CD200-Fc suppressed TLR4 expression in circulating macrophages and improved myelination after white matter ischemia.","method":"Primary cell culture phagocytosis assays, TLR4 blocking, CD200-Fc treatment in endothelin-1 white matter ischemia model","journal":"Journal of cerebral blood flow and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro mechanism (TLR4 downregulation) confirmed in vivo with functional outcome","pmids":["26661156"],"is_preprint":false},{"year":2019,"finding":"Leishmania amazonensis induces CD200 expression in macrophages through phagocytosis-mediated activation of endosomal TLR9/MyD88/TRIF signaling; Leishmania microvesicles containing DNA fragments activate TLR9-dependent CD200 expression, which then inhibits iNOS/NO signaling to promote intracellular parasite survival.","method":"Genetic knockouts/knockdowns of TLR9/MyD88/TRIF, microvesicle isolation, iNOS/NO pathway analysis, in vivo infection model","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic loss-of-function experiments establishing pathway order with functional outcome","pmids":["31092731"],"is_preprint":false},{"year":2022,"finding":"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 signaling, blocking IFN-γ release and direct killing, and reduced ERK phosphorylation activates PPARγ-regulated gene transcription leading to Fas/FADD membrane accumulation and activation-induced NK cell apoptosis.","method":"MMP inhibitor studies, CD200R blocking, MAPK/ERK pathway analysis, PPARγ pathway analysis, Fas/FADD expression assays, NK cell killing assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal mechanistic experiments identifying shedding enzymes, receptor, and downstream signaling cascade","pmids":["36074574"],"is_preprint":false},{"year":2016,"finding":"CD200 undergoes ectodomain shedding (partially mediated by ADAM28) to generate soluble CD200 that retains the functional extracellular domain but lacks the cytoplasmic domain; shed CD200 can bind to and phosphorylate CD200R1 on receptor-expressing cells.","method":"Western blot with extracellular vs. cytoplasmic domain antibodies, ADAM28 silencing, flow cytometry of surface CD200 loss, functional CD200R1 phosphorylation assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical characterization of shed fragment with functional receptor binding/phosphorylation confirmed","pmids":["27111430"],"is_preprint":false},{"year":2021,"finding":"CD200R on ILC2s is inducible, and CD200R engagement inhibits ILC2 activation, proliferation, and type 2 cytokine production by inhibiting both canonical and non-canonical NF-κB signaling pathways.","method":"Flow cytometry of CD200R expression on murine and human ILC2s, CD200R engagement functional assays, NF-κB pathway analysis, in vivo asthma models","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — pathway analysis with in vitro and in vivo functional validation","pmids":["33953190"],"is_preprint":false},{"year":2021,"finding":"CD200 expression on AML cells suppresses OXPHOS metabolic activity in T cells, impairing their effector function; this represents a stem cell-specific immune evasion mechanism.","method":"Isogenic CD200+ vs CD200- cell line models, CyTOF, RNA-sequencing, PBMC-humanized mouse models, metabolic assays","journal":"Journal for immunotherapy of cancer","confidence":"Medium","confidence_rationale":"Tier 2 — isogenic models with mechanistic metabolic readout in multiple experimental systems","pmids":["34326171"],"is_preprint":false},{"year":2021,"finding":"CD200-CD200R1 signaling from pro-resolving CD200+DKK3+ fibroblasts stabilizes type 2 innate lymphoid cell phenotype and induces resolution of arthritis.","method":"Single-cell RNA-sequencing, spatial transcriptomics, CD200-CD200R1 signaling blocking experiments, in vivo arthritis model","journal":"Nature immunology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic/antibody blocking of CD200-CD200R1 with defined cellular phenotypic readout","pmids":["38396288"],"is_preprint":false},{"year":2023,"finding":"CD200-CD200R signaling between amacrine cells and microglia is dysregulated in early diabetic retinopathy; targeting CD200R attenuates high glucose-induced microglial inflammation and phagocytosis in vitro, and CD200R targeting in vivo prevents visual dysfunction and retinal inflammation in diabetic mice.","method":"Microglia ablation, flow cytometry, transcriptomics, CD200R pharmacological targeting in vitro and in vivo diabetic mouse model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 — cell-specific signaling dissection with in vivo pharmacological intervention and functional outcome","pmids":["37903272"],"is_preprint":false},{"year":2021,"finding":"CD200 expression on cSCC tumors induces cathepsin K (Ctsk) expression in CD11B+CD200R+ infiltrating myeloid cells via engagement of the CD200-CD200R axis; Ctsk inhibition (but not MMP inhibition) blocks cSCC cell migration, and CD200 disruption plus Ctsk inhibition reduces metastasis in vivo.","method":"RNA sequencing of tumor-infiltrating myeloid cells, coculture system establishing CD200-CD200R-dependent Ctsk induction, pharmacological Ctsk inhibition, in vivo metastasis model with CD200 knockout","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — coculture mechanistic validation with in vivo genetic and pharmacological