{"gene":"CD200R1","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2005,"finding":"CD200R1 cytoplasmic tail tyrosine residues Y286 and Y297 are the major phosphorylation sites required for CD200R-mediated inhibition of mast cell activation; Y289 is dispensable. Src family kinase mediates phosphorylation of CD200R and Dok. Phosphorylated CD200R recruits inhibitory adaptor proteins Dok1 and Dok2, leading to inhibition of Ras/MAPK activation.","method":"Site-directed mutagenesis of tyrosine residues, in vitro mast cell activation assays","journal":"Journal of leukocyte biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — site-directed mutagenesis with functional readout in cellular assay, single lab with multiple mutants tested","pmids":["16330532"],"is_preprint":false},{"year":2004,"finding":"CD200Fc (extracellular domain of CD200) physically binds to each of the CD200R isoforms (CD200R1–R4) expressed on the cell surface, as shown by FACS with FITC-labeled CD200Fc on transfected COS7 cells. Anti-CD200R1/R4 mAbs elicit immunomodulatory responses comparable to CD200Fc (suppressing CTL and IL-2/IL-4), while anti-CD200R2/R3 show significantly lesser effects.","method":"FACS binding assay with FITC-labeled CD200Fc on transfected COS7 cells; functional assays with mAbs","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding demonstrated by FACS, functional differentiation between isoforms, single lab","pmids":["15187158"],"is_preprint":false},{"year":2004,"finding":"A family of CD200R isoforms (CD200R1–R4) was identified on mouse chromosome 16 juxtaposed to the CD200 gene. The isoforms show distinct tissue and cell-type expression patterns. Anti-CD200R1/R4 mAbs modulate allogeneic mixed-lymphocyte responses comparably to CD200Fc, whereas anti-CD200R2/R3 show different functional effects. CD200Fc physically interacts with each CD200R isoform on the cell surface.","method":"5'-RACE, cDNA and genomic DNA cloning, Northern blot, RT-PCR, FACS with rabbit polyclonal and rat monoclonal antibodies, mixed-lymphocyte response assays","journal":"American journal of reproductive immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (cloning, expression, FACS, functional assay), single lab","pmids":["15274657"],"is_preprint":false},{"year":2007,"finding":"CD200R1 knockout mice show that the CD200:CD200R1 interaction is required for suppression of LPS-induced splenic TNF-α production and for CD200Fc-mediated suppression of mixed leukocyte culture alloreactivity. CD200R1 on both antigen-presenting cells and T responder cells contributes to maximal immunoregulation. CD200Fc fails to suppress graft rejection in CD200R1−/− mice.","method":"CD200R1 knockout mice generated by ES cell transformation; FACS, ELISA for TNF-α, mixed leukocyte culture, skin graft rejection model","journal":"Transplantation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with multiple orthogonal functional readouts, loss-of-function confirmed in vivo and in vitro","pmids":["17667818"],"is_preprint":false},{"year":2007,"finding":"CD200R (expressed on myeloid cells including osteoclast precursors) engagement by CD200 (expressed on macrophages at onset of fusion) is required for macrophage fusion and osteoclast differentiation. CD200R knockdown by shRNA or addition of soluble CD200R extracellular domain prevents macrophage fusion. CD200−/− mice have fewer osteoclasts and more bone, consistent with CD200-CD200R controlling osteoclastogenesis via NF-κB and MAPK pathways downstream of RANK.","method":"shRNA silencing of CD200R, soluble recombinant CD200R extracellular domain addition, CD200−/− mice, in vitro differentiation assays, immunohistochemistry","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout, shRNA, and recombinant protein rescue experiments with multiple orthogonal readouts","pmids":["17726108"],"is_preprint":false},{"year":2012,"finding":"CD200R1 signaling inhibits microglial activation downstream via the Dok1 pathway. CD200Fc treatment after germinal matrix hemorrhage increased Dok1 expression and decreased IL-1β and TNF-α; these effects were abolished by CD200R1 siRNA and Dok1 siRNA, identifying a CD200R1/Dok1 signaling axis.","method":"siRNA knockdown of CD200R1 and Dok1, Western blot, CD200Fc treatment in rat GMH model","journal":"Journal of cerebral blood flow and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA loss-of-function for both receptor and adaptor with functional readouts, single lab in vivo model","pmids":["28792282"],"is_preprint":false},{"year":2012,"finding":"CD200R1 expression in microglia is negatively regulated by the transcription factor C/EBPβ: LPS-induced decrease in CD200R1 mRNA/protein is absent in C/EBPβ-deficient mice; C/EBPβ overexpression in BV2 cells reduces basal CD200R1 expression. C/EBPβ binds the CD200R1 promoter in LPS-treated glial cells. HDAC1 co-immunoprecipitates with C/EBPβ and binds the CD200R1 promoter region, and HDAC1 inhibitors reverse LPS-induced CD200R1 downregulation.","method":"Primary microglial cultures from WT and C/EBPβ-KO mice, C/EBPβ overexpression in BV2 cells, qChIP, co-immunoprecipitation, HDAC inhibitor treatment, qRT-PCR, Western blot","journal":"Journal of neuroinflammation","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — chromatin immunoprecipitation, genetic KO, overexpression, and co-IP with multiple orthogonal methods in single lab","pmids":["22776069"],"is_preprint":false},{"year":2014,"finding":"PPAR-γ activation by the endogenous ligand 15d-PGJ2 prevents LPS/IFN-γ-induced downregulation of CD200R1 in reactive microglial cells and upregulation of CD200 in astrocytes. PPAR-γ-mediated neuroprotection in neuron-microglia co-cultures depends on CD200-CD200R1 interaction, as blocking this interaction abolishes the neuroprotective effect.","method":"Primary neuronal and glial cultures, neuron-microglia co-cultures, PPAR-γ agonist treatment, CD200-CD200R1 blocking, qRT-PCR, Western blot","journal":"Glia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and blocking experiments with functional readout of neuroprotection, single lab","pmids":["24639050"],"is_preprint":false},{"year":2012,"finding":"CD200R1 expression in microglia is regulated posttranscriptionally by miR-129-5p, which binds the 3'-UTR of CD200R1 mRNA and shuttles it to cytoplasmic processing bodies. Arsenic demethylates the miR-129-5p promoter, increasing its expression and repressing CD200R1. Anti-miR-129 in vivo reversed CD200R1 downregulation and reduced IL-6 and TNF-α. A miR-129-5p→CD200R1→IL-6/TNF-α axis was confirmed by CD200R1 siRNA loss-of-function.","method":"In silico analysis, primary neonatal microglia and BV2 cells, stereotaxic anti-miR injection in mice, CD200R1 siRNA, qRT-PCR, promoter methylation analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo validation with siRNA and anti-miR, single lab with multiple orthogonal methods","pmids":["34952004"],"is_preprint":false},{"year":2018,"finding":"N-glycosylation of CD200R1 at asparagine 44 (Asn44) is required for CD200-CD200R1 interaction; mutation of this site disrupts CD200 binding and upregulates proinflammatory markers (iNOS, CD86, IL-1β, TNF-α) in a neuronal-microglia co-culture system.","method":"Site-directed mutagenesis of glycosylation site, neuronal-microglia co-culture, cytokine measurement, binding assay","journal":"Journal of inflammation","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — mutagenesis with functional readout but single lab, single paper","pmids":["30574022"],"is_preprint":false},{"year":2021,"finding":"Type I interferon (IFN-α) rewires CD200R1 signaling from inhibitory to proinflammatory by inducing cleavage of p120-RasGAP, a downstream effector of CD200R1. In the presence of cleaved p120-RasGAP, CD200R loses its capacity to inhibit rpS6 phosphorylation (mTORC1). After IFN-α pretreatment, CD200R switches from inhibiting to potentiating TLR7/8-induced IFN-γ expression. SLE patient PBMCs have increased cleaved