{"gene":"CD80","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":1989,"finding":"CD80 (B7) was identified as a type I transmembrane glycoprotein of the immunoglobulin superfamily, with two extracellular Ig-like domains (one V-like, one C-like), expressed on activated B cells and B cell malignancies, functioning as a costimulatory ligand for T cells.","method":"cDNA cloning, expression in COS cells, immunoprecipitation, Northern blot","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 — original molecular cloning with structural characterization and functional validation, foundational paper with >500 citations","pmids":["2794510"],"is_preprint":false},{"year":1991,"finding":"CD80 (B7) delivers a costimulatory signal to T cells through direct binding to CD28, stimulating T cell proliferation and IL-2 mRNA accumulation; CD28-Ig fusion protein bound CD80 with Kd ~200 nM, and B7-transfected CHO cells costimulated T cell activation.","method":"Fusion protein binding assay (125I-labeled B7-Ig), CD28-transfected CHO cell binding, T cell proliferation assay, IL-2 mRNA measurement","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1 — reconstituted binding with defined Kd, functional costimulation demonstrated with transfected cells, >1200 citations","pmids":["1847722"],"is_preprint":false},{"year":1991,"finding":"Murine CD80 (B7) was cloned; the predicted protein shares 44% amino acid identity with human B7 with conserved Ig-V and Ig-C domains; murine B7-transfected cells provided costimulatory signal to human CD28+ T lymphocytes, demonstrating conservation of the ligand attachment site.","method":"cDNA cloning, sequence analysis, transfection into CHO cells, T cell costimulation assay","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1 — molecular cloning with cross-species functional validation, >360 citations","pmids":["1714935"],"is_preprint":false},{"year":1994,"finding":"CD80 (B7-1) and CD86 (B7-2) are both ligands for CD28 and CTLA-4; both molecules are expressed on multiple APC types (B cells, T cells, macrophages, dendritic cells); their expression can be independently regulated by the same stimulus; blocking CD86 (B7-2) costimulatory activity inhibits TCR-dependent T cell proliferation and cytokine production without affecting early TCR signals (CD69, IL-2Rα induction).","method":"Flow cytometry, blocking antibody experiments, T cell proliferation and cytokine production assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — multiple cell types, reciprocal blocking with functional readouts, >600 citations","pmids":["7519245"],"is_preprint":false},{"year":1994,"finding":"The extracellular V-like domains of CD80 (B7-1) and CD86 (B7-2) share sequence similarities with MHC-encoded Ig superfamily members (butyrophilin, myelin/oligodendrocyte glycoprotein, chicken B-G), suggesting an evolutionary link between B7 molecules and MHC-encoded costimulatory molecules.","method":"Sequence analysis, structural comparison","journal":"Protein science","confidence":"Low","confidence_rationale":"Tier 4 — computational sequence/structural analysis only","pmids":["7527261"],"is_preprint":false},{"year":1994,"finding":"The C-like domain of CD80 is structurally compatible with IgSF C-set structures (best recognized by β2-microglobulin of MHC Class I), while the N-terminal V-like domain is not compatible with known IgSF V-set structures; 11 of 17 conserved residues in the C-like domain of B7-1/B7-2 are not standard IgSF C-1 set consensus residues and cluster on the surface, suggesting they mediate protein-protein interactions.","method":"Inverse folding methodology, sequence comparison mapped onto β2-microglobulin structure","journal":"Protein science","confidence":"Low","confidence_rationale":"Tier 4 — computational structural analysis without experimental validation","pmids":["7535614"],"is_preprint":false},{"year":1994,"finding":"Ligation of CD28 by monoclonal antibody (but not by its physiological ligand B7-1/CD80) stimulates p21ras and downstream Ras-dependent events (ERK2 activation, Raf-1 hyperphosphorylation); both anti-CD28 mAb and B7-1 activate cellular PTKs and induce Vav tyrosine phosphorylation, but only anti-CD28 mAb induces tyrosine phosphorylation of the Grb2-associated p36 protein, which correlates with p21ras activation.","method":"In vitro kinase assays, anti-phosphotyrosine immunoblotting, Ras activation assay, co-immunoprecipitation","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 — multiple biochemical assays with functional dissection of CD28 vs B7-1 signaling, single lab","pmids":["7520466"],"is_preprint":false},{"year":1994,"finding":"BCL6 directly represses CD80 transcription: BCL6 binds the CD80 promoter in vivo and suppresses NF-κB-mediated transcriptional activation induced by CD40 signaling; BCL6-deficient mice show increased CD80 expression on B cells, and BCL6 and CD80 expression are mutually exclusive in normal B cells.","method":"Chromatin immunoprecipitation (ChIP), reporter assays, B cell expression analysis in BCL6-knockout mice, Western blot","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — ChIP demonstrating direct promoter binding, corroborated by knockout mouse data and mutual exclusion in vivo, replicated by multiple orthogonal methods","pmids":["12860928"],"is_preprint":false},{"year":1995,"finding":"CD80 (B7-1) and CD86 (B7-2) differentially activate the Th1/Th2 developmental pathways: blockade of B7-1 reduced EAE incidence and favored Th2 clone generation (mediating IL-4-dependent disease amelioration), while blockade of B7-2 increased EAE severity; thus, shared counterreceptors CD28 and CTLA-4 yield very different outcomes depending on which B7 ligand is engaged.","method":"In vitro T cell differentiation assays, in vivo EAE model with anti-B7 antibody treatment, cytokine profiling, adoptive transfer","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 — in vivo and in vitro epistasis, adoptive transfer, cytokine blocking, >1499 citations","pmids":["7534215"],"is_preprint":false},{"year":1995,"finding":"CD80 and CD86 provide similar costimulatory signals for T cell proliferation, cytokine production (IL-2, IFN-γ), and CTL generation; CTLA-4-Ig binds both ligands with higher affinity than CD28-Ig; blocking both ligands simultaneously is required to optimally inhibit CD28-dependent proliferation in allogeneic MLR.","method":"Stable transfectants, anti-CD3 proliferation assay, cytokine ELISA, CTL generation, CD28-Ig/CTLA-4-Ig binding assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal functional assays with defined transfectants, >440 citations","pmids":["7527824"],"is_preprint":false},{"year":1996,"finding":"CD80 (B7-1) functions as a triggering signal for NK cell-mediated cytotoxicity that overrides MHC class I protection; this NK cell triggering by B7-1 occurs even in the absence of CD28 and cannot be blocked by anti-CD28 or anti-CTLA-4 antibodies, indicating NK cells use receptors other than CD28/CTLA-4 to interact with B7-1.","method":"NK cell cytotoxicity assays with purified populations, blocking antibody experiments, CD28-knockout mouse NK cells","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 — purified NK cells, CD28-KO genetic control, functional blocking with defined antibodies","pmids":["8885864"],"is_preprint":false},{"year":1996,"finding":"CD40 signaling induces CD80 expression through a pathway involving specific threonine residues (T227 and T234) in the CD40 cytoplasmic tail; cAMP synergizes with CD40 signaling to induce high-level CD80 expression; a distinct CD40 domain (with only six cytoplasmic amino acids) retains growth-inhibitory function but loses CD80 induction capacity, demonstrating at least two distinct CD40 signaling domains.","method":"Transfection of wild-type and mutant CD40 constructs into M12 B lymphoma, flow cytometry for CD80 expression, cAMP treatment","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — systematic deletion/point mutagenesis identifying specific residues, single lab","pmids":["8816387"],"is_preprint":false},{"year":1996,"finding":"The V domain of CD86 (but not CD80) is sufficient for CTLA-4 binding; insertion of two residues between the two Ig domains of CD80 decreased affinity for CTLA-4, while the same insertion in CD86 had no effect, demonstrating a fundamental structural difference between CD80 and CD86 in receptor recognition.","method":"Domain-swapping constructs, binding assays with CTLA-4 and CD28","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — systematic domain-swapping and insertion mutagenesis, single lab","pmids":["8609386"],"is_preprint":false},{"year":1997,"finding":"CD80 binds both CD28 and CTLA-4 with low affinity and very fast kinetics: at 37°C, soluble CD80 binds CTLA-4 with Kd ~0.42 μM and CD28 with Kd ~4 μM, with very fast dissociation rate constants (koff ≥ 0.43 s⁻¹ for CTLA-4 and ≥ 1.6 s⁻¹ for CD28), as measured by surface plasmon resonance.","method":"Surface plasmon resonance (BIAcore) with soluble recombinant proteins at physiological temperature","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1 — quantitative biophysical measurement with recombinant proteins, precise kinetic constants determined, >430 citations","pmids":["9053440"],"is_preprint":false},{"year":1998,"finding":"CTLA-4 can potently inhibit T cell activation in the absence of CD28 through B7-1 engagement: CD28-deficient T cells primed with antigen-expressing tumor cells showed strong inhibition of cytokine production and proliferation when B7-1 was present on stimulators, and this inhibition was reversed by anti-B7-1 or anti-CTLA-4 antibodies, indicating CTLA-4 antagonizes TCR-mediated signals independent of CD28.","method":"TCR transgenic/RAG2-deficient/CD28 knockout mouse model, antigen-specific stimulation assays, antibody blocking","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — genetic CD28-knockout model with antigen-specific readout and antibody rescue, mechanistic dissection","pmids":["9653097"],"is_preprint":false},{"year":2000,"finding":"The crystal structure of soluble B7-1 (sB7-1) at 3 Å resolution reveals a novel combination of two Ig-like domains: an IgV-like domain (characteristic of adhesion molecules) and an IgC-like domain (previously seen only in antigen receptors); sB7-1 forms parallel, 2-fold rotationally symmetric homodimers in the crystal lattice and also dimerizes in solution as demonstrated by analytical ultracentrifugation, suggesting avidity-enhanced binding to CTLA-4 homodimers favors stable inhibitory signaling complexes.","method":"X-ray crystallography (3 Å resolution), analytical ultracentrifugation","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus solution biophysics confirming dimerization, >195 citations","pmids":["10661405"],"is_preprint":false},{"year":2000,"finding":"An alternatively spliced soluble form of porcine B7-1 (sB7-1) lacking both transmembrane and cytoplasmic domains was identified; porcine sB7-1-His interacted with both human CD28 and CTLA-4 and effectively blocked IL-2 production and T cell proliferation in response to porcine or human stimulator cells.","method":"cDNA cloning, Northern blot, His-tagged protein binding assay, T cell proliferation inhibition assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — identification of splice variant with demonstrated functional activity, single lab","pmids":["10843688"],"is_preprint":false},{"year":2001,"finding":"The crystal structure of the human CTLA-4/B7-1 complex at 3.0 Å resolution reveals: (1) an unusually high degree of shape complementarity at the binding interface; (2) CTLA-4 forms homodimers through a newly defined interface of highly conserved residues; (3) in the crystal lattice, bivalent CTLA-4 homodimers bridge bivalent B7-1 homodimers in a zipper-like oligomeric arrangement that provides the structural basis for unusually stable inhibitory signaling complexes.","method":"X-ray crystallography at 3.0 Å resolution","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — high-resolution crystal structure of the complex, >369 citations","pmids":["11279502"],"is_preprint":false},{"year":2001,"finding":"The crystal structure of human CTLA-4/B7-2 complex at 3.2 Å shows that the unique dimerization properties of both CTLA-4 and B7-2 place ligand-binding sites distal to dimer interfaces, promoting alternating bivalent CTLA-4/B7-2 dimer networks throughout the crystal, providing a model for periodic organization within the immunological synapse.","method":"X-ray crystallography at 3.2 Å resolution","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — crystal structure of related complex providing structural context for CD80 signaling","pmids":["11279501"],"is_preprint":false},{"year":2001,"finding":"Small molecules that inhibit CD80 binding to both CD28 and CTLA4 bind to the GFCC'C\" face of the N-terminal V-set domain of human CD80; both classes of compounds appear to bind the same site, which is not present in homologous B7-2 or mouse B7-1, defining a species- and paralog-specific hot spot on CD80.","method":"Small molecule screening, competitive binding assay, domain mapping","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — binding site defined by competitive inhibition with two compound classes, single lab","pmids":["11741888"],"is_preprint":false},{"year":2001,"finding":"Naive CD4+ T cells acquire CD80 (B7-1) protein from syngeneic APCs after activation; this acquisition is CD28-dependent (absent in CD28-KO T cells), does not involve CD80 mRNA expression in T cells, is proportional to both signal 1 strength and APC CD80 level, and does not occur for other APC molecules (e.g., CD40); T cells that acquire CD80 can themselves act as APCs, while memory T cells that acquire CD80 undergo apoptosis in the presence of strong TCR signals.","method":"CD80/CD86 knockout mouse B cells as APC source, cyclohexamide treatment, confocal microscopy, CD28-KO T cells, RT-PCR for CD80 mRNA","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal controls (KO mice, protein synthesis inhibition, mRNA analysis, confocal), functional demonstration of acquired CD80","pmids":["11160311"],"is_preprint":false},{"year":2002,"finding":"CD80 binds CTLA-4 and CD28 with higher affinity than CD86; relative to its CTLA-4 binding affinity, CD86 binds CD28 2-3 fold more effectively than CD80; unlike CD80, CD86 does not self-associate; CD28 homodimers are monovalent (not bivalent as previously assumed); CD80 markedly favors CTLA-4 over CD28 engagement, while CD86 exhibits much less bias, explaining their overlapping but distinct T cell response outcomes.","method":"Surface plasmon resonance, analytical ultracentrifugation, recombinant protein binding assays","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1 — quantitative biophysical measurements with recombinant