{"gene":"CD84","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":1997,"finding":"CD84 was identified as a novel member of the Ig superfamily with two extracellular Ig-like domains, a transmembrane region, and an 83-amino acid cytoplasmic domain, encoded by a gene mapping to chromosome 1q24, and expressed predominantly on hematopoietic cells including B lymphocytes and monocytes.","method":"cDNA cloning, Northern blot, flow cytometry with monoclonal antibodies","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 — original molecular characterization with multiple orthogonal methods","pmids":["9310491"],"is_preprint":false},{"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, and this interaction is mediated exclusively by the first extracellular Ig-like domain and is independent of the cytoplasmic tail.","method":"CD84-Ig soluble fusion protein binding assays, domain chimera analysis, anti-CD84 mAb blocking","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 — reconstituted binding with soluble fusion protein plus mutagenesis using domain chimeras","pmids":["11564780"],"is_preprint":false},{"year":2001,"finding":"CD84 co-stimulates IFN-γ secretion in human lymphocytes when co-ligated with CD3, demonstrating a costimulatory function.","method":"In vitro stimulation assay with anti-CD84 mAbs or CD84-Ig fusion protein plus anti-CD3","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — functional assay in primary human lymphocytes with defined readout","pmids":["11564780"],"is_preprint":false},{"year":2001,"finding":"The cytoplasmic tails of CD84 and Ly-9 recruit SAP (SH2D1A) via specific tyrosine residues; this interaction is most efficient when those tyrosines are phosphorylated, placing CD84 in the SAP-dependent signaling network disrupted in X-linked lymphoproliferative disease.","method":"Yeast two-hybrid, COS cell transfections, biochemical binding assays in lymphoid cells","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 — multiple systems (yeast 2-hybrid, mammalian transfection, endogenous lymphoid cells) with phosphorylation requirement defined","pmids":["11389028"],"is_preprint":false},{"year":2002,"finding":"CD84 is rapidly tyrosine-phosphorylated upon antibody-mediated ligation on primary human B cells and recruits both SAP and EAT-2 via its cytoplasmic tail, suggesting a signaling role in memory B cell activation.","method":"Anti-CD84 mAb ligation, immunoprecipitation, Western blot for tyrosine phosphorylation and SAP/EAT-2 recruitment","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP/pulldown in primary human B cells with phosphorylation data","pmids":["12115647"],"is_preprint":false},{"year":2003,"finding":"CD84 is tyrosine-phosphorylated on activated T cells via the Src kinase Lck; phosphorylation at Y262 in the cytoplasmic domain is required for SAP recruitment, which also requires R32 in the SAP SH2 domain. CD84 ligation enhances anti-CD3-stimulated T cell proliferation via both SAP-dependent and SAP-independent mechanisms.","method":"Site-directed mutagenesis of CD84 cytoplasmic domain and SAP SH2 domain, Lck inhibition, T cell proliferation assays with XLP patient (SAP-deficient) T cells","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis defining precise interaction residues plus functional validation in 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 similar to NTB-A. Solution studies show CD84 self-associates with a Kd in the submicromolar range. Structural differences at homophilic interfaces prevent undesired heterodimer formation among SLAM family members, and the ~140 Å end-to-end dimension allows colocalization within the immunological synapse.","method":"X-ray crystallography (2.0 Å), analytical ultracentrifugation for Kd measurement","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with biophysical affinity measurement","pmids":["17563375"],"is_preprint":false},{"year":2008,"finding":"CD84 inhibits FcεRI-mediated mast cell degranulation through homophilic interaction; this inhibitory mechanism is independent of SAP and SHP-2 recruitment but requires tyrosines Y279 and Y324 in the CD84 cytoplasmic domain, and is associated with increased phosphorylation of Dok-1 and c-Cbl and impaired MAP kinase (ERK1/2, JNK, p38) phosphorylation.","method":"CD84 transfection in RBL-2H3 cells, tyrosine mutants (Y279F, ΔY324), degranulation assays, Western blot for signaling intermediates","journal":"Molecular immunology","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis of specific residues plus mechanistic signaling readouts","pmids":["18243321"],"is_preprint":false},{"year":2010,"finding":"The SLAM family member CD84 is required for prolonged T cell:B cell contact, optimal T follicular helper function, and germinal center formation in vivo. T cell:B cell interactions have both an early integrin-dependent phase and a sustained SAP-dependent phase requiring CD84 and Ly108.","method":"CD84-deficient mice, intravital two-photon microscopy, in vitro T:B adhesion assays, in vivo germinal center analysis","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with multiple in vitro and in vivo readouts, replicated with Ly108","pmids":["20153220"],"is_preprint":false},{"year":2010,"finding":"In mouse macrophages, CD84 modulates TLR4 downstream signaling: transfection of CD84 in RAW-264.7 cells increases MAPK phosphorylation and NF-κB activation upon LPS stimulation, elevates TNF-α and MCP-1, and reduces IL-10 and IL-6 production. This modulatory effect is mediated specifically by Y300 within the second ITSM of CD84.","method":"CD84 transfection and knockdown in RAW-264.7 macrophages and bone-marrow-derived macrophages, ITSM tyrosine mutant (Y300), MAPK/NF-κB reporter assays, cytokine ELISA","journal":"Journal of leukocyte biology","confidence":"High","confidence_rationale":"Tier 1 — site-directed mutagenesis of specific signaling residue plus gain- and loss-of-function","pmids":["20628063"],"is_preprint":false},{"year":2010,"finding":"EAT-2A and EAT-2B adapters positively regulate CD84- and CD244-dependent NK cell killing of tumor cells in C57BL/6 mice and mediate phosphorylation of Vav-1 downstream of these SLAM family receptors.","method":"EAT-2A/B-deficient mice (C57BL/6 background), NK cytotoxicity assays, Vav-1 phosphorylation by Western blot","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic KO mice with functional NK killing assay and defined signaling readout","pmids":["20962259"],"is_preprint":false},{"year":2011,"finding":"In human mast cells, which lack SAP and EAT-2, CD84 is tyrosine-phosphorylated upon FcεRI engagement and inhibits FcεRI-mediated degranulation and cytokine release. Inhibition is mediated by the Fes kinase (which phosphorylates the CD84 inhibitory motif) and by increased SHP-1 phosphorylation, and is accompanied by dampened calcium mobilization and reduced Syk-LAT-PLCγ1 axis activity.","method":"FcεRI/CD84 co-cross-linking in LAD2 cells and primary human CD34+-derived mast cells, calcium flux assay, Western blot for Syk, LAT, PLCγ1, Fes, SHP-1 phosphorylation","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1–2 — mechanistic pathway dissection in primary human cells with multiple orthogonal readouts","pmids":["22068234"],"is_preprint":false},{"year":2012,"finding":"CD84 is shed from platelets by ADAM10-mediated ectodomain cleavage and simultaneously cleaved intracellularly by calpain. ADAM10 is the principal sheddase (ADAM17 is dispensable), and CD84 is constitutively shed in vivo.","method":"Biochemical shedding assays in human and murine platelets, ADAM10-deficient, ADAM17-deficient, and calpain-inhibited/deficient mouse models, Western blot","journal":"Journal of thrombosis and haemostasis","confidence":"High","confidence_rationale":"Tier 2 — three distinct transgenic mouse lines identifying specific proteases","pmids":["23025437"],"is_preprint":false},{"year":2013,"finding":"CD84 expression in CLL cells is regulated by macrophage migration inhibitory factor (MIF) via its