p120-RasGAP and altered CD200R function.","method":"Human PBMC treatment with IFN-α, Western blot for cleaved p120-RasGAP and rpS6 phosphorylation, cytokine measurement, patient samples from SLE","journal":"Science signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic signaling experiments in primary human cells with patient validation, single lab","pmids":["34637328"],"is_preprint":false},{"year":2012,"finding":"CD200R1 is required for TLR2-mediated pro-inflammatory signaling in macrophages: CD200R1−/− peritoneal macrophages show 70–75% reduction in IL-6 and CCL5 in response to TLR2 agonist Pam2CSK4 and HSV-1. CD200R1−/− macrophages cannot upregulate TLR2 or assemble a functional inflammasome in response to HSV-1. CD200R1−/− mice are protected from HSV-1 infection, and CD200R1−/− fibroblasts and macrophages show reduced ability to support HSV-1 replication.","method":"CD200R1−/− mice, ex vivo macrophage assays, ELISA for cytokines, HSV-1 infection model, TLR2 expression assay","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with multiple orthogonal in vitro and in vivo readouts, unexpected proinflammatory licensing role established","pmids":["23082204"],"is_preprint":false},{"year":2016,"finding":"CD200R engagement on ILC3s promotes IL-17A production by enhancing STAT3 activation, contrary to its inhibitory role in myeloid cells. CD200R1-deficient mice show reduced psoriasis severity due to reduced IL-17 production, identifying a cell-intrinsic role of CD200R1 on ILC3s.","method":"CD200R1-deficient mice, psoriasis models, cytokine production assays, STAT3 phosphorylation analysis","journal":"Mucosal immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with cell-type-specific and signaling readouts, single lab","pmids":["36623588"],"is_preprint":false},{"year":2019,"finding":"CD200R1 deletion in mice leads to increased bacterial burden in neutrophils after Francisella tularensis infection. CD200R1-deficient neutrophils have significantly reduced reactive oxygen species (ROS) production, indicating CD200R1-mediated ROS production in neutrophils limits bacterial colonization. Depletion of the neutrophil niche in CD200R1−/− mice restores infection to wild-type levels.","method":"CD200R1−/− mice, in vivo F. tularensis infection, ROS assay, neutrophil depletion, bacterial burden quantification","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with mechanistic ROS assay and rescue experiment in vivo","pmids":["31073183"],"is_preprint":false},{"year":2017,"finding":"Stress-induced reduction of CD200R expression in hippocampal microglia primes neuroinflammatory responses. CAAT/Enhancer Binding Protein β (C/EBPβ) is induced by stress and inversely associated with CD200R expression. Intracisterna magna administration of soluble CD200 (mCD200Fc) blocked stress-induced microglial priming, and mCD200R1Fc recapitulated the priming effect. CD200Fc also blocked stress-induced hippocampal HMGB1 increase.","method":"In vivo stressor exposure (inescapable tailshock), intracisterna magna injection of mCD200Fc or mCD200R1Fc, ex vivo microglial assays, qRT-PCR for CD200R and C/EBPβ, HMGB1 measurement","journal":"Brain, behavior, and immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological gain and loss of CD200R function in vivo with multiple mechanistic readouts, single lab","pmids":["29104062"],"is_preprint":false},{"year":2019,"finding":"Glucocorticoids mediate stress-induced reduction of CD200R1 in microglia: pharmacological GC receptor blockade (RU486) and adrenalectomy mitigated stress-induced CD200R1 downregulation; exogenous corticosterone reduced CD200R1 expression in vivo and in primary microglia in vitro, indicating direct GC action on microglia.","method":"Pharmacological blockade (RU486), adrenalectomy, exogenous CORT administration, primary microglia culture, qRT-PCR and protein expression","journal":"Brain, behavior, and immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological interventions and in vitro confirmation, single lab","pmids":["31078691"],"is_preprint":false},{"year":2014,"finding":"DNA aptamers binding murine CD200R1 act as agonists in the absence of CD200, inducing rapid phosphorylation of the CD200R1 cytoplasmic tail and initiating immune inhibitory signaling. They suppress CTL induction in allogeneic mixed leukocyte culture. Suppression is abolished with CD200R1−/− responder cells, confirming CD200R1-dependent mechanism. PEGylated aptamers enhance allogeneic skin graft survival comparably to CD200Fc in vivo.","method":"DNA aptamer SELEX, CD200R1 phosphorylation assay, mixed leukocyte culture CTL assay, CD200R1−/− cells as controls, in vivo skin graft model","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct phosphorylation assay plus genetic KO control and in vivo efficacy, single lab","pmids":["25158092"],"is_preprint":false},{"year":2017,"finding":"A CD200R-CD28 fusion protein (immunomodulatory fusion protein, IFP) converts CD200R inhibitory signaling into CD28 costimulatory signaling in CD8+ T cells. IFPs containing a dimerizing motif and predicted tumor-T cell distance for immunological synapse localization provide strongest costimulation. T cells transduced with CD200R-CD28 IFP show enhanced proliferation and effector function against CD200+ leukemic cells and eradicate disseminated leukemia in vivo more efficiently than wild-type T cells.","method":"Fusion protein engineering, in vitro T cell proliferation and cytokine assays, adoptive transfer in disseminated leukemia mouse model, human primary T cell transduction","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional fusion protein with multiple in vitro and in vivo readouts, single lab","pmids":["29042364"],"is_preprint":false},{"year":2025,"finding":"CD200R1 inhibits macrophage phagocytosis via the kinase Csk (not SHP-1/SHP-2 as used by SIRPα). Blocking or removing CD200R1 from macrophages or CD200 from tumor cells increases phagocytosis and suppresses tumor growth. In humans, CD200R1 is mainly expressed on immunosuppressive macrophages and is induced by IL-4. Combined blockade of CD200R1-CD200 and SIRPα-CD47 further boosts phagocytosis beyond either alone.","method":"CD200R1-deficient mice and macrophages, CD200 knockout tumor cells, phagocytosis assays, signaling pathway analysis (Csk vs SHP), IL-4 induction experiments, tumor growth models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — genetic KO with mechanistic identification of Csk as the effector kinase, in vitro and in vivo orthogonal readouts, single lab","pmids":["40461553"],"is_preprint":false},{"year":2023,"finding":"A humanized effectorless IgG1 antibody (23ME-00610) against CD200R1 binds human CD200R1 with high affinity (KD <0.1 nM), blocks CD200 binding, and inhibits recruitment of the downstream adaptor DOK2. It induces T-cell cytokine production and enhances T cell-mediated tumor cell killing in vitro and inhibits tumor growth in vivo.","method":"Antibody binding assay (KD measurement), CD200 competition assay, DOK2 recruitment assay, T cell cytokine and killing assays, in vivo tumor model","journal":"Oncoimmunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding, DOK2 recruitment inhibition, and functional T cell assays, single lab","pmids":["37288324"],"is_preprint":false},{"year":2016,"finding":"CD200R engagement on CD200R+ myeloid cells within CD200+ squamous cell carcinomas induces expression of cathepsin K (Ctsk), which promotes tumor cell migration and metastasis. Ctsk induction depends on CD200-CD200R axis engagement (shown in coculture system). Ctsk inhibition blocks cSCC migration in vitro, and CD200 disruption reduces metastasis in vivo.","method":"RNA sequencing of CD11B+CD200R+ cells, CD200R+ myeloid-cSCC coculture, Ctsk inhibition assays, CD200 disruption in tumor cells, in vivo metastasis model","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — coculture system demonstrating CD200-CD200R-dependent Ctsk induction plus in vivo