{"gene":"CD84","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2001,"finding":"CD84 functions as a homophilic adhesion molecule: a soluble CD84-Ig fusion protein binds specifically to CD84-transfected cells but not to cells expressing other CD2 subfamily receptors, establishing CD84 as its own ligand. Blocking with anti-CD84 mAbs recognizing epitopes in domain 1 abolished this binding, and CD84/mouse chimeras showed only the first extracellular Ig-like domain mediates ligand-receptor recognition. The CD84-CD84 interaction was independent of its cytoplasmic tail.","method":"Soluble Ig fusion protein binding assay, anti-CD84 mAb blocking, human/mouse domain chimeras","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with soluble fusion protein, domain mapping with chimeras, multiple orthogonal methods in one study","pmids":["11564780"],"is_preprint":false},{"year":2001,"finding":"CD84 cytoplasmic tail recruits SAP (SH2D1A, the X-linked lymphoproliferative disease gene product) via phosphorylated tyrosine residues in its cytoplasmic tail; recruitment is most efficient when specific tyrosine residues are phosphorylated, as demonstrated by yeast two-hybrid, COS cell transfection assays, and experiments in lymphoid cells.","method":"Yeast two-hybrid, COS cell transfection, co-immunoprecipitation in lymphoid cells","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (yeast two-hybrid, transfection, lymphoid cell assays) replicated across SLAM family members","pmids":["11389028"],"is_preprint":false},{"year":2002,"finding":"CD84 is rapidly tyrosine phosphorylated following antibody ligation on B cells and recruits the cytoplasmic adaptor proteins SAP and EAT-2 via phosphorylated tyrosine residues in its cytoplasmic tail, as shown in primary human B cells.","method":"Anti-CD84 mAb ligation, tyrosine phosphorylation assay, co-immunoprecipitation of SAP and EAT-2","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal pulldown of SAP and EAT-2 from primary human B cells, replicated SAP recruitment finding from PMID 11389028","pmids":["12115647"],"is_preprint":false},{"year":2003,"finding":"SAP recruitment to CD84 requires tyrosine phosphorylation of CD84, is mediated specifically by Y262 within the CD84 cytoplasmic domain and by R32 within the SH2 domain of SAP. The Src kinase Lck is required for CD84 tyrosine phosphorylation upon receptor ligation in activated T cells. CD84 ligation also enhances T cell proliferation via a SAP-independent mechanism.","method":"Site-directed mutagenesis of CD84 (Y262) and SAP (R32), in vitro phosphorylation, co-immunoprecipitation, T cell proliferation assay using SAP-deficient XLP patient cells","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis of specific residues combined with functional assays in primary SAP-deficient patient cells","pmids":["12928397"],"is_preprint":false},{"year":2007,"finding":"Crystal structure of the human CD84 immunoglobulin variable domain at 2.0 Å resolution reveals an orthogonal homophilic dimer. Solution studies showed CD84 self-associates with a Kd in the submicromolar range. Structural and chemical differences in the homophilic interfaces provide a mechanism to prevent formation of undesired heterodimers among SLAM family homophilic receptors.","method":"X-ray crystallography (2.0 Å), analytical ultracentrifugation for solution Kd measurement","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with quantitative solution binding measurements, rigorous structural study","pmids":["17563375"],"is_preprint":false},{"year":2010,"finding":"CD84 is required for prolonged T cell:B cell contact, optimal T follicular helper function, and germinal center formation in vivo. While T cell:DC interactions were primarily integrin-dependent, T cell:B cell interactions had an early integrin-dependent phase and a sustained SAP- and CD84-dependent phase. Both CD84 and Ly108 mediated T cell adhesion and participated in stable T cell:B cell interactions in vitro.","method":"In vivo immunization of CD84-deficient mice, in vitro T cell:B cell conjugation assays, intravital two-photon microscopy","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with defined in vivo GC phenotype plus in vitro adhesion assay, replicated with Ly108 as orthogonal control","pmids":["20153220"],"is_preprint":false},{"year":2010,"finding":"Mouse CD84 modulates TLR4-downstream signaling in macrophages: transfection of CD84 in RAW-264.7 macrophages increased MAPK phosphorylation and NF-κB activation upon LPS stimulation and altered cytokine secretion (increased TNF-α and MCP-1, decreased IL-10 and IL-6). This modulatory effect was dependent on Y300 within the second ITSM of CD84. CD84 knockdown in bone marrow-derived macrophages decreased TNF-α and IL-6 production.","method":"CD84 transfection in RAW-264.7 cells, site-directed mutagenesis (Y300), MAPK/NF-κB phosphorylation assays, cytokine ELISA, CD84 siRNA knockdown in BMDMs","journal":"Journal of leukocyte biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis identifying the functional ITSM tyrosine, combined with gain- and loss-of-function assays in multiple macrophage systems","pmids":["20628063"],"is_preprint":false},{"year":2010,"finding":"EAT-2A and EAT-2B adapters are positive regulators of CD84-dependent NK cell cytotoxicity in C57BL/6 mice. NK cells from EAT-2A- and EAT-2A/B-deficient mice were unable to kill tumor cells in a CD84-dependent manner. EAT-2A/B positively regulate phosphorylation of Vav-1 downstream of CD84.","method":"EAT-2A/B-deficient mouse generation (CRISPR/gene targeting in C57BL/6 ES cells), NK cell cytotoxicity assays, Vav-1 phosphorylation analysis","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean genetic knockout with defined NK cytotoxicity phenotype and downstream signaling readout (Vav-1 phosphorylation)","pmids":["20962259"],"is_preprint":false},{"year":2008,"finding":"CD84 inhibits FcεRI-mediated mast cell degranulation through homophilic interaction in CD84-transfected RBL-2H3 cells. This inhibition involves phosphorylation of Dok-1 and c-Cbl and impairs MAP kinase phosphorylation (ERK1/2, JNK, p38) and cytokine synthesis. CD84 mutants at tyrosines Y279F and ΔY324 reversed the inhibitory profile, and the mechanism is independent of SAP and SHP-2 recruitment.","method":"CD84 transfection in RBL-2H3 cells, site-directed mutagenesis (Y279F, ΔY324), Western blot for Dok-1/c-Cbl phosphorylation, MAPK phosphorylation assays, degranulation assays","journal":"Molecular immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis of functional tyrosines combined with multiple signaling pathway readouts","pmids":["18243321"],"is_preprint":false},{"year":2011,"finding":"In human mast cells, CD84 is tyrosine phosphorylated upon FcεRI engagement, inhibits FcεRI-mediated calcium mobilization and the Syk-LAT-PLCγ1 signaling axis, and reduces degranulation and cytokine (IL-8, GM-CSF) release. The inhibitory mechanism is SAP- and EAT-2-independent but depends on the inhibitory kinase Fes (which phosphorylates the inhibitory ITSM motif on CD84 and itself becomes phosphorylated upon CD84 coexpression) and SHP-1.","method":"Co-cross-linking of FcεRI and CD84 in LAD2 and primary CD34+-derived human mast cells, calcium flux assay, phosphorylation assays, Fes co-expression/phosphorylation experiments","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mechanistic dissection with multiple signaling pathway assays in both cell line and primary human cells, with identification of Fes as the responsible kinase","pmids":["22068234"],"is_preprint":false},{"year":2012,"finding":"CD84 on platelets is subject to dual regulation by ectodomain shedding and intracellular cleavage. ADAM10 is the principal sheddase responsible for CD84 ectodomain cleavage (ADAM17 is dispensable), while calpain mediates intracellular cleavage of the CD84 C-terminus simultaneously with but independently of ectodomain shedding. CD84 is also constitutively shed from the platelet surface by ADAM10 in vivo.","method":"Biochemical shedding assays, ADAM10-deficient, ADAM17-deficient, and calpain-inhibitor-treated mouse and human platelets, Western blot, plasma/serum analysis from transgenic mice","journal":"Journal of thrombosis and haemostasis","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic mouse models (ADAM10 KO, ADAM17 KO) combined with pharmacological inhibition and in vitro/in vivo biochemical validation, multiple orthogonal approaches","pmids":["23025437"],"is_preprint":false},{"year":2013,"finding":"In CLL, CD84 expression is regulated by macrophage migration inhibitory factor (MIF) and its receptor CD74. Activation of surface CD84 initiates a signaling cascade that enhances CLL cell survival. Downmodulation of CD84 or its immune-mediated blockade induces cell death in vitro and in vivo. Downstream, CD84 activation correlates with Bcl-2 and Mcl-1 expression.","method":"CD84 knockdown/blocking antibody in CLL cells in vitro and in vivo, MIF/CD74 stimulation assays, Bcl-2/Mcl-1 protein level