{"gene":"CD300C","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2013,"finding":"CD300C delivers an FcR-γ-dependent activating signal in mast cells and monocytes; FcR-γ is indispensable for both efficient surface expression and activating functions of CD300C. Phosphatidylethanolamine (PE) and apoptotic cells were identified as ligands for CD300C, though PE binds less strongly to CD300C than to CD300A. The differential recognition of PE by CD300A versus CD300C depends on distinct amino acid residues (CD300A F56-L57 vs CD300C L63-R64). Co-expression of full-length CD300A dampens CD300C-mediated PE signaling.","method":"Reporter cell lines expressing chimeric receptors (extracellular CD300C + intracellular CD3ζ), antibody cross-linking, cytokine/chemokine production assays, co-expression experiments, generation of discriminating antibodies","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (reporter assays, cross-linking, co-expression, discriminating antibodies), single lab with rigorous controls","pmids":["23372157"],"is_preprint":false},{"year":2013,"finding":"CD300C is an activating receptor expressed exclusively on monocytes among freshly isolated blood leukocytes; cross-linking of CD300C induces calcium mobilization, upregulation of CD86, and production of inflammatory cytokines. LPS-mediated cytokine production is further enhanced by simultaneous CD300C engagement.","method":"Flow cytometry with specific monoclonal antibody (clone TX45), calcium mobilization assay, cytokine production assays, in vitro monocyte differentiation experiments","journal":"Journal of innate immunity","confidence":"High","confidence_rationale":"Tier 2 — specific antibody-based functional assays with multiple readouts, confirmed on primary cells","pmids":["23571507"],"is_preprint":false},{"year":2016,"finding":"CD300C is uniquely and specifically expressed on CD56bright NK cells (not CD56dim) upon IL-2 or IL-15 stimulation; upregulation requires STAT5 signaling and is inhibited by IL-4. Cross-linking CD300C on CD56bright NK cells enhances degranulation and cytokine/chemokine secretion. CD300C and CD300A differ in binding strength to phosphatidylethanolamine (PE) and phosphatidylserine (PS), and differentially affect CD56bright NK cell functions.","method":"Flow cytometry, cytokine neutralization, STAT5 inhibition experiments, antibody cross-linking, degranulation assays","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal experiments (signaling pathway, ligand binding, functional assays) on primary cells","pmids":["27040328"],"is_preprint":false},{"year":2018,"finding":"CD300C functions as a costimulatory activating receptor on basophils; coligation of FcεRI and CD300C increases intracellular calcium mobilization and phosphorylation of signaling intermediates beyond FcεRI alone, and enhances degranulation and cytokine production. The natural ligands phosphatidylserine and phosphatidylethanolamine modulate IgE-mediated basophil activation through CD300C.","method":"Flow cytometry, calcium mobilization assay, phosphorylation assays, degranulation assays, cytokine production assays, basophil isolation and stimulation","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal assays with primary human basophils establishing ligand and signaling mechanism","pmids":["29906528"],"is_preprint":false},{"year":2018,"finding":"CD300C functions as a novel T cell co-inhibitory molecule; soluble CD300c-Fc fusion protein significantly inhibits proliferation, activation, and cytokine production by CD4+ and CD8+ T cells in vitro, and its putative counter-receptor is expressed on T cells and upregulated upon activation. In vivo, CD300c-Fc protein attenuates graft-versus-host disease in mice.","method":"Soluble Fc-fusion protein experiments, T cell proliferation and cytokine assays, in vivo GVHD mouse model","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 — functional in vitro and in vivo data, but the counter-receptor remains unidentified","pmids":["30498497"],"is_preprint":false},{"year":2022,"finding":"CD300c-Ig fusion protein attenuates collagen-induced arthritis in mice, with reduced T cell expansion and activation in spleen, reduced pro-inflammatory cytokines in joints, inhibition of CII-specific T cell proliferation and Th1/Th17 cytokine production, and reduced CII autoantibody production.","method":"CIA mouse model (prevention and treatment), histopathological scoring, cytokine ELISA, T cell proliferation assays, flow cytometry","journal":"Rheumatology (Oxford, England)","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo model with multiple mechanistic readouts confirming T cell