validation, single lab","pmids":["34183355"],"is_preprint":false},{"year":2008,"finding":"Antibody-mediated blockade of CD200R1 in vivo aggravates experimental autoimmune encephalomyelitis (EAE) clinical course, with augmented T cell and activated iNOS+ macrophage infiltration. In vitro blockade of CD200R on macrophages co-cultured with CD200-expressing hippocampal neurons enhances IFN-γ-induced IL-6 release and neuronal cell death.","method":"Anti-CD200R blocking antibody in vivo (EAE model), co-culture of macrophages and neurons with CD200R blockade, cytokine ELISA, immunohistochemistry","journal":"Journal of neuroimmunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological blockade with in vivo and in vitro functional readouts, single lab","pmids":["18164423"],"is_preprint":false},{"year":2013,"finding":"Soluble CD200 inhibits osteoclast differentiation from precursors and their maturation into bone-resorbing cells in vitro by inhibiting the RANKL signaling pathway and gene expression of osteoclast markers OSCAR and NFATc1. MSC-mediated inhibition of osteoclast formation depends on cell-cell contact and is associated with CD200 expression on MSC surface (engaging CD200R on osteoclast precursors).","method":"In vitro osteoclast differentiation assay, soluble CD200 addition, gene expression analysis (RANKL pathway, OSCAR, NFATc1), MSC-osteoclast co-culture with CD200 expression correlation","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro reconstitution with pathway analysis, single lab","pmids":["23940819"],"is_preprint":false},{"year":2006,"finding":"CD200:CD200R1 interaction alters OPG:RANKL ratios to modulate bone formation: CD200Fc or endogenous CD200 overexpression in osteoblast precursors increases OPG:RANKL ratios and bone nodule growth in culture, while anti-CD200 abolishes this effect.","method":"Real-time PCR for OPG/RANKL mRNA, bone nodule quantification, CD200-overexpressing transgenic mouse calvariae, CD200Fc and anti-CD200 mAb treatments","journal":"Immunology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic and pharmacological approaches with functional bone formation readout, single lab","pmids":["16530849"],"is_preprint":false},{"year":2016,"finding":"Novel CD200 homologues iSEC1 and iSEC2, expressed exclusively by gastrointestinal secretory cells, bind CD200R1 (but not other CD200R family members). Binding of iSEC1 to CD200R on intraepithelial lymphocytes suppresses their cytokine production and cytolytic activity.","method":"Binding assay (iSEC1/iSEC2 to CD200R family members), IEL cytokine production and cytolysis assay after iSEC1 treatment","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding specificity and functional suppression assay, single lab","pmids":["27819346"],"is_preprint":false}],"current_model":"CD200R1 is an inhibitory immunoreceptor that, upon engagement by CD200 (or novel ligands such as iSEC1/iSEC2), undergoes Src-family-kinase-mediated phosphorylation at Y286 and Y297 in its cytoplasmic NPxY and adjacent motifs, recruiting the adaptors Dok1/Dok2 and the RasGAP p120-RasGAP to suppress Ras/MAPK and mTORC1 signaling in myeloid cells; in neutrophils, CD200R1 additionally mediates ROS production via Csk (rather than SHP-1/SHP-2) to inhibit phagocytosis and limit bacterial colonization; in ILC3s, CD200R1 paradoxically promotes STAT3 activation and IL-17 production; CD200R1 expression is transcriptionally repressed by C/EBPβ-HDAC1 in response to inflammatory stimuli, further regulated posttranscriptionally by miR-129-5p, and suppressed by stress-induced glucocorticoids, while PPAR-γ activation preserves its expression; type I IFN rewires CD200R1 signaling by causing cleavage of p120-RasGAP, converting the receptor from inhibitory to proinflammatory for TLR7/8-induced IFN-γ; CD200R1 also unexpectedly licenses TLR2 pro-inflammatory signaling and supports HSV-1 replication; and the receptor regulates osteoclastogenesis via the RANKL/NF-κB/MAPK axis downstream of RANK."},"narrative":{"mechanistic_narrative":"CD200R1 is an inhibitory immunoreceptor on myeloid and other immune cells that, upon engagement by its ligand CD200, dampens inflammatory and effector responses [PMID:17667818, PMID:40461553]. Ligand binding triggers Src-family-kinase-mediated phosphorylation of the cytoplasmic tail at Y286 and Y297, which recruits the inhibitory adaptors Dok1/Dok2 to suppress Ras/MAPK signaling [PMID:16330532]; the receptor relies on N-glycosylation at Asn44 for CD200 binding [PMID:30574022]. Through this axis CD200R1 restrains microglial activation via Dok1 [PMID:28792282], limits LPS-induced TNF-α and alloreactivity in vivo [PMID:17667818], and inhibits macrophage phagocytosis through the kinase Csk rather than the SHP phosphatases used by SIRPα, thereby supporting an immunosuppressive tumor-associated macrophage phenotype induced by IL-4 [PMID:40461553]. CD200R1 signaling is not uniformly inhibitory: type I interferon induces cleavage of the downstream effector p120-RasGAP, rewiring the receptor from inhibitory to proinflammatory for TLR7/8-induced IFN-γ [PMID:34637328]; in macrophages CD200R1 licenses TLR2 pro-inflammatory signaling and inflammasome assembly and supports HSV-1 replication [PMID:23082204]; in neutrophils it drives ROS production to limit bacterial colonization [PMID:31073183]; and in ILC3s it promotes STAT3 activation and IL-17 production [PMID:36623588]. Receptor abundance is tightly controlled: C/EBPβ together with HDAC1 represses CD200R1 transcription under inflammatory and stress conditions [PMID:22776069, PMID:29104062], miR-129-5p represses it posttranscriptionally [PMID:34952004], stress-induced glucocorticoids downregulate it [PMID:31078691], and PPAR-γ activation preserves its expression [PMID:24639050]. The CD200–CD200R1 axis additionally governs osteoclastogenesis through the RANKL/NF-κB/MAPK pathway downstream of RANK [PMID:17726108, PMID:23940819]. Beyond CD200, the gastrointestinal secretory-cell homologues iSEC1/iSEC2 are CD200R1-selective ligands that suppress intraepithelial lymphocyte function [PMID:27819346].","teleology":[{"year":2004,"claim":"Establishing that the secreted CD200 ectodomain physically engages a family of cell-surface CD200R isoforms defined which receptor (CD200R1) transduces immunomodulation.","evidence":"FACS binding of FITC-CD200Fc to transfected COS7 cells plus isoform-specific mAb functional assays and cloning of CD200R1–R4","pmids":["15187158","15274657"],"confidence":"Medium","gaps":["Binding affinities and structural basis of the CD200–CD200R1 interface not defined","Functional divergence among R2/R3 isoforms left unresolved"]},{"year":2005,"claim":"Identifying Y286/Y297 phosphorylation and Dok1/Dok2 recruitment defined the proximal inhibitory signaling machinery distinguishing CD200R1 from ITIM-bearing receptors.","evidence":"Site-directed tyrosine mutagenesis with mast cell activation readouts","pmids":["16330532"],"confidence":"High","gaps":["Which Src-family kinase phosphorylates the receptor in vivo not specified","Link to downstream RasGAP not yet established in this work"]},{"year":2007,"claim":"Genetic knockout proved the CD200:CD200R1 interaction is required for suppression of inflammatory cytokine output and alloreactivity in vivo, moving the receptor from correlation to causation.","evidence":"CD200R1−/− mice with TNF-α ELISA, mixed leukocyte culture, and skin graft rejection","pmids":["17667818"],"confidence":"High","gaps":["Cell-type-specific contributions only partially dissected","Downstream signaling in knockout not profiled"]},{"year":2007,"claim":"Demonstrating CD200R engagement is required for macrophage fusion and osteoclast differentiation extended the receptor's role beyond immune suppression into bone biology.","evidence":"shRNA silencing, soluble receptor ectodomain, and CD200−/− mice with in vitro differentiation and IHC","pmids":["17726108"],"confidence":"High","gaps":["Precise intracellular signaling linking