proteins, multiple orthogonal methods, >520 citations","pmids":["12196291"],"is_preprint":false},{"year":2003,"finding":"B7-1 and B7-2 exist in different oligomeric states on the cell surface: B7-1 (CD80) is present as a dimer while B7-2 (CD86) exists as a monomer, as demonstrated by photobleaching-based FRET; B7-1 and B7-2 do not form hetero-oligomers on the cell surface.","method":"Fluorescence resonance energy transfer (FRET) via photobleaching on live cells","journal":"Immunology letters","confidence":"Medium","confidence_rationale":"Tier 2 — direct imaging method on live cells, single lab","pmids":["16413062"],"is_preprint":false},{"year":2004,"finding":"Ligation of B7-1/B7-2 on dendritic cells by CTLA4/CD28 expressed on CD4+ T cells is required to trigger functional IDO (indoleamine 2,3-dioxygenase) activity; IDO protein is constitutively expressed but requires this B7-1/B7-2 engagement signal to become functionally active; the ability to trigger IDO was strictly confined to CD4+ T cells, allowing them to dominantly inhibit CD8+ T cell proliferation via IDO-conditioned DCs.","method":"IDO activity assays, blocking antibody experiments (anti-B7-1/B7-2), direct B7-1/B7-2 crosslinking, T cell subset depletion experiments","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — mechanism dissected with blocking antibodies, direct crosslinking rescue, T cell subset specificity demonstrated, >378 citations","pmids":["15034022"],"is_preprint":false},{"year":2004,"finding":"B7-1 (CD80) is expressed in podocytes upon injury and acts as an inducible modifier of glomerular permselectivity; LPS signaling through TLR-4 reorganizes the podocyte actin cytoskeleton in vitro; activation of B7-1 in cultured podocytes leads to reorganization of slit diaphragm proteins; mice lacking B7-1 are protected from LPS-induced nephrotic syndrome, establishing a non-immune cell role for CD80 in barrier function.","method":"B7-1 knockout mouse model, LPS treatment in vivo, in vitro podocyte culture with actin cytoskeleton analysis, immunofluorescence for slit diaphragm proteins","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — genetic knockout with defined phenotypic readout (proteinuria), in vitro mechanistic studies, >471 citations","pmids":["15146236"],"is_preprint":false},{"year":2009,"finding":"Direct B7-1/2 signaling in B cells enhances IgG secretion: B7-2 engagement on already class-switched B cells dramatically induced IgG (but not IgM) secretion and induced XBP-1 splicing (a marker of increased protein synthesis); in vivo, B7-1/2 expression on B cells is crucial for maximal local IgG responses to influenza infection, demonstrated in mixed bone marrow chimeras lacking B7-1/2 only on B cells.","method":"Mixed bone marrow irradiation chimeric mice, in vitro B7-2 crosslinking, XBP-1 splicing assay (RT-PCR), antibody ELISA","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic chimera model isolating B cell-intrinsic B7 function, in vitro mechanistic validation, multiple orthogonal methods","pmids":["19933871"],"is_preprint":false},{"year":2011,"finding":"CTLA-4 removes CD80 and CD86 from opposing cells by trans-endocytosis: CTLA-4-expressing cells capture CD80/CD86 from antigen-presenting cells, and these costimulatory ligands are subsequently degraded inside the CTLA-4-expressing cells; CD86 acquisition is stimulated by TCR engagement and observed both in vitro and in vivo; this depletion of ligands impairs CD28 costimulation.","method":"Co-culture assays with CTLA-4-expressing cells, flow cytometry tracking ligand loss, intracellular degradation assays, in vivo confirmation","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 — mechanism demonstrated in vitro and in vivo with multiple cell types, >1400 citations","pmids":["21474713"],"is_preprint":false},{"year":2014,"finding":"CD80 expression in CTCL cells is strictly dependent on STAT5a and STAT5b transcription factors: in IL-2-dependent CTCL cells, IL-2 induces CD80 in a Jak1/3- and STAT5a/b-dependent manner; CTLA-4 engagement on T cells (via CD80 on CTCL cells) inhibits normal T cell proliferation, revealing a CD80-CTLA-4 axis as an immune evasion mechanism.","method":"STAT5a/b knockdown (siRNA), Jak inhibitor treatment, CTLA-4 mRNA transfection in T cells, co-culture proliferation assays","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic pathway dissection with siRNA and pharmacological inhibitors, functional co-culture validation, single lab","pmids":["24523507"],"is_preprint":false},{"year":2018,"finding":"PD-L1 binds to B7-1 (CD80) only in cis on the same cell surface, not in trans between two different cells; this cis interaction was demonstrated by NanoBiT proximity assays and cell-to-cell binding assays; PD-L1 and B7-1 interact when PD-L1 is flexible (via its 11-amino-acid stalk) and bind at a site competitive with PD-L1/PD-1 and B7-1/CD28 interactions; coexpression of PD-L1 and B7-1 occurs on tumor-infiltrating myeloid cells.","method":"NanoBiT proximity assay, cell-to-cell binding assays, ELISA with purified proteins, flow cytometry, competitive binding assays","journal":"Cancer immunology research","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods demonstrating cis-only interaction, functional competitive binding characterization","pmids":["29871885"],"is_preprint":false},{"year":2019,"finding":"CD80 (B7-1) on antigen-presenting cells interacts with PD-L1 in cis to disrupt PD-L1/PD-1 binding, thereby restricting PD-1 coinhibitory signaling during T cell activation; in knock-in mice where cis-PD-L1/CD80 interaction cannot occur, tumor immunity and autoimmune responses were greatly attenuated by PD-1, confirming that CD80 on APCs limits PD-1 signaling while promoting CD28-mediated costimulation.","method":"Knock-in mouse model (cis-interaction deficient), tumor immunity assays, autoimmune response measurement, cis-interaction biochemical assays","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 — genetic knock-in model with defined functional phenotype, mechanistic in vivo confirmation, >317 citations","pmids":["31000591"],"is_preprint":false},{"year":2020,"finding":"The PD-L1 binding site on B7-1 (mB7-1) maps to the dimer interface surface of B7-1, distal from the CTLA-4/CD28 recognition surface; CTLA-4 and CD28 do not directly compete with PD-L1 for binding to B7-1, but can disrupt the cis PD-L1:B7-1 complex by reorganizing B7-1 on the cell surface; mPD-L1 mutants with selective binding for either mB7-1 or mPD-1 were generated.","method":"Cell microarray and high-throughput FACS binding screen, site-directed mutagenesis of PD-L1 and B7-1, cis interaction assays with two independent approaches","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — systematic mutagenesis mapping binding interface, cis-interaction confirmed by two independent methods, functionally selective mutants generated","pmids":["32497097"],"is_preprint":false},{"year":2022,"finding":"B7-1 mediates podocyte injury and glomerulosclerosis through a signaling pathway involving Hsp90ab1 and LRP5/β-catenin: LC-MS/MS identified Hsp90ab1 as an anchor transmitting signals from B7-1 to β-catenin; molecular docking and mutant analysis identified residue K69 in the N-terminal domain of Hsp90ab1 as the key binding site for B7-1 to activate LRP5/β-catenin; B7-1 is itself a downstream target of β-catenin, creating a positive feedback loop.","method":"LC-MS/MS proteomics, molecular docking, site-directed mutagenesis (K69 in Hsp90ab1), B7-1 transgenic mouse model, adriamycin nephropathy model, co-immunoprecipitation, transcriptomic analysis","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods including proteomics, mutagenesis, and in vivo models, single lab","pmids":["35710882"],"is_preprint":false},{"year":2008,"finding":"Human B7-1 (CD80) interacts with human PD-L1 with affinity greater than that of B7-1 with CD28, but less than B7-1 with CTLA-4 or PD-L1 with PD-1; anti-PD-L1 antibodies were identified that can selectively block PD-L1 interactions with B7-1, PD-1, or both; PD-L1 is induced to higher levels on CD28high versus CD28low CD8+ T cells upon activation.","method":"Surface plasmon resonance (Biacore), blocking antibody characterization, flow cytometry","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 1 — quantitative SPR biophysics, single lab","pmids":["18585785"],"is_preprint":false}],"current_model":"CD80 (B7-1) is a homodimeric IgSF glycoprotein on APCs that delivers costimulatory signals to T cells by binding CD28 (Kd ~4 μM) or inhibitory signals by binding CTLA-4 (Kd ~0.42 μM) with very fast kinetics; crystal structures reveal a zipper-like CD80/CTLA-4 oligomeric network; CTLA-4 removes CD80 from APCs by trans-endocytosis; CD80 interacts with PD-L1 exclusively in cis on the same cell surface to block PD-1 inhibitory signaling; CD80 transcription is induced by CD40/NF-κB and repressed by BCL6; in podocytes CD80 signals through an Hsp90ab1-LRP5-β-catenin pathway to cause cytoskeletal injury; CD80 also directly signals in B cells to enhance IgG secretion and can trigger NK cell cytotoxicity through a CD28/CTLA-4-independent receptor."},"narrative":{"teleology":[{"year":1989,"claim":"The molecular identity of the T cell costimulatory ligand on activated B cells was unknown; cloning of CD80 (B7) established it as a type I transmembrane IgSF glycoprotein with V-like and C-like extracellular domains, providing the molecular basis for costimulation research.","evidence":"cDNA cloning from activated B cells with expression in COS cells, immunoprecipitation, and Northern blot","pmids":["2794510"],"confidence":"High","gaps":["Counterreceptor on T cells not yet identified","Signaling mechanism downstream of CD80 engagement unknown"]},{"year":1991,"claim":"The identity of the T cell receptor for CD80 was resolved when CD28 was shown to be the direct binding partner mediating costimulatory proliferation and IL-2 production, with cross-species conservation confirmed by murine CD80 cloning.","evidence":"Fusion protein binding assay (Kd ~200 nM), CD28-transfected CHO costimulation assay, and murine B7 cloning with cross-species functional validation","pmids":["1847722","1714935"],"confidence":"High","gaps":["CTLA-4 as second receptor not yet recognized","Distinction between CD80 and CD86 not yet established"]},{"year":1995,"claim":"The discovery that both CD80 and CD86 serve as shared ligands for CD28 and CTLA-4, yet differentially bias Th1/Th2 responses and EAE outcomes, established that the two B7 family members are functionally non-redundant despite binding the same counterreceptors.","evidence":"Anti-B7 blocking antibodies in EAE models, T cell differentiation assays, cytokine profiling, and stable transfectant costimulation assays","pmids":["7534215","7527824","7519245"],"confidence":"High","gaps":["Molecular basis for differential Th1/Th2 skewing by CD80 vs CD86 unresolved","Relative binding affinities for CD28 vs CTLA-4 not yet quantified"]},{"year":1996,"claim":"CD80 was shown to trigger NK cell cytotoxicity through a receptor distinct from both CD28 and CTLA-4, revealing a non-canonical immune function, while CD40 signaling through specific cytoplasmic threonine residues was identified as a transcriptional inducer of CD80 expression.","evidence":"NK cytotoxicity assays with CD28-KO NK cells and blocking antibodies; CD40 mutant transfection with flow cytometry for CD80 induction","pmids":["8885864","8816387"],"confidence":"High","gaps":["Identity of the NK cell receptor for CD80 remains unknown","Full CD40-to-CD80 transcriptional pathway not mapped"]},{"year":1997,"claim":"Quantitative biophysical measurement resolved the binding hierarchy: CD80 binds CTLA-4 with ~10-fold higher affinity than CD28, with extremely fast kinetics at physiological temperature, establishing the thermodynamic basis for preferential CTLA-4 engagement.","evidence":"Surface plasmon resonance (BIAcore) at 37°C with soluble recombinant proteins","pmids":["9053440"],"confidence":"High","gaps":["How fast kinetics translate to signaling dynamics at the immunological synapse not determined"]},{"year":2000,"claim":"The crystal structure of CD80 revealed a novel IgV/IgC domain combination that forms rotationally symmetric homodimers, explaining how bivalent CD80 dimers can engage bivalent CTLA-4 dimers to build ordered signaling lattices; subsequent structures of CTLA-4/CD80 and CTLA-4/CD86 complexes defined the zipper-like oligomeric network architecture.","evidence":"X-ray crystallography (3.0 Å) of CD80 alone and in complex with CTLA-4, analytical ultracentrifugation confirming solution dimerization","pmids":["10661405","11279502","11279501"],"confidence":"High","gaps":["Structure of CD80/CD28 complex not solved","How lattice organization relates to signaling output in live cells unresolved"]},{"year":2002,"claim":"Comprehensive biophysical comparison established that CD80 homodimerization (absent in monomeric CD86) and preferential CTLA-4 binding bias CD80 toward inhibitory signaling, while CD86 is relatively less biased toward CTLA-4 over CD28, explaining their distinct functional outputs despite shared receptors.","evidence":"Surface plasmon resonance and analytical ultracentrifugation comparing CD80/CD86 oligomerization and receptor affinities","pmids":["12196291"],"confidence":"High","gaps":["Whether CD80 dimerization is regulated in vivo is unknown","Monovalent CD28 binding geometry implications not fully explored"]},{"year":2003,"claim":"BCL6 was identified as a direct transcriptional repressor of CD80, binding its promoter to suppress NF-κB-mediated induction downstream of CD40, establishing the transcriptional logic of CD80 regulation in germinal center B cells.","evidence":"ChIP demonstrating BCL6 binding to CD80 promoter, reporter assays, BCL6-KO mouse B cell analysis","pmids":["12860928"],"confidence":"High","gaps":["Other transcription factors cooperating with or antagonizing BCL6 at the CD80 locus not characterized"]},{"year":2004,"claim":"Two unexpected non-canonical functions were discovered: CD80 on podocytes regulates actin cytoskeleton and glomerular permselectivity (with B7-1 KO mice protected from nephrotic syndrome), and reverse signaling through B7-1/B7-2 on dendritic cells triggers IDO enzymatic activation, establishing CD80 as a bidirectional signaling molecule.","evidence":"B7-1 KO mouse LPS-induced nephrotic syndrome model with podocyte cytoskeleton analysis; IDO activity assays with B7-1/B7-2 crosslinking and T cell subset depletion","pmids":["15146236","15034022"],"confidence":"High","gaps":["Signaling intermediates between CD80 and actin reorganization in podocytes not yet mapped","Whether IDO activation by B7 requires CTLA-4 or CD28 or both remains debated"]},{"year":2009,"claim":"B cell-intrinsic B7-1/B7-2 signaling was shown to enhance IgG secretion