receptor CD74. Activation of surface CD84 initiates a signaling cascade that enhances CLL cell survival; downmodulation or immune-mediated blockade of CD84 induces cell death in vitro and in vivo, with concomitant reduction of Bcl-2 and Mcl-1 expression.","method":"CD84 knockdown and blocking antibodies in CLL cells in vitro and in vivo mouse models, Western blot for Bcl-2/Mcl-1, analysis of clinical trial samples (milatuzumab treatment)","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — in vitro and in vivo loss-of-function with defined survival pathway and upstream regulator identified","pmids":["23435417"],"is_preprint":false},{"year":2015,"finding":"B cell-intrinsic CD84 and Ly108 maintain germinal center B cell tolerance; lupus-associated alleles of CD84 and Ly108 on GC B cells are sufficient to break tolerance and increase autoantibody production, and B6.Sle1b B cells have reduced B cell-T cell conjugate formation reversed by B6 CD84/Ly108 alleles.","method":"BAC-transgenic mice overexpressing B6 alleles of CD84/Ly108 on autoimmune-prone background, GC response measurement, B cell-T cell conjugate assays, BCR signaling assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — in vivo transgenic rescue combined with cellular conjugate and signaling assays","pmids":["25801429"],"is_preprint":false},{"year":2015,"finding":"SLAMF1, SLAMF5 (CD84), and SLAMF6 act as negative regulators of humoral immunity; triple-knockout mice show ~2-fold higher T-dependent and T-independent antibody responses. B cell-intrinsic activity accounts for the predominant effect, and anti-SLAMF6 antibody treatment inhibits Tfh and GC B cell development.","method":"Single and triple Slamf1/5/6 knockout mice, adoptive co-transfer assays, anti-SLAMF6 antibody treatment, antibody titer measurement","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with multiple KO combinations and adoptive transfer to assign cell-intrinsic roles","pmids":["25926831"],"is_preprint":false},{"year":2016,"finding":"CD84 bridges CLL cells and stromal microenvironment cells through homophilic self-association; CD84 expressed on CLL cells interacts with CD84 on stromal cells inducing survival signaling in both cell types. Blocking CD84 in vitro and in vivo disrupts this interaction and induces cell death.","method":"Co-culture assays, CD84 blocking antibodies in vitro and in vivo mouse models, cell survival/death assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — in vitro and in vivo loss-of-function with defined homophilic mechanism","pmids":["27452524"],"is_preprint":false},{"year":2016,"finding":"CRISPR-mediated triple knockout of SLAMF1, SLAMF5, and SLAMF6 worsens defects in iNKT cell development seen in SLAMF6 single-knockout mice, supporting positive signaling roles for these receptors in iNKT development, with potential redundancy among them.","method":"Cas9/CRISPR triple-knockout mice, flow cytometric analysis of iNKT and conventional lymphocyte populations, germinal center analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis using CRISPR triple KO in vivo","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 PD-1 expression on T cells, resulting in suppression of T cell function in vitro and in vivo. This identifies CD84 as a regulator of PD-1/PD-L1 immune checkpoints in CLL.","method":"Human and mouse CD84-mediated cell-cell interaction assays, PD-L1/PD-1 expression by flow cytometry, T cell functional assays in vitro and in vivo","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — functional mechanistic link between CD84 engagement and checkpoint upregulation validated in vitro and in vivo","pmids":["30277471"],"is_preprint":false},{"year":2020,"finding":"CD84 mediates cerebral thrombo-inflammation in ischemic stroke: platelet-derived soluble CD84 enhances motility of CD4+ T cells through homophilic CD84 interaction. Mice lacking CD84 on either platelets or T cells show reduced cerebral CD4+ T cell infiltration and thrombotic activity after experimental stroke.","method":"CD84-deficient mice (cell-type specific), experimental stroke models, in vitro T cell motility assays with soluble CD84, clinical analysis of arterial blood from ischemic patients","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 — cell-type-specific KO mice with mechanistic in vitro validation and translational human data","pmids":["32762491"],"is_preprint":false},{"year":2021,"finding":"In multiple myeloma, myeloma cells secrete MIF which induces CD84 expression on microenvironmental cells. CD84 activation on these cells upregulates genes regulating M-MDSC and G-MDSC differentiation and increases PD-L1 expression on MDSCs, suppressing T cell function. Downregulation or blocking of CD84 reduces MDSC accumulation and elevates T cell activity.","method":"In vitro co-culture, CD84 knockdown and blocking antibodies, flow cytometry for MDSC markers and PD-L1, in vivo tumor models","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 — mechanistic pathway (MIF→CD84→MDSC/PD-L1→T cell suppression) validated in vitro and in vivo","pmids":["33465053"],"is_preprint":false},{"year":2024,"finding":"CD84 is a kinase substrate of BTK (identified by liquid chromatography-tandem mass spectrometry); CD84 promotes alcohol-induced IL-1β and TNF-α in primary human neutrophils, an effect inhibited by CD84-blocking antibody, placing CD84 downstream of BTK in alcohol-induced granulopoiesis and neutrophil inflammation.","method":"LC-MS/MS kinase substrate identification, BTK inhibitor treatment, myeloid-specific Btk knockout mice, CD84-blocking antibody in vitro","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 1–2 — mass spectrometry identification of CD84 as BTK substrate combined with in vitro and in vivo functional validation","pmids":["39110779"],"is_preprint":false},{"year":2024,"finding":"In TNBC, CD84 activates a Breg cascade involving β-catenin and Tcf4, which drive transcription of IL-10 by binding to its promoter and the promoter of its regulator AhR, leading to Breg expansion and suppression of other immune cells.","method":"In vitro CD84 stimulation, ChIP/promoter binding assays for β-catenin/Tcf4, IL-10 reporter, Breg expansion assays, in vivo tumor models","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — transcriptional mechanism with promoter binding data in defined cell type","pmids":["39466774"],"is_preprint":false},{"year":2024,"finding":"In glioma, CCL2 from mesenchymal glioma stem cells induces IKZF1 expression in tumor-associated macrophages, which promotes M2 polarization via the CD84-SHP2 pathway.","method":"GSC-TAM co-culture, bioinformatics, knockdown experiments, determination of TAM polarization phenotypes","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 — co-culture mechanistic assay with pathway identification but single lab","pmids":["39112517"],"is_preprint":false},{"year":2025,"finding":"In AML, CD84 regulates energy metabolism and mitochondrial dynamics; CD84 depletion alters mitochondrial ultrastructure, reduces oxidative phosphorylation and fatty acid oxidation, blocks Akt phosphorylation, and downmodulates NRF2, impairing antioxidant defense. Conversely, CD84 overexpression stabilizes NRF2 and promotes its transcriptional activation.","method":"CD84 knockdown and overexpression in AML cell lines and patient-derived xenografts, MLL-AF9 and inv(16) mouse models, electron microscopy for mitochondrial ultrastructure, metabolic flux assays, Western blot for Akt/NRF2","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods across human and mouse models establishing CD84→Akt→NRF2 metabolic axis","pmids":["40198133"],"is_preprint":false},{"year":2025,"finding":"In AML, CD84 promotes expression of NHEJ DNA repair core factors (PRKDC, LIG4, XRCC5, DCLRE1C) by recruiting SAP and activating the AKT signaling pathway; CD84 knockdown inhibits NHEJ repair, causing double-strand break accumulation and apoptosis.","method":"CD84 knockdown in AML cells, SAP co-immunoprecipitation, AKT phosphorylation