inhibitory function, single lab","pmids":["34021311"],"is_preprint":false},{"year":2023,"finding":"CD300C engagement by monoclonal antibody CL7 induces monocyte differentiation to M1 macrophages, evidenced by upregulated M1-specific surface markers and increased M1-specific cytokine secretion. The mechanism involves MAPK and NF-κB signaling pathways. CL7 treatment upregulated PD-L1 on THP-1 cells and reduced tumor size in a CT26 mouse model.","method":"Monoclonal antibody engagement, flow cytometry, cytokine secretion assays, NF-κB and MAPK pathway inhibition, in vivo tumor mouse model","journal":"Immunobiology","confidence":"Medium","confidence_rationale":"Tier 2 — defined signaling pathway (MAPK/NF-κB) with functional phenotype, in vitro and in vivo, single lab","pmids":["38159528"],"is_preprint":false},{"year":1998,"finding":"The CMRF-35 antigen (a founding member of the CD300 family encoded by the CMRF-35-H9 cDNA, which was later designated CD300C) is a type I cell surface glycoprotein with a single Ig V-like domain; its cytoplasmic tail contains motifs similar to inhibitory motifs found in some leukocyte surface receptors, suggesting a regulatory role in leukocyte function.","method":"Expression cloning, cDNA isolation, structural analysis of predicted cytoplasmic motifs","journal":"International immunology","confidence":"Medium","confidence_rationale":"Tier 3 — initial molecular characterization by cloning, single method, foundational but limited functional follow-up in the paper","pmids":["9701027"],"is_preprint":false},{"year":2025,"finding":"CD300c-specific antibody CB201 promotes differentiation of monocytes to monocyte-derived macrophages (MDMs), reduces cerebral amyloid-β plaque load, and improves memory and behavior in 5xFAD mice; CB201-differentiated macrophages express cytokines and chemokines that alleviate AD-related pathology.","method":"Surface plasmon resonance, ELISAs, in vitro macrophage differentiation assays, 5xFAD mouse model behavioral and histological analyses","journal":"Biomedicines","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro and in vivo data, single lab, multiple readouts","pmids":["40426995"],"is_preprint":false},{"year":2025,"finding":"Evolutionary analysis confirms CD300A and CD300C form a paired receptor system recognizing shared lipid ligands (phosphatidylserine, phosphatidylethanolamine) but mediating opposing signals (CD300A inhibitory, CD300C activating); evidence of gene conversion between CD300A and CD300C preserves extracellular domain similarity despite divergent signaling functions.","method":"Phylogenetic reconstruction, synteny analysis, functional motif conservation analysis, pseudogene identification across 62 sequences from 33 primate species","journal":"Frontiers in immunology","confidence":"Low","confidence_rationale":"Tier 4 — computational/evolutionary analysis only, no direct functional experiment","pmids":["40977689"],"is_preprint":false}],"current_model":"CD300C is an activating immunoreceptor expressed on monocytes, mast cells, basophils, and CD56bright NK cells that signals through association with FcR-γ (required for surface expression and activation); it recognizes phosphatidylethanolamine and phosphatidylserine on apoptotic cells as natural ligands, triggers calcium mobilization, MAPK, and NF-κB signaling to induce cytokine production, degranulation, and macrophage M1 polarization, and functions as a T cell co-inhibitory molecule when presented by antigen-presenting cells via an unidentified counter-receptor."},"narrative":{"teleology":[{"year":1998,"claim":"Initial molecular cloning established CD300C (CMRF-35-H9) as a type I transmembrane glycoprotein with a single IgV-like ectodomain and cytoplasmic regulatory motifs, placing it among leukocyte receptors with potential signaling roles.","evidence":"Expression cloning and cDNA structural analysis","pmids":["9701027"],"confidence":"Medium","gaps":["No functional signaling data provided","Cell-type expression pattern not systematically defined","No ligand identified"]},{"year":2013,"claim":"Two studies established that CD300C is an FcR-γ-dependent activating receptor on monocytes and mast cells, identified phosphatidylethanolamine and apoptotic cells as ligands, and showed that co-expression of the inhibitory receptor CD300A dampens CD300C-mediated signaling, revealing a paired receptor system.","evidence":"Reporter cell lines with chimeric receptors, antibody cross-linking, calcium mobilization, cytokine assays, co-expression experiments on primary monocytes","pmids":["23372157","23571507"],"confidence":"High","gaps":["Structural basis for