through XBP-1 splicing induction, demonstrating that CD80/CD86 are not merely passive ligands but deliver direct signals in B cells affecting antibody production.","evidence":"Mixed bone marrow chimeras with B7-deficient B cells, in vitro B7-2 crosslinking, XBP-1 splicing RT-PCR, and antibody ELISA","pmids":["19933871"],"confidence":"High","gaps":["Whether B7-1 and B7-2 activate identical or distinct B cell-intrinsic signaling cascades not resolved","Downstream pathway linking B7 engagement to XBP-1 splicing not identified"]},{"year":2011,"claim":"The mechanism by which CTLA-4 depletes costimulatory ligands was resolved: CTLA-4 physically captures CD80 and CD86 from APCs by trans-endocytosis and routes them for intracellular degradation, establishing ligand depletion as a cell-extrinsic suppressive mechanism complementing intrinsic signaling.","evidence":"Co-culture assays tracking fluorescently labeled ligand transfer, intracellular degradation assays, in vivo confirmation","pmids":["21474713"],"confidence":"High","gaps":["Relative contribution of trans-endocytosis versus signaling-based suppression in vivo not quantified","Whether CD80 and CD86 are endocytosed with equal efficiency under physiological conditions unclear"]},{"year":2018,"claim":"The discovery that PD-L1 binds CD80 exclusively in cis on the same cell surface—competing with both PD-1 and CD28 binding—revealed a previously unknown checkpoint crosstalk mechanism whereby CD80 on APCs restricts PD-1-mediated coinhibition.","evidence":"NanoBiT proximity assay, cell-to-cell binding assays, competitive ELISA with purified proteins","pmids":["29871885"],"confidence":"High","gaps":["Stoichiometry and dynamics of cis complex formation on myeloid cells in tumors not resolved"]},{"year":2019,"claim":"Genetic validation using knock-in mice in which the cis PD-L1/CD80 interaction was abolished confirmed that this interaction is essential for limiting PD-1 coinhibition during tumor immunity and autoimmunity, establishing it as a physiologically critical regulatory axis.","evidence":"Knock-in mouse model deficient in cis interaction, tumor immunity assays, autoimmune response measurements","pmids":["31000591"],"confidence":"High","gaps":["Whether therapeutic anti-PD-L1 antibodies disrupt the cis interaction differently than anti-PD-1 antibodies needs characterization","Role of cis interaction in human cancers not directly validated genetically"]},{"year":2020,"claim":"Structural mapping revealed that PD-L1 binds CD80 at its dimer interface surface, distal from the CTLA-4/CD28 binding face, clarifying that CTLA-4 and CD28 do not directly compete with PD-L1 but can disrupt the cis complex by reorganizing CD80 on the cell surface.","evidence":"High-throughput FACS-based mutagenesis screen, site-directed mutagenesis of PD-L1 and B7-1, two independent cis interaction assays","pmids":["32497097"],"confidence":"High","gaps":["Atomic-resolution structure of the PD-L1/CD80 cis complex not yet solved"]},{"year":2022,"claim":"The podocyte injury signaling pathway downstream of CD80 was molecularly defined: CD80 engages Hsp90ab1 at residue K69, which activates LRP5/β-catenin signaling to promote cytoskeletal reorganization and glomerulosclerosis, with β-catenin feeding back to sustain CD80 expression.","evidence":"LC-MS/MS proteomics, K69 site-directed mutagenesis of Hsp90ab1, B7-1 transgenic and adriamycin nephropathy mouse models, co-immunoprecipitation","pmids":["35710882"],"confidence":"Medium","gaps":["Single-lab finding; independent replication of the Hsp90ab1–K69 interaction needed","Whether this pathway operates in human podocyte disease not confirmed","Structural basis for CD80–Hsp90ab1 interaction not resolved"]},{"year":null,"claim":"Key unresolved questions include the identity of the NK cell receptor that recognizes CD80 independently of CD28/CTLA-4, the atomic structure of the PD-L1/CD80 cis complex, the mechanism by which CD80 versus CD86 differentially skew Th1/Th2 responses, and whether B cell-intrinsic CD80 signaling proceeds through distinct pathways from B cell-intrinsic CD86 signaling.","evidence":"","pmids":[],"confidence":"Low","gaps":["NK receptor for CD80 not identified","PD-L1/CD80 cis complex structure not solved","Mechanism of Th1/Th2 differential skewing by CD80 vs CD86 unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[1,9,13,21]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,15,17]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,22,28,30]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,8,9,10,14,23,26,29]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,11,28,29]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[17,22,28,30]}],"complexes":["CD80 homodimer","CD80/CTLA-4 zipper-like lattice","cis CD80/PD-L1 complex"],"partners":["CD28","CTLA4","CD274","CD86","HSP90AB1","LRP5","BCL6"],"other_free_text":[]},"mechanistic_narrative":"CD80 (B7-1) is a homodimeric type I transmembrane glycoprotein of the immunoglobulin superfamily expressed on activated antigen-presenting cells that functions as a central costimulatory and coinhibitory ligand governing T cell activation, tolerance, and immune checkpoint signaling. CD80 binds CD28 (Kd ~4 μM) to deliver T cell costimulatory signals promoting proliferation and IL-2 production, and binds CTLA-4 (Kd ~0.42 μM) with ~10-fold higher affinity and very fast kinetics to form zipper-like oligomeric lattices that favor stable inhibitory signaling; CTLA-4 additionally depletes CD80 from APCs by trans-endocytosis, reducing costimulatory capacity [PMID:9053440, PMID:11279502, PMID:21474713]. On the same cell surface, CD80 interacts with PD-L1 exclusively in cis, sequestering PD-L1 from engaging PD-1 on T cells and thereby restricting PD-1-mediated coinhibition while preserving CD28-dependent costimulation [PMID:29871885, PMID:31000591]. Beyond its canonical immune role, CD80 is induced on podocytes upon injury and signals through an Hsp90ab1–LRP5–β-catenin pathway to reorganize the actin cytoskeleton and promote glomerulosclerosis, while in B cells, B7-1/B7-2 engagement directly enhances IgG secretion through XBP-1-dependent mechanisms [PMID:15146236, PMID:35710882, PMID:19933871]."},"prefetch_data":{"uniprot":{"accession":"P33681","full_name":"T-lymphocyte activation antigen CD80","aliases":["Activation B7-1 antigen","BB1","CTLA-4 counter-receptor B7.1","B7"],"length_aa":288,"mass_kda":33.0,"function":"Costimulatory molecule that belongs to the immunoglobulin superfamily that plays an important role in T-lymphocyte activation (PubMed:38467718). Acts as the primary auxiliary signal augmenting the MHC/TCR signal in naive T-cells by acting as a ligand for the CD28 receptor which is constitutively expressed on the cell surface of T-cells (PubMed:12196291). In turn, activates different signaling pathways such as NF-kappa-B or MAPK leading to the production of different cytokines (PubMed:10438913). Also acts as an inhibitor of T-cell activation by acting as a ligand for CTLA4, a decoy receptor, thereby blocking CD28-mediated T-cell priming (PubMed:10583602, PubMed:11279502). In addition, CD28/CD80 costimulatory signal stimulates glucose metabolism and ATP synthesis of T-cells by activating the PI3K/Akt signaling pathway (PubMed:12121659). Also acts as a regulator of PDL1/PDCD1 interactions to limit excess engagement of PDL1 and its inhibitory role in immune responses (PubMed:36727298). Expressed on B-cells, plays a critical role in regulating interactions between B-cells and T-cells in both early and late germinal center responses, which are crucial for the generation of effective humoral immune responses (By similarity) (Microbial infection) Acts as a receptor for adenovirus subgroup B","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P33681/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CD80","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/CD80","total_profiled":1310},"omim":[{"mim_id":"619573","title":"IMMUNODEFICIENCY 87 AND AUTOIMMUNITY; IMD87","url":"https://www.omim.org/entry/619573"},{"mim_id":"616100","title":"IMMUNE DYSREGULATION WITH AUTOIMMUNITY, IMMUNODEFICIENCY, AND LYMPHOPROLIFERATION; IDAIL","url":"https://www.omim.org/entry/616100"},{"mim_id":"613714","title":"NATURAL KILLER CELL CYTOTOXICITY RECEPTOR 3 LIGAND 1; NCR3LG1","url":"https://www.omim.org/entry/613714"},{"mim_id":"611550","title":"NATURAL CYTOTOXICITY TRIGGERING RECEPTOR 3; NCR3","url":"https://www.omim.org/entry/611550"},{"mim_id":"610859","title":"CAPPING PROTEIN REGULATOR AND MYOSIN 1 LINKER 2; CARMIL2","url":"https://www.omim.org/entry/610859"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"lung","ntpm":2.8},{"tissue":"lymphoid tissue","ntpm":6.4}],"url":"https://www.proteinatlas.org/search/CD80"},"hgnc":{"alias_symbol":["B7.1","B7-1"],"prev_symbol":["CD28LG","CD28LG1"]},"alphafold":{"accession":"P33681","domains":[{"cath_id":"2.60.40.10","chopping":"34-138","consensus_level":"high","plddt":95.0634,"start":34,"end":138},{"cath_id":"2.60.40.10","chopping":"145-230","consensus_level":"high","plddt":95.6486,"start":145,"end":230}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P33681","model_url":"https://alphafold.ebi.ac.uk/files/AF-P33681-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P33681-F1-predicted_aligned_error_v6.png","plddt_mean":86.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CD80","jax_strain_url":"https://www.jax.org/strain/search?query=CD80"},"sequence":{"accession":"P33681","fasta_url":"https://rest.uniprot.org/uniprotkb/P33681.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P33681/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P33681"}},"corpus_meta":[{"pmid":"7534215","id":"PMC_7534215","title":"B7-1 and B7-2 costimulatory molecules activate differentially the Th1/Th2 developmental pathways: application to autoimmune disease therapy.","date":"1995","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/7534215","citation_count":1499,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7519245","id":"PMC_7519245","title":"Comparative analysis of B7-1 and B7-2 costimulatory ligands: expression and function.","date":"1994","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/7519245","citation_count":616,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15146236","id":"PMC_15146236","title":"Induction of B7-1 in podocytes is associated with nephrotic syndrome.","date":"2004","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/15146236","citation_count":471,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9053440","id":"PMC_9053440","title":"CD80 (B7-1) binds both CD28 and CTLA-4 with a low affinity and very fast kinetics.","date":"1997","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/9053440","citation_count":435,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15034022","id":"PMC_15034022","title":"Ligation of B7-1/B7-2 by human CD4+ T cells triggers indoleamine 2,3-dioxygenase activity in dendritic cells.","date":"2004","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/15034022","citation_count":378,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11279502","id":"PMC_11279502","title":"Crystal structure of the B7-1/CTLA-4 complex that inhibits human immune responses.","date":"2001","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/11279502","citation_count":369,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24206430","id":"PMC_24206430","title":"Abatacept in B7-1-positive proteinuric kidney disease.","date":"2013","source":"The New England journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24206430","citation_count":294,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8777719","id":"PMC_8777719","title":"Blockade of CD28/B7-1 interaction prevents epitope spreading and clinical relapses of murine EAE.","date":"1995","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/8777719","citation_count":263,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10661405","id":"PMC_10661405","title":"Structure and dimerization of a soluble form of B7-1.","date":"2000","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/10661405","citation_count":195,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8885864","id":"PMC_8885864","title":"Triggering of natural killer cells by the costimulatory molecule CD80 (B7-1).","date":"1996","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/8885864","citation_count":195,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7595212","id":"PMC_7595212","title":"A reassessment of the role of B7-1 expression in tumor rejection.","date":"1995","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/7595212","citation_count":173,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29871885","id":"PMC_29871885","title":"PD-L1 Binds to B7-1 Only In Cis on the Same Cell Surface.","date":"2018","source":"Cancer immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/29871885","citation_count":157,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7520466","id":"PMC_7520466","title":"The role of p21ras in CD28 signal transduction: triggering of CD28 with antibodies, but not the ligand B7-1, activates p21ras.","date":"1994","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/7520466","citation_count":155,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11350882","id":"PMC_11350882","title":"The influence of granulocyte macrophage colony-stimulating factor and prior chemotherapy on the immunological response to a vaccine (ALVAC-CEA B7.1) in patients with metastatic carcinoma.","date":"2001","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/11350882","citation_count":147,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11604477","id":"PMC_11604477","title":"Effects of survivin antagonists on growth of established tumors and B7-1 immunogene therapy.","date":"2001","source":"Journal of the National Cancer Institute","url":"https://pubmed.ncbi.nlm.nih.gov/11604477","citation_count":145,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9380730","id":"PMC_9380730","title":"Interleukin 12 and B7-1 costimulatory molecule expressed by an adenovirus vector act synergistically to facilitate tumor regression.","date":"1997","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/9380730","citation_count":135,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9653097","id":"PMC_9653097","title":"B7-1 engagement of cytotoxic T lymphocyte antigen 4 inhibits T cell activation in the absence of CD28.","date":"1998","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/9653097","citation_count":135,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7537118","id":"PMC_7537118","title":"Role of B7-1 in mediating an immune response to myeloid leukemia cells.","date":"1995","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/7537118","citation_count":119,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16489051","id":"PMC_16489051","title":"Low