Western blot, NHEJ reporter assays, γH2AX foci (DSB accumulation), in vivo xenograft models","journal":"Molecules and cells","confidence":"Medium","confidence_rationale":"Tier 2 — SAP recruitment and AKT activation linked to NHEJ factor expression with functional DNA repair readout","pmids":["40633676"],"is_preprint":false},{"year":2025,"finding":"SLAMF5/CD84 deficiency in myeloid cells (microglia and border-associated macrophages) reduces expression of activation and costimulatory molecules MHC II and CD80, delays EAE onset and progression. This is mediated at least in part through the transcription factor BHLHE40 and its regulation of CD52. Pharmacological blockade of SLAMF5 in the brain halts disease progression.","method":"Total and brain-specific SLAMF5-deficient mice, EAE model, flow cytometry for activation markers, BHLHE40/CD52 mechanistic analysis, pharmacological blockade, human iPSC-derived microglia","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 — conditional KO plus pharmacological blockade in vivo with defined transcription factor pathway","pmids":["40920820"],"is_preprint":false}],"current_model":"CD84 (SLAMF5) is a homophilic adhesion receptor of the SLAM family whose extracellular Ig-V domain mediates submicromolar self-association forming an orthogonal dimer; upon engagement, specific cytoplasmic ITSM tyrosines are phosphorylated by Src-family kinases (Lck) or Fes, recruiting adaptor proteins SAP and/or EAT-2 to activate downstream signaling (MAPK, NF-κB, Vav-1, Akt/NRF2) or recruiting SHP-1/Dok-1 to inhibit signaling (e.g., in mast cells), while ADAM10 and calpain regulate its surface levels by ectodomain shedding and intracellular cleavage; functionally, CD84 sustains T:B cell adhesion required for germinal center formation, modulates macrophage cytokine responses to LPS, supports CLL and AML cell survival through microenvironmental homophilic bridging and metabolic/NHEJ pathways, drives MDSC-mediated immune suppression via PD-L1 upregulation, and mediates platelet-T cell crosstalk in cerebral thrombo-inflammation."},"narrative":{"teleology":[{"year":1997,"claim":"Identification of CD84 as a new Ig-superfamily member on hematopoietic cells established the molecular identity and expression pattern of the receptor, enabling subsequent functional studies.","evidence":"cDNA cloning, Northern blot, and flow cytometry with mAbs on human hematopoietic cells","pmids":["9310491"],"confidence":"High","gaps":["No ligand or signaling function defined","Expression on non-hematopoietic tissues not examined"]},{"year":2001,"claim":"Demonstration that CD84 is a homophilic receptor whose first Ig-like domain mediates self-binding, and that ligation costimulates IFN-γ production, established both the binding mode and a functional consequence of engagement.","evidence":"Soluble CD84-Ig fusion binding assays, domain chimeras, and T cell costimulation assays with anti-CD84 mAbs","pmids":["11564780"],"confidence":"High","gaps":["Structural basis of homophilic interaction unknown","Downstream signaling pathway not mapped"]},{"year":2001,"claim":"Discovery that SAP binds phosphorylated CD84 cytoplasmic tyrosines connected CD84 to the SAP-dependent signaling network disrupted in X-linked lymphoproliferative disease.","evidence":"Yeast two-hybrid, COS cell transfection, and biochemical binding assays in lymphoid cells","pmids":["11389028"],"confidence":"High","gaps":["Specific phosphotyrosine residues not mapped","In vivo relevance of SAP recruitment to CD84 not tested"]},{"year":2002,"claim":"Showing that CD84 is rapidly phosphorylated on primary B cells and recruits both SAP and EAT-2 expanded the adaptor repertoire and implicated CD84 in memory B cell signaling.","evidence":"Anti-CD84 ligation, immunoprecipitation, and Western blot in primary human B cells","pmids":["12115647"],"confidence":"Medium","gaps":["EAT-2 binding site on CD84 not mapped","Functional consequence in B cell differentiation not shown"]},{"year":2003,"claim":"Mapping the critical phosphotyrosine Y262 for SAP binding and identifying Lck as the upstream kinase defined the proximal signaling mechanism; use of SAP-deficient XLP patient cells revealed SAP-independent costimulatory pathways.","evidence":"Site-directed mutagenesis, Lck inhibition, and T cell proliferation assays including XLP patient cells","pmids":["12928397"],"confidence":"High","gaps":["SAP-independent pathway components not identified","Role of other Src-family kinases not excluded"]},{"year":2007,"claim":"The 2.0 Å crystal structure of the CD84 Ig-V domain revealed the orthogonal homodimer geometry and submicromolar self-association affinity, explaining specificity among SLAM family members and compatibility with immunological synapse dimensions.","evidence":"X-ray crystallography and analytical ultracentrifugation","pmids":["17563375"],"confidence":"High","gaps":["Full-length extracellular structure not solved","Dynamics of dimer at the cell surface not characterized"]},{"year":2008,"claim":"CD84 was shown to function as an inhibitory receptor in mast cells via Y279/Y324-dependent recruitment of Dok-1 and c-Cbl, dampening MAP kinase signaling—demonstrating that CD84 can switch between activating and inhibitory outputs depending on cellular context.","evidence":"Tyrosine mutants in RBL-2H3 cells, degranulation assays, and signaling Western blots","pmids":["18243321"],"confidence":"High","gaps":["Direct interaction between CD84 and Dok-1/c-Cbl not shown by co-IP","Physiological ligand engagement in mast cells not addressed"]},{"year":2010,"claim":"Genetic deletion of CD84 in mice proved it is required for sustained T:B cell contact and germinal center formation, and separately, CD84 modulates macrophage TLR4 responses via its second ITSM (Y300), activating MAPK/NF-κB—establishing dual in vivo roles in adaptive and innate immunity.","evidence":"CD84-knockout mice with intravital imaging, GC analysis, and macrophage gain/loss-of-function with ITSM mutants","pmids":["20153220","20628063"],"confidence":"High","gaps":["Relative contribution of CD84 versus Ly108 to GC formation not fully dissected","Downstream transcriptional targets of NF-κB in macrophages not defined"]},{"year":2010,"claim":"EAT-2 adaptors were shown to positively regulate CD84-dependent NK cell cytotoxicity through Vav-1 phosphorylation, extending CD84's functional repertoire to innate cytotoxicity.","evidence":"EAT-2A/B-deficient mice, NK killing assays, Vav-1 phosphorylation Western blot","pmids":["20962259"],"confidence":"High","gaps":["Direct EAT-2–Vav-1 interaction downstream of CD84 not shown","Contribution of CD84 versus CD244 not individually dissected"]},{"year":2011,"claim":"In SAP/EAT-2-negative human mast cells, identification of Fes as the kinase phosphorylating CD84 and SHP-1 as the effector phosphatase revealed the molecular logic of CD84's inhibitory mode, explaining context-dependent signaling switching.","evidence":"FcεRI/CD84 co-cross-linking in LAD2 and primary mast cells, calcium flux, and phospho-signaling analysis","pmids":["22068234"],"confidence":"High","gaps":["Direct Fes–CD84 physical interaction not demonstrated","Relative roles of SHP-1 versus SHP-2 not fully resolved"]},{"year":2012,"claim":"Identification of ADAM10 and calpain as the sheddase and intracellular protease regulating CD84 surface levels on platelets established a post-translational control mechanism for receptor availability.","evidence":"ADAM10-, ADAM17-deficient, and calpain-inhibited mouse platelets with shedding assays","pmids":["23025437"],"confidence":"High","gaps":["Cleavage sites not mapped at amino-acid resolution","Functional consequence of soluble CD84 ectodomain from platelets not tested"]},{"year":2013,"claim":"Discovery that MIF/CD74 induces CD84 expression on CLL cells, whose homophilic engagement sustains survival via Bcl-2/Mcl-1, established CD84 as a druggable pro-survival factor in CLL.","evidence":"CD84 knockdown/blocking antibodies in CLL cells in vitro