differential PE binding between CD300A and CD300C not resolved at atomic level","Signaling intermediates downstream of FcR-γ not fully mapped","In vivo significance of paired receptor balance not tested"]},{"year":2016,"claim":"CD300C was shown to be selectively induced on CD56bright NK cells by IL-2/IL-15 via STAT5 signaling, extending its functional relevance beyond myeloid cells and demonstrating that it enhances NK cell degranulation and cytokine secretion.","evidence":"Flow cytometry, STAT5 inhibition, cytokine neutralization, degranulation assays on primary NK cell subsets","pmids":["27040328"],"confidence":"High","gaps":["Whether CD300C ligands on target cells directly trigger NK killing not tested","Functional interplay with CD300A on NK cells in vivo not addressed"]},{"year":2018,"claim":"CD300C was identified as a costimulatory activating receptor on basophils that amplifies FcεRI-mediated responses, and separately as a T cell co-inhibitory molecule whose soluble form suppresses T cell activation and attenuates GVHD in vivo, revealing a dual role depending on cellular context.","evidence":"Basophil phosphorylation/degranulation assays with primary cells; soluble CD300c-Fc fusion protein T cell proliferation assays and in vivo GVHD mouse model","pmids":["29906528","30498497"],"confidence":"High","gaps":["T cell counter-receptor for CD300C not identified","Whether the T cell inhibitory function operates in cis or trans on antigen-presenting cells not resolved","Relative contribution of PS versus PE binding to basophil costimulation unclear"]},{"year":2022,"claim":"The T cell co-inhibitory function of CD300C was validated in a second autoimmune model, showing that CD300c-Ig fusion attenuates collagen-induced arthritis by suppressing Th1/Th17 responses and autoantibody production.","evidence":"CIA mouse model with prevention and treatment arms, cytokine ELISA, T cell proliferation, flow cytometry","pmids":["34021311"],"confidence":"Medium","gaps":["Counter-receptor identity still unknown","Mechanism of action on antigen-specific T cells (direct vs indirect) not delineated","All in vivo data from single laboratory"]},{"year":2023,"claim":"The downstream signaling mechanism of CD300C in monocyte-to-macrophage differentiation was defined as MAPK- and NF-κB-dependent, and antibody-mediated CD300C engagement drove M1 polarization with PD-L1 upregulation and antitumor activity in vivo.","evidence":"Monoclonal antibody CL7, pathway inhibition in THP-1 cells, CT26 tumor mouse model","pmids":["38159528"],"confidence":"Medium","gaps":["Whether antitumor effect is macrophage-autonomous or requires adaptive immunity not resolved","Direct NF-κB/MAPK activation versus indirect effects not fully dissected","Relevance to human tumors not established"]},{"year":2025,"claim":"Antibody-mediated CD300C engagement was shown to promote macrophage differentiation that clears amyloid-β plaques and improves cognition in a 5xFAD Alzheimer's disease mouse model, extending the receptor's therapeutic relevance to neurodegeneration.","evidence":"CB201 antibody, surface plasmon resonance, in vitro macrophage differentiation, 5xFAD mouse behavioral and histological analysis","pmids":["40426995"],"confidence":"Medium","gaps":["Mechanism by which CD300C-differentiated macrophages clear Aβ not defined","Single mouse model, single lab","Human CNS relevance of peripheral monocyte-derived macrophage effects unconfirmed"]},{"year":null,"claim":"The identity of the T cell counter-receptor for CD300C remains unknown, and the structural basis for how the same IgV domain mediates activating signaling on myeloid/NK cells while delivering co-inhibitory signals to T cells has not been resolved.","evidence":"","pmids":[],"confidence":"High","gaps":["Counter-receptor identification needed","No crystal structure of CD300C ectodomain or CD300C–lipid complex","In vivo relevance of paired CD300A/CD300C balance in human disease not directly demonstrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,2,3]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,2,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,2,3,7]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,2,3,6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3,6]}],"complexes":[],"partners":["FCER1G","CD300A"],"other_free_text":[]},"mechanistic_narrative":"CD300C is an activating immunoreceptor of the immunoglobulin superfamily that functions as a paired counterpart to the inhibitory receptor CD300A, recognizing the shared lipid ligands phosphatidylethanolamine and phosphatidylserine on apoptotic cells but transducing activating signals through obligate