surface expression of B7-1 (CD80) is an immunoescape mechanism of colon carcinoma.","date":"2006","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/16489051","citation_count":116,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8617961","id":"PMC_8617961","title":"IL-12 is an effective adjuvant to recombinant vaccinia virus-based tumor vaccines: enhancement by simultaneous B7-1 expression.","date":"1996","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/8617961","citation_count":112,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24676639","id":"PMC_24676639","title":"Role of podocyte B7-1 in diabetic nephropathy.","date":"2014","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/24676639","citation_count":110,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9014827","id":"PMC_9014827","title":"Differential expression and function of CD80 (B7-1) and CD86 (B7-2) on human peripheral blood monocytes.","date":"1996","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/9014827","citation_count":110,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7538528","id":"PMC_7538528","title":"Costimulation with B7-1, IL-6, and IL-12 is sufficient for primary generation of murine antitumor cytolytic T lymphocytes in vitro.","date":"1995","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/7538528","citation_count":108,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8543795","id":"PMC_8543795","title":"B7-1 but not B7-2 efficiently costimulates CD8+ T lymphocytes in the P815 tumor system in vitro.","date":"1996","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/8543795","citation_count":107,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17020994","id":"PMC_17020994","title":"Enhanced antitumor effect of oncolytic adenovirus expressing interleukin-12 and B7-1 in an immunocompetent murine model.","date":"2006","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/17020994","citation_count":107,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20145927","id":"PMC_20145927","title":"Clinical significance of B7-H1 and B7-1 expressions in pancreatic carcinoma.","date":"2010","source":"World journal of surgery","url":"https://pubmed.ncbi.nlm.nih.gov/20145927","citation_count":106,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15937544","id":"PMC_15937544","title":"Targeting the local tumor microenvironment with vaccinia virus expressing B7.1 for the treatment of melanoma.","date":"2005","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/15937544","citation_count":104,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11576355","id":"PMC_11576355","title":"Anti-B7-1 blocks mononuclear cell adherence in vasa recta after ischemia.","date":"2001","source":"Kidney international","url":"https://pubmed.ncbi.nlm.nih.gov/11576355","citation_count":102,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16413062","id":"PMC_16413062","title":"B7-1 and B7-2: similar costimulatory ligands with different biochemical, oligomeric and signaling properties.","date":"2005","source":"Immunology letters","url":"https://pubmed.ncbi.nlm.nih.gov/16413062","citation_count":94,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8639914","id":"PMC_8639914","title":"Irradiated B7-1 transduced primary acute myelogenous leukemia (AML) cells can be used as therapeutic vaccines in murine AML.","date":"1996","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/8639914","citation_count":91,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12690043","id":"PMC_12690043","title":"Muscle fibres and cultured muscle cells express the B7.1/2-related inducible co-stimulatory molecule, ICOSL: implications for the pathogenesis of inflammatory myopathies.","date":"2003","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/12690043","citation_count":90,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19933871","id":"PMC_19933871","title":"B7-1/2 (CD80/CD86) direct signaling to B cells enhances IgG secretion.","date":"2009","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/19933871","citation_count":87,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16525479","id":"PMC_16525479","title":"Concurrent delivery of GM-CSF and B7-1 using an oncolytic adenovirus elicits potent antitumor effect.","date":"2006","source":"Gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/16525479","citation_count":85,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9574529","id":"PMC_9574529","title":"Presentation of proteolipid protein epitopes and B7-1-dependent activation of encephalitogenic T cells by IFN-gamma-activated SJL/J astrocytes.","date":"1998","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/9574529","citation_count":84,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18676757","id":"PMC_18676757","title":"Combination chemotherapy and ALVAC-CEA/B7.1 vaccine in patients with metastatic colorectal cancer.","date":"2008","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/18676757","citation_count":82,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9141426","id":"PMC_9141426","title":"Expression of costimulatory molecules B7-1 (CD80) and B7-2 (CD86) on human hepatocellular carcinoma.","date":"1997","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/9141426","citation_count":82,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11160311","id":"PMC_11160311","title":"Acquisition of CD80 (B7-1) by T cells.","date":"2001","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/11160311","citation_count":81,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8627175","id":"PMC_8627175","title":"Costimulation by CD48 and B7-1 induces immunity against poorly immunogenic tumors.","date":"1996","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/8627175","citation_count":78,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12860928","id":"PMC_12860928","title":"BCL6 controls the expression of the B7-1/CD80 costimulatory receptor in germinal center B cells.","date":"2003","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/12860928","citation_count":78,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11196154","id":"PMC_11196154","title":"In situ expression of soluble B7-1 in the context of oncolytic herpes simplex virus induces potent antitumor immunity.","date":"2001","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/11196154","citation_count":76,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7533646","id":"PMC_7533646","title":"A negative regulatory function of B7 revealed in B7-1 transgenic mice.","date":"1994","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/7533646","citation_count":74,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7533734","id":"PMC_7533734","title":"Expression of the co-stimulator molecule B7-1 in pancreatic beta-cells accelerates diabetes in the NOD mouse.","date":"1995","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/7533734","citation_count":68,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7527261","id":"PMC_7527261","title":"Extending the B7 (CD80) gene family.","date":"1994","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/7527261","citation_count":66,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12759417","id":"PMC_12759417","title":"A role for the B7-1/B7-2:CD28/CTLA-4 pathway during negative selection.","date":"2003","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/12759417","citation_count":60,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9126967","id":"PMC_9126967","title":"Effects of blocking B7-1 and B7-2 interactions during a type 2 in vivo immune response.","date":"1997","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/9126967","citation_count":60,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9541571","id":"PMC_9541571","title":"Absence of B7.1-CD28/CTLA-4-mediated co-stimulation in human NK cells.","date":"1998","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/9541571","citation_count":59,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10078962","id":"PMC_10078962","title":"Regression of intracerebral rat glioma isografts by therapeutic subcutaneous immunization with interferon-gamma, interleukin-7, or B7-1-transfected tumor cells.","date":"1999","source":"Cancer gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/10078962","citation_count":59,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9449507","id":"PMC_9449507","title":"Upregulation of B7.2, but not B7.1, on B cells from patients with allergic asthma.","date":"1998","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/9449507","citation_count":58,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11259473","id":"PMC_11259473","title":"Large nontransplanted hepatocellular carcinoma in woodchucks: treatment with adenovirus-mediated delivery of interleukin 12/B7.1 genes.","date":"2001","source":"Journal of the National Cancer Institute","url":"https://pubmed.ncbi.nlm.nih.gov/11259473","citation_count":56,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10820290","id":"PMC_10820290","title":"Costimulation by B7-1 and B7-2 is required for autoimmune disease in MRL-Faslpr mice.","date":"2000","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/10820290","citation_count":56,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31448437","id":"PMC_31448437","title":"Targeting B7-1 in immunotherapy.","date":"2019","source":"Medicinal research reviews","url":"https://pubmed.ncbi.nlm.nih.gov/31448437","citation_count":55,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7513205","id":"PMC_7513205","title":"T lymphocytes in skin lesions of psoriasis and mycosis fungoides express B7-1: a ligand for CD28.","date":"1994","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/7513205","citation_count":55,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8992978","id":"PMC_8992978","title":"The role of B7-1 and LFA-3 in costimulation of CD8+ T cells.","date":"1997","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/8992978","citation_count":54,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8609386","id":"PMC_8609386","title":"Interactions of CD80 and CD86 with CD28 and CTLA4.","date":"1996","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/8609386","citation_count":53,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10792289","id":"PMC_10792289","title":"gamma-ray irradiation induces B7.1 expression in myeloid leukaemic cells.","date":"2000","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/10792289","citation_count":52,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21458378","id":"PMC_21458378","title":"IL-10-conditioned dendritic cells prevent autoimmune diabetes in NOD and humanized HLA-DQ8/RIP-B7.1 mice.","date":"2011","source":"Clinical immunology (Orlando, Fla.)","url":"https://pubmed.ncbi.nlm.nih.gov/21458378","citation_count":52,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9282170","id":"PMC_9282170","title":"Enhanced immune costimulatory activity of primary acute myeloid leukaemia blasts after retrovirus-mediated gene transfer of B7.1.","date":"1997","source":"Gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/9282170","citation_count":50,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9820499","id":"PMC_9820499","title":"B7.1 is a quantitatively stronger costimulus than B7.2 in the activation of naive CD8+ TCR-transgenic T cells.","date":"1998","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/9820499","citation_count":47,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7528926","id":"PMC_7528926","title":"Keratinocyte expression of B7-1 in transgenic mice amplifies the primary immune response to cutaneous antigens.","date":"1994","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/7528926","citation_count":46,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26697986","id":"PMC_26697986","title":"Any value of podocyte B7-1 as a biomarker in human MCD and FSGS?","date":"2015","source":"American journal of physiology. Renal physiology","url":"https://pubmed.ncbi.nlm.nih.gov/26697986","citation_count":44,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9647224","id":"PMC_9647224","title":"Tissue-specific up-regulation of B7-1 expression and function during the course of murine relapsing experimental autoimmune encephalomyelitis.","date":"1998","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/9647224","citation_count":44,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21263067","id":"PMC_21263067","title":"Host APCs augment in vivo expansion of donor natural regulatory T cells via B7H1/B7.1 in allogeneic recipients.","date":"2011","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/21263067","citation_count":41,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24670178","id":"PMC_24670178","title":"Abatacept in B7-1-positive proteinuric kidney disease.","date":"2014","source":"The New England journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24670178","citation_count":40,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10540152","id":"PMC_10540152","title":"The modulation of B7.2 and B7.1 on B cells by immunosuppressive agents.","date":"1999","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/10540152","citation_count":40,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10843688","id":"PMC_10843688","title":"Primary structure and functional characterization of a soluble, alternatively spliced form of B7-1.","date":"2000","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/10843688","citation_count":39,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11741888","id":"PMC_11741888","title":"Small molecule ligands define a binding site on the immune regulatory protein B7.1.