and in vivo, Bcl-2/Mcl-1 Western blot","pmids":["23435417"],"confidence":"High","gaps":["Signaling intermediates between CD84 and Bcl-2/Mcl-1 not defined","Patient genetic heterogeneity effects not examined"]},{"year":2015,"claim":"Lupus-associated CD84 alleles on GC B cells break tolerance, and triple SLAM-family knockouts show enhanced antibody responses, positioning CD84 as both a positive regulator of GC tolerance and a negative regulator of humoral output.","evidence":"BAC-transgenic rescue on autoimmune background, single/triple SLAMF1/5/6 KO mice, adoptive transfers","pmids":["25801429","25926831"],"confidence":"High","gaps":["Molecular basis of allelic functional differences in CD84 not defined","Individual contribution of CD84 versus SLAMF6 in triple KO not separable"]},{"year":2016,"claim":"CD84 was shown to bridge CLL cells to stromal cells through homophilic trans-interaction, with blocking antibodies disrupting this bridge and inducing death in vivo, validating the therapeutic concept.","evidence":"Co-culture, blocking antibodies in vitro and in mouse CLL models","pmids":["27452524"],"confidence":"High","gaps":["Downstream signaling in stromal cells not characterized","Resistance mechanisms to CD84 blockade not explored"]},{"year":2018,"claim":"CD84 homophilic engagement was found to upregulate PD-L1 on CLL cells and PD-1 on T cells, connecting CD84 to immune checkpoint regulation and explaining microenvironmental T cell exhaustion.","evidence":"Human and mouse CD84-mediated cell interaction assays, flow cytometry for PD-L1/PD-1, T cell functional assays","pmids":["30277471"],"confidence":"High","gaps":["Signaling intermediates from CD84 to PD-L1 transcription not identified","Synergy with anti-PD-1 therapy not tested"]},{"year":2020,"claim":"Cell-type-specific CD84 knockouts demonstrated that platelet-derived soluble CD84 drives CD4+ T cell motility and cerebral infiltration after ischemic stroke, extending CD84 function beyond classical immunity to thrombo-inflammation.","evidence":"Platelet- and T cell-specific CD84 KO mice, experimental stroke models, in vitro T cell motility assays, human patient arterial blood analysis","pmids":["32762491"],"confidence":"High","gaps":["Receptor on T cells mediating response to soluble CD84 assumed to be CD84 but not formally excluded to be another receptor","Downstream T cell signaling pathway not mapped"]},{"year":2021,"claim":"MIF-induced CD84 on microenvironmental cells was shown to drive MDSC differentiation and PD-L1 upregulation in myeloma, suppressing T cell function—generalizing the CD84–PD-L1 axis beyond CLL.","evidence":"Co-culture, CD84 knockdown/blocking, flow cytometry, in vivo myeloma models","pmids":["33465053"],"confidence":"High","gaps":["Signaling from CD84 to MDSC differentiation transcription factors not fully defined","Role in solid tumors beyond breast not explored"]},{"year":2024,"claim":"Identification of CD84 as a BTK substrate placed it within alcohol-induced neutrophil inflammatory signaling; separately, CD84 was linked to β-catenin/Tcf4-driven IL-10 transcription in Bregs and to IKZF1–SHP2-mediated TAM polarization in glioma, revealing new lineage-specific downstream pathways.","evidence":"LC-MS/MS kinase substrate identification, myeloid Btk KO mice, ChIP/promoter binding for β-catenin/Tcf4, GSC-TAM co-culture with knockdown","pmids":["39110779","39466774","39112517"],"confidence":"High","gaps":["BTK phosphorylation site(s) on CD84 not mapped","β-catenin activation mechanism downstream of CD84 not defined","SHP2 role in glioma context from single study"]},{"year":2025,"claim":"CD84 was shown to regulate AML cell metabolism (oxidative phosphorylation, fatty acid oxidation) via Akt/NRF2, NHEJ DNA repair via SAP–AKT–PRKDC/LIG4 upregulation, and myeloid cell activation in EAE via BHLHE40/CD52—demonstrating broad cell-intrinsic roles in metabolic fitness, genomic stability, and neuroinflammation.","evidence":"CD84 KD/OE in AML cells, PDX and mouse leukemia models, electron microscopy, metabolic flux assays, NHEJ reporter, conditional myeloid KO in EAE, pharmacological blockade, human iPSC-derived microglia","pmids":["40198133","40633676","40920820"],"confidence":"High","gaps":["How CD84 surface engagement is transduced to mitochondrial dynamics is unknown","Whether NHEJ regulation is SAP-dependent in primary AML patient cells not confirmed","BHLHE40 regulation by CD84 signaling intermediates not mapped"]},{"year":null,"claim":"How CD84 switches between activating (SAP/EAT-2-dependent) and inhibitory (SHP-1/Dok-1-dependent) signaling modes in different cell types remains mechanistically undefined; the structural basis for adaptor selectivity at ITSM motifs and the identity of SAP-independent costimulatory pathways are open questions.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of CD84 cytoplasmic domain with adaptors","SAP-independent costimulatory pathway components unidentified","Context-dependent adaptor selection mechanism unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[1,6,8,16]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[3,5,9,11]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,9,18,20]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,6,12]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,5,8,10,14,15,18,20,26]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,5,7,9,11,24,25]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[13,16,24,25]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[13,16,25]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[24]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[25]}],"complexes":[],"partners":["SH2D1A","SH2D1B","PTPN6","DOK1","FES","LCK","BTK","PTPN11"],"other_free_text":[]},"mechanistic_narrative":"CD84 (SLAMF5) is a homophilic cell-surface receptor of the SLAM/CD2 immunoglobulin superfamily that functions as a context-dependent signaling hub orchestrating intercellular adhesion, immune activation, immune suppression, and metabolic regulation across hematopoietic lineages. Its N-terminal Ig-V domain forms an orthogonal homodimer with submicromolar affinity, enabling homophilic trans-interactions that sustain T cell–B cell contacts required for germinal center formation and that bridge CLL or AML cells to their supportive microenvironment [PMID:17563375, PMID:20153220, PMID:27452524]. Upon engagement, cytoplasmic ITSM tyrosines are phosphorylated by Src-family kinases (Lck), Fes, or BTK, recruiting SAP or EAT-2 to activate MAPK, NF-κB, Akt/NRF2, and Vav-1 pathways, or alternatively recruiting SHP-1/Dok-1 to inhibit mast-cell degranulation and dampen Syk–LAT–PLCγ1 signaling [PMID:12928397, PMID:22068234, PMID:20628063, PMID:39110779, PMID:40198133]. CD84 homophilic interactions also drive PD-L1 upregulation that suppresses T cell function in CLL and myeloma microenvironments, promote MDSC differentiation, regulate NHEJ DNA repair in AML through SAP–AKT signaling, and mediate platelet–T cell crosstalk in cerebral thrombo-inflammation, while its surface levels are controlled by ADAM10 ectodomain shedding and calpain-mediated intracellular cleavage [PMID:30277471, PMID:33465053, PMID:40633676, PMID:32762491, PMID:23025437]."},"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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antibodies\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original molecular characterization with multiple orthogonal methods\",\n      \"pmids\": [\"9310491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"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, and this interaction is mediated exclusively by the first extracellular Ig-like domain and is independent of the cytoplasmic tail.\",\n      \"method\": \"CD84-Ig soluble fusion protein binding assays, domain chimera analysis, anti-CD84 mAb blocking\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted binding with soluble fusion protein plus mutagenesis using domain chimeras\",\n      \"pmids\": [\"11564780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CD84 co-stimulates IFN-γ secretion in human lymphocytes when co-ligated with CD3, demonstrating a costimulatory function.