measurements, clinical sample analysis (milatuzumab trial)","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined survival phenotype in vitro and in vivo, but mechanistic pathway placement (MIF→CD74→CD84→Bcl-2/Mcl-1) is partially correlative","pmids":["23435417"],"is_preprint":false},{"year":2015,"finding":"SLAMF1, SLAMF5, and SLAMF6 act as negative regulators of humoral immunity. In triple knockout mice, both T-dependent and T-independent antibody responses were approximately twofold higher. Adoptive co-transfer experiments showed both [Slamf1+5+6]-/- B and T cells contributed to enhanced responses, with B cell-intrinsic activity being more pronounced. SLAMF5-deficient B cells enhanced T-independent type 2 antigen responses, indicating a B cell-intrinsic suppressive role.","method":"Triple knockout mice (Slamf1/5/6), adoptive co-transfer assays, T-dependent and T-independent immunization, anti-SLAMF6 mAb treatment","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic triple knockout with adoptive transfer establishing B cell-intrinsic mechanism, but SLAMF5-specific contribution is not fully dissected from combined phenotype","pmids":["25926831"],"is_preprint":false},{"year":2015,"finding":"B cell-intrinsic expression of CD84 (and Ly108) at germinal center B cells maintains B cell tolerance. Overexpression of B6 alleles of CD84 and Ly108 on autoimmune-prone B6.Sle1b background reduced GC response and autoantibody production. Lupus-associated CD84/Ly108 alleles on GC B cells were sufficient to break B cell tolerance. B6.Sle1b B cells showed reduced BCR signaling and lower B cell-T cell conjugate frequency.","method":"BAC-transgenic mice overexpressing B6 alleles of CD84 and Ly108, autoantibody ELISA, GC B cell analysis by flow cytometry, B cell-T cell conjugate assay, BCR signaling assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic gain-of-function with functional tolerance readouts, but CD84 and Ly108 are studied together and individual contributions are not fully separated","pmids":["25801429"],"is_preprint":false},{"year":2016,"finding":"CD84 expressed on CLL cells interacts homophilically with CD84 on stromal microenvironment cells, promoting survival signaling in both CLL and stromal cells. Blocking CD84 in vitro and in vivo disrupts CLL-microenvironment interaction and induces cell death in CLL cells.","method":"In vitro co-culture of CLL cells with stromal cells, CD84-blocking antibody in vitro and in vivo CLL mouse model, cell death/survival assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — both in vitro and in vivo blocking experiments with defined survival phenotype, consistent with homophilic interaction mechanism","pmids":["27452524"],"is_preprint":false},{"year":2016,"finding":"CRISPR-mediated triple disruption of Slamf1, Slamf5, and Slamf6 in mice worsened iNKT cell developmental defects seen in SLAMF6 single gene-targeted mice, supporting positive signaling roles for these receptors and potential functional redundancy among them in iNKT development.","method":"Cas9/CRISPR triple knockout generation in C57BL/6 mice, flow cytometric analysis of iNKT and conventional lymphocyte populations","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic triple KO with defined iNKT developmental phenotype, but SLAMF5-specific contribution cannot be fully separated from SLAMF1/6","pmids":["27258160"],"is_preprint":false},{"year":2018,"finding":"Cell-cell interaction mediated through CD84 upregulates PD-L1 expression on CLL cells and their microenvironment, and upregulates PD-1 expression on T cells. This resulted in suppression of T cell responses in vitro and in vivo, establishing CD84 as a regulator of PD-1/PD-L1 immune checkpoint expression in CLL.","method":"CD84 homophilic cell-cell interaction assays, CD84 blocking/KO in human and mouse CLL models in vitro and in vivo, PD-L1/PD-1 expression by flow cytometry, T cell functional assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic linkage of CD84 interaction to PD-L1/PD-1 upregulation demonstrated in both human and mouse systems in vitro and in vivo","pmids":["30277471"],"is_preprint":false},{"year":2020,"finding":"CD84 on platelets drives cerebral thromboinflammation after ischemic stroke. Platelet-derived soluble CD84 (shed by ADAM10) enhances motility of wild-type but not CD84-deficient CD4+ T cells in vitro, demonstrating that homophilic CD84 interactions between platelet-derived sCD84 and T cell-expressed CD84 drive T cell migration.","method":"CD84 conditional knockout mice (platelet- or T cell-specific), in vitro T cell motility assay with platelet-derived sCD84, experimental stroke (tMCAO) model, flow cytometry for T cell infiltration, clinical sample analysis","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific genetic knockouts combined with defined mechanistic in vitro assay (sCD84-driven T cell motility), with clinical validation","pmids":["32762491"],"is_preprint":false},{"year":2021,"finding":"SLAMF5 (CD84) negatively controls the survival and function of IL-10-producing regulatory B cells. SLAMF5 deficiency in B cells causes accumulation of IL-10+ Bregs in EAE. Blocking SLAMF5 in vitro induces IL-10-producing Breg cells and increases their survival with a concomitant increase in transcription factor c-Maf. In vivo SLAMF5 blocking elevates IL-10+ Breg levels and ameliorates EAE severity.","method":"SLAMF5 conditional B cell knockout in EAE model, in vitro SLAMF5 blocking antibody in human and mouse B cells, c-Maf expression analysis, in vivo blocking experiment","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout and pharmacological blocking in both mouse and human cells, mechanistic link to c-Maf identified, in vivo functional consequence demonstrated","pmids":["33767202"],"is_preprint":false},{"year":2021,"finding":"In multiple myeloma, tumor cells secrete MIF, which induces CD84 expression on microenvironmental cells. CD84 activation on these cells elevates expression of genes regulating differentiation toward M-MDSCs and G-MDSCs and upregulates PD-L1 expression on MDSCs, which suppresses T cell function. Downregulation or blocking of CD84 reduces MDSC accumulation and elevated T cell activity.","method":"MIF stimulation of microenvironment cells, CD84 knockdown/blocking antibody, MDSC differentiation assays, PD-L1 expression by flow cytometry, T cell functional assays, in vivo tumor models","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined MDSC/PD-L1/T cell phenotype, MIF-to-CD84 pathway established by stimulation assay, single lab","pmids":["33465053"],"is_preprint":false},{"year":2024,"finding":"CD84 is a substrate/target of BTK kinase in neutrophils during alcohol-induced granulopoiesis. BTK inhibition (evobrutinib) or myeloid-specific Btk knockout reduced granulopoiesis and liver neutrophil infiltration in alcohol-associated hepatitis. CD84 was identified as a BTK substrate by liquid chromatography-tandem mass spectrometry, and CD84-blocking antibody inhibited alcohol-induced IL-1β and TNF-α in primary human neutrophils.","method":"LC-MS/MS kinase substrate identification, BTK inhibitor treatment, Btk myeloid-specific KO mice, CD84-blocking antibody in primary human neutrophils, cytokine ELISA","journal":"Science translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-based substrate identification combined with in vivo genetic KO and in vitro blocking assay, but direct phosphorylation site validation not described in abstract","pmids":["39110779"],"is_preprint":false},{"year":2024,"finding":"CD84 induces a signaling cascade in regulatory B cells (Bregs) in triple-negative breast cancer involving the β-catenin and Tcf4 pathway, leading to transcription of IL-10 by direct binding to the IL-10 promoter and the promoter of its regulator AhR. This expands Bregs and suppresses anti-tumor immune activity.","method":"CD84 manipulation in Bregs, β-catenin/Tcf4 pathway analysis, promoter binding (ChIP or reporter assay implied), IL-10 production assays, immune cell activity assays, in vivo TNBC models","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway (CD84→β-catenin/Tcf4→IL-10/AhR) identified with promoter binding evidence; single lab study","pmids":["39466774"],"is_preprint":false},{"year":2024,"finding":"CCL2-secreted by mesenchymal glioma stem cells induces IKZF1 expression, which promotes CD84 expression on tumor-associated macrophages. CD84 activates the SHP2 pathway to drive M2 polarization of TAMs.","method":"GSC-TAM co-culture, CCL2 stimulation, IKZF1 knockdown/inhibition, CD84 expression analysis, SHP2 pathway assays, animal glioma models with IKZF1 inhibitors","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway (CCL2→IKZF1→CD84→SHP2) demonstrated by co-culture and gene manipulation, single lab","pmids":["39112517"],"is_preprint":false},{"year":2025,"finding":"In AML, CD84 regulates energy metabolism and mitochondrial dynamics. CD84 depletion altered mitochondrial ultrastructure and function, caused downmodulation of oxidative