association with the FcR-γ adaptor chain [PMID:23372157, PMID:29906528]. Expressed on monocytes, basophils, mast cells, and cytokine-stimulated CD56bright NK cells, CD300C cross-linking triggers calcium mobilization, MAPK and NF-κB signaling, degranulation, inflammatory cytokine production, and monocyte-to-M1 macrophage differentiation [PMID:23571507, PMID:27040328, PMID:38159528]. CD300C also functions as a T cell co-inhibitory molecule when presented as a soluble Fc-fusion protein, suppressing T cell proliferation and cytokine secretion and attenuating graft-versus-host disease and collagen-induced arthritis in mouse models, though its T cell counter-receptor remains unidentified [PMID:30498497, PMID:34021311]. Antibody-mediated CD300C engagement on monocytes promotes macrophage differentiation that reduces amyloid-β plaque burden in a mouse model of Alzheimer's disease [PMID:40426995]."},"prefetch_data":{"uniprot":{"accession":"Q08708","full_name":"CMRF35-like molecule 6","aliases":["CD300 antigen-like family member C","CMRF35-A1","CMRF-35","Immunoglobulin superfamily member 16","IgSF16"],"length_aa":224,"mass_kda":24.8,"function":"","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q08708/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CD300C","classification":"Not Classified","n_dependent_lines":18,"n_total_lines":1208,"dependency_fraction":0.014900662251655629},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CD300C","total_profiled":1310},"omim":[{"mim_id":"616560","title":"CD300H ANTIGEN; CD300H","url":"https://www.omim.org/entry/616560"},{"mim_id":"616301","title":"CD300 ANTIGEN-LIKE FAMILY, MEMBER D; CD300LD","url":"https://www.omim.org/entry/616301"},{"mim_id":"610705","title":"CD300 ANTIGEN-LIKE FAMILY, MEMBER B; CD300LB","url":"https://www.omim.org/entry/610705"},{"mim_id":"609807","title":"CD300 ANTIGEN-LIKE FAMILY, MEMBER F; CD300LF","url":"https://www.omim.org/entry/609807"},{"mim_id":"609801","title":"CD300E ANTIGEN; CD300E","url":"https://www.omim.org/entry/609801"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Golgi apparatus","reliability":"Uncertain"},{"location":"Vesicles","reliability":"Additional"},{"location":"Mitochondria","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":9.2},{"tissue":"lung","ntpm":7.9},{"tissue":"lymphoid tissue","ntpm":6.9}],"url":"https://www.proteinatlas.org/search/CD300C"},"hgnc":{"alias_symbol":["CMRF35","LIR","CMRF-35A","CMRF35A","IGSF16"],"prev_symbol":[]},"alphafold":{"accession":"Q08708","domains":[{"cath_id":"2.60.40.10","chopping":"28-135","consensus_level":"medium","plddt":91.4229,"start":28,"end":135}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q08708","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q08708-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q08708-F1-predicted_aligned_error_v6.png","plddt_mean":74.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CD300C","jax_strain_url":"https://www.jax.org/strain/search?query=CD300C"},"sequence":{"accession":"Q08708","fasta_url":"https://rest.uniprot.org/uniprotkb/Q08708.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q08708/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q08708"}},"corpus_meta":[{"pmid":"23908376","id":"PMC_23908376","title":"The 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Phosphatidylethanolamine (PE) and apoptotic cells were identified as ligands for CD300C, though PE binds less strongly to CD300C than to CD300A. The differential recognition of PE by CD300A versus CD300C depends on distinct amino acid residues (CD300A F56-L57 vs CD300C L63-R64). Co-expression of full-length CD300A dampens CD300C-mediated PE signaling.\",\n      \"method\": \"Reporter cell lines expressing chimeric receptors (extracellular CD300C + intracellular CD3ζ), antibody cross-linking, cytokine/chemokine production assays, co-expression experiments, generation of discriminating antibodies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (reporter assays, cross-linking, co-expression, discriminating antibodies), single lab with rigorous controls\",\n      \"pmids\": [\"23372157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CD300C is an activating receptor expressed exclusively on monocytes among freshly isolated blood leukocytes; cross-linking of CD300C induces calcium mobilization, upregulation of CD86, and production of inflammatory cytokines. LPS-mediated cytokine production is further enhanced by simultaneous CD300C engagement.