confirmation","pmids":["34183355"],"is_preprint":false},{"year":2014,"finding":"RRV vCD200 (viral CD200 orthologue) limits immune responses against RRV at early times post-infection and impacts viral loads in vivo, demonstrating that viral CD200 mimic functionally engages host CD200R to suppress antiviral immunity.","method":"vCD200-deletion mutant RRV in vivo infection of rhesus macaques, viral load measurements, immune response quantification","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo genetic loss-of-function in relevant primate model","pmids":["24991004"],"is_preprint":false}],"current_model":"CD200 is a cell-surface immunoglobulin superfamily glycoprotein expressed broadly on neurons, endothelium, and other cell types that functions as an inhibitory ligand for CD200R on myeloid cells and other immune cells; upon ligation, CD200R is phosphorylated on its NPLY motif, recruiting Dok2 (and Dok1 in mice) which in turn recruits RasGAP to suppress Ras/MAPK signaling, thereby inhibiting myeloid cell activation, degranulation, cytokine production, and phagocytosis, while CD200 can also bind FGFR to promote neurotrophic signaling, and is subject to metalloproteinase-mediated ectodomain shedding (by MMP3/MMP11/ADAM28) that releases biologically active soluble CD200 capable of suppressing NK cells via MAPK/PPARγ-dependent induction of apoptosis."},"narrative":{"teleology":[{"year":1984,"claim":"Establishing that CD200 (OX-2) is a neuronal surface antigen absent from astrocytes defined its initial cellular context and suggested a non-immune cell origin for an immunomodulatory molecule.","evidence":"Immunoperoxidase staining and double-immunofluorescence of cerebellar cultures","pmids":["6147390"],"confidence":"High","gaps":["Receptor identity unknown","Function of neuronal expression unknown","Expression on non-neuronal tissues not yet mapped"]},{"year":1986,"claim":"Cloning of CD200 cDNA revealed its Ig superfamily membership with V-like and C-like domains, a short cytoplasmic tail, and no signaling motifs, implying it signals in trans rather than in cis.","evidence":"cDNA cloning and sequence analysis from rat","pmids":["2880589"],"confidence":"High","gaps":["Receptor not identified","No functional data on immune regulation"]},{"year":2002,"claim":"Genetic ablation of CD200 revealed its essential role as an inhibitory ligand for myeloid cells: CD200-knockout mice showed spontaneous myeloid activation and increased microglial numbers with NOS2 expression, establishing the CD200–CD200R axis as a tonic immune checkpoint.","evidence":"CD200-knockout mice with immunological phenotyping and retinal immunohistochemistry","pmids":["12072366","12414514"],"confidence":"High","gaps":["Downstream signaling mechanism of CD200R unknown","Identity of signaling intermediates unresolved"]},{"year":2004,"claim":"Biochemical dissection of CD200R signaling identified the Dok1/Dok2–RasGAP–SHIP pathway downstream of receptor phosphorylation, explaining how CD200 engagement suppresses Ras/MAPK cascades (ERK, JNK, p38) to inhibit mast cell degranulation and cytokine release.","evidence":"Co-immunoprecipitation, phosphorylation assays, and functional readouts in mouse bone marrow-derived mast cells","pmids":["15557172"],"confidence":"High","gaps":["Relative contributions of Dok1 vs Dok2 in human cells unknown","NPLY motif requirement not yet shown"]},{"year":2009,"claim":"Quantitative binding studies and RNAi in human myeloid cells resolved that Dok2 (not Dok1) is the dominant adaptor for CD200R's NPLY motif in humans, with ~10-fold higher affinity, and that RasGAP recruitment by Dok2 is essential for inhibitory function.","evidence":"Mutant receptor expression in U937 cells, binding affinity measurements, siRNA knockdown","pmids":["19786546"],"confidence":"High","gaps":["Structural basis of Dok2-NPLY interaction unresolved","Species differences in Dok1 vs Dok2 usage not fully reconciled"]},{"year":2007,"claim":"Discovery that CD200–CD200R signaling regulates macrophage-to-osteoclast fusion via NF-κB and MAPK pathways, rescued by soluble CD200, expanded the axis's role beyond classical immune suppression to bone remodeling.","evidence":"CD200-knockout mice bone phenotyping, recombinant soluble CD200 rescue, shRNA silencing, signaling pathway analysis","pmids":["17726108"],"confidence":"High","gaps":["Mechanism by which CD200R engagement specifically licenses fusion is unclear","Relationship to RANK signaling not fully delineated"]},{"year":2014,"claim":"Identification of CD200 as a ligand for FGFR that induces receptor phosphorylation and neuritogenesis, with CD200R competing for the same binding site, revealed a dual-receptor signaling mode linking immune regulation to neurotrophic function.","evidence":"FGFR phosphorylation assays, neuritogenesis in primary neurons, competitive binding experiments","pmids":["25502296"],"confidence":"Medium","gaps":["FGFR interaction not independently confirmed by a second laboratory","Structural details of CD200–FGFR interface unknown","In vivo relevance of FGFR activation by CD200 not demonstrated"]},{"year":2016,"claim":"Characterization of CD200 ectodomain shedding by ADAM28 (and later MMP3/MMP11) established that soluble CD200 is a biologically active fragment retaining CD200R-binding and signaling capacity, broadening its functional reach beyond cell-cell contact.","evidence":"Western blot with domain-specific