phosphorylation and fatty acid oxidation pathways, blocked Akt phosphorylation, and downmodulated NRF2. Conversely, CD84 overexpression stabilized NRF2 and promoted its transcriptional activation, supporting redox homeostasis and mitochondrial function. CD84 loss blocked leukemia engraftment and clonogenicity in MLL-AF9 and inv(16) AML mouse models.","method":"CD84 knockdown in human AML cell lines and PDX cells, CD84 overexpression, Akt/NRF2 pathway analysis, mitochondrial ultrastructure/function assays (electron microscopy implied), AML mouse models (MLL-AF9, inv(16))","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain- and loss-of-function with defined metabolic mechanism (Akt/NRF2/mitochondria) validated in both human cells and two independent mouse AML models","pmids":["40198133"],"is_preprint":false},{"year":2025,"finding":"CD84 promotes AML cell growth via the NHEJ DNA repair pathway. CD84 recruits SAP and activates the AKT signaling pathway to promote expression of NHEJ core factors (PRKDC, LIG4, XRCC5, DCLRE1C). Knockdown of CD84 inhibits NHEJ repair, leading to double-strand break accumulation and apoptosis. CD84 is required for proliferation and self-renewal of human leukemia-initiating cells.","method":"CD84 knockdown in AML cell lines and xenograft models, SAP co-immunoprecipitation, AKT pathway analysis, NHEJ factor expression analysis, DSB accumulation (γH2AX), LIC functional assays","journal":"Molecules and cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined mechanistic pathway (CD84→SAP→AKT→NHEJ factors) with multiple molecular readouts in a single lab, consistent with PMID 40198133 but different mechanism proposed","pmids":["40633676"],"is_preprint":false},{"year":2025,"finding":"SLAMF5 deficiency in myeloid cells (microglia and macrophages) leads to decreased expression of activation and costimulatory molecules including MHC class II and CD80 in EAE. This downregulation is mediated through transcription factor BHLHE40 and its regulation of CD52, resulting in delayed onset and reduced EAE progression. Pharmacological blockade of SLAMF5 in the brain halted disease progression. In human iPSC-derived microglia and MS patient monocytes, SLAMF5 blockade reduced HLA-DR, CD80, and CD52 expression.","method":"Total and brain-specific SLAMF5 myeloid conditional KO in EAE, BHLHE40 pathway analysis, pharmacological brain blockade, iPSC-derived microglia from MS patients, flow cytometry","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — myeloid cell-specific genetic KO with defined molecular mechanism (BHLHE40/CD52 axis), validated pharmacologically and in human cells across multiple orthogonal approaches","pmids":["40920820"],"is_preprint":false},{"year":2000,"finding":"CD84 exists as five isoforms (CD84a–e) generated by alternative exon usage, reading frame shifts, cryptic splice sites, or absence of splicing. The five isoforms differ in their cytoplasmic domains and contain differentially distributed potentially phosphorylatable residues, providing a potential mechanism to regulate signal transduction activity.","method":"cDNA library screening, RT-PCR, genomic structure determination (at least 8 exons identified)","journal":"Tissue antigens","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct genomic/cDNA characterization across multiple isoforms, but functional consequences of isoform differences not directly tested","pmids":["10746783"],"is_preprint":false}],"current_model":"CD84 (SLAMF5) is a self-ligand homophilic adhesion molecule of the SLAM immunoreceptor family whose Ig-like variable domain forms a submicromolar orthogonal dimer (crystal structure resolved at 2.0 Å); upon receptor engagement and Lck-dependent tyrosine phosphorylation of its ITSM motifs, the cytoplasmic tail recruits SAP (via Y262) and EAT-2 as positive signaling adapters, or Fes kinase and SHP-1 as inhibitory mediators depending on cell type; homophilic CD84 trans-interactions stabilize prolonged T:B cell contact required for germinal center formation, bridge CLL cells to their stromal microenvironment to promote survival, and drive platelet-T cell thromboinflammatory crosstalk via ADAM10-shed soluble CD84; in macrophages CD84 amplifies TLR4/LPS-induced MAPK/NF-κB signaling through its second ITSM tyrosine (Y300), in mast cells it negatively regulates FcεRI via Fes/SHP-1, in NK cells EAT-2A/B mediate CD84-dependent cytotoxicity through Vav-1 phosphorylation, in regulatory B cells SLAMF5 suppresses IL-10 production and c-Maf, and in AML cells CD84 sustains survival through NRF2-dependent redox homeostasis/mitochondrial function and Akt-driven NHEJ DNA repair."},"narrative":{"mechanistic_narrative":"CD84 (SLAMF5) is a self-ligand homophilic cell-surface adhesion receptor of the SLAM immunoreceptor family that converts cell-cell contact into intracellular signaling to regulate immune cell interactions, survival, and effector function [PMID:11564780, PMID:17563375]. Homophilic recognition is mediated exclusively by the membrane-distal Ig-like domain 1, which forms a submicromolar orthogonal dimer whose interface chemistry discriminates CD84 from other SLAM family members to prevent heterodimerization [PMID:11564780, PMID:17563375]. Engagement triggers Lck-dependent tyrosine phosphorylation of cytoplasmic ITSM motifs, which then function as a phospho-tyrosine switch: phosphorylated Y262 recruits the adaptors SAP and EAT-2 as positive signaling mediators, while in other cell contexts the receptor instead engages the inhibitory kinase Fes and the phosphatase SHP-1 [PMID:11389028, PMID:12115647, PMID:12928397, PMID:22068234]. This bidirectional output underlies opposing cell-type-specific roles: CD84 sustains prolonged T:B cell contact required for T follicular helper function and germinal center formation [PMID:20153220], drives EAT-2/Vav-1-dependent NK cytotoxicity [PMID:20962259], and amplifies TLR4/LPS-induced MAPK and NF-κB signaling in macrophages through the second ITSM tyrosine Y300 [PMID:20628063], yet negatively regulates FcεRI signaling in mast cells via Fes/SHP-1 [PMID:22068234] and suppresses IL-10-producing regulatory B cells through c-Maf [PMID:33767202]. In disease, homophilic CD84 trans-interactions bridge chronic lymphocytic leukemia cells to their stromal microenvironment to promote survival and upregulate PD-L1/PD-1 checkpoint expression [PMID:27452524, PMID:30277471], platelet-derived soluble CD84 shed by ADAM10 enhances T cell motility to drive cerebral thromboinflammation after stroke [PMID:23025437, PMID:32762491], and in AML CD84 sustains leukemic survival through NRF2-dependent redox/mitochondrial homeostasis and SAP/Akt-driven NHEJ DNA repair [PMID:40198133, PMID:40633676].","teleology":[{"year":2001,"claim":"Establishing that CD84 is its own ligand answered whether this orphan SLAM-family receptor signals through homophilic contact, and localized recognition to a single Ig domain.","evidence":"Soluble CD84-Ig fusion binding, anti-CD84 domain-1 mAb blocking, and human/mouse domain chimeras","pmids":["11564780"],"confidence":"High","gaps":["Did not resolve the structural basis or affinity of the homophilic interaction","Cytoplasmic signaling output not addressed"]},{"year":2002,"claim":"Identifying SAP and EAT-2 recruitment to the phosphorylated cytoplasmic tail defined the intracellular signaling adaptors that link CD84 ligation to downstream events in B cells.","evidence":"Yeast two-hybrid, COS transfection, and co-immunoprecipitation of SAP and EAT-2 from primary human B cells after mAb ligation","pmids":["11389028","12115647"],"confidence":"High","gaps":["Specific tyrosine residues and the kinase responsible were not yet mapped","Functional consequence of adaptor recruitment unresolved"]},{"year":2003,"claim":"Mapping SAP recruitment to CD84 Y262 and SAP R32 and identifying Lck as the kinase established the precise phospho-tyrosine switch driving positive signaling.","evidence":"Site-directed mutagenesis of CD84 and SAP, in vitro phosphorylation, and T cell proliferation assays in SAP-deficient XLP patient cells","pmids":["12928397"],"confidence":"High","gaps":["SAP-independent proliferation pathway not mechanistically defined","Did not address inhibitory signaling outputs"]},{"year":2007,"claim":"The 2.0 Å crystal structure and solution Kd answered how CD84 achieves homophilic specificity, revealing an orthogonal dimer with an interface that excludes heterodimers.","evidence":"X-ray crystallography of the Ig variable domain and analytical ultracentrifugation","pmids":["17563375"],"confidence":"High","gaps":["Did not capture full-length receptor or cytoplasmic conformation","In situ clustering geometry at cell contacts not resolved"]},{"year":2010,"claim":"Genetic and imaging studies established CD84 as a physiological mediator of sustained T:B contact required for germinal center formation, giving the homophilic receptor an in vivo developmental function.","evidence":"In vivo immunization of CD84-deficient mice, in vitro conjugation assays, and intravital