CD200R1 to RANK-driven NF-κB/MAPK not resolved here"]},{"year":2013,"claim":"Soluble CD200 inhibition of osteoclast differentiation via the RANKL pathway clarified that the axis modulates OSCAR/NFATc1 induction during osteoclastogenesis.","evidence":"In vitro osteoclast differentiation with soluble CD200 and RANKL-pathway gene expression; MSC co-culture; earlier OPG:RANKL modulation in osteoblast cultures","pmids":["23940819","16530849"],"confidence":"Medium","gaps":["Apparent opposing effects on osteoclast formation across studies not mechanistically reconciled","Direct receptor-proximal signaling not assayed"]},{"year":2012,"claim":"Defining transcriptional (C/EBPβ-HDAC1) and posttranscriptional (miR-129-5p) repression explained how inflammatory stimuli lower CD200R1 to release the inhibitory brake.","evidence":"C/EBPβ-KO mice, ChIP, co-IP, HDAC inhibitors, and miR-129-5p 3'-UTR targeting with anti-miR rescue in microglia","pmids":["22776069","34952004"],"confidence":"High","gaps":["Integration of transcriptional and miRNA control into a single regulatory circuit not tested","Stimulus specificity of each mechanism incompletely mapped"]},{"year":2012,"claim":"The unexpected finding that CD200R1 is required for TLR2 pro-inflammatory signaling and HSV-1 replication revealed the receptor can act non-inhibitorily depending on context.","evidence":"CD200R1−/− macrophages, cytokine ELISA, inflammasome and TLR2 expression assays, HSV-1 infection model","pmids":["23082204"],"confidence":"High","gaps":["Molecular mechanism by which CD200R1 licenses TLR2 not defined","Relationship to canonical Dok/RasGAP signaling unknown"]},{"year":2016,"claim":"Discovery of CD200R1-selective ligands iSEC1/iSEC2 and a STAT3-promoting role in ILC3s showed the receptor has tissue-specific ligands and context-dependent, even pro-inflammatory, outputs.","evidence":"iSEC1/iSEC2 binding specificity and IEL suppression assays; CD200R1-deficient mice in psoriasis with STAT3 phosphorylation readout; cathepsin K induction in tumor myeloid cells","pmids":["27819346","36623588","34183355"],"confidence":"Medium","gaps":["Signaling distinction between inhibitory and STAT3-promoting outputs not resolved","How alternative ligands engage shared cytoplasmic machinery unknown"]},{"year":2019,"claim":"Identifying CD200R1-driven neutrophil ROS production as antibacterial established a protective, effector-promoting function in a defined infection.","evidence":"CD200R1−/− mice, F. tularensis infection, ROS assays, and neutrophil-niche depletion rescue","pmids":["31073183"],"confidence":"High","gaps":["Receptor-proximal signaling driving ROS not mapped","Ligand engaged in this setting not identified"]},{"year":2021,"claim":"Showing type I IFN cleaves p120-RasGAP to convert CD200R1 from inhibitory to proinflammatory provided a molecular switch explaining context-dependent receptor output and a link to SLE.","evidence":"IFN-α-treated human PBMCs, Western blot for cleaved p120-RasGAP and rpS6, TLR7/8-induced IFN-γ, SLE patient samples","pmids":["34637328"],"confidence":"Medium","gaps":["Protease responsible for p120-RasGAP cleavage not identified","Causal contribution to SLE pathology not established"]},{"year":2025,"claim":"Defining Csk (not SHP-1/SHP-2) as the effector kinase for CD200R1-mediated inhibition of phagocytosis distinguished its mechanism from SIRPα and rationalized combination blockade.","evidence":"CD200R1-deficient mice/macrophages, CD200-KO tumor cells, phagocytosis assays, Csk-vs-SHP signaling analysis, IL-4 induction, and combination with anti-CD47/SIRPα","pmids":["40461553"],"confidence":"High","gaps":["Direct biochemical link between phosphorylated CD200R1 and Csk recruitment not detailed","How Csk integrates with Dok/RasGAP axis unclear"]},{"year":null,"claim":"How a single receptor and its conserved Y286/Y297-Dok-RasGAP module produces opposite (inhibitory vs proinflammatory/STAT3-promoting) outputs across myeloid cells, neutrophils, and ILC3s remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model connecting Csk, Dok/RasGAP, p120-RasGAP cleavage, and STAT3 outputs","Structural basis of ligand-selective signaling (CD200 vs iSEC1/2) unknown","Cell-intrinsic determinants of inhibitory-versus-activating output undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,3,18]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,5,18]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,9]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,11,13,18]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,10]}],"complexes":[],"partners":["CD200","DOK1","DOK2","RASA1","CSK","ISEC1","ISEC2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8TD46","full_name":"Cell surface glycoprotein CD200 receptor 1","aliases":["CD200 cell surface glycoprotein receptor","Cell surface glycoprotein OX2 receptor 1"],"length_aa":348,"mass_kda":39.0,"function":"Inhibitory receptor for the CD200/OX2 cell surface glycoprotein. Limits inflammation by inhibiting the expression of pro-inflammatory molecules including TNF, interferons, and inducible nitric oxide synthase (iNOS) in response to selected stimuli. Also binds to HHV-8 K14 viral CD200 homolog with identical affinity and kinetics as the host CD200","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q8TD46/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CD200R1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CD200R1","total_profiled":1310},"omim":[{"mim_id":"621205","title":"MICRO RNA 129-2; MIR129-2","url":"https://www.omim.org/entry/621205"},{"mim_id":"621204","title":"MICRO RNA 129-1; MIR129-1","url":"https://www.omim.org/entry/621204"},{"mim_id":"607546","title":"CD200 RECEPTOR 1; 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Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/30195773","citation_count":14,"is_preprint":false},{"pmid":"26923638","id":"PMC_26923638","title":"Constitutively expressed Siglec-9 inhibits LPS-induced CCR7, but enhances IL-4-induced CD200R expression in human macrophages.","date":"2016","source":"Bioscience, biotechnology, and biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26923638","citation_count":14,"is_preprint":false},{"pmid":"20548263","id":"PMC_20548263","title":"Potent immunosuppression by a bivalent molecule binding to CD200R and TGF-betaR.","date":"2010","source":"Transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/20548263","citation_count":14,"is_preprint":false},{"pmid":"40461553","id":"PMC_40461553","title":"CD200R1-CD200 checkpoint inhibits phagocytosis differently from SIRPα-CD47 to suppress tumor growth.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/40461553","citation_count":13,"is_preprint":false},{"pmid":"38311677","id":"PMC_38311677","title":"CD200Rhigh neutrophils with dysfunctional autophagy establish systemic immunosuppression by increasing regulatory T cells.","date":"2024","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38311677","citation_count":13,"is_preprint":false},{"pmid":"35296683","id":"PMC_35296683","title":"Altered expression of the immunoregulatory ligand-receptor pair CD200-CD200R1 in the brain of Parkinson's disease patients.","date":"2022","source":"NPJ Parkinson's disease","url":"https://pubmed.ncbi.nlm.nih.gov/35296683","citation_count":13,"is_preprint":false},{"pmid":"27819346","id":"PMC_27819346","title":"Novel CD200 homologues iSEC1 and iSEC2 are gastrointestinal secretory cell-specific ligands of inhibitory receptor CD200R.