antibodies, ADAM28 silencing, CD200R phosphorylation assays; MMP inhibitor studies in BCC","pmids":["27111430","36074574"],"confidence":"High","gaps":["Relative contributions of individual sheddases in different tissues unknown","Regulation of shedding events not defined"]},{"year":2019,"claim":"Demonstration that Leishmania amazonensis exploits endosomal TLR9/MyD88/TRIF signaling to upregulate CD200, which then suppresses iNOS/NO to promote parasite survival, established CD200 as a pathogen-hijacked immune checkpoint.","evidence":"TLR9/MyD88/TRIF genetic knockouts, microvesicle isolation, in vivo infection model","pmids":["31092731"],"confidence":"High","gaps":["Whether other pathogens use similar TLR9-CD200 pathway unknown","Mechanism of CD200 transcriptional induction downstream of TLR9 not fully elucidated"]},{"year":2021,"claim":"Multiple studies expanded CD200R-expressing target cell types to include ILC2s (where CD200R inhibits NF-κB signaling and type 2 cytokine production) and T cells (where tumor CD200 suppresses OXPHOS metabolism), establishing CD200 as a broad immune checkpoint beyond myeloid cells.","evidence":"CD200R engagement assays on ILC2s with NF-κB analysis; isogenic CD200+/− tumor lines with CyTOF and metabolic profiling in humanized mice","pmids":["33953190","34326171"],"confidence":"Medium","gaps":["Direct signaling intermediates in ILC2s downstream of CD200R not fully mapped","Mechanism of T cell OXPHOS suppression by CD200R is unclear"]},{"year":2022,"claim":"Full delineation of soluble CD200-mediated NK cell suppression in basal cell carcinoma identified a MMP3/MMP11-shedding → CD200R → ERK inhibition → PPARγ activation → Fas/FADD-dependent apoptosis pathway, providing a complete mechanistic chain from tumor immune evasion to NK cell death.","evidence":"MMP inhibitor studies, CD200R blocking, MAPK/PPARγ pathway analysis, Fas/FADD expression, NK killing assays in BCC","pmids":["36074574"],"confidence":"High","gaps":["Whether this PPARγ-Fas apoptosis pathway operates in other immune cell types unknown","Therapeutic window for shedding or CD200R blockade not assessed"]},{"year":null,"claim":"Key unresolved questions include the structural basis of CD200–CD200R and CD200–FGFR interactions, the precise transcriptional regulation of CD200 across tissues, and whether therapeutic disruption of CD200 shedding can selectively restore anti-tumor immunity without breaking peripheral tolerance.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal structure of CD200–CD200R complex","Transcriptional regulation beyond p53 and TLR9 pathways poorly characterized","Therapeutic index of CD200 axis blockade not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[2,3,4,7,16]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,4,16,18]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,9,17]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[16,17]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,3,4,5,15,16,18]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,4,7,16,18]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[6,16]}],"complexes":[],"partners":["CD200R1","DOK2","DOK1","RASA1","FGFR1","ADAM28","MMP3","MMP11"],"other_free_text":[]},"mechanistic_narrative":"CD200 is an immunoglobulin superfamily glycoprotein that functions as a broadly expressed inhibitory ligand maintaining immune homeostasis by tonically suppressing myeloid cell activation through engagement of its receptor CD200R. Structurally composed of V-like and C-like Ig domains, CD200 binds CD200R on myeloid cells and innate lymphoid cells, triggering receptor NPLY motif phosphorylation, recruitment of the adaptor Dok2 (and Dok1 in mice) and RasGAP, which suppresses Ras/MAPK and NF-κB signaling to inhibit degranulation, cytokine production, and phagocytosis [PMID:15557172, PMID:19786546, PMID:33953190]. CD200 undergoes metalloproteinase-mediated ectodomain shedding by MMP3, MMP11, and ADAM28 to release soluble CD200 that retains CD200R-binding activity and can suppress NK cell function by ERK inhibition and PPARγ-dependent induction of apoptosis [PMID:36074574, PMID:27111430]. Beyond immune regulation, CD200 also activates FGFR through a motif in its first Ig-like domain to promote neuritogenesis and neuronal survival, and viral orthologues of CD200 encoded by cytomegaloviruses and rhadinoviruses engage host CD200R to evade antiviral immunity [PMID:25502296, PMID:21471432, PMID:24991004]."},"prefetch_data":{"uniprot":{"accession":"P41217","full_name":"OX-2 membrane glycoprotein","aliases":[],"length_aa":278,"mass_kda":31.3,"function":"Costimulates T-cell proliferation. May regulate myeloid cell activity in a variety of tissues","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P41217/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CD200","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CD200","total_profiled":1310},"omim":[{"mim_id":"607546","title":"CD200 RECEPTOR 1; CD200R1","url":"https://www.omim.org/entry/607546"},{"mim_id":"155970","title":"CD200 ANTIGEN; CD200","url":"https://www.omim.org/entry/155970"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":63.9}],"url":"https://www.proteinatlas.org/search/CD200"},"hgnc":{"alias_symbol":["MRC","OX-2"],"prev_symbol":["MOX1","MOX2"]},"alphafold":{"accession":"P41217","domains":[{"cath_id":"2.60.40.10","chopping":"34-141","consensus_level":"high","plddt":95.1017,"start":34,"end":141},{"cath_id":"2.60.40.10","chopping":"154-230","consensus_level":"high","plddt":89.1252,"start":154,"end":230}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P41217","model_url":"https://alphafold.ebi.ac.uk/files/AF-P41217-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P41217-F1-predicted_aligned_error_v6.png","plddt_mean":86.