two-photon microscopy","pmids":["20153220"],"confidence":"High","gaps":["Contribution of CD84 separated only partially from Ly108","Downstream signaling sustaining contact not detailed"]},{"year":2008,"claim":"Discovering that CD84 inhibits FcεRI signaling in mast cells revealed that the same receptor can produce inhibitory output, and that this is SAP-independent.","evidence":"CD84 transfection in RBL-2H3 cells, tyrosine mutagenesis (Y279F, ΔY324), and MAPK/degranulation assays","pmids":["18243321"],"confidence":"High","gaps":["Inhibitory effector not yet identified","Mechanism in primary human mast cells untested"]},{"year":2011,"claim":"Identifying Fes and SHP-1 as the inhibitory mediators in human mast cells defined the alternative effector arm of CD84 signaling distinct from SAP/EAT-2.","evidence":"Co-cross-linking of FcεRI and CD84 in LAD2 and primary human mast cells, calcium flux, and Fes co-expression/phosphorylation","pmids":["22068234"],"confidence":"High","gaps":["What determines positive versus inhibitory adaptor selection across cell types is unresolved","Stoichiometry of Fes/SHP-1 recruitment not quantified"]},{"year":2010,"claim":"Demonstrating Y300-dependent amplification of TLR4 signaling in macrophages extended CD84 function beyond adhesion into innate immune signal modulation via the second ITSM.","evidence":"CD84 transfection and Y300 mutagenesis in RAW-264.7 cells, MAPK/NF-κB and cytokine assays, and siRNA knockdown in BMDMs","pmids":["20628063"],"confidence":"High","gaps":["Adaptor coupling Y300 to MAPK/NF-κB not identified","Ligand triggering CD84 in macrophages not defined"]},{"year":2010,"claim":"Showing EAT-2A/B are required for CD84-dependent NK cytotoxicity placed CD84 in an activating NK pathway acting through Vav-1.","evidence":"EAT-2A/B-deficient mice, NK cytotoxicity assays, and Vav-1 phosphorylation analysis","pmids":["20962259"],"confidence":"High","gaps":["Did not separate EAT-2A from EAT-2B contributions fully","Relevant NK target ligand context not defined"]},{"year":2012,"claim":"Defining ADAM10 as the platelet CD84 sheddase and calpain as the intracellular protease established post-translational regulation generating soluble CD84.","evidence":"ADAM10-KO, ADAM17-KO, and calpain-inhibitor-treated platelets with biochemical and plasma analysis","pmids":["23025437"],"confidence":"High","gaps":["Functional role of soluble CD84 not yet established","Trigger for constitutive shedding not defined"]},{"year":2016,"claim":"Identifying homophilic CD84 bridging between CLL cells and stroma defined a tumor-microenvironment survival circuit and a therapeutic target.","evidence":"CLL-stroma co-culture and in vivo CD84-blocking antibody with survival readouts","pmids":["27452524","23435417"],"confidence":"Medium","gaps":["MIF/CD74-to-Bcl-2/Mcl-1 pathway placement partly correlative","Direct signaling intermediates downstream of stromal CD84 not detailed"]},{"year":2018,"claim":"Linking CD84 cell-cell interaction to PD-L1/PD-1 upregulation connected CD84 adhesion to immune checkpoint induction in CLL.","evidence":"CD84 blocking/KO in human and mouse CLL models with PD-L1/PD-1 flow cytometry and T cell assays","pmids":["30277471"],"confidence":"High","gaps":["Signaling pathway from CD84 to PD-L1 transcription not mapped","Generality beyond CLL untested at this stage"]},{"year":2020,"claim":"Cell-type-specific knockouts showed platelet-derived soluble CD84 drives T cell motility, mechanistically connecting CD84 shedding to thromboinflammatory stroke injury.","evidence":"Platelet- and T cell-specific CD84 conditional KO mice, in vitro sCD84 motility assays, tMCAO stroke model","pmids":["32762491"],"confidence":"High","gaps":["Signaling triggered in T cells by sCD84 not detailed","Whether shed monomer or oligomer drives motility unresolved"]},{"year":2021,"claim":"Demonstrating that SLAMF5 negatively controls IL-10-producing Bregs via c-Maf defined an immunoregulatory brake relevant to autoimmunity.","evidence":"SLAMF5 conditional B cell KO in EAE, in vitro blocking in mouse and human B cells, c-Maf analysis","pmids":["33767202"],"confidence":"High","gaps":["Signaling adaptor coupling SLAMF5 to c-Maf suppression not identified","Relationship to the SAP/Fes switch unresolved"]},{"year":2025,"claim":"Identifying NRF2/Akt-redox and SAP/Akt/NHEJ pathways established CD84 as a survival dependency in AML, broadening its role to leukemic metabolism and DNA repair.","evidence":"CD84 knockdown/overexpression in human AML cells and PDX, mitochondrial and NRF2/Akt analysis, SAP co-IP, NHEJ factor and γH2AX readouts, MLL-AF9 and inv(16) mouse models","pmids":["40198133","40633676"],"confidence":"High","gaps":["Two distinct mechanisms (NRF2/metabolism vs SAP/NHEJ) not reconciled into one model","Upstream ligand engaging CD84 in AML cells not defined"]},{"year":2025,"claim":"Defining a SLAMF5-BHLHE40-CD52 axis in myeloid cells extended CD84 function to microglial/macrophage activation and neuroinflammation.","evidence":"Myeloid-specific SLAMF5 KO in EAE, BHLHE40/CD52 analysis, pharmacological brain blockade, MS patient iPSC-microglia and monocytes","pmids":["40920820"],"confidence":"High","gaps":["Proximal signaling linking SLAMF5 engagement to BHLHE40 not mapped","Ligand for myeloid SLAMF5 in CNS not identified"]},{"year":null,"claim":"What molecular logic determines whether CD84 engages positive (SAP/EAT-2) versus inhibitory (Fes/SHP-1) effectors in a given cell type, and how isoform-specific cytoplasmic tails tune this, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model linking cell context to adaptor selection","Functional consequences of the five cytoplasmic isoforms untested in physiological settings","Endogenous ligand/trigger in non-immunological-synapse contexts undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,4,14]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2,3,6,9]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,10,17]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,7,9,18]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,6]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,5,14,16]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[14,16,23,24]}],"complexes":[],"partners":["SH2D1A","SH2D2A","LCK","FES","PTPN6","VAV1","CD84"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UIB8","full_name":"SLAM family member 5","aliases":["Cell surface antigen MAX.3","Hly9-beta","Leukocyte differentiation antigen CD84","Signaling lymphocytic activation molecule 5"],"length_aa":345,"mass_kda":38.8,"function":"Self-ligand receptor of the signaling lymphocytic activation molecule (SLAM) family. SLAM receptors triggered by homo- or heterotypic cell-cell interactions are modulating the activation and differentiation of a wide variety of immune cells and thus are involved in the regulation and interconnection of both innate and adaptive immune response. Activities are controlled by presence or absence of small cytoplasmic adapter proteins, SH2D1A/SAP and/or SH2D1B/EAT-2. Can mediate natural killer (NK) cell cytotoxicity dependent on SH2D1A and SH2D1B (By similarity). Increases proliferative responses of activated T-cells and SH2D1A/SAP does not seem be required for this process. Homophilic interactions enhance interferon gamma/IFNG secretion in lymphocytes and induce platelet stimulation via a SH2D1A-dependent pathway. May serve as a marker for hematopoietic progenitor cells (PubMed:11564780, PubMed:12115647, PubMed:12928397, PubMed:12962726, PubMed:16037392) Required for a prolonged T-cell:B-cell contact, optimal T follicular helper function, and germinal center formation. In germinal centers involved in maintaining B-cell tolerance and in preventing autoimmunity (By similarity). In mast cells negatively regulates high affinity immunoglobulin epsilon receptor signaling; independent of SH2D1A and SH2D1B but implicating FES and PTPN6/SHP-1 (PubMed:22068234). In macrophages enhances LPS-induced MAPK phosphorylation and NF-kappaB activation and modulates LPS-induced cytokine secretion; involving ITSM 2 (By similarity). Positively regulates macroautophagy in primary dendritic cells via stabilization of IRF8; inhibits TRIM21-mediated proteasomal degradation of IRF8 (PubMed:29434592)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9UIB8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CD84","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CD84","total_profiled":1310},"omim":[{"mim_id":"608510","title":"SH2 DOMAIN-CONTAINING 1B; SH2D1B","url":"https://www.omim.org/entry/608510"},{"mim_id":"605554","title":"CD244 ANTIGEN; CD244","url":"https://www.omim.org/entry/605554"},{"mim_id":"604513","title":"CD84 ANTIGEN; CD84","url":"https://www.omim.org/entry/604513"},{"mim_id":"300490","title":"SH2 DOMAIN PROTEIN 1A; SH2D1A","url":"https://www.omim.org/entry/300490"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Plasma membrane","reliability":"Enhanced"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":22.6}],"url":"https://www.proteinatlas.org/search/CD84"},"hgnc":{"alias_symbol":["SLAMF5","hCD84","mCD84"],"prev_symbol":[]},"alphafold":{"accession":"Q9UIB8","domains":[{"cath_id":"2.60.40.10","chopping":"23-130","consensus_level":"high","plddt":92.9289,"start":23,"end":130},{"cath_id":"2.60.40.10","chopping":"137-212","consensus_level":"high","plddt":87.8636,"start":137,"end":212},{"cath_id":"1.20.5","chopping":"213-247","consensus_level":"medium","plddt":80.5937,"start":213,"end":247}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UIB8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UIB8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UIB8-F1-predicted_aligned_error_v6.png","plddt_mean":74.