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27819346","citation_count":13,"is_preprint":false},{"pmid":"34952004","id":"PMC_34952004","title":"MicroRNA-129-5p-regulated microglial expression of the surface receptor CD200R1 controls neuroinflammation.","date":"2021","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34952004","citation_count":12,"is_preprint":false},{"pmid":"37011735","id":"PMC_37011735","title":"Jingfang Granule alleviates bleomycin-induced acute lung injury via CD200-CD200R immunoregulatory pathway.","date":"2023","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37011735","citation_count":12,"is_preprint":false},{"pmid":"36623588","id":"PMC_36623588","title":"CD200R1 promotes interleukin-17 production by group 3 innate lymphoid cells by enhancing signal transducer and activator of transcription 3 activation.","date":"2023","source":"Mucosal immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36623588","citation_count":12,"is_preprint":false},{"pmid":"38237226","id":"PMC_38237226","title":"Activation of the CD200/CD200R1 axis improves cognitive impairment by enhancing hippocampal neurogenesis via suppression of M1 microglial polarization and neuroinflammation in hypoxic-ischemic neonatal rats.","date":"2024","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38237226","citation_count":12,"is_preprint":false},{"pmid":"34540085","id":"PMC_34540085","title":"The CD200/CD200R mechanism in mesenchymal stem cells' regulation of dendritic cells.","date":"2021","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/34540085","citation_count":12,"is_preprint":false},{"pmid":"32606391","id":"PMC_32606391","title":"Parkinsonian neurotoxicants impair the anti-inflammatory response induced by IL4 in glial cells: involvement of the CD200-CD200R1 ligand-receptor pair.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32606391","citation_count":12,"is_preprint":false},{"pmid":"29937142","id":"PMC_29937142","title":"High Expression of CD200 and CD200R1 Distinguishes Stem and Progenitor Cell Populations within Mammary Repopulating Units.","date":"2018","source":"Stem cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/29937142","citation_count":11,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52800,"output_tokens":7056,"usd":0.13212,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16235,"output_tokens":4127,"usd":0.092175,"stage2_stop_reason":"end_turn"},"total_usd":0.224295,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"CD200R1 cytoplasmic tail tyrosine residues Y286 and Y297 are the major phosphorylation sites required for CD200R-mediated inhibition of mast cell activation; Y289 is dispensable. Src family kinase mediates phosphorylation of CD200R and Dok. Phosphorylated CD200R recruits inhibitory adaptor proteins Dok1 and Dok2, leading to inhibition of Ras/MAPK activation.\",\n      \"method\": \"Site-directed mutagenesis of tyrosine residues, in vitro mast cell activation assays\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — site-directed mutagenesis with functional readout in cellular assay, single lab with multiple mutants tested\",\n      \"pmids\": [\"16330532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CD200Fc (extracellular domain of CD200) physically binds to each of the CD200R isoforms (CD200R1–R4) expressed on the cell surface, as shown by FACS with FITC-labeled CD200Fc on transfected COS7 cells. Anti-CD200R1/R4 mAbs elicit immunomodulatory responses comparable to CD200Fc (suppressing CTL and IL-2/IL-4), while anti-CD200R2/R3 show significantly lesser effects.\",\n      \"method\": \"FACS binding assay with FITC-labeled CD200Fc on transfected COS7 cells; functional assays with mAbs\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding demonstrated by FACS, functional differentiation between isoforms, single lab\",\n      \"pmids\": [\"15187158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"A family of CD200R isoforms (CD200R1–R4) was identified on mouse chromosome 16 juxtaposed to the CD200 gene. The isoforms show distinct tissue and cell-type expression patterns. Anti-CD200R1/R4 mAbs modulate allogeneic mixed-lymphocyte responses comparably to CD200Fc, whereas anti-CD200R2/R3 show different functional effects. CD200Fc physically interacts with each CD200R isoform on the cell surface.\",\n      \"method\": \"5'-RACE, cDNA and genomic DNA cloning, Northern blot, RT-PCR, FACS with rabbit polyclonal and rat monoclonal antibodies, mixed-lymphocyte response assays\",\n      \"journal\": \"American journal of reproductive immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (cloning, expression, FACS, functional assay), single lab\",\n      \"pmids\": [\"15274657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CD200R1 knockout mice show that the CD200:CD200R1 interaction is required for suppression of LPS-induced splenic TNF-α production and for CD200Fc-mediated suppression of mixed leukocyte culture alloreactivity. CD200R1 on both antigen-presenting cells and T responder cells contributes to maximal immunoregulation. CD200Fc fails to suppress graft rejection in CD200R1−/− mice.\",\n      \"method\": \"CD200R1 knockout mice generated by ES cell transformation; FACS, ELISA for TNF-α, mixed leukocyte culture, skin graft rejection model\",\n      \"journal\": \"Transplantation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with multiple orthogonal functional readouts, loss-of-function confirmed in vivo and in vitro\",\n      \"pmids\": [\"17667818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CD200R (expressed on myeloid cells including osteoclast precursors) engagement by CD200 (expressed on macrophages at onset of fusion) is required for macrophage fusion and osteoclast differentiation. CD200R knockdown by shRNA or addition of soluble CD200R extracellular domain prevents macrophage fusion. CD200−/− mice have fewer osteoclasts and more bone, consistent with CD200-CD200R controlling osteoclastogenesis via NF-κB and MAPK pathways downstream of RANK.\",\n      \"method\": \"shRNA silencing of CD200R, soluble recombinant CD200R extracellular domain addition, CD200−/− mice, in vitro differentiation assays, immunohistochemistry\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout, shRNA, and recombinant protein rescue experiments with multiple orthogonal readouts\",\n      \"pmids\": [\"17726108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD200R1 signaling inhibits microglial activation downstream via the Dok1 pathway. CD200Fc treatment after germinal matrix hemorrhage increased Dok1 expression and decreased IL-1β and TNF-α; these effects were abolished by CD200R1 siRNA and Dok1 siRNA, identifying a CD200R1/Dok1 signaling axis.\",\n      \"method\": \"siRNA knockdown of CD200R1 and Dok1, Western blot, CD200Fc treatment in rat GMH model\",\n      \"journal\": \"Journal of cerebral blood flow and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA loss-of-function for both receptor and adaptor with functional readouts, single lab in vivo model\",\n      \"pmids\": [\"28792282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD200R1 expression in microglia is negatively regulated by the transcription factor C/EBPβ: LPS-induced decrease in CD200R1 mRNA/protein is absent in C/EBPβ-deficient mice; C/EBPβ overexpression in BV2 cells reduces basal CD200R1 expression. C/EBPβ binds the CD200R1 promoter in LPS-treated glial cells. HDAC1 co-immunoprecipitates with C/EBPβ and binds the CD200R1 promoter region, and HDAC1 inhibitors reverse LPS-induced CD200R1 downregulation.\",\n      \"method\": \"Primary microglial cultures from WT and C/EBPβ-KO mice, C/EBPβ overexpression in BV2 cells, qChIP, co-immunoprecipitation, HDAC inhibitor treatment, qRT-PCR, Western blot\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — chromatin immunoprecipitation, genetic KO, overexpression, and co-IP with multiple orthogonal methods in single lab\",\n      \"pmids\": [\"22776069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PPAR-γ activation by the endogenous ligand 15d-PGJ2 prevents LPS/IFN-γ-induced downregulation of CD200R1 in reactive microglial cells and upregulation of CD200 in astrocytes. PPAR-γ-mediated neuroprotection in neuron-microglia co-cultures depends on CD200-CD200R1 interaction, as blocking this interaction abolishes the neuroprotective effect.