\",\n      \"method\": \"In vitro stimulation assay with anti-CD84 mAbs or CD84-Ig fusion protein plus anti-CD3\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional assay in primary human lymphocytes with defined readout\",\n      \"pmids\": [\"11564780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The cytoplasmic tails of CD84 and Ly-9 recruit SAP (SH2D1A) via specific tyrosine residues; this interaction is most efficient when those tyrosines are phosphorylated, placing CD84 in the SAP-dependent signaling network disrupted in X-linked lymphoproliferative disease.\",\n      \"method\": \"Yeast two-hybrid, COS cell transfections, biochemical binding assays in lymphoid cells\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple systems (yeast 2-hybrid, mammalian transfection, endogenous lymphoid cells) with phosphorylation requirement defined\",\n      \"pmids\": [\"11389028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CD84 is rapidly tyrosine-phosphorylated upon antibody-mediated ligation on primary human B cells and recruits both SAP and EAT-2 via its cytoplasmic tail, suggesting a signaling role in memory B cell activation.\",\n      \"method\": \"Anti-CD84 mAb ligation, immunoprecipitation, Western blot for tyrosine phosphorylation and SAP/EAT-2 recruitment\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP/pulldown in primary human B cells with phosphorylation data\",\n      \"pmids\": [\"12115647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CD84 is tyrosine-phosphorylated on activated T cells via the Src kinase Lck; phosphorylation at Y262 in the cytoplasmic domain is required for SAP recruitment, which also requires R32 in the SAP SH2 domain. CD84 ligation enhances anti-CD3-stimulated T cell proliferation via both SAP-dependent and SAP-independent mechanisms.\",\n      \"method\": \"Site-directed mutagenesis of CD84 cytoplasmic domain and SAP SH2 domain, Lck inhibition, T cell proliferation assays with XLP patient (SAP-deficient) T cells\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis defining precise interaction residues plus functional validation in 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 similar to NTB-A. Solution studies show CD84 self-associates with a Kd in the submicromolar range. Structural differences at homophilic interfaces prevent undesired heterodimer formation among SLAM family members, and the ~140 Å end-to-end dimension allows colocalization within the immunological synapse.\",\n      \"method\": \"X-ray crystallography (2.0 Å), analytical ultracentrifugation for 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 — crystal structure with biophysical affinity measurement\",\n      \"pmids\": [\"17563375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CD84 inhibits FcεRI-mediated mast cell degranulation through homophilic interaction; this inhibitory mechanism is independent of SAP and SHP-2 recruitment but requires tyrosines Y279 and Y324 in the CD84 cytoplasmic domain, and is associated with increased phosphorylation of Dok-1 and c-Cbl and impaired MAP kinase (ERK1/2, JNK, p38) phosphorylation.\",\n      \"method\": \"CD84 transfection in RBL-2H3 cells, tyrosine mutants (Y279F, ΔY324), degranulation assays, Western blot for signaling intermediates\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis of specific residues plus mechanistic signaling readouts\",\n      \"pmids\": [\"18243321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The SLAM family member CD84 is required for prolonged T cell:B cell contact, optimal T follicular helper function, and germinal center formation in vivo. T cell:B cell interactions have both an early integrin-dependent phase and a sustained SAP-dependent phase requiring CD84 and Ly108.\",\n      \"method\": \"CD84-deficient mice, intravital two-photon microscopy, in vitro T:B adhesion assays, in vivo germinal center analysis\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with multiple in vitro and in vivo readouts, replicated with Ly108\",\n      \"pmids\": [\"20153220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In mouse macrophages, CD84 modulates TLR4 downstream signaling: transfection of CD84 in RAW-264.7 cells increases MAPK phosphorylation and NF-κB activation upon LPS stimulation, elevates TNF-α and MCP-1, and reduces IL-10 and IL-6 production. This modulatory effect is mediated specifically by Y300 within the second ITSM of CD84.\",\n      \"method\": \"CD84 transfection and knockdown in RAW-264.7 macrophages and bone-marrow-derived macrophages, ITSM tyrosine mutant (Y300), MAPK/NF-κB reporter assays, cytokine ELISA\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — site-directed mutagenesis of specific signaling residue plus gain- and loss-of-function\",\n      \"pmids\": [\"20628063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"EAT-2A and EAT-2B adapters positively regulate CD84- and CD244-dependent NK cell killing of tumor cells in C57BL/6 mice and mediate phosphorylation of Vav-1 downstream of these SLAM family receptors.\",\n      \"method\": \"EAT-2A/B-deficient mice (C57BL/6 background), NK cytotoxicity assays, Vav-1 phosphorylation by Western blot\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO mice with functional NK killing assay and defined signaling readout\",\n      \"pmids\": [\"20962259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In human mast cells, which lack SAP and EAT-2, CD84 is tyrosine-phosphorylated upon FcεRI engagement and inhibits FcεRI-mediated degranulation and cytokine release. Inhibition is mediated by the Fes kinase (which phosphorylates the CD84 inhibitory motif) and by increased SHP-1 phosphorylation, and is accompanied by dampened calcium mobilization and reduced Syk-LAT-PLCγ1 axis activity.\",\n      \"method\": \"FcεRI/CD84 co-cross-linking in LAD2 cells and primary human CD34+-derived mast cells, calcium flux assay, Western blot for Syk, LAT, PLCγ1, Fes, SHP-1 phosphorylation\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mechanistic pathway dissection in primary human cells with multiple orthogonal readouts\",\n      \"pmids\": [\"22068234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD84 is shed from platelets by ADAM10-mediated ectodomain cleavage and simultaneously cleaved intracellularly by calpain. ADAM10 is the principal sheddase (ADAM17 is dispensable), and CD84 is constitutively shed in vivo.\",\n      \"method\": \"Biochemical shedding assays in human and murine platelets, ADAM10-deficient, ADAM17-deficient, and calpain-inhibited/deficient mouse models, Western blot\",\n      \"journal\": \"Journal of thrombosis and haemostasis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — three distinct transgenic mouse lines identifying specific proteases\",\n      \"pmids\": [\"23025437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CD84 expression in CLL cells is regulated by macrophage migration inhibitory factor (MIF) via its receptor CD74. Activation of surface CD84 initiates a signaling cascade that enhances CLL cell survival; downmodulation or immune-mediated blockade of CD84 induces cell death in vitro and in vivo, with concomitant reduction of Bcl-2 and Mcl-1 expression.\",\n      \"method\": \"CD84 knockdown and blocking antibodies in CLL cells in vitro and in vivo mouse models, Western blot for Bcl-2/Mcl-1, analysis of clinical trial samples (milatuzumab treatment)\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo loss-of-function with defined survival pathway and upstream regulator identified\",\n      \"pmids\": [\"23435417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"B cell-intrinsic CD84 and Ly108 maintain germinal center B cell tolerance; lupus-associated alleles of CD84 and Ly108 on GC B cells are sufficient to break tolerance and increase autoantibody production, and B6.Sle1b B cells have reduced B cell-T cell conjugate formation reversed by B6 CD84/Ly108 alleles.