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CD84","jax_strain_url":"https://www.jax.org/strain/search?query=CD84"},"sequence":{"accession":"Q9UIB8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UIB8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UIB8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UIB8"}},"corpus_meta":[{"pmid":"20153220","id":"PMC_20153220","title":"Optimal 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cells but not to cells expressing other CD2 subfamily receptors, establishing CD84 as its own ligand. Blocking with anti-CD84 mAbs recognizing epitopes in domain 1 abolished this binding, and CD84/mouse chimeras showed only the first extracellular Ig-like domain mediates ligand-receptor recognition. The CD84-CD84 interaction was independent of its cytoplasmic tail.\",\n      \"method\": \"Soluble Ig fusion protein binding assay, anti-CD84 mAb blocking, human/mouse domain chimeras\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with soluble fusion protein, domain mapping with chimeras, multiple orthogonal methods in one study\",\n      \"pmids\": [\"11564780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CD84 cytoplasmic tail recruits SAP (SH2D1A, the X-linked lymphoproliferative disease gene product) via phosphorylated tyrosine residues in its cytoplasmic tail; recruitment is most efficient when specific tyrosine residues are phosphorylated, as demonstrated by yeast two-hybrid, COS cell transfection assays, and experiments in lymphoid cells.\",\n      \"method\": \"Yeast two-hybrid, COS cell transfection, co-immunoprecipitation in lymphoid cells\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (yeast two-hybrid, transfection, lymphoid cell assays) replicated across SLAM family members\",\n      \"pmids\": [\"11389028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CD84 is rapidly tyrosine phosphorylated following antibody ligation on B cells and recruits the cytoplasmic adaptor proteins SAP and EAT-2 via phosphorylated tyrosine residues in its cytoplasmic tail, as shown in primary human B cells.\",\n      \"method\": \"Anti-CD84 mAb ligation, tyrosine phosphorylation assay, co-immunoprecipitation of SAP and EAT-2\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal pulldown of SAP and EAT-2 from primary human B cells, replicated SAP recruitment finding from PMID 11389028\",\n      \"pmids\": [\"12115647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SAP recruitment to CD84 requires tyrosine phosphorylation of CD84, is mediated specifically by Y262 within the CD84 cytoplasmic domain and by R32 within the SH2 domain of SAP. The Src kinase Lck is required for CD84 tyrosine phosphorylation upon receptor ligation in activated T cells. CD84 ligation also enhances T cell proliferation via a SAP-independent mechanism.\",\n      \"method\": \"Site-directed mutagenesis of CD84 (Y262) and SAP (R32), in vitro phosphorylation, co-immunoprecipitation, T cell proliferation assay using SAP-deficient XLP patient cells\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis of specific residues combined with functional assays in primary SAP-deficient patient cells\",\n      \"pmids\": [\"12928397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Crystal structure of the human CD84 immunoglobulin variable domain at 2.0 Å resolution reveals an orthogonal homophilic dimer. Solution studies showed CD84 self-associates with a Kd in the submicromolar range. Structural and chemical differences in the homophilic interfaces provide a mechanism to prevent formation of undesired heterodimers among SLAM family homophilic receptors.\",\n      \"method\": \"X-ray crystallography (2.0 Å), analytical ultracentrifugation for solution Kd measurement\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with quantitative solution binding measurements, rigorous structural study\",\n      \"pmids\": [\"17563375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CD84 is required for prolonged T cell:B cell contact, optimal T follicular helper function, and germinal center formation in vivo. While T cell:DC interactions were primarily integrin-dependent, T cell:B cell interactions had an early integrin-dependent phase and a sustained SAP- and CD84-dependent phase. Both CD84 and Ly108 mediated T cell adhesion and participated in stable T cell:B cell interactions in vitro.\",\n      \"method\": \"In vivo immunization of CD84-deficient mice, in vitro T cell:B cell conjugation assays, intravital two-photon microscopy\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with defined in vivo GC phenotype plus in vitro adhesion assay, replicated with Ly108 as orthogonal control\",\n      \"pmids\": [\"20153220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Mouse CD84 modulates TLR4-downstream signaling in macrophages: transfection of CD84 in RAW-264.7 macrophages increased MAPK phosphorylation and NF-κB activation upon LPS stimulation and altered cytokine secretion (increased TNF-α and MCP-1, decreased IL-10 and IL-6). This modulatory effect was dependent on Y300 within the second ITSM of CD84. CD84 knockdown in bone marrow-derived macrophages decreased TNF-α and IL-6 production.\",\n      \"method\": \"CD84 transfection in RAW-264.7 cells, site-directed mutagenesis (Y300), MAPK/NF-κB phosphorylation assays, cytokine ELISA, CD84 siRNA knockdown in BMDMs\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis identifying the functional ITSM tyrosine, combined with gain- and loss-of-function assays in multiple macrophage systems\",\n      \"pmids\": [\"20628063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"EAT-2A and EAT-2B adapters are positive regulators of CD84-dependent NK cell cytotoxicity in C57BL/6 mice. NK cells from EAT-2A- and EAT-2A/B-deficient mice were unable to kill tumor cells in a CD84-dependent manner. EAT-2A/B positively regulate phosphorylation of Vav-1 downstream of CD84.\",\n      \"method\": \"EAT-2A/B-deficient mouse generation (CRISPR/gene targeting in C57BL/6 ES cells), NK cell cytotoxicity assays, Vav-1 phosphorylation analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic knockout with defined NK cytotoxicity phenotype and downstream signaling readout (Vav-1 phosphorylation)\",\n      \"pmids\": [\"20962259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CD84 inhibits FcεRI-mediated mast cell degranulation through homophilic interaction in CD84-transfected RBL-2H3 cells. This inhibition involves phosphorylation of Dok-1 and c-Cbl and impairs MAP kinase phosphorylation (ERK1/2, JNK, p38) and cytokine synthesis. CD84 mutants at tyrosines Y279F and ΔY324 reversed the inhibitory profile, and the mechanism is independent of SAP and SHP-2 recruitment.\",\n      \"method\": \"CD84 transfection in RBL-2H3 cells, site-directed mutagenesis (Y279F, ΔY324), Western blot for Dok-1/c-Cbl phosphorylation, MAPK phosphorylation assays, degranulation assays\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis of functional tyrosines combined with multiple signaling pathway readouts\",\n      \"pmids\": [\"18243321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In human mast cells, CD84 is tyrosine phosphorylated upon FcεRI engagement, inhibits FcεRI-mediated calcium mobilization and the Syk-LAT-PLCγ1 signaling axis, and reduces degranulation and cytokine (IL-8, GM-CSF) release. The inhibitory mechanism is SAP- and EAT-2-independent but depends on the inhibitory kinase Fes (which phosphorylates the inhibitory ITSM motif on CD84 and itself becomes phosphorylated upon CD84 coexpression) and SHP-1.\",\n      \"method\": \"Co-cross-linking of FcεRI and CD84 in LAD2 and primary CD34+-derived human mast cells, calcium flux assay, phosphorylation assays, Fes co-expression/phosphorylation experiments\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mechanistic dissection with multiple signaling pathway assays in both cell line and primary human cells, with identification of Fes as the responsible kinase\",\n      \"pmids\": [\"22068234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD84 on platelets is subject to dual regulation by ectodomain shedding and intracellular cleavage. ADAM10 is the principal sheddase responsible for CD84 ectodomain cleavage (ADAM17 is dispensable), while calpain mediates intracellular cleavage of the CD84 C-terminus simultaneously with but independently of ectodomain shedding. CD84 is also constitutively shed from the platelet surface by ADAM10 in vivo.