\",\n      \"method\": \"Flow cytometry with specific monoclonal antibody (clone TX45), calcium mobilization assay, cytokine production assays, in vitro monocyte differentiation experiments\",\n      \"journal\": \"Journal of innate immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — specific antibody-based functional assays with multiple readouts, confirmed on primary cells\",\n      \"pmids\": [\"23571507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD300C is uniquely and specifically expressed on CD56bright NK cells (not CD56dim) upon IL-2 or IL-15 stimulation; upregulation requires STAT5 signaling and is inhibited by IL-4. Cross-linking CD300C on CD56bright NK cells enhances degranulation and cytokine/chemokine secretion. CD300C and CD300A differ in binding strength to phosphatidylethanolamine (PE) and phosphatidylserine (PS), and differentially affect CD56bright NK cell functions.\",\n      \"method\": \"Flow cytometry, cytokine neutralization, STAT5 inhibition experiments, antibody cross-linking, degranulation assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal experiments (signaling pathway, ligand binding, functional assays) on primary cells\",\n      \"pmids\": [\"27040328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CD300C functions as a costimulatory activating receptor on basophils; coligation of FcεRI and CD300C increases intracellular calcium mobilization and phosphorylation of signaling intermediates beyond FcεRI alone, and enhances degranulation and cytokine production. The natural ligands phosphatidylserine and phosphatidylethanolamine modulate IgE-mediated basophil activation through CD300C.\",\n      \"method\": \"Flow cytometry, calcium mobilization assay, phosphorylation assays, degranulation assays, cytokine production assays, basophil isolation and stimulation\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal assays with primary human basophils establishing ligand and signaling mechanism\",\n      \"pmids\": [\"29906528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CD300C functions as a novel T cell co-inhibitory molecule; soluble CD300c-Fc fusion protein significantly inhibits proliferation, activation, and cytokine production by CD4+ and CD8+ T cells in vitro, and its putative counter-receptor is expressed on T cells and upregulated upon activation. In vivo, CD300c-Fc protein attenuates graft-versus-host disease in mice.\",\n      \"method\": \"Soluble Fc-fusion protein experiments, T cell proliferation and cytokine assays, in vivo GVHD mouse model\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional in vitro and in vivo data, but the counter-receptor remains unidentified\",\n      \"pmids\": [\"30498497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CD300c-Ig fusion protein attenuates collagen-induced arthritis in mice, with reduced T cell expansion and activation in spleen, reduced pro-inflammatory cytokines in joints, inhibition of CII-specific T cell proliferation and Th1/Th17 cytokine production, and reduced CII autoantibody production.\",\n      \"method\": \"CIA mouse model (prevention and treatment), histopathological scoring, cytokine ELISA, T cell proliferation assays, flow cytometry\",\n      \"journal\": \"Rheumatology (Oxford, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo model with multiple mechanistic readouts confirming T cell inhibitory function, single lab\",\n      \"pmids\": [\"34021311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CD300C engagement by monoclonal antibody CL7 induces monocyte differentiation to M1 macrophages, evidenced by upregulated M1-specific surface markers and increased M1-specific cytokine secretion. The mechanism involves MAPK and NF-κB signaling pathways. CL7 treatment upregulated PD-L1 on THP-1 cells and reduced tumor size in a CT26 mouse model.\",\n      \"method\": \"Monoclonal antibody engagement, flow cytometry, cytokine secretion assays, NF-κB and MAPK pathway inhibition, in vivo tumor mouse model\",\n      \"journal\": \"Immunobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined signaling pathway (MAPK/NF-κB) with functional phenotype, in vitro and in vivo, single lab\",\n      \"pmids\": [\"38159528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The CMRF-35 antigen (a founding member of the CD300 family encoded by the CMRF-35-H9 cDNA, which was later designated CD300C) is a type I cell surface glycoprotein with a single Ig V-like domain; its cytoplasmic tail contains motifs similar to inhibitory motifs found in some leukocyte surface receptors, suggesting a regulatory role in leukocyte function.