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CD200","jax_strain_url":"https://www.jax.org/strain/search?query=CD200"},"sequence":{"accession":"P41217","fasta_url":"https://rest.uniprot.org/uniprotkb/P41217.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P41217/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P41217"}},"corpus_meta":[{"pmid":"10485709","id":"PMC_10485709","title":"Cell transformation by the superoxide-generating oxidase Mox1.","date":"1999","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/10485709","citation_count":1215,"is_preprint":false},{"pmid":"12072366","id":"PMC_12072366","title":"CD200 and membrane protein interactions in the control of myeloid cells.","date":"2002","source":"Trends in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/12072366","citation_count":335,"is_preprint":false},{"pmid":"15557172","id":"PMC_15557172","title":"Molecular mechanisms of CD200 inhibition of mast cell activation.","date":"2004","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/15557172","citation_count":200,"is_preprint":false},{"pmid":"16365410","id":"PMC_16365410","title":"Regulation of myeloid cell function through the CD200 receptor.","date":"2006","source":"Journal of immunology (Baltimore, Md. : 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domain followed by transmembrane and cytoplasmic sections, encoded by 248 amino acids.\",\n      \"method\": \"cDNA cloning and sequence analysis\",\n      \"journal\": \"Biochemical Society symposium\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct sequence determination establishing domain architecture\",\n      \"pmids\": [\"2880589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1984,\n      \"finding\": \"CD200 (OX-2 antigen) is localized on the surfaces of neurons (all tetanus toxin-positive cells in cerebellar interneurone cultures) but not on GFAP-positive astrocytes, establishing its neuronal membrane localization.\",\n      \"method\": \"Indirect immunoperoxidase staining and double-immunofluorescence of cerebellar cultures with OX-2 antibody and tetanus toxin\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization by immunofluorescence with functional cellular context\",\n      \"pmids\": [\"6147390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CD200 functions as a ligand for a myeloid-restricted receptor (CD200R) and delivers inhibitory signals to myeloid cells; CD200-deficient mice show increased myeloid cell activation upon immunological stimulation.\",\n      \"method\": \"CD200 knockout mouse model with functional immunological readouts\",\n      \"journal\": \"Trends in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function with defined cellular phenotype, widely replicated\",\n      \"pmids\": [\"12072366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Upon CD200 binding, CD200R is phosphorylated on tyrosine and recruits adaptor proteins Dok1 and Dok2; Dok1 then binds SHIP and both Dok1 and Dok2 recruit RasGAP, which inhibits Ras/MAPK pathways (ERK, JNK, p38), resulting in inhibition of mast cell degranulation and cytokine production.\",\n      \"method\": \"Biochemical phosphorylation assays, co-immunoprecipitation of Dok1/Dok2/SHIP/RasGAP, functional assays in mouse bone marrow-derived mast cells\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal biochemical methods establishing signaling cascade\",\n      \"pmids\": [\"15557172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In human myeloid cells, CD200R inhibition is mediated via its NPLY motif; Dok2 binds directly to the phosphorylated NPLY motif with ~10-fold higher affinity than Dok1 (Kd ~1 µM at 37°C), is phosphorylated upon CD200R engagement, and recruits RasGAP. Knockdown of Dok2 and RasGAP (but not Dok1 or SHIP) abolishes CD200R-mediated inhibition.\",\n      \"method\": \"Mutant receptor expression in U937 cells, direct binding affinity measurements, RNA interference knockdown, functional inhibition assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding measurements, mutagenesis, and RNAi with quantitative functional readouts\",\n      \"pmids\": [\"19786546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CD200 expressed constitutively on retinal neurons and vascular endothelium regulates retinal microglial activation; CD200-deficient mice show increased microglial numbers and inducible NOS2 expression in microglia at baseline, demonstrating that CD200:CD200R axis controls tonic microglial suppression.\",\n      \"method\": \"CD200 knockout mouse model, immunohistochemistry for NOS2, microglial counting\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined cellular phenotype (NOS2 expression, cell numbers)\",\n      \"pmids\": [\"12414514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CD200 is a p53-target gene; its expression increases on dendritic cells undergoing apoptosis through both p53-dependent and caspase-dependent pathways, and CD200 expression on apoptotic DCs suppresses proinflammatory cytokine responses to self-antigens and is required for UVB-mediated tolerance.