\",\n      \"method\": \"Biochemical shedding assays, ADAM10-deficient, ADAM17-deficient, and calpain-inhibitor-treated mouse and human platelets, Western blot, plasma/serum analysis from transgenic mice\",\n      \"journal\": \"Journal of thrombosis and haemostasis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic mouse models (ADAM10 KO, ADAM17 KO) combined with pharmacological inhibition and in vitro/in vivo biochemical validation, multiple orthogonal approaches\",\n      \"pmids\": [\"23025437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In CLL, CD84 expression is regulated by macrophage migration inhibitory factor (MIF) and its receptor CD74. Activation of surface CD84 initiates a signaling cascade that enhances CLL cell survival. Downmodulation of CD84 or its immune-mediated blockade induces cell death in vitro and in vivo. Downstream, CD84 activation correlates with Bcl-2 and Mcl-1 expression.\",\n      \"method\": \"CD84 knockdown/blocking antibody in CLL cells in vitro and in vivo, MIF/CD74 stimulation assays, Bcl-2/Mcl-1 protein level measurements, clinical sample analysis (milatuzumab trial)\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined survival phenotype in vitro and in vivo, but mechanistic pathway placement (MIF→CD74→CD84→Bcl-2/Mcl-1) is partially correlative\",\n      \"pmids\": [\"23435417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SLAMF1, SLAMF5, and SLAMF6 act as negative regulators of humoral immunity. In triple knockout mice, both T-dependent and T-independent antibody responses were approximately twofold higher. Adoptive co-transfer experiments showed both [Slamf1+5+6]-/- B and T cells contributed to enhanced responses, with B cell-intrinsic activity being more pronounced. SLAMF5-deficient B cells enhanced T-independent type 2 antigen responses, indicating a B cell-intrinsic suppressive role.\",\n      \"method\": \"Triple knockout mice (Slamf1/5/6), adoptive co-transfer assays, T-dependent and T-independent immunization, anti-SLAMF6 mAb treatment\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic triple knockout with adoptive transfer establishing B cell-intrinsic mechanism, but SLAMF5-specific contribution is not fully dissected from combined phenotype\",\n      \"pmids\": [\"25926831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"B cell-intrinsic expression of CD84 (and Ly108) at germinal center B cells maintains B cell tolerance. Overexpression of B6 alleles of CD84 and Ly108 on autoimmune-prone B6.Sle1b background reduced GC response and autoantibody production. Lupus-associated CD84/Ly108 alleles on GC B cells were sufficient to break B cell tolerance. B6.Sle1b B cells showed reduced BCR signaling and lower B cell-T cell conjugate frequency.\",\n      \"method\": \"BAC-transgenic mice overexpressing B6 alleles of CD84 and Ly108, autoantibody ELISA, GC B cell analysis by flow cytometry, B cell-T cell conjugate assay, BCR signaling assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic gain-of-function with functional tolerance readouts, but CD84 and Ly108 are studied together and individual contributions are not fully separated\",\n      \"pmids\": [\"25801429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD84 expressed on CLL cells interacts homophilically with CD84 on stromal microenvironment cells, promoting survival signaling in both CLL and stromal cells. Blocking CD84 in vitro and in vivo disrupts CLL-microenvironment interaction and induces cell death in CLL cells.\",\n      \"method\": \"In vitro co-culture of CLL cells with stromal cells, CD84-blocking antibody in vitro and in vivo CLL mouse model, cell death/survival assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — both in vitro and in vivo blocking experiments with defined survival phenotype, consistent with homophilic interaction mechanism\",\n      \"pmids\": [\"27452524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CRISPR-mediated triple disruption of Slamf1, Slamf5, and Slamf6 in mice worsened iNKT cell developmental defects seen in SLAMF6 single gene-targeted mice, supporting positive signaling roles for these receptors and potential functional redundancy among them in iNKT development.\",\n      \"method\": \"Cas9/CRISPR triple knockout generation in C57BL/6 mice, flow cytometric analysis of iNKT and conventional lymphocyte populations\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic triple KO with defined iNKT developmental phenotype, but SLAMF5-specific contribution cannot be fully separated from SLAMF1/6\",\n      \"pmids\": [\"27258160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cell-cell interaction mediated through CD84 upregulates PD-L1 expression on CLL cells and their microenvironment, and upregulates PD-1 expression on T cells. This resulted in suppression of T cell responses in vitro and in vivo, establishing CD84 as a regulator of PD-1/PD-L1 immune checkpoint expression in CLL.\",\n      \"method\": \"CD84 homophilic cell-cell interaction assays, CD84 blocking/KO in human and mouse CLL models in vitro and in vivo, PD-L1/PD-1 expression by flow cytometry, T cell functional assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic linkage of CD84 interaction to PD-L1/PD-1 upregulation demonstrated in both human and mouse systems in vitro and in vivo\",\n      \"pmids\": [\"30277471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD84 on platelets drives cerebral thromboinflammation after ischemic stroke. Platelet-derived soluble CD84 (shed by ADAM10) enhances motility of wild-type but not CD84-deficient CD4+ T cells in vitro, demonstrating that homophilic CD84 interactions between platelet-derived sCD84 and T cell-expressed CD84 drive T cell migration.\",\n      \"method\": \"CD84 conditional knockout mice (platelet- or T cell-specific), in vitro T cell motility assay with platelet-derived sCD84, experimental stroke (tMCAO) model, flow cytometry for T cell infiltration, clinical sample analysis\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific genetic knockouts combined with defined mechanistic in vitro assay (sCD84-driven T cell motility), with clinical validation\",\n      \"pmids\": [\"32762491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SLAMF5 (CD84) negatively controls the survival and function of IL-10-producing regulatory B cells. SLAMF5 deficiency in B cells causes accumulation of IL-10+ Bregs in EAE. Blocking SLAMF5 in vitro induces IL-10-producing Breg cells and increases their survival with a concomitant increase in transcription factor c-Maf. In vivo SLAMF5 blocking elevates IL-10+ Breg levels and ameliorates EAE severity.\",\n      \"method\": \"SLAMF5 conditional B cell knockout in EAE model, in vitro SLAMF5 blocking antibody in human and mouse B cells, c-Maf expression analysis, in vivo blocking experiment\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout and pharmacological blocking in both mouse and human cells, mechanistic link to c-Maf identified, in vivo functional consequence demonstrated\",\n      \"pmids\": [\"33767202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In multiple myeloma, tumor cells secrete MIF, which induces CD84 expression on microenvironmental cells. CD84 activation on these cells elevates expression of genes regulating differentiation toward M-MDSCs and G-MDSCs and upregulates PD-L1 expression on MDSCs, which suppresses T cell function. Downregulation or blocking of CD84 reduces MDSC accumulation and elevated T cell activity.\",\n      \"method\": \"MIF stimulation of microenvironment cells, CD84 knockdown/blocking antibody, MDSC differentiation assays, PD-L1 expression by flow cytometry, T cell functional assays, in vivo tumor models\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined MDSC/PD-L1/T cell phenotype, MIF-to-CD84 pathway established by stimulation assay, single lab\",\n      \"pmids\": [\"33465053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CD84 is a substrate/target of BTK kinase in neutrophils during alcohol-induced granulopoiesis. BTK inhibition (evobrutinib) or myeloid-specific Btk knockout reduced granulopoiesis and liver neutrophil infiltration in alcohol-associated hepatitis. CD84 was identified as a BTK substrate by liquid chromatography-tandem mass spectrometry, and CD84-blocking antibody inhibited alcohol-induced IL-1β and TNF-α in primary human neutrophils.\",\n      \"method\": \"LC-MS/MS kinase substrate identification, BTK inhibitor treatment, Btk myeloid-specific KO mice, CD84-blocking antibody in primary human neutrophils, cytokine ELISA\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based substrate identification combined with in vivo genetic KO and in vitro blocking assay, but direct phosphorylation site validation not described in abstract\",\n      \"pmids\": [\"39110779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CD84 induces a signaling cascade in regulatory B cells (Bregs) in triple-negative breast cancer involving the β-catenin and Tcf4 pathway, leading to transcription of IL-10 by direct binding to the IL-10 promoter and the promoter of its regulator AhR. This expands Bregs and suppresses anti-tumor immune activity.