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11741888","citation_count":38,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33199209","id":"PMC_33199209","title":"PD-L1 and B7-1 Cis-Interaction: New Mechanisms in Immune Checkpoints and Immunotherapies.","date":"2020","source":"Trends in molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33199209","citation_count":37,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9541590","id":"PMC_9541590","title":"The threshold for autoimmune T cell killing is influenced by B7-1.","date":"1998","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/9541590","citation_count":36,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9529166","id":"PMC_9529166","title":"Effects of in vivo administration of anti-B7-1/B7-2 monoclonal antibodies on murine acute myocarditis caused by coxsackievirus B3.","date":"1998","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/9529166","citation_count":36,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8624620","id":"PMC_8624620","title":"Differential expression of the costimulatory molecules B7.1 (CD80) and B7.2 (CD86) in rheumatoid synovial tissue.","date":"1996","source":"British journal of rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/8624620","citation_count":36,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9394783","id":"PMC_9394783","title":"Treatment with intact anti-B7-1 mAb during disease remission enhances epitope spreading and exacerbates relapses in R-EAE.","date":"1997","source":"Journal of neuroimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/9394783","citation_count":35,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8816387","id":"PMC_8816387","title":"Identification of distinct domains in CD40 involved in B7-1 induction or growth inhibition.","date":"1996","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/8816387","citation_count":34,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7518845","id":"PMC_7518845","title":"Exaggerated and persistent cutaneous delayed-type hypersensitivity in transgenic mice whose epidermal keratinocytes constitutively express B7-1 antigen.","date":"1994","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/7518845","citation_count":34,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9054522","id":"PMC_9054522","title":"Irradiated NC adenocarcinoma cells transduced with both B7.1 and interleukin-2 induce CD4+-mediated rejection of established tumors.","date":"1997","source":"Human gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/9054522","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22334018","id":"PMC_22334018","title":"Cancer immunotherapy using a membrane-bound interleukin-12 with B7-1 transmembrane and cytoplasmic domains.","date":"2012","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/22334018","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7535614","id":"PMC_7535614","title":"Immunoglobulin fold characteristics of B7-1 (CD80) and B7-2 (CD86).","date":"1994","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/7535614","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26319246","id":"PMC_26319246","title":"B7-1 Is Not Induced in Podocytes of Human and Experimental Diabetic Nephropathy.","date":"2015","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/26319246","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9628461","id":"PMC_9628461","title":"Costimulatory CD80 (B7-1) and CD86 (B7-2) on cerebrospinal fluid cells in multiple sclerosis.","date":"1998","source":"Journal of neuroimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/9628461","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19234186","id":"PMC_19234186","title":"Preferential use of B7.2 and not B7.1 in priming of vaccinia virus-specific CD8 T cells.","date":"2009","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/19234186","citation_count":30,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12884869","id":"PMC_12884869","title":"Recovery from EAE is associated with decreased survival of encephalitogenic T cells in the CNS of B7-1/B7-2-deficient mice.","date":"2003","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/12884869","citation_count":30,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10676654","id":"PMC_10676654","title":"Interleukin-7/B7.1-encoding adenoviruses induce rejection of transplanted but not nontransplanted tumors.","date":"2000","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/10676654","citation_count":30,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8757319","id":"PMC_8757319","title":"Coexpression of B7-1 and antigen blocks tolerance induction to antigen presented by resting B cells.","date":"1996","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/8757319","citation_count":29,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9310829","id":"PMC_9310829","title":"Antigen-specific regression of established tumors induced by active immunization with irradiated IL-12- but not B7-1-transfected tumor cells.","date":"1997","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/9310829","citation_count":29,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9690456","id":"PMC_9690456","title":"Gamma-ray irradiation induces B7.1 costimulatory molecule neoexpression in various murine tumor cells.","date":"1998","source":"Cancer immunology, immunotherapy : CII","url":"https://pubmed.ncbi.nlm.nih.gov/9690456","citation_count":29,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10233753","id":"PMC_10233753","title":"Enhancement of B7-1 (CD80) expression on B-lymphoma cells by irradiation.","date":"1999","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/10233753","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32497097","id":"PMC_32497097","title":"Mechanistic dissection of the PD-L1:B7-1 co-inhibitory immune complex.","date":"2020","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/32497097","citation_count":27,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9171934","id":"PMC_9171934","title":"Immune responsiveness to a murine mammary carcinoma modified to express B7-1, interleukin-12, or GM-CSF.","date":"1997","source":"Cancer gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/9171934","citation_count":27,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9147700","id":"PMC_9147700","title":"Induction of autologous tumor-specific cytotoxic T-lymphocyte activity against a human renal carcinoma cell line by B7-1 (CD8O) costimulation.","date":"1996","source":"Journal of immunotherapy with emphasis on tumor immunology : official journal of the Society for Biological Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/9147700","citation_count":27,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9407942","id":"PMC_9407942","title":"Gene therapy with B7.1 and GM-CSF vaccines in a murine AML model.","date":"1997","source":"Journal of pediatric hematology/oncology","url":"https://pubmed.ncbi.nlm.nih.gov/9407942","citation_count":27,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11687895","id":"PMC_11687895","title":"Angiostatin enhances B7.1-mediated cancer immunotherapy independently of effects on vascular endothelial growth factor expression.","date":"2001","source":"Cancer gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/11687895","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35710882","id":"PMC_35710882","title":"B7-1 mediates podocyte injury and glomerulosclerosis through communication with Hsp90ab1-LRP5-β-catenin pathway.","date":"2022","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/35710882","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7538898","id":"PMC_7538898","title":"B7-1 expression by a non-antigen presenting cell-derived tumor.","date":"1995","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/7538898","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9365164","id":"PMC_9365164","title":"B7-1 (CD80) as target for immunotoxin therapy for Hodgkin's disease.","date":"1997","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/9365164","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9472661","id":"PMC_9472661","title":"Potential role of B7-1 and CD28 molecules in immunosuppression in leprosy.","date":"1998","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/9472661","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18848987","id":"PMC_18848987","title":"B7-1 and B7-2 differentially control peripheral homeostasis of CD4(+)CD25(+)Foxp3(+) regulatory T cells.","date":"2008","source":"Transplant immunology","url":"https://pubmed.ncbi.nlm.nih.gov/18848987","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26409459","id":"PMC_26409459","title":"CTLA4-Ig in B7-1-positive diabetic and non-diabetic kidney disease.","date":"2015","source":"Diabetologia","url":"https://pubmed.ncbi.nlm.nih.gov/26409459","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9379015","id":"PMC_9379015","title":"Differential effects of B7-1 blockade in the rat experimental autoimmune encephalomyelitis model.","date":"1997","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/9379015","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10546154","id":"PMC_10546154","title":"Protein transfer of glycosyl-phosphatidylinositol (GPI)-modified murine B7-1 and B7-2 costimulators.","date":"1999","source":"Journal of immunotherapy (Hagerstown, Md. : 1997)","url":"https://pubmed.ncbi.nlm.nih.gov/10546154","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24523507","id":"PMC_24523507","title":"Cutaneous T cell lymphoma expresses immunosuppressive CD80 (B7-1) cell surface protein in a STAT5-dependent manner.","date":"2014","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/24523507","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33419027","id":"PMC_33419027","title":"Peptide Blocking CTLA-4 and B7-1 Interaction.","date":"2021","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/33419027","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11015443","id":"PMC_11015443","title":"Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation.","date":"2000","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/11015443","citation_count":4219,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23470321","id":"PMC_23470321","title":"Molecular mechanisms of T cell co-stimulation and co-inhibition.","date":"2013","source":"Nature reviews. Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23470321","citation_count":2399,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21474713","id":"PMC_21474713","title":"Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4.","date":"2011","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/21474713","citation_count":1407,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"1847722","id":"PMC_1847722","title":"Binding of the B cell activation antigen B7 to CD28 costimulates T cell proliferation and interleukin 2 mRNA accumulation.","date":"1991","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/1847722","citation_count":1219,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20190752","id":"PMC_20190752","title":"Multiple common variants for celiac disease influencing immune gene expression.","date":"2010","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20190752","citation_count":801,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33961781","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"2794510","id":"PMC_2794510","title":"B7, a new member of the Ig superfamily with unique expression on activated and neoplastic B cells.","date":"1989","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/2794510","citation_count":526,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12196291","id":"PMC_12196291","title":"The interaction properties of costimulatory molecules revisited.","date":"2002","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/12196291","citation_count":524,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10807504","id":"PMC_10807504","title":"Local control of the immune response in the liver.","date":"2000","source":"Immunological reviews","url":"https://pubmed.ncbi.nlm.nih.gov/10807504","citation_count":460,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"7527824","id":"PMC_7527824","title":"CD80 (B7) and CD86 (B70) provide similar costimulatory signals for T cell proliferation, cytokine production, and generation of CTL.","date":"1995","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/7527824","citation_count":443,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15489334","id":"PMC_15489334","title":"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).","date":"2004","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/15489334","citation_count":438,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12660731","id":"PMC_12660731","title":"The role of PI3K in immune cells.","date":"2003","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/12660731","citation_count":391,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21399635","id":"PMC_21399635","title":"Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis.","date":"2011","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21399635","citation_count":387,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"1714935","id":"PMC_1714935","title":"Structure, expression, and T cell costimulatory activity of the murine homologue of the human B lymphocyte activation antigen B7.","date":"1991","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/1714935","citation_count":368,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"31000591","id":"PMC_31000591","title":"Restriction of PD-1 function by cis-PD-L1/CD80 interactions is required for optimal T cell responses.","date":"2019","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/31000591","citation_count":317,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8484124","id":"PMC_8484124","title":"Tyrosine kinase-stimulated guanine nucleotide exchange activity of Vav in T cell activation.","date":"1993","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/8484124","citation_count":297,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11279501","id":"PMC_11279501","title":"Structural basis for co-stimulation by the human CTLA-4/B7-2 complex.","date":"2001","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/11279501","citation_count":269,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23417675","id":"PMC_23417675","title":"Structure and interactions of the human programmed cell death 1 receptor.