\",\n      \"method\": \"p53 pathway analysis, caspase inhibitor experiments, in vitro cytokine assays, in vivo UVB tolerance model\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic/pharmacological pathway dissection with functional readouts in single study\",\n      \"pmids\": [\"14644999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CD200 engagement of CD200R at the initiation of macrophage fusion regulates further differentiation to osteoclasts; CD200-deficient mice have fewer osteoclasts and more bone, and a soluble CD200 extracellular domain rescues fusion and RANK-downstream NF-κB and MAP kinase signaling in CD200-/- macrophages.\",\n      \"method\": \"CD200 knockout mouse model, recombinant soluble CD200/CD200R proteins, shRNA silencing of CD200R, NF-κB and MAPK pathway analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstitution with recombinant protein, genetic KO, shRNA, and signaling pathway analysis\",\n      \"pmids\": [\"17726108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CD200 receptor-like 3 (a CD200R family member) associates with the activating adaptor DAP12 at the cell surface; the second Ig-like domain (exon 4) is required for cell surface expression and DAP12 recruitment, and splice variants generate unique cytoplasmic domains contributing to DAP12 pairing.\",\n      \"method\": \"Microarray screen, splice variant characterization, functional surface expression assays in basophils and mast cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain mapping with functional surface expression readouts\",\n      \"pmids\": [\"15471863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Endothelial CD200 mediates T-cell adhesion to endothelium through physical CD200-CD200R binding; a synthetic CD200 agonist peptide can trigger CD200R signaling in macrophages to suppress their adhesion to endothelium. Endothelial CD200 expression is differentially regulated by LPS in different vascular beds.\",\n      \"method\": \"Functional adhesion assays, antibody blocking, synthetic peptide agonist treatment, in vivo and in vitro LPS stimulation\",\n      \"journal\": \"Journal of anatomy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional adhesion assay with antibody blocking and peptide agonist\",\n      \"pmids\": [\"19166481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Rat cytomegalovirus encodes a CD200 orthologue (e127) that is expressed at the cell surface on infected cells and binds the host CD200R with the same affinity as the host CD200 protein, acting as a viral mimic to potentially downregulate immune responses.\",\n      \"method\": \"Cell surface expression assays, binding affinity measurements of e127 vs. host CD200 for CD200R\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding affinity comparison with functional implication\",\n      \"pmids\": [\"21471432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CD200 can interact with and activate the fibroblast growth factor receptor (FGFR), inducing neuritogenesis and promoting neuronal survival; CD200R abrogates CD200-induced FGFR phosphorylation, and a minimal FGFR-binding motif was identified in the first Ig-like module of CD200 that overlaps with the CD200R binding site.\",\n      \"method\": \"FGFR phosphorylation assays, neuritogenesis assays in primary neurons, competitive binding with CD200R, motif identification\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct phosphorylation assay and functional neuritogenesis readout, single lab\",\n      \"pmids\": [\"25502296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD200 expression is regulated by PPAR-γ in glial cells; the PPAR-γ agonist 15d-PGJ2 prevents CD200 upregulation and CD200R1 downregulation in reactive glia, and CD200-CD200R1 interaction mediates the anti-inflammatory and neuroprotective effects of PPAR-γ agonists in neuron-microglia cocultures.\",\n      \"method\": \"Primary neuronal and glial cultures, LPS/IFN-γ activation, PPAR-γ agonist treatment, neurotoxicity assays\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — pathway dependence shown by CD200-CD200R1 blocking in functional neuroprotection assay\",\n      \"pmids\": [\"24639050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD200 deficiency in microglia leads to increased phagocytic activity associated with increased lysosomal activity and decreased mTOR signaling; inhibiting mTOR with rapamycin increases phagocytosis similarly, indicating that CD200-CD200R signaling regulates lysosomal/mTOR-dependent phagocytosis in microglia.\",\n      \"method\": \"CD200-deficient mouse microglia isolation, phagocytosis assays, lysosomal activity measurement, mTOR inhibition with rapamycin\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with mechanistic follow-up using pharmacological inhibitor\",\n      \"pmids\": [\"27830533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD200-Fc (soluble CD200 fusion protein) downregulates toll-like receptor 4 (TLR4) expression in macrophages, thereby inhibiting macrophage phagocytosis of oligodendrocyte precursor cells; in vivo treatment with CD200-Fc suppressed TLR4 expression in circulating macrophages and improved myelination after white matter ischemia.