\",\n      \"method\": \"CD84 manipulation in Bregs, β-catenin/Tcf4 pathway analysis, promoter binding (ChIP or reporter assay implied), IL-10 production assays, immune cell activity assays, in vivo TNBC models\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway (CD84→β-catenin/Tcf4→IL-10/AhR) identified with promoter binding evidence; single lab study\",\n      \"pmids\": [\"39466774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CCL2-secreted by mesenchymal glioma stem cells induces IKZF1 expression, which promotes CD84 expression on tumor-associated macrophages. CD84 activates the SHP2 pathway to drive M2 polarization of TAMs.\",\n      \"method\": \"GSC-TAM co-culture, CCL2 stimulation, IKZF1 knockdown/inhibition, CD84 expression analysis, SHP2 pathway assays, animal glioma models with IKZF1 inhibitors\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway (CCL2→IKZF1→CD84→SHP2) demonstrated by co-culture and gene manipulation, single lab\",\n      \"pmids\": [\"39112517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In AML, CD84 regulates energy metabolism and mitochondrial dynamics. CD84 depletion altered mitochondrial ultrastructure and function, caused downmodulation of oxidative phosphorylation and fatty acid oxidation pathways, blocked Akt phosphorylation, and downmodulated NRF2. Conversely, CD84 overexpression stabilized NRF2 and promoted its transcriptional activation, supporting redox homeostasis and mitochondrial function. CD84 loss blocked leukemia engraftment and clonogenicity in MLL-AF9 and inv(16) AML mouse models.\",\n      \"method\": \"CD84 knockdown in human AML cell lines and PDX cells, CD84 overexpression, Akt/NRF2 pathway analysis, mitochondrial ultrastructure/function assays (electron microscopy implied), AML mouse models (MLL-AF9, inv(16))\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain- and loss-of-function with defined metabolic mechanism (Akt/NRF2/mitochondria) validated in both human cells and two independent mouse AML models\",\n      \"pmids\": [\"40198133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CD84 promotes AML cell growth via the NHEJ DNA repair pathway. CD84 recruits SAP and activates the AKT signaling pathway to promote expression of NHEJ core factors (PRKDC, LIG4, XRCC5, DCLRE1C). Knockdown of CD84 inhibits NHEJ repair, leading to double-strand break accumulation and apoptosis. CD84 is required for proliferation and self-renewal of human leukemia-initiating cells.\",\n      \"method\": \"CD84 knockdown in AML cell lines and xenograft models, SAP co-immunoprecipitation, AKT pathway analysis, NHEJ factor expression analysis, DSB accumulation (γH2AX), LIC functional assays\",\n      \"journal\": \"Molecules and cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined mechanistic pathway (CD84→SAP→AKT→NHEJ factors) with multiple molecular readouts in a single lab, consistent with PMID 40198133 but different mechanism proposed\",\n      \"pmids\": [\"40633676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SLAMF5 deficiency in myeloid cells (microglia and macrophages) leads to decreased expression of activation and costimulatory molecules including MHC class II and CD80 in EAE. This downregulation is mediated through transcription factor BHLHE40 and its regulation of CD52, resulting in delayed onset and reduced EAE progression. Pharmacological blockade of SLAMF5 in the brain halted disease progression. In human iPSC-derived microglia and MS patient monocytes, SLAMF5 blockade reduced HLA-DR, CD80, and CD52 expression.\",\n      \"method\": \"Total and brain-specific SLAMF5 myeloid conditional KO in EAE, BHLHE40 pathway analysis, pharmacological brain blockade, iPSC-derived microglia from MS patients, flow cytometry\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — myeloid cell-specific genetic KO with defined molecular mechanism (BHLHE40/CD52 axis), validated pharmacologically and in human cells across multiple orthogonal approaches\",\n      \"pmids\": [\"40920820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CD84 exists as five isoforms (CD84a–e) generated by alternative exon usage, reading frame shifts, cryptic splice sites, or absence of splicing. The five isoforms differ in their cytoplasmic domains and contain differentially distributed potentially phosphorylatable residues, providing a potential mechanism to regulate signal transduction activity.\",\n      \"method\": \"cDNA library screening, RT-PCR, genomic structure determination (at least 8 exons identified)\",\n      \"journal\": \"Tissue antigens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct genomic/cDNA characterization across multiple isoforms, but functional consequences of isoform differences not directly tested\",\n      \"pmids\": [\"10746783\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD84 (SLAMF5) is a self-ligand homophilic adhesion molecule of the SLAM immunoreceptor family whose Ig-like variable domain forms a submicromolar orthogonal dimer (crystal structure resolved at 2.0 Å); upon receptor engagement and Lck-dependent tyrosine phosphorylation of its ITSM motifs, the cytoplasmic tail recruits SAP (via Y262) and EAT-2 as positive signaling adapters, or Fes kinase and SHP-1 as inhibitory mediators depending on cell type; homophilic CD84 trans-interactions stabilize prolonged T:B cell contact required for germinal center formation, bridge CLL cells to their stromal microenvironment to promote survival, and drive platelet-T cell thromboinflammatory crosstalk via ADAM10-shed soluble CD84; in macrophages CD84 amplifies TLR4/LPS-induced MAPK/NF-κB signaling through its second ITSM tyrosine (Y300), in mast cells it negatively regulates FcεRI via Fes/SHP-1, in NK cells EAT-2A/B mediate CD84-dependent cytotoxicity through Vav-1 phosphorylation, in regulatory B cells SLAMF5 suppresses IL-10 production and c-Maf, and in AML cells CD84 sustains survival through NRF2-dependent redox homeostasis/mitochondrial function and Akt-driven NHEJ DNA repair.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CD84 (SLAMF5) is a self-ligand homophilic cell-surface adhesion receptor of the SLAM immunoreceptor family that converts cell-cell contact into intracellular signaling to regulate immune cell interactions, survival, and effector function [#0, #4]. Homophilic recognition is mediated exclusively by the membrane-distal Ig-like domain 1, which forms a submicromolar orthogonal dimer whose interface chemistry discriminates CD84 from other SLAM family members to prevent heterodimerization [#0, #4]. Engagement triggers Lck-dependent tyrosine phosphorylation of cytoplasmic ITSM motifs, which then function as a phospho-tyrosine switch: phosphorylated Y262 recruits the adaptors SAP and EAT-2 as positive signaling mediators, while in other cell contexts the receptor instead engages the inhibitory kinase Fes and the phosphatase SHP-1 [#1, #2, #3, #9]. This bidirectional output underlies opposing cell-type-specific roles: CD84 sustains prolonged T:B cell contact required for T follicular helper function and germinal center formation [#5], drives EAT-2/Vav-1-dependent NK cytotoxicity [#7], and amplifies TLR4/LPS-induced MAPK and NF-\\u03baB signaling in macrophages through the second ITSM tyrosine Y300 [#6], yet negatively regulates Fc\\u03b5RI signaling in mast cells via Fes/SHP-1 [#9] and suppresses IL-10-producing regulatory B cells through c-Maf [#18]. In disease, homophilic CD84 trans-interactions bridge chronic lymphocytic leukemia cells to their stromal microenvironment to promote survival and upregulate PD-L1/PD-1 checkpoint expression [#14, #16], platelet-derived soluble CD84 shed by ADAM10 enhances T cell motility to drive cerebral thromboinflammation after stroke [#10, #17], and in AML CD84 sustains leukemic survival through NRF2-dependent redox/mitochondrial homeostasis and SAP/Akt-driven NHEJ DNA repair [#23, #24].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing that CD84 is its own ligand answered whether this orphan SLAM-family receptor signals through homophilic contact, and localized recognition to a single Ig domain.\",\n      \"evidence\": \"Soluble CD84-Ig fusion binding, anti-CD84 domain-1 mAb blocking, and human/mouse domain chimeras\",\n      \"pmids\": [\"11564780\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural basis or affinity of the homophilic interaction\", \"Cytoplasmic signaling output not addressed\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identifying SAP and EAT-2 recruitment to the phosphorylated cytoplasmic tail defined the intracellular signaling adaptors that link CD84 ligation to downstream events in B cells.