\",\n      \"method\": \"Primary neuronal and glial cultures, neuron-microglia co-cultures, PPAR-γ agonist treatment, CD200-CD200R1 blocking, qRT-PCR, Western blot\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and blocking experiments with functional readout of neuroprotection, single lab\",\n      \"pmids\": [\"24639050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD200R1 expression in microglia is regulated posttranscriptionally by miR-129-5p, which binds the 3'-UTR of CD200R1 mRNA and shuttles it to cytoplasmic processing bodies. Arsenic demethylates the miR-129-5p promoter, increasing its expression and repressing CD200R1. Anti-miR-129 in vivo reversed CD200R1 downregulation and reduced IL-6 and TNF-α. A miR-129-5p→CD200R1→IL-6/TNF-α axis was confirmed by CD200R1 siRNA loss-of-function.\",\n      \"method\": \"In silico analysis, primary neonatal microglia and BV2 cells, stereotaxic anti-miR injection in mice, CD200R1 siRNA, qRT-PCR, promoter methylation analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo validation with siRNA and anti-miR, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"34952004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"N-glycosylation of CD200R1 at asparagine 44 (Asn44) is required for CD200-CD200R1 interaction; mutation of this site disrupts CD200 binding and upregulates proinflammatory markers (iNOS, CD86, IL-1β, TNF-α) in a neuronal-microglia co-culture system.\",\n      \"method\": \"Site-directed mutagenesis of glycosylation site, neuronal-microglia co-culture, cytokine measurement, binding assay\",\n      \"journal\": \"Journal of inflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — mutagenesis with functional readout but single lab, single paper\",\n      \"pmids\": [\"30574022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Type I interferon (IFN-α) rewires CD200R1 signaling from inhibitory to proinflammatory by inducing cleavage of p120-RasGAP, a downstream effector of CD200R1. In the presence of cleaved p120-RasGAP, CD200R loses its capacity to inhibit rpS6 phosphorylation (mTORC1). After IFN-α pretreatment, CD200R switches from inhibiting to potentiating TLR7/8-induced IFN-γ expression. SLE patient PBMCs have increased cleaved p120-RasGAP and altered CD200R function.\",\n      \"method\": \"Human PBMC treatment with IFN-α, Western blot for cleaved p120-RasGAP and rpS6 phosphorylation, cytokine measurement, patient samples from SLE\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic signaling experiments in primary human cells with patient validation, single lab\",\n      \"pmids\": [\"34637328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD200R1 is required for TLR2-mediated pro-inflammatory signaling in macrophages: CD200R1−/− peritoneal macrophages show 70–75% reduction in IL-6 and CCL5 in response to TLR2 agonist Pam2CSK4 and HSV-1. CD200R1−/− macrophages cannot upregulate TLR2 or assemble a functional inflammasome in response to HSV-1. CD200R1−/− mice are protected from HSV-1 infection, and CD200R1−/− fibroblasts and macrophages show reduced ability to support HSV-1 replication.\",\n      \"method\": \"CD200R1−/− mice, ex vivo macrophage assays, ELISA for cytokines, HSV-1 infection model, TLR2 expression assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with multiple orthogonal in vitro and in vivo readouts, unexpected proinflammatory licensing role established\",\n      \"pmids\": [\"23082204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD200R engagement on ILC3s promotes IL-17A production by enhancing STAT3 activation, contrary to its inhibitory role in myeloid cells. CD200R1-deficient mice show reduced psoriasis severity due to reduced IL-17 production, identifying a cell-intrinsic role of CD200R1 on ILC3s.\",\n      \"method\": \"CD200R1-deficient mice, psoriasis models, cytokine production assays, STAT3 phosphorylation analysis\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with cell-type-specific and signaling readouts, single lab\",\n      \"pmids\": [\"36623588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD200R1 deletion in mice leads to increased bacterial burden in neutrophils after Francisella tularensis infection. CD200R1-deficient neutrophils have significantly reduced reactive oxygen species (ROS) production, indicating CD200R1-mediated ROS production in neutrophils limits bacterial colonization. Depletion of the neutrophil niche in CD200R1−/− mice restores infection to wild-type levels.\",\n      \"method\": \"CD200R1−/− mice, in vivo F. tularensis infection, ROS assay, neutrophil depletion, bacterial burden quantification\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with mechanistic ROS assay and rescue experiment in vivo\",\n      \"pmids\": [\"31073183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Stress-induced reduction of CD200R expression in hippocampal microglia primes neuroinflammatory responses. CAAT/Enhancer Binding Protein β (C/EBPβ) is induced by stress and inversely associated with CD200R expression. Intracisterna magna administration of soluble CD200 (mCD200Fc) blocked stress-induced microglial priming, and mCD200R1Fc recapitulated the priming effect. CD200Fc also blocked stress-induced hippocampal HMGB1 increase.\",\n      \"method\": \"In vivo stressor exposure (inescapable tailshock), intracisterna magna injection of mCD200Fc or mCD200R1Fc, ex vivo microglial assays, qRT-PCR for CD200R and C/EBPβ, HMGB1 measurement\",\n      \"journal\": \"Brain, behavior, and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological gain and loss of CD200R function in vivo with multiple mechanistic readouts, single lab\",\n      \"pmids\": [\"29104062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Glucocorticoids mediate stress-induced reduction of CD200R1 in microglia: pharmacological GC receptor blockade (RU486) and adrenalectomy mitigated stress-induced CD200R1 downregulation; exogenous corticosterone reduced CD200R1 expression in vivo and in primary microglia in vitro, indicating direct GC action on microglia.\",\n      \"method\": \"Pharmacological blockade (RU486), adrenalectomy, exogenous CORT administration, primary microglia culture, qRT-PCR and protein expression\",\n      \"journal\": \"Brain, behavior, and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological interventions and in vitro confirmation, single lab\",\n      \"pmids\": [\"31078691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DNA aptamers binding murine CD200R1 act as agonists in the absence of CD200, inducing rapid phosphorylation of the CD200R1 cytoplasmic tail and initiating immune inhibitory signaling. They suppress CTL induction in allogeneic mixed leukocyte culture. Suppression is abolished with CD200R1−/− responder cells, confirming CD200R1-dependent mechanism. PEGylated aptamers enhance allogeneic skin graft survival comparably to CD200Fc in vivo.\",\n      \"method\": \"DNA aptamer SELEX, CD200R1 phosphorylation assay, mixed leukocyte culture CTL assay, CD200R1−/− cells as controls, in vivo skin graft model\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct phosphorylation assay plus genetic KO control and in vivo efficacy, single lab\",\n      \"pmids\": [\"25158092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A CD200R-CD28 fusion protein (immunomodulatory fusion protein, IFP) converts CD200R inhibitory signaling into CD28 costimulatory signaling in CD8+ T cells. IFPs containing a dimerizing motif and predicted tumor-T cell distance for immunological synapse localization provide strongest costimulation. T cells transduced with CD200R-CD28 IFP show enhanced proliferation and effector function against CD200+ leukemic cells and eradicate disseminated leukemia in vivo more efficiently than wild-type T cells.