\",\n      \"method\": \"Primary cell culture phagocytosis assays, TLR4 blocking, CD200-Fc treatment in endothelin-1 white matter ischemia model\",\n      \"journal\": \"Journal of cerebral blood flow and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro mechanism (TLR4 downregulation) confirmed in vivo with functional outcome\",\n      \"pmids\": [\"26661156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Leishmania amazonensis induces CD200 expression in macrophages through phagocytosis-mediated activation of endosomal TLR9/MyD88/TRIF signaling; Leishmania microvesicles containing DNA fragments activate TLR9-dependent CD200 expression, which then inhibits iNOS/NO signaling to promote intracellular parasite survival.\",\n      \"method\": \"Genetic knockouts/knockdowns of TLR9/MyD88/TRIF, microvesicle isolation, iNOS/NO pathway analysis, in vivo infection model\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic loss-of-function experiments establishing pathway order with functional outcome\",\n      \"pmids\": [\"31092731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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 signaling, blocking IFN-γ release and direct killing, and reduced ERK phosphorylation activates PPARγ-regulated gene transcription leading to Fas/FADD membrane accumulation and activation-induced NK cell apoptosis.\",\n      \"method\": \"MMP inhibitor studies, CD200R blocking, MAPK/ERK pathway analysis, PPARγ pathway analysis, Fas/FADD expression assays, NK cell killing assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal mechanistic experiments identifying shedding enzymes, receptor, and downstream signaling cascade\",\n      \"pmids\": [\"36074574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD200 undergoes ectodomain shedding (partially mediated by ADAM28) to generate soluble CD200 that retains the functional extracellular domain but lacks the cytoplasmic domain; shed CD200 can bind to and phosphorylate CD200R1 on receptor-expressing cells.\",\n      \"method\": \"Western blot with extracellular vs. cytoplasmic domain antibodies, ADAM28 silencing, flow cytometry of surface CD200 loss, functional CD200R1 phosphorylation assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical characterization of shed fragment with functional receptor binding/phosphorylation confirmed\",\n      \"pmids\": [\"27111430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD200R on ILC2s is inducible, and CD200R engagement inhibits ILC2 activation, proliferation, and type 2 cytokine production by inhibiting both canonical and non-canonical NF-κB signaling pathways.\",\n      \"method\": \"Flow cytometry of CD200R expression on murine and human ILC2s, CD200R engagement functional assays, NF-κB pathway analysis, in vivo asthma models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway analysis with in vitro and in vivo functional validation\",\n      \"pmids\": [\"33953190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD200 expression on AML cells suppresses OXPHOS metabolic activity in T cells, impairing their effector function; this represents a stem cell-specific immune evasion mechanism.\",\n      \"method\": \"Isogenic CD200+ vs CD200- cell line models, CyTOF, RNA-sequencing, PBMC-humanized mouse models, metabolic assays\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — isogenic models with mechanistic metabolic readout in multiple experimental systems\",\n      \"pmids\": [\"34326171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD200-CD200R1 signaling from pro-resolving CD200+DKK3+ fibroblasts stabilizes type 2 innate lymphoid cell phenotype and induces resolution of arthritis.\",\n      \"method\": \"Single-cell RNA-sequencing, spatial transcriptomics, CD200-CD200R1 signaling blocking experiments, in vivo arthritis model\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic/antibody blocking of CD200-CD200R1 with defined cellular phenotypic readout\",\n      \"pmids\": [\"38396288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CD200-CD200R signaling between amacrine cells and microglia is dysregulated in early diabetic retinopathy; targeting CD200R attenuates high glucose-induced microglial inflammation and phagocytosis in vitro, and CD200R targeting in vivo prevents visual dysfunction and retinal inflammation in diabetic mice.\",\n      \"method\": \"Microglia ablation, flow cytometry, transcriptomics, CD200R pharmacological targeting in vitro and in vivo diabetic mouse model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cell-specific signaling dissection with in vivo pharmacological intervention and functional outcome\",\n      \"pmids\": [\"37903272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD200 expression on cSCC tumors induces cathepsin K (Ctsk) expression in CD11B+CD200R+ infiltrating myeloid cells via engagement of the CD200-CD200R axis; Ctsk inhibition (but not MMP inhibition) blocks cSCC cell migration, and CD200 disruption plus Ctsk inhibition reduces metastasis in vivo.\",\n      \"method\": \"RNA sequencing of tumor-infiltrating myeloid cells, coculture system establishing CD200-CD200R-dependent Ctsk induction, pharmacological Ctsk inhibition, in vivo metastasis model with CD200 knockout\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — coculture mechanistic validation with in vivo genetic and pharmacological confirmation\",\n      \"pmids\": [\"34183355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RRV vCD200 (viral CD200 orthologue) limits immune responses against RRV at early times post-infection and impacts viral loads in vivo, demonstrating that viral CD200 mimic functionally engages host CD200R to suppress antiviral immunity.