\",\n      \"method\": \"Expression cloning, cDNA isolation, structural analysis of predicted cytoplasmic motifs\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — initial molecular characterization by cloning, single method, foundational but limited functional follow-up in the paper\",\n      \"pmids\": [\"9701027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CD300c-specific antibody CB201 promotes differentiation of monocytes to monocyte-derived macrophages (MDMs), reduces cerebral amyloid-β plaque load, and improves memory and behavior in 5xFAD mice; CB201-differentiated macrophages express cytokines and chemokines that alleviate AD-related pathology.\",\n      \"method\": \"Surface plasmon resonance, ELISAs, in vitro macrophage differentiation assays, 5xFAD mouse model behavioral and histological analyses\",\n      \"journal\": \"Biomedicines\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo data, single lab, multiple readouts\",\n      \"pmids\": [\"40426995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Evolutionary analysis confirms CD300A and CD300C form a paired receptor system recognizing shared lipid ligands (phosphatidylserine, phosphatidylethanolamine) but mediating opposing signals (CD300A inhibitory, CD300C activating); evidence of gene conversion between CD300A and CD300C preserves extracellular domain similarity despite divergent signaling functions.\",\n      \"method\": \"Phylogenetic reconstruction, synteny analysis, functional motif conservation analysis, pseudogene identification across 62 sequences from 33 primate species\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — computational/evolutionary analysis only, no direct functional experiment\",\n      \"pmids\": [\"40977689\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD300C is an activating immunoreceptor expressed on monocytes, mast cells, basophils, and CD56bright NK cells that signals through association with FcR-γ (required for surface expression and activation); it recognizes phosphatidylethanolamine and phosphatidylserine on apoptotic cells as natural ligands, triggers calcium mobilization, MAPK, and NF-κB signaling to induce cytokine production, degranulation, and macrophage M1 polarization, and functions as a T cell co-inhibitory molecule when presented by antigen-presenting cells via an unidentified counter-receptor.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CD300C is an activating immunoreceptor of the immunoglobulin superfamily that functions as a paired counterpart to the inhibitory receptor CD300A, recognizing the shared lipid ligands phosphatidylethanolamine and phosphatidylserine on apoptotic cells but transducing activating signals through obligate association with the FcR-γ adaptor chain [PMID:23372157, PMID:29906528]. Expressed on monocytes, basophils, mast cells, and cytokine-stimulated CD56bright NK cells, CD300C cross-linking triggers calcium mobilization, MAPK and NF-κB signaling, degranulation, inflammatory cytokine production, and monocyte-to-M1 macrophage differentiation [PMID:23571507, PMID:27040328, PMID:38159528]. CD300C also functions as a T cell co-inhibitory molecule when presented as a soluble Fc-fusion protein, suppressing T cell proliferation and cytokine secretion and attenuating graft-versus-host disease and collagen-induced arthritis in mouse models, though its T cell counter-receptor remains unidentified [PMID:30498497, PMID:34021311]. Antibody-mediated CD300C engagement on monocytes promotes macrophage differentiation that reduces amyloid-β plaque burden in a mouse model of Alzheimer's disease [PMID:40426995].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Initial molecular cloning established CD300C (CMRF-35-H9) as a type I transmembrane glycoprotein with a single IgV-like ectodomain and cytoplasmic regulatory motifs, placing it among leukocyte receptors with potential signaling roles.\",\n      \"evidence\": \"Expression cloning and cDNA structural analysis\",\n      \"pmids\": [\"9701027\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional signaling data provided\", \"Cell-type expression pattern not systematically defined\", \"No ligand identified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Two studies established that CD300C is an FcR-γ-dependent activating receptor on monocytes and mast cells, identified phosphatidylethanolamine and apoptotic cells as ligands, and showed that co-expression of the inhibitory receptor CD300A dampens CD300C-mediated signaling, revealing a paired receptor system.