\",\n      \"method\": \"Fusion protein engineering, in vitro T cell proliferation and cytokine assays, adoptive transfer in disseminated leukemia mouse model, human primary T cell transduction\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional fusion protein with multiple in vitro and in vivo readouts, single lab\",\n      \"pmids\": [\"29042364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CD200R1 inhibits macrophage phagocytosis via the kinase Csk (not SHP-1/SHP-2 as used by SIRPα). Blocking or removing CD200R1 from macrophages or CD200 from tumor cells increases phagocytosis and suppresses tumor growth. In humans, CD200R1 is mainly expressed on immunosuppressive macrophages and is induced by IL-4. Combined blockade of CD200R1-CD200 and SIRPα-CD47 further boosts phagocytosis beyond either alone.\",\n      \"method\": \"CD200R1-deficient mice and macrophages, CD200 knockout tumor cells, phagocytosis assays, signaling pathway analysis (Csk vs SHP), IL-4 induction experiments, tumor growth models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — genetic KO with mechanistic identification of Csk as the effector kinase, in vitro and in vivo orthogonal readouts, single lab\",\n      \"pmids\": [\"40461553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A humanized effectorless IgG1 antibody (23ME-00610) against CD200R1 binds human CD200R1 with high affinity (KD <0.1 nM), blocks CD200 binding, and inhibits recruitment of the downstream adaptor DOK2. It induces T-cell cytokine production and enhances T cell-mediated tumor cell killing in vitro and inhibits tumor growth in vivo.\",\n      \"method\": \"Antibody binding assay (KD measurement), CD200 competition assay, DOK2 recruitment assay, T cell cytokine and killing assays, in vivo tumor model\",\n      \"journal\": \"Oncoimmunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding, DOK2 recruitment inhibition, and functional T cell assays, single lab\",\n      \"pmids\": [\"37288324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD200R engagement on CD200R+ myeloid cells within CD200+ squamous cell carcinomas induces expression of cathepsin K (Ctsk), which promotes tumor cell migration and metastasis. Ctsk induction depends on CD200-CD200R axis engagement (shown in coculture system). Ctsk inhibition blocks cSCC migration in vitro, and CD200 disruption reduces metastasis in vivo.\",\n      \"method\": \"RNA sequencing of CD11B+CD200R+ cells, CD200R+ myeloid-cSCC coculture, Ctsk inhibition assays, CD200 disruption in tumor cells, in vivo metastasis model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — coculture system demonstrating CD200-CD200R-dependent Ctsk induction plus in vivo validation, single lab\",\n      \"pmids\": [\"34183355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Antibody-mediated blockade of CD200R1 in vivo aggravates experimental autoimmune encephalomyelitis (EAE) clinical course, with augmented T cell and activated iNOS+ macrophage infiltration. In vitro blockade of CD200R on macrophages co-cultured with CD200-expressing hippocampal neurons enhances IFN-γ-induced IL-6 release and neuronal cell death.\",\n      \"method\": \"Anti-CD200R blocking antibody in vivo (EAE model), co-culture of macrophages and neurons with CD200R blockade, cytokine ELISA, immunohistochemistry\",\n      \"journal\": \"Journal of neuroimmunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological blockade with in vivo and in vitro functional readouts, single lab\",\n      \"pmids\": [\"18164423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Soluble CD200 inhibits osteoclast differentiation from precursors and their maturation into bone-resorbing cells in vitro by inhibiting the RANKL signaling pathway and gene expression of osteoclast markers OSCAR and NFATc1. MSC-mediated inhibition of osteoclast formation depends on cell-cell contact and is associated with CD200 expression on MSC surface (engaging CD200R on osteoclast precursors).\",\n      \"method\": \"In vitro osteoclast differentiation assay, soluble CD200 addition, gene expression analysis (RANKL pathway, OSCAR, NFATc1), MSC-osteoclast co-culture with CD200 expression correlation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro reconstitution with pathway analysis, single lab\",\n      \"pmids\": [\"23940819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CD200:CD200R1 interaction alters OPG:RANKL ratios to modulate bone formation: CD200Fc or endogenous CD200 overexpression in osteoblast precursors increases OPG:RANKL ratios and bone nodule growth in culture, while anti-CD200 abolishes this effect.\",\n      \"method\": \"Real-time PCR for OPG/RANKL mRNA, bone nodule quantification, CD200-overexpressing transgenic mouse calvariae, CD200Fc and anti-CD200 mAb treatments\",\n      \"journal\": \"Immunology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic and pharmacological approaches with functional bone formation readout, single lab\",\n      \"pmids\": [\"16530849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Novel CD200 homologues iSEC1 and iSEC2, expressed exclusively by gastrointestinal secretory cells, bind CD200R1 (but not other CD200R family members). Binding of iSEC1 to CD200R on intraepithelial lymphocytes suppresses their cytokine production and cytolytic activity.\",\n      \"method\": \"Binding assay (iSEC1/iSEC2 to CD200R family members), IEL cytokine production and cytolysis assay after iSEC1 treatment\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding specificity and functional suppression assay, single lab\",\n      \"pmids\": [\"27819346\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD200R1 is an inhibitory immunoreceptor that, upon engagement by CD200 (or novel ligands such as iSEC1/iSEC2), undergoes Src-family-kinase-mediated phosphorylation at Y286 and Y297 in its cytoplasmic NPxY and adjacent motifs, recruiting the adaptors Dok1/Dok2 and the RasGAP p120-RasGAP to suppress Ras/MAPK and mTORC1 signaling in myeloid cells; in neutrophils, CD200R1 additionally mediates ROS production via Csk (rather than SHP-1/SHP-2) to inhibit phagocytosis and limit bacterial colonization; in ILC3s, CD200R1 paradoxically promotes STAT3 activation and IL-17 production; CD200R1 expression is transcriptionally repressed by C/EBPβ-HDAC1 in response to inflammatory stimuli, further regulated posttranscriptionally by miR-129-5p, and suppressed by stress-induced glucocorticoids, while PPAR-γ activation preserves its expression; type I IFN rewires CD200R1 signaling by causing cleavage of p120-RasGAP, converting the receptor from inhibitory to proinflammatory for TLR7/8-induced IFN-γ; CD200R1 also unexpectedly licenses TLR2 pro-inflammatory signaling and supports HSV-1 replication; and the receptor regulates osteoclastogenesis via the RANKL/NF-κB/MAPK axis downstream of RANK.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CD200R1 is an inhibitory immunoreceptor on myeloid and other immune cells that, upon engagement by its ligand CD200, dampens inflammatory and effector responses [#3, #18]. Ligand binding triggers Src-family-kinase-mediated phosphorylation of the cytoplasmic tail at Y286 and Y297, which recruits the inhibitory adaptors Dok1/Dok2 to suppress Ras/MAPK signaling [#0]; the receptor relies on N-glycosylation at Asn44 for CD200 binding [#9]. Through this axis CD200R1 restrains microglial activation via Dok1 [#5], limits LPS-induced TNF-\\u03b1 and alloreactivity in vivo [#3], and inhibits macrophage phagocytosis through the kinase Csk rather than the SHP phosphatases used by SIRP\\u03b1, thereby supporting an immunosuppressive tumor-associated macrophage phenotype induced by IL-4 [#18]. CD200R1 signaling is not uniformly inhibitory: type I interferon induces cleavage of the downstream effector p120-RasGAP, rewiring the receptor from inhibitory to proinflammatory for TLR7/8-induced IFN-\\u03b3 [#10]; in macrophages CD200R1 licenses TLR2 pro-inflammatory signaling and inflammasome assembly and supports HSV-1 replication [#11]; in neutrophils it drives ROS production to limit bacterial colonization [#13]; and in ILC3s it promotes STAT3 activation and IL-17 production [#12]. Receptor abundance is tightly controlled: C/EBP\\u03b2 together with HDAC1 represses CD200R1 transcription under inflammatory and stress conditions [#6, #14], miR-129-5p represses it posttranscriptionally [#8], stress-induced glucocorticoids downregulate it [#15], and PPAR-\\u03b3 activation preserves its expression [#7]. The CD200\\u2013CD200R1 axis additionally governs osteoclastogenesis through the RANKL/NF-\\u03baB/MAPK pathway downstream of RANK [#4, #22]. Beyond CD200, the gastrointestinal secretory-cell homologues iSEC1/iSEC2 are CD200R1-selective ligands that suppress intraepithelial lymphocyte function [#24].