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23417675","citation_count":268,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"9032261","id":"PMC_9032261","title":"Lck regulates Vav activation of members of the Rho family of GTPases.","date":"1997","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9032261","citation_count":264,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22561518","id":"PMC_22561518","title":"Genome-wide association analyses identify 13 new susceptibility loci for generalized vitiligo.","date":"2012","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22561518","citation_count":257,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18026115","id":"PMC_18026115","title":"T cell-encoded CD80 and 4-1BBL induce auto- and transcostimulation, resulting in potent tumor rejection.","date":"2007","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/18026115","citation_count":241,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14978077","id":"PMC_14978077","title":"CD86 and CD80 differentially modulate the suppressive function of human regulatory T cells.","date":"2004","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/14978077","citation_count":224,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17703412","id":"PMC_17703412","title":"Genetic susceptibility to respiratory syncytial virus bronchiolitis is predominantly associated with innate immune genes.","date":"2007","source":"The Journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/17703412","citation_count":223,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23000144","id":"PMC_23000144","title":"Genome-wide association study identifies TNFSF15 and POU2AF1 as susceptibility loci for primary biliary cirrhosis in the Japanese population.","date":"2012","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23000144","citation_count":213,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20587542","id":"PMC_20587542","title":"PD-L1 and PD-L2 differ in their molecular mechanisms of interaction with PD-1.","date":"2010","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/20587542","citation_count":192,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18585785","id":"PMC_18585785","title":"Interaction of human PD-L1 and B7-1.","date":"2008","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/18585785","citation_count":191,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11726649","id":"PMC_11726649","title":"Distinct role of CD80 and CD86 in the regulation of the activation of B cell and B cell lymphoma.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11726649","citation_count":180,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23273568","id":"PMC_23273568","title":"Meta-analysis followed by replication identifies loci in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as associated with systemic lupus erythematosus in Asians.","date":"2012","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23273568","citation_count":173,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49798,"output_tokens":6130,"usd":0.120672},"stage2":{"model":"claude-opus-4-6","input_tokens":9756,"output_tokens":3564,"usd":0.20682},"total_usd":0.727494,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":62858,"output_tokens":8349,"usd":0.156905},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":12393,"output_tokens":4004,"usd":0.243097}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"Surface plasmon resonance measurements showed that CD80 (B7-1) binds both CD28 and CTLA-4 with low affinity (Kd ~4 µM and ~0.42 µM at 37°C, respectively) and very fast dissociation kinetics (koff ≥1.6 s⁻¹ for CD28, ≥0.43 s⁻¹ for CTLA-4), indicating that rapid binding kinetics underlie the transient nature of T cell–APC contacts.\",\n      \"method\": \"Surface plasmon resonance (in vitro binding assay with recombinant proteins)\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — quantitative in vitro reconstitution with recombinant proteins, rigorous kinetic analysis\",\n      \"pmids\": [\"9053440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Crystal structure of the human CTLA-4/B7-1 complex at 3.0 Å resolution revealed an unusually high degree of shape complementarity at the binding interface; CTLA-4 forms homodimers through a conserved interface, and in the crystal lattice bivalent CTLA-4 homodimers bridge bivalent B7-1 homodimers in a zipper-like oligomeric arrangement, providing a structural basis for formation of stable inhibitory signaling complexes.\",\n      \"method\": \"X-ray crystallography (crystal structure at 3.0 Å)\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution crystal structure with functional implications validated by structural analysis\",\n      \"pmids\": [\"11279502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Crystal structure of the extracellular region of soluble B7-1 at 3 Å resolution revealed a novel combination of two Ig-like domains; B7-1 forms parallel, 2-fold rotationally symmetric homodimers both in the crystal lattice and in solution (confirmed by analytical ultracentrifugation), suggesting avidity-enhanced binding to CTLA-4 homodimers favors formation of stable inhibitory complexes.\",\n      \"method\": \"X-ray crystallography and analytical ultracentrifugation\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus orthogonal solution-phase biophysical validation\",\n      \"pmids\": [\"10661405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Using FRET-based photobleaching assays on living cell surfaces, B7-1 (CD80) was shown to exist as a homodimer on the APC cell surface, whereas B7-2 (CD86) exists as a monomer, indicating that distinct oligomeric states of the two ligands may underlie their different T cell functional outcomes; B7-1 and B7-2 do not form hetero-oligomers.\",\n      \"method\": \"Fluorescence resonance energy transfer (FRET) by photobleaching on live cells\",\n      \"journal\": \"Immunology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — live-cell FRET with functional implications, single lab\",\n      \"pmids\": [\"16413062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PD-L1 binds B7-1 (CD80) exclusively in cis on the same cell surface, not in trans between two cells; demonstrated by cell-to-cell binding assays, ELISA with purified proteins, and NanoBiT proximity assays. Soluble PD-1 and B7-1 compete for binding to PD-L1, and the cis PD-L1/B7-1 interaction can block PD-L1 binding to PD-1 or B7-1 binding to CD28.\",\n      \"method\": \"Cell-to-cell binding assays, ELISA, flow cytometry with purified proteins, NanoBiT proximity (split luciferase) assays\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods in one study rigorously establishing cis interaction\",\n      \"pmids\": [\"29871885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Mutagenesis mapping using cell microarray and high-throughput FACS identified the PD-L1 binding site on B7-1 at the dimer interface surface of B7-1, distal from the CTLA-4/CD28 recognition surface. CTLA-4 and CD28 do not directly compete with PD-L1 for binding to B7-1, but can disrupt the cis PD-L1:B7-1 complex by reorganizing B7-1 on the cell surface. Confirmed that PD-L1 and B7-1 bind in cis via two independent approaches.\",\n      \"method\": \"Cell microarray/FACS-based binding assays, mutagenesis of PD-L1 and B7-1, proximity assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis combined with multiple orthogonal binding assays to map interface\",\n      \"pmids\": [\"32497097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Using anti-B7 antibodies in vitro and in vivo in experimental allergic encephalomyelitis, B7-1 and B7-2 were shown to differentially activate Th1 and Th2 developmental pathways: anti-B7-1 reduced disease and promoted Th2 generation, while anti-B7-2 increased disease severity. Anti-IL-4 co-treatment reversed disease amelioration, indicating that B7-1/B7-2 influence initial cytokine secretion by T helper precursors.\",\n      \"method\": \"In vivo antibody blockade in EAE model, cytokine profiling, T cell transfer, cytokine neutralization\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo epistasis with multiple genetic/antibody interventions, replicated across contexts, highly cited foundational study\",\n      \"pmids\": [\"7534215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Blocking B7-2 costimulatory activity inhibited TCR-dependent T cell proliferation and cytokine production without affecting early TCR signaling (CD69, IL-2Rα induction), demonstrating that B7-1 and B7-2 can be independently regulated and both provide distinct costimulatory signals through shared receptors CD28 and CTLA-4.\",\n      \"method\": \"Anti-B7 antibody blocking, flow cytometry, proliferation and cytokine assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional blocking experiments with multiple readouts, single study\",\n      \"pmids\": [\"7519245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Ligation of CD28 by the natural ligand B7-1 (in contrast to anti-CD28 monoclonal antibody) does not stimulate p21ras signaling pathways or ERK2/Raf-1 hyperphosphorylation, but does activate cellular PTKs and induces prolonged Vav tyrosine phosphorylation. This demonstrates qualitative differences between antibody-mediated and physiological B7-1-mediated CD28 signaling.\",\n      \"method\": \"In vitro signaling assays (Ras activation, ERK2/Raf-1 phosphorylation, tyrosine phosphorylation of Vav and p36) with B7-1 protein stimulation vs. CD28 mAb\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical readouts comparing B7-1 vs. antibody ligation, single study\",\n      \"pmids\": [\"7520466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Ligation of B7-1/B7-2 molecules on dendritic cells by CTLA-4/CD28 expressed on CD4+ T cells triggers functional indoleamine 2,3-dioxygenase (IDO) activity in DCs, converting constitutively expressed but inactive IDO to an active state that suppresses T cell proliferation. Direct antibody cross-linking of B7-1/B7-2 was sufficient to activate IDO, and this signal was strictly confined to CD4+ T cell engagement.\",\n      \"method\": \"DC/T cell co-culture, antibody-mediated B7-1/B7-2 cross-linking, IDO activity assays, T cell proliferation assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional reconstitution with antibody cross-linking plus genetic/pharmacologic dissection, single lab\",\n      \"pmids\": [\"15034022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"B7-1 (CD80) is expressed in podocytes under pathological conditions (LPS, genetic, immune-mediated, and toxin-induced injury) and its activation in cultured podocytes reorganizes vital slit diaphragm proteins and the actin cytoskeleton. Mice lacking B7-1 are protected from LPS-induced nephrotic syndrome, establishing a direct functional link between podocyte B7-1 expression and proteinuria.\",\n      \"method\": \"LPS-treated WT and SCID mice, B7-1 knockout mice (loss-of-function), in vitro podocyte activation with actin cytoskeleton readout, immunostaining of slit diaphragm proteins\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined phenotype plus in vitro mechanistic follow-up, single lab\",\n      \"pmids\": [\"15146236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"BCL6, a transcriptional repressor, directly controls CD80 (B7-1) expression in germinal center B cells by binding the CD80 promoter region and suppressing its transcriptional activation by NF-κB downstream of CD40 signaling. BCL6-deficient mice show increased CD80 expression on B cells, and BCL6 and CD80 expression are mutually exclusive in normal B cells.\",\n      \"method\": \"Chromatin immunoprecipitation (BCL6 binding to CD80 promoter), BCL6 knockout mouse B cells, CD40 signaling experiments, NF-κB reporter assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP demonstrating direct promoter binding plus KO mouse validation and mechanistic pathway dissection\",\n      \"pmids\": [\"12860928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"CD80 (B7-1) functions as a triggering signal for NK cell-mediated cytotoxicity that overrides MHC class I-mediated protection, and this NK cell activation by B7-1 occurs independently of CD28 and cannot be blocked by anti-CD28 or anti-CTLA-4 antibodies, indicating that NK cells use B7-1 receptors other than CD28 and CTLA-4.\",\n      \"method\": \"NK cell cytotoxicity assays with B7-1-expressing targets, antibody blocking (anti-CD28, anti-CTLA-4), CD28-deficient models\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional cytotoxicity assays with antibody blockade establishing CD28/CTLA-4-independent mechanism\",\n      \"pmids\": [\"8885864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"CTLA-4 engagement of B7-1 can potently inhibit T cell activation in the complete absence of CD28, demonstrating that CTLA-4 delivers a signal that directly antagonizes TCR-mediated signals rather than merely competing with CD28 for B7 binding.\",\n      \"method\": \"TCR transgenic/RAG2-deficient/CD28-deficient mouse model; tumor immunization; B7-1 antibody blocking; cytokine and proliferation assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with CD28-KO plus antibody blocking clearly establishing CD28-independent CTLA-4 inhibitory mechanism\",\n      \"pmids\": [\"9653097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Small molecule inhibitors of human B7-1 were identified that inhibit binding of B7-1 to both CD28 and CTLA4. Both classes of compounds bind the same site on the GFCC'C\\\" face of the N-terminal V-set domain of human B7-1, a site not present in B7-2 or mouse B7-1, defining a functional hotspot for antagonist design.\",\n      \"method\": \"Small molecule binding assays, competitive binding with CD28 and CTLA4, domain mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — binding site mapping with functional validation using competitive inhibition assays\",\n      \"pmids\": [\"11741888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The V domain of CD86 (B7-2) alone is sufficient for CTLA-4 binding, whereas the V domain of CD80 (B7-1) alone is not, indicating a fundamental structural difference in how the two B7 ligands interact with their shared receptors. Insertion of two residues between the Ig domains of CD80 decreased affinity for CTLA-4, but a similar mutation in CD86 had no effect.\",\n      \"method\": \"Domain deletion/insertion mutagenesis of CD80 and CD86, binding assays with CTLA-4\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis with functional binding validation, single study\",\n      \"pmids\": [\"8609386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Naive CD4+ T cells acquire CD80 (B7-1) protein from syngeneic APCs after activation via CD28-dependent membrane transfer (not endogenous expression, as shown by cyclohexamide treatment and absence of CD80 mRNA in T cells). T cells that acquired CD80 could themselves function as APCs; memory T cells that acquired CD80 underwent apoptosis in the presence of strong TCR signals.\",\n      \"method\": \"Transfer experiments using CD80/CD86 knockout APC, cyclohexamide treatment, CD28-KO T cells, confocal microscopy, RT-PCR for CD80 mRNA\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal controls (KO mice, protein synthesis inhibitor, mRNA analysis, confocal) establishing mechanism of CD28-dependent membrane transfer\",\n      \"pmids\": [\"11160311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Direct signaling through B7-1/B7-2 (CD80/CD86) on B cells promotes IgG secretion by class-switched B cells and induces expression of XBP-1 and spliced XBP1 (markers of increased protein synthesis), independent of effects on germinal center formation or CD4+ T cell activation. This was established using mixed bone marrow irradiation chimeras lacking B7-1/2 only on B cells.