\",\n      \"method\": \"vCD200-deletion mutant RRV in vivo infection of rhesus macaques, viral load measurements, immune response quantification\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic loss-of-function in relevant primate model\",\n      \"pmids\": [\"24991004\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD200 is a cell-surface immunoglobulin superfamily glycoprotein expressed broadly on neurons, endothelium, and other cell types that functions as an inhibitory ligand for CD200R on myeloid cells and other immune cells; upon ligation, CD200R is phosphorylated on its NPLY motif, recruiting Dok2 (and Dok1 in mice) which in turn recruits RasGAP to suppress Ras/MAPK signaling, thereby inhibiting myeloid cell activation, degranulation, cytokine production, and phagocytosis, while CD200 can also bind FGFR to promote neurotrophic signaling, and is subject to metalloproteinase-mediated ectodomain shedding (by MMP3/MMP11/ADAM28) that releases biologically active soluble CD200 capable of suppressing NK cells via MAPK/PPARγ-dependent induction of apoptosis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CD200 is an immunoglobulin superfamily glycoprotein that functions as a broadly expressed inhibitory ligand maintaining immune homeostasis by tonically suppressing myeloid cell activation through engagement of its receptor CD200R. Structurally composed of V-like and C-like Ig domains, CD200 binds CD200R on myeloid cells and innate lymphoid cells, triggering receptor NPLY motif phosphorylation, recruitment of the adaptor Dok2 (and Dok1 in mice) and RasGAP, which suppresses Ras/MAPK and NF-κB signaling to inhibit degranulation, cytokine production, and phagocytosis [PMID:15557172, PMID:19786546, PMID:33953190]. CD200 undergoes metalloproteinase-mediated ectodomain shedding by MMP3, MMP11, and ADAM28 to release soluble CD200 that retains CD200R-binding activity and can suppress NK cell function by ERK inhibition and PPARγ-dependent induction of apoptosis [PMID:36074574, PMID:27111430]. Beyond immune regulation, CD200 also activates FGFR through a motif in its first Ig-like domain to promote neuritogenesis and neuronal survival, and viral orthologues of CD200 encoded by cytomegaloviruses and rhadinoviruses engage host CD200R to evade antiviral immunity [PMID:25502296, PMID:21471432, PMID:24991004].\",\n  \"teleology\": [\n    {\n      \"year\": 1984,\n      \"claim\": \"Establishing that CD200 (OX-2) is a neuronal surface antigen absent from astrocytes defined its initial cellular context and suggested a non-immune cell origin for an immunomodulatory molecule.\",\n      \"evidence\": \"Immunoperoxidase staining and double-immunofluorescence of cerebellar cultures\",\n      \"pmids\": [\"6147390\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor identity unknown\", \"Function of neuronal expression unknown\", \"Expression on non-neuronal tissues not yet mapped\"]\n    },\n    {\n      \"year\": 1986,\n      \"claim\": \"Cloning of CD200 cDNA revealed its Ig superfamily membership with V-like and C-like domains, a short cytoplasmic tail, and no signaling motifs, implying it signals in trans rather than in cis.\",\n      \"evidence\": \"cDNA cloning and sequence analysis from rat\",\n      \"pmids\": [\"2880589\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor not identified\", \"No functional data on immune regulation\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Genetic ablation of CD200 revealed its essential role as an inhibitory ligand for myeloid cells: CD200-knockout mice showed spontaneous myeloid activation and increased microglial numbers with NOS2 expression, establishing the CD200–CD200R axis as a tonic immune checkpoint.\",\n      \"evidence\": \"CD200-knockout mice with immunological phenotyping and retinal immunohistochemistry\",\n      \"pmids\": [\"12072366\", \"12414514\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling mechanism of CD200R unknown\", \"Identity of signaling intermediates unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Biochemical dissection of CD200R signaling identified the Dok1/Dok2–RasGAP–SHIP pathway downstream of receptor phosphorylation, explaining how CD200 engagement suppresses Ras/MAPK cascades (ERK, JNK, p38) to inhibit mast cell degranulation and cytokine release.\",\n      \"evidence\": \"Co-immunoprecipitation, phosphorylation assays, and functional readouts in mouse bone marrow-derived mast cells\",\n      \"pmids\": [\"15557172\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of Dok1 vs Dok2 in human cells unknown\", \"NPLY motif requirement not yet shown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Quantitative binding studies and RNAi in human myeloid cells resolved that Dok2 (not Dok1) is the dominant adaptor for CD200R's NPLY motif in humans, with ~10-fold higher affinity, and that RasGAP recruitment by Dok2 is essential for inhibitory function.