\",\n      \"evidence\": \"Reporter cell lines with chimeric receptors, antibody cross-linking, calcium mobilization, cytokine assays, co-expression experiments on primary monocytes\",\n      \"pmids\": [\"23372157\", \"23571507\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for differential PE binding between CD300A and CD300C not resolved at atomic level\", \"Signaling intermediates downstream of FcR-γ not fully mapped\", \"In vivo significance of paired receptor balance not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"CD300C was shown to be selectively induced on CD56bright NK cells by IL-2/IL-15 via STAT5 signaling, extending its functional relevance beyond myeloid cells and demonstrating that it enhances NK cell degranulation and cytokine secretion.\",\n      \"evidence\": \"Flow cytometry, STAT5 inhibition, cytokine neutralization, degranulation assays on primary NK cell subsets\",\n      \"pmids\": [\"27040328\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CD300C ligands on target cells directly trigger NK killing not tested\", \"Functional interplay with CD300A on NK cells in vivo not addressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"CD300C was identified as a costimulatory activating receptor on basophils that amplifies FcεRI-mediated responses, and separately as a T cell co-inhibitory molecule whose soluble form suppresses T cell activation and attenuates GVHD in vivo, revealing a dual role depending on cellular context.\",\n      \"evidence\": \"Basophil phosphorylation/degranulation assays with primary cells; soluble CD300c-Fc fusion protein T cell proliferation assays and in vivo GVHD mouse model\",\n      \"pmids\": [\"29906528\", \"30498497\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"T cell counter-receptor for CD300C not identified\", \"Whether the T cell inhibitory function operates in cis or trans on antigen-presenting cells not resolved\", \"Relative contribution of PS versus PE binding to basophil costimulation unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The T cell co-inhibitory function of CD300C was validated in a second autoimmune model, showing that CD300c-Ig fusion attenuates collagen-induced arthritis by suppressing Th1/Th17 responses and autoantibody production.\",\n      \"evidence\": \"CIA mouse model with prevention and treatment arms, cytokine ELISA, T cell proliferation, flow cytometry\",\n      \"pmids\": [\"34021311\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Counter-receptor identity still unknown\", \"Mechanism of action on antigen-specific T cells (direct vs indirect) not delineated\", \"All in vivo data from single laboratory\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The downstream signaling mechanism of CD300C in monocyte-to-macrophage differentiation was defined as MAPK- and NF-κB-dependent, and antibody-mediated CD300C engagement drove M1 polarization with PD-L1 upregulation and antitumor activity in vivo.\",\n      \"evidence\": \"Monoclonal antibody CL7, pathway inhibition in THP-1 cells, CT26 tumor mouse model\",\n      \"pmids\": [\"38159528\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether antitumor effect is macrophage-autonomous or requires adaptive immunity not resolved\", \"Direct NF-κB/MAPK activation versus indirect effects not fully dissected\", \"Relevance to human tumors not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Antibody-mediated CD300C engagement was shown to promote macrophage differentiation that clears amyloid-β plaques and improves cognition in a 5xFAD Alzheimer's disease mouse model, extending the receptor's therapeutic relevance to neurodegeneration.\",\n      \"evidence\": \"CB201 antibody, surface plasmon resonance, in vitro macrophage differentiation, 5xFAD mouse behavioral and histological analysis\",\n      \"pmids\": [\"40426995\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which CD300C-differentiated macrophages clear Aβ not defined\", \"Single mouse model, single lab\", \"Human CNS relevance of peripheral monocyte-derived macrophage effects unconfirmed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The identity of the T cell counter-receptor for CD300C remains unknown, and the structural basis for how the same IgV domain mediates activating signaling on myeloid/NK cells while delivering co-inhibitory signals to T cells has not been resolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Counter-receptor identification needed\", \"No crystal structure of CD300C ectodomain or CD300C–lipid complex\", \"In vivo relevance of paired CD300A/CD300C balance in human disease not directly demonstrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 2, 3]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 2, 3, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 2, 3, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"FCER1G\",\n      \"CD300A\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}