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing that the secreted CD200 ectodomain physically engages a family of cell-surface CD200R isoforms defined which receptor (CD200R1) transduces immunomodulation.\",\n      \"evidence\": \"FACS binding of FITC-CD200Fc to transfected COS7 cells plus isoform-specific mAb functional assays and cloning of CD200R1\\u2013R4\",\n      \"pmids\": [\"15187158\", \"15274657\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding affinities and structural basis of the CD200\\u2013CD200R1 interface not defined\", \"Functional divergence among R2/R3 isoforms left unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identifying Y286/Y297 phosphorylation and Dok1/Dok2 recruitment defined the proximal inhibitory signaling machinery distinguishing CD200R1 from ITIM-bearing receptors.\",\n      \"evidence\": \"Site-directed tyrosine mutagenesis with mast cell activation readouts\",\n      \"pmids\": [\"16330532\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which Src-family kinase phosphorylates the receptor in vivo not specified\", \"Link to downstream RasGAP not yet established in this work\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Genetic knockout proved the CD200:CD200R1 interaction is required for suppression of inflammatory cytokine output and alloreactivity in vivo, moving the receptor from correlation to causation.\",\n      \"evidence\": \"CD200R1\\u2212/\\u2212 mice with TNF-\\u03b1 ELISA, mixed leukocyte culture, and skin graft rejection\",\n      \"pmids\": [\"17667818\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type-specific contributions only partially dissected\", \"Downstream signaling in knockout not profiled\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrating CD200R engagement is required for macrophage fusion and osteoclast differentiation extended the receptor's role beyond immune suppression into bone biology.\",\n      \"evidence\": \"shRNA silencing, soluble receptor ectodomain, and CD200\\u2212/\\u2212 mice with in vitro differentiation and IHC\",\n      \"pmids\": [\"17726108\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise intracellular signaling linking CD200R1 to RANK-driven NF-\\u03baB/MAPK not resolved here\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Soluble CD200 inhibition of osteoclast differentiation via the RANKL pathway clarified that the axis modulates OSCAR/NFATc1 induction during osteoclastogenesis.\",\n      \"evidence\": \"In vitro osteoclast differentiation with soluble CD200 and RANKL-pathway gene expression; MSC co-culture; earlier OPG:RANKL modulation in osteoblast cultures\",\n      \"pmids\": [\"23940819\", \"16530849\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Apparent opposing effects on osteoclast formation across studies not mechanistically reconciled\", \"Direct receptor-proximal signaling not assayed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defining transcriptional (C/EBP\\u03b2-HDAC1) and posttranscriptional (miR-129-5p) repression explained how inflammatory stimuli lower CD200R1 to release the inhibitory brake.\",\n      \"evidence\": \"C/EBP\\u03b2-KO mice, ChIP, co-IP, HDAC inhibitors, and miR-129-5p 3'-UTR targeting with anti-miR rescue in microglia\",\n      \"pmids\": [\"22776069\", \"34952004\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Integration of transcriptional and miRNA control into a single regulatory circuit not tested\", \"Stimulus specificity of each mechanism incompletely mapped\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"The unexpected finding that CD200R1 is required for TLR2 pro-inflammatory signaling and HSV-1 replication revealed the receptor can act non-inhibitorily depending on context.\",\n      \"evidence\": \"CD200R1\\u2212/\\u2212 macrophages, cytokine ELISA, inflammasome and TLR2 expression assays, HSV-1 infection model\",\n      \"pmids\": [\"23082204\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which CD200R1 licenses TLR2 not defined\", \"Relationship to canonical Dok/RasGAP signaling unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Discovery of CD200R1-selective ligands iSEC1/iSEC2 and a STAT3-promoting role in ILC3s showed the receptor has tissue-specific ligands and context-dependent, even pro-inflammatory, outputs.\",\n      \"evidence\": \"iSEC1/iSEC2 binding specificity and IEL suppression assays; CD200R1-deficient mice in psoriasis with STAT3 phosphorylation readout; cathepsin K induction in tumor myeloid cells\",\n      \"pmids\": [\"27819346\", \"36623588\", \"34183355\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling distinction between inhibitory and STAT3-promoting outputs not resolved\", \"How alternative ligands engage shared cytoplasmic machinery unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identifying CD200R1-driven neutrophil ROS production as antibacterial established a protective, effector-promoting function in a defined infection.\",\n      \"evidence\": \"CD200R1\\u2212/\\u2212 mice, F. tularensis infection, ROS assays, and neutrophil-niche depletion rescue\",\n      \"pmids\": [\"31073183\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor-proximal signaling driving ROS not mapped\", \"Ligand engaged in this setting not identified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showing type I IFN cleaves p120-RasGAP to convert CD200R1 from inhibitory to proinflammatory provided a molecular switch explaining context-dependent receptor output and a link to SLE.\",\n      \"evidence\": \"IFN-\\u03b1-treated human PBMCs, Western blot for cleaved p120-RasGAP and rpS6, TLR7/8-induced IFN-\\u03b3, SLE patient samples\",\n      \"pmids\": [\"34637328\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Protease responsible for p120-RasGAP cleavage not identified\", \"Causal contribution to SLE pathology not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defining Csk (not SHP-1/SHP-2) as the effector kinase for CD200R1-mediated inhibition of phagocytosis distinguished its mechanism from SIRP\\u03b1 and rationalized combination blockade.\",\n      \"evidence\": \"CD200R1-deficient mice/macrophages, CD200-KO tumor cells, phagocytosis assays, Csk-vs-SHP signaling analysis, IL-4 induction, and combination with anti-CD47/SIRP\\u03b1\",\n      \"pmids\": [\"40461553\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical link between phosphorylated CD200R1 and Csk recruitment not detailed\", \"How Csk integrates with Dok/RasGAP axis unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single receptor and its conserved Y286/Y297-Dok-RasGAP module produces opposite (inhibitory vs proinflammatory/STAT3-promoting) outputs across myeloid cells, neutrophils, and ILC3s remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model connecting Csk, Dok/RasGAP, p120-RasGAP cleavage, and STAT3 outputs\", \"Structural basis of ligand-selective signaling (CD200 vs iSEC1/2) unknown\", \"Cell-intrinsic determinants of inhibitory-versus-activating output undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 3, 18]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 5, 18]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 11, 13, 18]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CD200\", \"DOK1\", \"DOK2\", \"RASA1\", \"CSK\", \"iSEC1\", \"iSEC2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}