\",\n      \"evidence\": \"Yeast two-hybrid, COS transfection, and co-immunoprecipitation of SAP and EAT-2 from primary human B cells after mAb ligation\",\n      \"pmids\": [\"11389028\", \"12115647\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific tyrosine residues and the kinase responsible were not yet mapped\", \"Functional consequence of adaptor recruitment unresolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Mapping SAP recruitment to CD84 Y262 and SAP R32 and identifying Lck as the kinase established the precise phospho-tyrosine switch driving positive signaling.\",\n      \"evidence\": \"Site-directed mutagenesis of CD84 and SAP, in vitro phosphorylation, and T cell proliferation assays in SAP-deficient XLP patient cells\",\n      \"pmids\": [\"12928397\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SAP-independent proliferation pathway not mechanistically defined\", \"Did not address inhibitory signaling outputs\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"The 2.0 \\u00c5 crystal structure and solution Kd answered how CD84 achieves homophilic specificity, revealing an orthogonal dimer with an interface that excludes heterodimers.\",\n      \"evidence\": \"X-ray crystallography of the Ig variable domain and analytical ultracentrifugation\",\n      \"pmids\": [\"17563375\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not capture full-length receptor or cytoplasmic conformation\", \"In situ clustering geometry at cell contacts not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Genetic and imaging studies established CD84 as a physiological mediator of sustained T:B contact required for germinal center formation, giving the homophilic receptor an in vivo developmental function.\",\n      \"evidence\": \"In vivo immunization of CD84-deficient mice, in vitro conjugation assays, and intravital two-photon microscopy\",\n      \"pmids\": [\"20153220\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Contribution of CD84 separated only partially from Ly108\", \"Downstream signaling sustaining contact not detailed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Discovering that CD84 inhibits Fc\\u03b5RI signaling in mast cells revealed that the same receptor can produce inhibitory output, and that this is SAP-independent.\",\n      \"evidence\": \"CD84 transfection in RBL-2H3 cells, tyrosine mutagenesis (Y279F, \\u0394Y324), and MAPK/degranulation assays\",\n      \"pmids\": [\"18243321\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Inhibitory effector not yet identified\", \"Mechanism in primary human mast cells untested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identifying Fes and SHP-1 as the inhibitory mediators in human mast cells defined the alternative effector arm of CD84 signaling distinct from SAP/EAT-2.\",\n      \"evidence\": \"Co-cross-linking of Fc\\u03b5RI and CD84 in LAD2 and primary human mast cells, calcium flux, and Fes co-expression/phosphorylation\",\n      \"pmids\": [\"22068234\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What determines positive versus inhibitory adaptor selection across cell types is unresolved\", \"Stoichiometry of Fes/SHP-1 recruitment not quantified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrating Y300-dependent amplification of TLR4 signaling in macrophages extended CD84 function beyond adhesion into innate immune signal modulation via the second ITSM.\",\n      \"evidence\": \"CD84 transfection and Y300 mutagenesis in RAW-264.7 cells, MAPK/NF-\\u03baB and cytokine assays, and siRNA knockdown in BMDMs\",\n      \"pmids\": [\"20628063\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Adaptor coupling Y300 to MAPK/NF-\\u03baB not identified\", \"Ligand triggering CD84 in macrophages not defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showing EAT-2A/B are required for CD84-dependent NK cytotoxicity placed CD84 in an activating NK pathway acting through Vav-1.\",\n      \"evidence\": \"EAT-2A/B-deficient mice, NK cytotoxicity assays, and Vav-1 phosphorylation analysis\",\n      \"pmids\": [\"20962259\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not separate EAT-2A from EAT-2B contributions fully\", \"Relevant NK target ligand context not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defining ADAM10 as the platelet CD84 sheddase and calpain as the intracellular protease established post-translational regulation generating soluble CD84.\",\n      \"evidence\": \"ADAM10-KO, ADAM17-KO, and calpain-inhibitor-treated platelets with biochemical and plasma analysis\",\n      \"pmids\": [\"23025437\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of soluble CD84 not yet established\", \"Trigger for constitutive shedding not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identifying homophilic CD84 bridging between CLL cells and stroma defined a tumor-microenvironment survival circuit and a therapeutic target.\",\n      \"evidence\": \"CLL-stroma co-culture and in vivo CD84-blocking antibody with survival readouts\",\n      \"pmids\": [\"27452524\", \"23435417\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"MIF/CD74-to-Bcl-2/Mcl-1 pathway placement partly correlative\", \"Direct signaling intermediates downstream of stromal CD84 not detailed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linking CD84 cell-cell interaction to PD-L1/PD-1 upregulation connected CD84 adhesion to immune checkpoint induction in CLL.\",\n      \"evidence\": \"CD84 blocking/KO in human and mouse CLL models with PD-L1/PD-1 flow cytometry and T cell assays\",\n      \"pmids\": [\"30277471\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling pathway from CD84 to PD-L1 transcription not mapped\", \"Generality beyond CLL untested at this stage\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Cell-type-specific knockouts showed platelet-derived soluble CD84 drives T cell motility, mechanistically connecting CD84 shedding to thromboinflammatory stroke injury.\",\n      \"evidence\": \"Platelet- and T cell-specific CD84 conditional KO mice, in vitro sCD84 motility assays, tMCAO stroke model\",\n      \"pmids\": [\"32762491\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling triggered in T cells by sCD84 not detailed\", \"Whether shed monomer or oligomer drives motility unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrating that SLAMF5 negatively controls IL-10-producing Bregs via c-Maf defined an immunoregulatory brake relevant to autoimmunity.\",\n      \"evidence\": \"SLAMF5 conditional B cell KO in EAE, in vitro blocking in mouse and human B cells, c-Maf analysis\",\n      \"pmids\": [\"33767202\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling adaptor coupling SLAMF5 to c-Maf suppression not identified\", \"Relationship to the SAP/Fes switch unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identifying NRF2/Akt-redox and SAP/Akt/NHEJ pathways established CD84 as a survival dependency in AML, broadening its role to leukemic metabolism and DNA repair.\",\n      \"evidence\": \"CD84 knockdown/overexpression in human AML cells and PDX, mitochondrial and NRF2/Akt analysis, SAP co-IP, NHEJ factor and \\u03b3H2AX readouts, MLL-AF9 and inv(16) mouse models\",\n      \"pmids\": [\"40198133\", \"40633676\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Two distinct mechanisms (NRF2/metabolism vs SAP/NHEJ) not reconciled into one model\", \"Upstream ligand engaging CD84 in AML cells not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defining a SLAMF5-BHLHE40-CD52 axis in myeloid cells extended CD84 function to microglial/macrophage activation and neuroinflammation.\",\n      \"evidence\": \"Myeloid-specific SLAMF5 KO in EAE, BHLHE40/CD52 analysis, pharmacological brain blockade, MS patient iPSC-microglia and monocytes\",\n      \"pmids\": [\"40920820\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Proximal signaling linking SLAMF5 engagement to BHLHE40 not mapped\", \"Ligand for myeloid SLAMF5 in CNS not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"What molecular logic determines whether CD84 engages positive (SAP/EAT-2) versus inhibitory (Fes/SHP-1) effectors in a given cell type, and how isoform-specific cytoplasmic tails tune this, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model linking cell context to adaptor selection\", \"Functional consequences of the five cytoplasmic isoforms untested in physiological settings\", \"Endogenous ligand/trigger in non-immunological-synapse contexts undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 4, 14]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2, 3, 6, 9]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 10, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 7, 9, 18]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 6]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 5, 14, 16]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [14, 16, 23, 24]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SH2D1A\", \"SH2D2A\", \"LCK\", \"FES\", \"PTPN6\", \"VAV1\", \"CD84\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}