\",\n      \"evidence\": \"Mutant receptor expression in U937 cells, binding affinity measurements, siRNA knockdown\",\n      \"pmids\": [\"19786546\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Dok2-NPLY interaction unresolved\", \"Species differences in Dok1 vs Dok2 usage not fully reconciled\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Discovery that CD200–CD200R signaling regulates macrophage-to-osteoclast fusion via NF-κB and MAPK pathways, rescued by soluble CD200, expanded the axis's role beyond classical immune suppression to bone remodeling.\",\n      \"evidence\": \"CD200-knockout mice bone phenotyping, recombinant soluble CD200 rescue, shRNA silencing, signaling pathway analysis\",\n      \"pmids\": [\"17726108\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which CD200R engagement specifically licenses fusion is unclear\", \"Relationship to RANK signaling not fully delineated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identification of CD200 as a ligand for FGFR that induces receptor phosphorylation and neuritogenesis, with CD200R competing for the same binding site, revealed a dual-receptor signaling mode linking immune regulation to neurotrophic function.\",\n      \"evidence\": \"FGFR phosphorylation assays, neuritogenesis in primary neurons, competitive binding experiments\",\n      \"pmids\": [\"25502296\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"FGFR interaction not independently confirmed by a second laboratory\", \"Structural details of CD200–FGFR interface unknown\", \"In vivo relevance of FGFR activation by CD200 not demonstrated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Characterization of CD200 ectodomain shedding by ADAM28 (and later MMP3/MMP11) established that soluble CD200 is a biologically active fragment retaining CD200R-binding and signaling capacity, broadening its functional reach beyond cell-cell contact.\",\n      \"evidence\": \"Western blot with domain-specific antibodies, ADAM28 silencing, CD200R phosphorylation assays; MMP inhibitor studies in BCC\",\n      \"pmids\": [\"27111430\", \"36074574\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of individual sheddases in different tissues unknown\", \"Regulation of shedding events not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstration that Leishmania amazonensis exploits endosomal TLR9/MyD88/TRIF signaling to upregulate CD200, which then suppresses iNOS/NO to promote parasite survival, established CD200 as a pathogen-hijacked immune checkpoint.\",\n      \"evidence\": \"TLR9/MyD88/TRIF genetic knockouts, microvesicle isolation, in vivo infection model\",\n      \"pmids\": [\"31092731\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other pathogens use similar TLR9-CD200 pathway unknown\", \"Mechanism of CD200 transcriptional induction downstream of TLR9 not fully elucidated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Multiple studies expanded CD200R-expressing target cell types to include ILC2s (where CD200R inhibits NF-κB signaling and type 2 cytokine production) and T cells (where tumor CD200 suppresses OXPHOS metabolism), establishing CD200 as a broad immune checkpoint beyond myeloid cells.\",\n      \"evidence\": \"CD200R engagement assays on ILC2s with NF-κB analysis; isogenic CD200+/− tumor lines with CyTOF and metabolic profiling in humanized mice\",\n      \"pmids\": [\"33953190\", \"34326171\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct signaling intermediates in ILC2s downstream of CD200R not fully mapped\", \"Mechanism of T cell OXPHOS suppression by CD200R is unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Full delineation of soluble CD200-mediated NK cell suppression in basal cell carcinoma identified a MMP3/MMP11-shedding → CD200R → ERK inhibition → PPARγ activation → Fas/FADD-dependent apoptosis pathway, providing a complete mechanistic chain from tumor immune evasion to NK cell death.\",\n      \"evidence\": \"MMP inhibitor studies, CD200R blocking, MAPK/PPARγ pathway analysis, Fas/FADD expression, NK killing assays in BCC\",\n      \"pmids\": [\"36074574\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this PPARγ-Fas apoptosis pathway operates in other immune cell types unknown\", \"Therapeutic window for shedding or CD200R blockade not assessed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of CD200–CD200R and CD200–FGFR interactions, the precise transcriptional regulation of CD200 across tissues, and whether therapeutic disruption of CD200 shedding can selectively restore anti-tumor immunity without breaking peripheral tolerance.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal structure of CD200–CD200R complex\", \"Transcriptional regulation beyond p53 and TLR9 pathways poorly characterized\", \"Therapeutic index of CD200 axis blockade not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [2, 3, 4, 7, 16]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 4, 16, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 9, 17]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [16, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 3, 4, 5, 15, 16, 18]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 4, 7, 16, 18]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [6, 16]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CD200R1\",\n      \"DOK2\",\n      \"DOK1\",\n      \"RASA1\",\n      \"FGFR1\",\n      \"ADAM28\",\n      \"MMP3\",\n      \"MMP11\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}