\",\n      \"method\": \"BAC-transgenic mice overexpressing B6 alleles of CD84/Ly108 on autoimmune-prone background, GC response measurement, B cell-T cell conjugate assays, BCR signaling assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo transgenic rescue combined with cellular conjugate and signaling assays\",\n      \"pmids\": [\"25801429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SLAMF1, SLAMF5 (CD84), and SLAMF6 act as negative regulators of humoral immunity; triple-knockout mice show ~2-fold higher T-dependent and T-independent antibody responses. B cell-intrinsic activity accounts for the predominant effect, and anti-SLAMF6 antibody treatment inhibits Tfh and GC B cell development.\",\n      \"method\": \"Single and triple Slamf1/5/6 knockout mice, adoptive co-transfer assays, anti-SLAMF6 antibody treatment, antibody titer measurement\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with multiple KO combinations and adoptive transfer to assign cell-intrinsic roles\",\n      \"pmids\": [\"25926831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD84 bridges CLL cells and stromal microenvironment cells through homophilic self-association; CD84 expressed on CLL cells interacts with CD84 on stromal cells inducing survival signaling in both cell types. Blocking CD84 in vitro and in vivo disrupts this interaction and induces cell death.\",\n      \"method\": \"Co-culture assays, CD84 blocking antibodies in vitro and in vivo mouse models, cell survival/death assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo loss-of-function with defined homophilic mechanism\",\n      \"pmids\": [\"27452524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CRISPR-mediated triple knockout of SLAMF1, SLAMF5, and SLAMF6 worsens defects in iNKT cell development seen in SLAMF6 single-knockout mice, supporting positive signaling roles for these receptors in iNKT development, with potential redundancy among them.\",\n      \"method\": \"Cas9/CRISPR triple-knockout mice, flow cytometric analysis of iNKT and conventional lymphocyte populations, germinal center analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis using CRISPR triple KO in vivo\",\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 PD-1 expression on T cells, resulting in suppression of T cell function in vitro and in vivo. This identifies CD84 as a regulator of PD-1/PD-L1 immune checkpoints in CLL.\",\n      \"method\": \"Human and mouse CD84-mediated cell-cell interaction assays, PD-L1/PD-1 expression by flow cytometry, T cell functional assays in vitro and in vivo\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional mechanistic link between CD84 engagement and checkpoint upregulation validated in vitro and in vivo\",\n      \"pmids\": [\"30277471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD84 mediates cerebral thrombo-inflammation in ischemic stroke: platelet-derived soluble CD84 enhances motility of CD4+ T cells through homophilic CD84 interaction. Mice lacking CD84 on either platelets or T cells show reduced cerebral CD4+ T cell infiltration and thrombotic activity after experimental stroke.\",\n      \"method\": \"CD84-deficient mice (cell-type specific), experimental stroke models, in vitro T cell motility assays with soluble CD84, clinical analysis of arterial blood from ischemic patients\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific KO mice with mechanistic in vitro validation and translational human data\",\n      \"pmids\": [\"32762491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In multiple myeloma, myeloma cells secrete MIF which induces CD84 expression on microenvironmental cells. CD84 activation on these cells upregulates genes regulating M-MDSC and G-MDSC differentiation and increases PD-L1 expression on MDSCs, suppressing T cell function. Downregulation or blocking of CD84 reduces MDSC accumulation and elevates T cell activity.\",\n      \"method\": \"In vitro co-culture, CD84 knockdown and blocking antibodies, flow cytometry for MDSC markers and PD-L1, in vivo tumor models\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway (MIF→CD84→MDSC/PD-L1→T cell suppression) validated in vitro and in vivo\",\n      \"pmids\": [\"33465053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CD84 is a kinase substrate of BTK (identified by liquid chromatography-tandem mass spectrometry); CD84 promotes alcohol-induced IL-1β and TNF-α in primary human neutrophils, an effect inhibited by CD84-blocking antibody, placing CD84 downstream of BTK in alcohol-induced granulopoiesis and neutrophil inflammation.\",\n      \"method\": \"LC-MS/MS kinase substrate identification, BTK inhibitor treatment, myeloid-specific Btk knockout mice, CD84-blocking antibody in vitro\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mass spectrometry identification of CD84 as BTK substrate combined with in vitro and in vivo functional validation\",\n      \"pmids\": [\"39110779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In TNBC, CD84 activates a Breg cascade involving β-catenin and Tcf4, which drive transcription of IL-10 by binding to its promoter and the promoter of its regulator AhR, leading to Breg expansion and suppression of other immune cells.\",\n      \"method\": \"In vitro CD84 stimulation, ChIP/promoter binding assays for β-catenin/Tcf4, IL-10 reporter, Breg expansion assays, in vivo tumor models\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transcriptional mechanism with promoter binding data in defined cell type\",\n      \"pmids\": [\"39466774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In glioma, CCL2 from mesenchymal glioma stem cells induces IKZF1 expression in tumor-associated macrophages, which promotes M2 polarization via the CD84-SHP2 pathway.\",\n      \"method\": \"GSC-TAM co-culture, bioinformatics, knockdown experiments, determination of TAM polarization phenotypes\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — co-culture mechanistic assay with pathway identification but 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 alters mitochondrial ultrastructure, reduces oxidative phosphorylation and fatty acid oxidation, blocks Akt phosphorylation, and downmodulates NRF2, impairing antioxidant defense. Conversely, CD84 overexpression stabilizes NRF2 and promotes its transcriptional activation.\",\n      \"method\": \"CD84 knockdown and overexpression in AML cell lines and patient-derived xenografts, MLL-AF9 and inv(16) mouse models, electron microscopy for mitochondrial ultrastructure, metabolic flux assays, Western blot for Akt/NRF2\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods across human and mouse models establishing CD84→Akt→NRF2 metabolic axis\",\n      \"pmids\": [\"40198133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In AML, CD84 promotes expression of NHEJ DNA repair core factors (PRKDC, LIG4, XRCC5, DCLRE1C) by recruiting SAP and activating the AKT signaling pathway; CD84 knockdown inhibits NHEJ repair, causing double-strand break accumulation and apoptosis.\",\n      \"method\": \"CD84 knockdown in AML cells, SAP co-immunoprecipitation, AKT phosphorylation Western blot, NHEJ reporter assays, γH2AX foci (DSB accumulation), in vivo xenograft models\",\n      \"journal\": \"Molecules and cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — SAP recruitment and AKT activation linked to NHEJ factor expression with functional DNA repair readout\",\n      \"pmids\": [\"40633676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SLAMF5/CD84 deficiency in myeloid cells (microglia and border-associated macrophages) reduces expression of activation and costimulatory molecules MHC II and CD80, delays EAE onset and progression. This is mediated at least in part through the transcription factor BHLHE40 and its regulation of CD52. Pharmacological blockade of SLAMF5 in the brain halts disease progression.