\",\n      \"method\": \"Mixed bone marrow irradiation chimeric mice (B cell-specific B7-1/2 KO), in vitro B7-2 engagement, IgG/IgM ELISA, XBP-1 expression analysis, influenza infection model\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cell-specific KO chimeras plus in vitro mechanistic follow-up, single lab\",\n      \"pmids\": [\"19933871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"CD40 signaling domains controlling B7-1 (CD80) induction were dissected: threonine residues at positions 227 and 234 in the CD40 cytoplasmic domain are critical for B7-1 induction, while a deletion mutant retaining only six cytoplasmic amino acids loses B7-1 induction capacity but retains some growth-inhibitory function, establishing at least two distinct signaling domains in CD40.\",\n      \"method\": \"Site-directed mutagenesis of human CD40 cytoplasmic tail, transfection into M12 B lymphoma, B7-1 expression assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis with defined functional readout, single study\",\n      \"pmids\": [\"8816387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CD80 (B7-1) expression in cutaneous T cell lymphoma (CTCL) cells is strictly dependent on STAT5a and STAT5b, which transcriptionally activate the CD80 gene. In IL-2-dependent CTCL cells, IL-2 induces CD80 in a Jak1/3- and STAT5a/b-dependent manner. CD80 on CTCL cells engages CTLA-4 on normal T cells to suppress their proliferation, constituting a mechanism of immune evasion.\",\n      \"method\": \"siRNA knockdown of STAT5a/b, Jak inhibitors, IL-2 stimulation assays, CTLA-4/CD80 co-culture proliferation assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic knockdowns and pharmacologic inhibitions with functional readout, single lab\",\n      \"pmids\": [\"24523507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Constitutive expression of B7-1 on B cells in B7-1 transgenic mice markedly depressed T-dependent antibody responses (while T-independent responses were normal). Treatment with anti-B7-1 restored the response, demonstrating that temporally dysregulated B7-1 expression can dominantly inhibit rather than activate T-dependent immune responses, revealing a negative regulatory function for B7-1.\",\n      \"method\": \"B7-1 transgenic mice on mature B cells, hapten-protein immunization, anti-B7-1 antibody rescue\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transgenic overexpression with antibody rescue establishing in vivo negative regulatory function\",\n      \"pmids\": [\"7533646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"B7-1 in podocytes mediates injury and glomerulosclerosis through interaction with Hsp90ab1 (identified by LC-MS/MS), which serves as a molecular anchor transmitting signals from B7-1 to LRP5/β-catenin. Mutagenesis identified residue K69 in the N-terminal domain of Hsp90ab1 as the key binding site for B7-1 activation of the LRP5/β-catenin pathway. B7-1 is also a downstream target of β-catenin, forming a positive feedback loop.\",\n      \"method\": \"LC-MS/MS proteomics, molecular docking, mutagenesis of Hsp90ab1 K69, Co-IP, B7-1 transgenic mice, adriamycin nephropathy model, in vitro podocyte assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — proteomics-identified interaction validated by mutagenesis and in vivo models, single lab\",\n      \"pmids\": [\"35710882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"An alternatively spliced soluble form of B7-1 (sB7-1) lacking transmembrane and cytoplasmic domains was cloned from porcine alveolar macrophages. Recombinant sB7-1 interacts with both CD28 and CTLA-4 and effectively blocks IL-2 production and human T cell proliferation in co-stimulation assays.\",\n      \"method\": \"cDNA cloning, Northern blot, recombinant protein production, CD28/CTLA-4 binding assays, T cell proliferation and IL-2 assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — molecular cloning plus functional reconstitution with recombinant protein, single study\",\n      \"pmids\": [\"10843688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"B7-1 and B7-2 contribute to negative selection of thymocytes induced by endogenous superantigens; studies in CD28-deficient and CD28/CTLA-4 double-deficient mice revealed that either CD28 or another undefined co-receptor mediates B7-dependent pro-selection signals, while CTLA-4 delivers inhibitory signals opposing selection.\",\n      \"method\": \"B7-1/B7-2 and CD28/CTLA-4 knockout mice, superantigen-induced thymocyte deletion assays, genetic epistasis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multi-KO epistasis establishing pathway position in thymic selection, single study\",\n      \"pmids\": [\"12759417\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD80 (B7-1) is a homodimeric Ig-superfamily glycoprotein expressed on antigen-presenting cells and, under pathological conditions, on non-immune cells such as podocytes; it delivers costimulatory signals to T cells via low-affinity, fast-kinetics interactions with CD28 (activating) and CTLA-4 (inhibitory), forms a zipper-like oligomeric complex with CTLA-4 homodimers that stabilizes inhibitory signaling, engages PD-L1 exclusively in cis on the same cell surface to competitively block PD-L1/PD-1 and B7-1/CD28 interactions, activates IDO in dendritic cells upon CTLA-4 ligation, signals in podocytes through an Hsp90ab1–LRP5–β-catenin axis, has its transcription controlled by BCL6 (repressor) and STAT5/NF-κB (activators), and can be transferred to T cells via CD28-dependent membrane acquisition to confer secondary APC function.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1989,\n      \"finding\": \"CD80 (B7) was identified as a type I transmembrane glycoprotein of the immunoglobulin superfamily, with two extracellular Ig-like domains (one V-like, one C-like), expressed on activated B cells and B cell malignancies, functioning as a costimulatory ligand for T cells.\",\n      \"method\": \"cDNA cloning, expression in COS cells, immunoprecipitation, Northern blot\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original molecular cloning with structural characterization and functional validation, foundational paper with >500 citations\",\n      \"pmids\": [\"2794510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"CD80 (B7) delivers a costimulatory signal to T cells through direct binding to CD28, stimulating T cell proliferation and IL-2 mRNA accumulation; CD28-Ig fusion protein bound CD80 with Kd ~200 nM, and B7-transfected CHO cells costimulated T cell activation.\",\n      \"method\": \"Fusion protein binding assay (125I-labeled B7-Ig), CD28-transfected CHO cell binding, T cell proliferation assay, IL-2 mRNA measurement\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted binding with defined Kd, functional costimulation demonstrated with transfected cells, >1200 citations\",\n      \"pmids\": [\"1847722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Murine CD80 (B7) was cloned; the predicted protein shares 44% amino acid identity with human B7 with conserved Ig-V and Ig-C domains; murine B7-transfected cells provided costimulatory signal to human CD28+ T lymphocytes, demonstrating conservation of the ligand attachment site.\",\n      \"method\": \"cDNA cloning, sequence analysis, transfection into CHO cells, T cell costimulation assay\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — molecular cloning with cross-species functional validation, >360 citations\",\n      \"pmids\": [\"1714935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"CD80 (B7-1) and CD86 (B7-2) are both ligands for CD28 and CTLA-4; both molecules are expressed on multiple APC types (B cells, T cells, macrophages, dendritic cells); their expression can be independently regulated by the same stimulus; blocking CD86 (B7-2) costimulatory activity inhibits TCR-dependent T cell proliferation and cytokine production without affecting early TCR signals (CD69, IL-2Rα induction).\",\n      \"method\": \"Flow cytometry, blocking antibody experiments, T cell proliferation and cytokine production assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple cell types, reciprocal blocking with functional readouts, >600 citations\",\n      \"pmids\": [\"7519245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The extracellular V-like domains of CD80 (B7-1) and CD86 (B7-2) share sequence similarities with MHC-encoded Ig superfamily members (butyrophilin, myelin/oligodendrocyte glycoprotein, chicken B-G), suggesting an evolutionary link between B7 molecules and MHC-encoded costimulatory molecules.\",\n      \"method\": \"Sequence analysis, structural comparison\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — computational sequence/structural analysis only\",\n      \"pmids\": [\"7527261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The C-like domain of CD80 is structurally compatible with IgSF C-set structures (best recognized by β2-microglobulin of MHC Class I), while the N-terminal V-like domain is not compatible with known IgSF V-set structures; 11 of 17 conserved residues in the C-like domain of B7-1/B7-2 are not standard IgSF C-1 set consensus residues and cluster on the surface, suggesting they mediate protein-protein interactions.\",\n      \"method\": \"Inverse folding methodology, sequence comparison mapped onto β2-microglobulin structure\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — computational structural analysis without experimental validation\",\n      \"pmids\": [\"7535614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Ligation of CD28 by monoclonal antibody (but not by its physiological ligand B7-1/CD80) stimulates p21ras and downstream Ras-dependent events (ERK2 activation, Raf-1 hyperphosphorylation); both anti-CD28 mAb and B7-1 activate cellular PTKs and induce Vav tyrosine phosphorylation, but only anti-CD28 mAb induces tyrosine phosphorylation of the Grb2-associated p36 protein, which correlates with p21ras activation.\",\n      \"method\": \"In vitro kinase assays, anti-phosphotyrosine immunoblotting, Ras activation assay, co-immunoprecipitation\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical assays with functional dissection of CD28 vs B7-1 signaling, single lab\",\n      \"pmids\": [\"7520466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"BCL6 directly represses CD80 transcription: BCL6 binds the CD80 promoter in vivo and suppresses NF-κB-mediated transcriptional activation induced by CD40 signaling; BCL6-deficient mice show increased CD80 expression on B cells, and BCL6 and CD80 expression are mutually exclusive in normal B cells.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), reporter assays, B cell expression analysis in BCL6-knockout mice, Western blot\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP demonstrating direct promoter binding, corroborated by knockout mouse data and mutual exclusion in vivo, replicated by multiple orthogonal methods\",\n      \"pmids\": [\"12860928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"CD80 (B7-1) and CD86 (B7-2) differentially activate the Th1/Th2 developmental pathways: blockade of B7-1 reduced EAE incidence and favored Th2 clone generation (mediating IL-4-dependent disease amelioration), while blockade of B7-2 increased EAE severity; thus, shared counterreceptors CD28 and CTLA-4 yield very different outcomes depending on which B7 ligand is engaged.\",\n      \"method\": \"In vitro T cell differentiation assays, in vivo EAE model with anti-B7 antibody treatment, cytokine profiling, adoptive transfer\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo and in vitro epistasis, adoptive transfer, cytokine blocking, >1499 citations\",\n      \"pmids\": [\"7534215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"CD80 and CD86 provide similar costimulatory signals for T cell proliferation, cytokine production (IL-2, IFN-γ), and CTL generation; CTLA-4-Ig binds both ligands with higher affinity than CD28-Ig; blocking both ligands simultaneously is required to optimally inhibit CD28-dependent proliferation in allogeneic MLR.\",\n      \"method\": \"Stable transfectants, anti-CD3 proliferation assay, cytokine ELISA, CTL generation, CD28-Ig/CTLA-4-Ig binding assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal functional assays with defined transfectants, >440 citations\",\n      \"pmids\": [\"7527824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"CD80 (B7-1) functions as a triggering signal for NK cell-mediated cytotoxicity that overrides MHC class I protection; this NK cell triggering by B7-1 occurs even in the absence of CD28 and cannot be blocked by anti-CD28 or anti-CTLA-4 antibodies, indicating NK cells use receptors other than CD28/CTLA-4 to interact with B7-1.\",\n      \"method\": \"NK cell cytotoxicity assays with purified populations, blocking antibody experiments, CD28-knockout mouse NK cells\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — purified NK cells, CD28-KO genetic control, functional blocking with defined antibodies\",\n      \"pmids\": [\"8885864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"CD40 signaling induces CD80 expression through a pathway involving specific threonine residues (T227 and T234) in the CD40 cytoplasmic tail; cAMP synergizes with CD40 signaling to induce high-level CD80 expression; a distinct CD40 domain (with only six cytoplasmic amino acids) retains growth-inhibitory function but loses CD80 induction capacity, demonstrating at least two distinct CD40 signaling domains.\",\n      \"method\": \"Transfection of wild-type and mutant CD40 constructs into M12 B lymphoma, flow cytometry for CD80 expression, cAMP treatment\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — systematic deletion/point mutagenesis identifying specific residues, single lab\",\n      \"pmids\": [\"8816387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The V domain of CD86 (but not CD80) is sufficient for CTLA-4 binding; insertion of two residues between the two Ig domains of CD80 decreased affinity for CTLA-4, while the same insertion in CD86 had no effect, demonstrating a fundamental structural difference between CD80 and CD86 in receptor recognition.\",\n      \"method\": \"Domain-swapping constructs, binding assays with CTLA-4 and CD28\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — systematic domain-swapping and insertion mutagenesis, single lab\",\n      \"pmids\": [\"8609386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"CD80 binds both CD28 and CTLA-4 with low affinity and very fast kinetics: at 37°C, soluble CD80 binds CTLA-4 with Kd ~0.42 μM and CD28 with Kd ~4 μM, with very fast dissociation rate constants (koff ≥ 0.43 s⁻¹ for CTLA-4 and ≥ 1.6 s⁻¹ for CD28), as measured by surface plasmon resonance.