\",\n      \"method\": \"Total and brain-specific SLAMF5-deficient mice, EAE model, flow cytometry for activation markers, BHLHE40/CD52 mechanistic analysis, pharmacological blockade, human iPSC-derived microglia\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO plus pharmacological blockade in vivo with defined transcription factor pathway\",\n      \"pmids\": [\"40920820\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD84 (SLAMF5) is a homophilic adhesion receptor of the SLAM family whose extracellular Ig-V domain mediates submicromolar self-association forming an orthogonal dimer; upon engagement, specific cytoplasmic ITSM tyrosines are phosphorylated by Src-family kinases (Lck) or Fes, recruiting adaptor proteins SAP and/or EAT-2 to activate downstream signaling (MAPK, NF-κB, Vav-1, Akt/NRF2) or recruiting SHP-1/Dok-1 to inhibit signaling (e.g., in mast cells), while ADAM10 and calpain regulate its surface levels by ectodomain shedding and intracellular cleavage; functionally, CD84 sustains T:B cell adhesion required for germinal center formation, modulates macrophage cytokine responses to LPS, supports CLL and AML cell survival through microenvironmental homophilic bridging and metabolic/NHEJ pathways, drives MDSC-mediated immune suppression via PD-L1 upregulation, and mediates platelet-T cell crosstalk in cerebral thrombo-inflammation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CD84 (SLAMF5) is a homophilic cell-surface receptor of the SLAM/CD2 immunoglobulin superfamily that functions as a context-dependent signaling hub orchestrating intercellular adhesion, immune activation, immune suppression, and metabolic regulation across hematopoietic lineages. Its N-terminal Ig-V domain forms an orthogonal homodimer with submicromolar affinity, enabling homophilic trans-interactions that sustain T cell–B cell contacts required for germinal center formation and that bridge CLL or AML cells to their supportive microenvironment [PMID:17563375, PMID:20153220, PMID:27452524]. Upon engagement, cytoplasmic ITSM tyrosines are phosphorylated by Src-family kinases (Lck), Fes, or BTK, recruiting SAP or EAT-2 to activate MAPK, NF-κB, Akt/NRF2, and Vav-1 pathways, or alternatively recruiting SHP-1/Dok-1 to inhibit mast-cell degranulation and dampen Syk–LAT–PLCγ1 signaling [PMID:12928397, PMID:22068234, PMID:20628063, PMID:39110779, PMID:40198133]. CD84 homophilic interactions also drive PD-L1 upregulation that suppresses T cell function in CLL and myeloma microenvironments, promote MDSC differentiation, regulate NHEJ DNA repair in AML through SAP–AKT signaling, and mediate platelet–T cell crosstalk in cerebral thrombo-inflammation, while its surface levels are controlled by ADAM10 ectodomain shedding and calpain-mediated intracellular cleavage [PMID:30277471, PMID:33465053, PMID:40633676, PMID:32762491, PMID:23025437].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Identification of CD84 as a new Ig-superfamily member on hematopoietic cells established the molecular identity and expression pattern of the receptor, enabling subsequent functional studies.\",\n      \"evidence\": \"cDNA cloning, Northern blot, and flow cytometry with mAbs on human hematopoietic cells\",\n      \"pmids\": [\"9310491\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No ligand or signaling function defined\", \"Expression on non-hematopoietic tissues not examined\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstration that CD84 is a homophilic receptor whose first Ig-like domain mediates self-binding, and that ligation costimulates IFN-γ production, established both the binding mode and a functional consequence of engagement.\",\n      \"evidence\": \"Soluble CD84-Ig fusion binding assays, domain chimeras, and T cell costimulation assays with anti-CD84 mAbs\",\n      \"pmids\": [\"11564780\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of homophilic interaction unknown\", \"Downstream signaling pathway not mapped\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Discovery that SAP binds phosphorylated CD84 cytoplasmic tyrosines connected CD84 to the SAP-dependent signaling network disrupted in X-linked lymphoproliferative disease.\",\n      \"evidence\": \"Yeast two-hybrid, COS cell transfection, and biochemical binding assays in lymphoid cells\",\n      \"pmids\": [\"11389028\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific phosphotyrosine residues not mapped\", \"In vivo relevance of SAP recruitment to CD84 not tested\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showing that CD84 is rapidly phosphorylated on primary B cells and recruits both SAP and EAT-2 expanded the adaptor repertoire and implicated CD84 in memory B cell signaling.\",\n      \"evidence\": \"Anti-CD84 ligation, immunoprecipitation, and Western blot in primary human B cells\",\n      \"pmids\": [\"12115647\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"EAT-2 binding site on CD84 not mapped\", \"Functional consequence in B cell differentiation not shown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Mapping the critical phosphotyrosine Y262 for SAP binding and identifying Lck as the upstream kinase defined the proximal signaling mechanism; use of SAP-deficient XLP patient cells revealed SAP-independent costimulatory pathways.\",\n      \"evidence\": \"Site-directed mutagenesis, Lck inhibition, and T cell proliferation assays including XLP patient cells\",\n      \"pmids\": [\"12928397\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SAP-independent pathway components not identified\", \"Role of other Src-family kinases not excluded\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"The 2.0 Å crystal structure of the CD84 Ig-V domain revealed the orthogonal homodimer geometry and submicromolar self-association affinity, explaining specificity among SLAM family members and compatibility with immunological synapse dimensions.\",\n      \"evidence\": \"X-ray crystallography and analytical ultracentrifugation\",\n      \"pmids\": [\"17563375\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length extracellular structure not solved\", \"Dynamics of dimer at the cell surface not characterized\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"CD84 was shown to function as an inhibitory receptor in mast cells via Y279/Y324-dependent recruitment of Dok-1 and c-Cbl, dampening MAP kinase signaling—demonstrating that CD84 can switch between activating and inhibitory outputs depending on cellular context.\",\n      \"evidence\": \"Tyrosine mutants in RBL-2H3 cells, degranulation assays, and signaling Western blots\",\n      \"pmids\": [\"18243321\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct interaction between CD84 and Dok-1/c-Cbl not shown by co-IP\", \"Physiological ligand engagement in mast cells not addressed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Genetic deletion of CD84 in mice proved it is required for sustained T:B cell contact and germinal center formation, and separately, CD84 modulates macrophage TLR4 responses via its second ITSM (Y300), activating MAPK/NF-κB—establishing dual in vivo roles in adaptive and innate immunity.\",\n      \"evidence\": \"CD84-knockout mice with intravital imaging, GC analysis, and macrophage gain/loss-of-function with ITSM mutants\",\n      \"pmids\": [\"20153220\", \"20628063\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of CD84 versus Ly108 to GC formation not fully dissected\", \"Downstream transcriptional targets of NF-κB in macrophages not defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"EAT-2 adaptors were shown to positively regulate CD84-dependent NK cell cytotoxicity through Vav-1 phosphorylation, extending CD84's functional repertoire to innate cytotoxicity.\",\n      \"evidence\": \"EAT-2A/B-deficient mice, NK killing assays, Vav-1 phosphorylation Western blot\",\n      \"pmids\": [\"20962259\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct EAT-2–Vav-1 interaction downstream of CD84 not shown\", \"Contribution of CD84 versus CD244 not individually dissected\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"In SAP/EAT-2-negative human mast cells, identification of Fes as the kinase phosphorylating CD84 and SHP-1 as the effector phosphatase revealed the molecular logic of CD84's inhibitory mode, explaining context-dependent signaling switching.\",\n      \"evidence\": \"FcεRI/CD84 co-cross-linking in LAD2 and primary mast cells, calcium flux, and phospho-signaling analysis\",\n      \"pmids\": [\"22068234\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct Fes–CD84 physical interaction not demonstrated\", \"Relative roles of SHP-1 versus SHP-2 not fully resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of ADAM10 and calpain as the sheddase and intracellular protease regulating CD84 surface levels on platelets established a post-translational control mechanism for receptor availability.\",\n      \"evidence\": \"ADAM10-, ADAM17-deficient, and calpain-inhibited mouse platelets with shedding assays\",\n      \"pmids\": [\"23025437\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cleavage sites not mapped at amino-acid resolution\", \"Functional consequence of soluble CD84 ectodomain from platelets not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery that MIF/CD74 induces CD84 expression on CLL cells, whose homophilic engagement sustains survival via Bcl-2/Mcl-1, established CD84 as a druggable pro-survival factor in CLL.\",\n      \"evidence\": \"CD84 knockdown/blocking antibodies in CLL cells in vitro and in vivo, Bcl-2/Mcl-1 Western blot\",\n      \"pmids\": [\"23435417\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling intermediates between CD84 and Bcl-2/Mcl-1 not defined\", \"Patient genetic heterogeneity effects not examined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Lupus-associated CD84 alleles on GC B cells break tolerance, and triple SLAM-family knockouts show enhanced antibody responses, positioning CD84 as both a positive regulator of GC tolerance and a negative regulator of humoral output.\",\n      \"evidence\": \"BAC-transgenic rescue on autoimmune background, single/triple SLAMF1/5/6 KO mice, adoptive transfers\",\n      \"pmids\": [\"25801429\", \"25926831\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of allelic functional differences in CD84 not defined\", \"Individual contribution of CD84 versus SLAMF6 in triple KO not separable\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"CD84 was shown to bridge CLL cells to stromal cells through homophilic trans-interaction, with blocking antibodies disrupting this bridge and inducing death in vivo, validating the therapeutic concept.\",\n      \"evidence\": \"Co-culture, blocking antibodies in vitro and in mouse CLL models\",\n      \"pmids\": [\"27452524\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling in stromal cells not characterized\", \"Resistance mechanisms to CD84 blockade not explored\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"CD84 homophilic engagement was found to upregulate PD-L1 on CLL cells and PD-1 on T cells, connecting CD84 to immune checkpoint regulation and explaining microenvironmental T cell exhaustion.\",\n      \"evidence\": \"Human and mouse CD84-mediated cell interaction assays, flow cytometry for PD-L1/PD-1, T cell functional assays\",\n      \"pmids\": [\"30277471\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling intermediates from CD84 to PD-L1 transcription not identified\", \"Synergy with anti-PD-1 therapy not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Cell-type-specific CD84 knockouts demonstrated that platelet-derived soluble CD84 drives CD4+ T cell motility and cerebral infiltration after ischemic stroke, extending CD84 function beyond classical immunity to thrombo-inflammation.\",\n      \"evidence\": \"Platelet- and T cell-specific CD84 KO mice, experimental stroke models, in vitro T cell motility assays, human patient arterial blood analysis\",\n      \"pmids\": [\"32762491\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor on T cells mediating response to soluble CD84 assumed to be CD84 but not formally excluded to be another receptor\", \"Downstream T cell signaling pathway not mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"MIF-induced CD84 on microenvironmental cells was shown to drive MDSC differentiation and PD-L1 upregulation in myeloma, suppressing T cell function—generalizing the CD84–PD-L1 axis beyond CLL.\",\n      \"evidence\": \"Co-culture, CD84 knockdown/blocking, flow cytometry, in vivo myeloma models\",\n      \"pmids\": [\"33465053\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling from CD84 to MDSC differentiation transcription factors not fully defined\", \"Role in solid tumors beyond breast not explored\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of CD84 as a BTK substrate placed it within alcohol-induced neutrophil inflammatory signaling; separately, CD84 was linked to β-catenin/Tcf4-driven IL-10 transcription in Bregs and to IKZF1–SHP2-mediated TAM polarization in glioma, revealing new lineage-specific downstream pathways.\",\n      \"evidence\": \"LC-MS/MS kinase substrate identification, myeloid Btk KO mice, ChIP/promoter binding for β-catenin/Tcf4, GSC-TAM co-culture with knockdown\",\n      \"pmids\": [\"39110779\", \"39466774\", \"39112517\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"BTK phosphorylation site(s) on CD84 not mapped\", \"β-catenin activation mechanism downstream of CD84 not defined\", \"SHP2 role in glioma context from single study\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"CD84 was shown to regulate AML cell metabolism (oxidative phosphorylation, fatty acid oxidation) via Akt/NRF2, NHEJ DNA repair via SAP–AKT–PRKDC/LIG4 upregulation, and myeloid cell activation in EAE via BHLHE40/CD52—demonstrating broad cell-intrinsic roles in metabolic fitness, genomic stability, and neuroinflammation.\",\n      \"evidence\": \"CD84 KD/OE in AML cells, PDX and mouse leukemia models, electron microscopy, metabolic flux assays, NHEJ reporter, conditional myeloid KO in EAE, pharmacological blockade, human iPSC-derived microglia\",\n      \"pmids\": [\"40198133\", \"40633676\", \"40920820\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CD84 surface engagement is transduced to mitochondrial dynamics is unknown\", \"Whether NHEJ regulation is SAP-dependent in primary AML patient cells not confirmed\", \"BHLHE40 regulation by CD84 signaling intermediates not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CD84 switches between activating (SAP/EAT-2-dependent) and inhibitory (SHP-1/Dok-1-dependent) signaling modes in different cell types remains mechanistically undefined; the structural basis for adaptor selectivity at ITSM motifs and the identity of SAP-independent costimulatory pathways are open questions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of CD84 cytoplasmic domain with adaptors\", \"SAP-independent costimulatory pathway components unidentified\", \"Context-dependent adaptor selection mechanism unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [1, 6, 8, 16]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [3, 5, 9, 11]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 9, 18, 20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 6, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 5, 8, 10, 14, 15, 18, 20, 26]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 5, 7, 9, 11, 24, 25]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [13, 16, 24, 25]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [13, 16, 25]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [24]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [25]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"SH2D1A\",\n      \"SH2D1B\",\n      \"PTPN6\",\n      \"DOK1\",\n      \"FES\",\n      \"LCK\",\n      \"BTK\",\n      \"PTPN11\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}