\",\n      \"method\": \"Surface plasmon resonance (BIAcore) with soluble recombinant proteins at physiological temperature\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — quantitative biophysical measurement with recombinant proteins, precise kinetic constants determined, >430 citations\",\n      \"pmids\": [\"9053440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"CTLA-4 can potently inhibit T cell activation in the absence of CD28 through B7-1 engagement: CD28-deficient T cells primed with antigen-expressing tumor cells showed strong inhibition of cytokine production and proliferation when B7-1 was present on stimulators, and this inhibition was reversed by anti-B7-1 or anti-CTLA-4 antibodies, indicating CTLA-4 antagonizes TCR-mediated signals independent of CD28.\",\n      \"method\": \"TCR transgenic/RAG2-deficient/CD28 knockout mouse model, antigen-specific stimulation assays, antibody blocking\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic CD28-knockout model with antigen-specific readout and antibody rescue, mechanistic dissection\",\n      \"pmids\": [\"9653097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The crystal structure of soluble B7-1 (sB7-1) at 3 Å resolution reveals a novel combination of two Ig-like domains: an IgV-like domain (characteristic of adhesion molecules) and an IgC-like domain (previously seen only in antigen receptors); sB7-1 forms parallel, 2-fold rotationally symmetric homodimers in the crystal lattice and also dimerizes in solution as demonstrated by analytical ultracentrifugation, suggesting avidity-enhanced binding to CTLA-4 homodimers favors stable inhibitory signaling complexes.\",\n      \"method\": \"X-ray crystallography (3 Å resolution), analytical ultracentrifugation\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus solution biophysics confirming dimerization, >195 citations\",\n      \"pmids\": [\"10661405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"An alternatively spliced soluble form of porcine B7-1 (sB7-1) lacking both transmembrane and cytoplasmic domains was identified; porcine sB7-1-His interacted with both human CD28 and CTLA-4 and effectively blocked IL-2 production and T cell proliferation in response to porcine or human stimulator cells.\",\n      \"method\": \"cDNA cloning, Northern blot, His-tagged protein binding assay, T cell proliferation inhibition assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — identification of splice variant with demonstrated functional activity, single lab\",\n      \"pmids\": [\"10843688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The crystal structure of the human CTLA-4/B7-1 complex at 3.0 Å resolution reveals: (1) an unusually high degree of shape complementarity at the binding interface; (2) CTLA-4 forms homodimers through a newly defined interface of highly conserved residues; (3) in the crystal lattice, bivalent CTLA-4 homodimers bridge bivalent B7-1 homodimers in a zipper-like oligomeric arrangement that provides the structural basis for unusually stable inhibitory signaling complexes.\",\n      \"method\": \"X-ray crystallography at 3.0 Å resolution\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution crystal structure of the complex, >369 citations\",\n      \"pmids\": [\"11279502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The crystal structure of human CTLA-4/B7-2 complex at 3.2 Å shows that the unique dimerization properties of both CTLA-4 and B7-2 place ligand-binding sites distal to dimer interfaces, promoting alternating bivalent CTLA-4/B7-2 dimer networks throughout the crystal, providing a model for periodic organization within the immunological synapse.\",\n      \"method\": \"X-ray crystallography at 3.2 Å resolution\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure of related complex providing structural context for CD80 signaling\",\n      \"pmids\": [\"11279501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Small molecules that inhibit CD80 binding to both CD28 and CTLA4 bind to the GFCC'C\\\" face of the N-terminal V-set domain of human CD80; both classes of compounds appear to bind the same site, which is not present in homologous B7-2 or mouse B7-1, defining a species- and paralog-specific hot spot on CD80.\",\n      \"method\": \"Small molecule screening, competitive binding assay, domain mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — binding site defined by competitive inhibition with two compound classes, single lab\",\n      \"pmids\": [\"11741888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Naive CD4+ T cells acquire CD80 (B7-1) protein from syngeneic APCs after activation; this acquisition is CD28-dependent (absent in CD28-KO T cells), does not involve CD80 mRNA expression in T cells, is proportional to both signal 1 strength and APC CD80 level, and does not occur for other APC molecules (e.g., CD40); T cells that acquire CD80 can themselves act as APCs, while memory T cells that acquire CD80 undergo apoptosis in the presence of strong TCR signals.\",\n      \"method\": \"CD80/CD86 knockout mouse B cells as APC source, cyclohexamide treatment, confocal microscopy, CD28-KO T cells, RT-PCR for CD80 mRNA\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal controls (KO mice, protein synthesis inhibition, mRNA analysis, confocal), functional demonstration of acquired CD80\",\n      \"pmids\": [\"11160311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CD80 binds CTLA-4 and CD28 with higher affinity than CD86; relative to its CTLA-4 binding affinity, CD86 binds CD28 2-3 fold more effectively than CD80; unlike CD80, CD86 does not self-associate; CD28 homodimers are monovalent (not bivalent as previously assumed); CD80 markedly favors CTLA-4 over CD28 engagement, while CD86 exhibits much less bias, explaining their overlapping but distinct T cell response outcomes.\",\n      \"method\": \"Surface plasmon resonance, analytical ultracentrifugation, recombinant protein binding assays\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — quantitative biophysical measurements with recombinant proteins, multiple orthogonal methods, >520 citations\",\n      \"pmids\": [\"12196291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"B7-1 and B7-2 exist in different oligomeric states on the cell surface: B7-1 (CD80) is present as a dimer while B7-2 (CD86) exists as a monomer, as demonstrated by photobleaching-based FRET; B7-1 and B7-2 do not form hetero-oligomers on the cell surface.\",\n      \"method\": \"Fluorescence resonance energy transfer (FRET) via photobleaching on live cells\",\n      \"journal\": \"Immunology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct imaging method on live cells, single lab\",\n      \"pmids\": [\"16413062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Ligation of B7-1/B7-2 on dendritic cells by CTLA4/CD28 expressed on CD4+ T cells is required to trigger functional IDO (indoleamine 2,3-dioxygenase) activity; IDO protein is constitutively expressed but requires this B7-1/B7-2 engagement signal to become functionally active; the ability to trigger IDO was strictly confined to CD4+ T cells, allowing them to dominantly inhibit CD8+ T cell proliferation via IDO-conditioned DCs.\",\n      \"method\": \"IDO activity assays, blocking antibody experiments (anti-B7-1/B7-2), direct B7-1/B7-2 crosslinking, T cell subset depletion experiments\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanism dissected with blocking antibodies, direct crosslinking rescue, T cell subset specificity demonstrated, >378 citations\",\n      \"pmids\": [\"15034022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"B7-1 (CD80) is expressed in podocytes upon injury and acts as an inducible modifier of glomerular permselectivity; LPS signaling through TLR-4 reorganizes the podocyte actin cytoskeleton in vitro; activation of B7-1 in cultured podocytes leads to reorganization of slit diaphragm proteins; mice lacking B7-1 are protected from LPS-induced nephrotic syndrome, establishing a non-immune cell role for CD80 in barrier function.\",\n      \"method\": \"B7-1 knockout mouse model, LPS treatment in vivo, in vitro podocyte culture with actin cytoskeleton analysis, immunofluorescence for slit diaphragm proteins\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout with defined phenotypic readout (proteinuria), in vitro mechanistic studies, >471 citations\",\n      \"pmids\": [\"15146236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Direct B7-1/2 signaling in B cells enhances IgG secretion: B7-2 engagement on already class-switched B cells dramatically induced IgG (but not IgM) secretion and induced XBP-1 splicing (a marker of increased protein synthesis); in vivo, B7-1/2 expression on B cells is crucial for maximal local IgG responses to influenza infection, demonstrated in mixed bone marrow chimeras lacking B7-1/2 only on B cells.\",\n      \"method\": \"Mixed bone marrow irradiation chimeric mice, in vitro B7-2 crosslinking, XBP-1 splicing assay (RT-PCR), antibody ELISA\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic chimera model isolating B cell-intrinsic B7 function, in vitro mechanistic validation, multiple orthogonal methods\",\n      \"pmids\": [\"19933871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CTLA-4 removes CD80 and CD86 from opposing cells by trans-endocytosis: CTLA-4-expressing cells capture CD80/CD86 from antigen-presenting cells, and these costimulatory ligands are subsequently degraded inside the CTLA-4-expressing cells; CD86 acquisition is stimulated by TCR engagement and observed both in vitro and in vivo; this depletion of ligands impairs CD28 costimulation.\",\n      \"method\": \"Co-culture assays with CTLA-4-expressing cells, flow cytometry tracking ligand loss, intracellular degradation assays, in vivo confirmation\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanism demonstrated in vitro and in vivo with multiple cell types, >1400 citations\",\n      \"pmids\": [\"21474713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CD80 expression in CTCL cells is strictly dependent on STAT5a and STAT5b transcription factors: in IL-2-dependent CTCL cells, IL-2 induces CD80 in a Jak1/3- and STAT5a/b-dependent manner; CTLA-4 engagement on T cells (via CD80 on CTCL cells) inhibits normal T cell proliferation, revealing a CD80-CTLA-4 axis as an immune evasion mechanism.\",\n      \"method\": \"STAT5a/b knockdown (siRNA), Jak inhibitor treatment, CTLA-4 mRNA transfection in T cells, co-culture proliferation assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway dissection with siRNA and pharmacological inhibitors, functional co-culture validation, single lab\",\n      \"pmids\": [\"24523507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PD-L1 binds to B7-1 (CD80) only in cis on the same cell surface, not in trans between two different cells; this cis interaction was demonstrated by NanoBiT proximity assays and cell-to-cell binding assays; PD-L1 and B7-1 interact when PD-L1 is flexible (via its 11-amino-acid stalk) and bind at a site competitive with PD-L1/PD-1 and B7-1/CD28 interactions; coexpression of PD-L1 and B7-1 occurs on tumor-infiltrating myeloid cells.\",\n      \"method\": \"NanoBiT proximity assay, cell-to-cell binding assays, ELISA with purified proteins, flow cytometry, competitive binding assays\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods demonstrating cis-only interaction, functional competitive binding characterization\",\n      \"pmids\": [\"29871885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD80 (B7-1) on antigen-presenting cells interacts with PD-L1 in cis to disrupt PD-L1/PD-1 binding, thereby restricting PD-1 coinhibitory signaling during T cell activation; in knock-in mice where cis-PD-L1/CD80 interaction cannot occur, tumor immunity and autoimmune responses were greatly attenuated by PD-1, confirming that CD80 on APCs limits PD-1 signaling while promoting CD28-mediated costimulation.\",\n      \"method\": \"Knock-in mouse model (cis-interaction deficient), tumor immunity assays, autoimmune response measurement, cis-interaction biochemical assays\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knock-in model with defined functional phenotype, mechanistic in vivo confirmation, >317 citations\",\n      \"pmids\": [\"31000591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The PD-L1 binding site on B7-1 (mB7-1) maps to the dimer interface surface of B7-1, distal from the CTLA-4/CD28 recognition surface; CTLA-4 and CD28 do not directly compete with PD-L1 for binding to B7-1, but can disrupt the cis PD-L1:B7-1 complex by reorganizing B7-1 on the cell surface; mPD-L1 mutants with selective binding for either mB7-1 or mPD-1 were generated.\",\n      \"method\": \"Cell microarray and high-throughput FACS binding screen, site-directed mutagenesis of PD-L1 and B7-1, cis interaction assays with two independent approaches\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — systematic mutagenesis mapping binding interface, cis-interaction confirmed by two independent methods, functionally selective mutants generated\",\n      \"pmids\": [\"32497097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"B7-1 mediates podocyte injury and glomerulosclerosis through a signaling pathway involving Hsp90ab1 and LRP5/β-catenin: LC-MS/MS identified Hsp90ab1 as an anchor transmitting signals from B7-1 to β-catenin; molecular docking and mutant analysis identified residue K69 in the N-terminal domain of Hsp90ab1 as the key binding site for B7-1 to activate LRP5/β-catenin; B7-1 is itself a downstream target of β-catenin, creating a positive feedback loop.\",\n      \"method\": \"LC-MS/MS proteomics, molecular docking, site-directed mutagenesis (K69 in Hsp90ab1), B7-1 transgenic mouse model, adriamycin nephropathy model, co-immunoprecipitation, transcriptomic analysis\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including proteomics, mutagenesis, and in vivo models, single lab\",\n      \"pmids\": [\"35710882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Human B7-1 (CD80) interacts with human PD-L1 with affinity greater than that of B7-1 with CD28, but less than B7-1 with CTLA-4 or PD-L1 with PD-1; anti-PD-L1 antibodies were identified that can selectively block PD-L1 interactions with B7-1, PD-1, or both; PD-L1 is induced to higher levels on CD28high versus CD28low CD8+ T cells upon activation.\",\n      \"method\": \"Surface plasmon resonance (Biacore), blocking antibody characterization, flow cytometry\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — quantitative SPR biophysics, single lab\",\n      \"pmids\": [\"18585785\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD80 (B7-1) is a homodimeric IgSF glycoprotein on APCs that delivers costimulatory signals to T cells by binding CD28 (Kd ~4 μM) or inhibitory signals by binding CTLA-4 (Kd ~0.42 μM) with very fast kinetics; crystal structures reveal a zipper-like CD80/CTLA-4 oligomeric network; CTLA-4 removes CD80 from APCs by trans-endocytosis; CD80 interacts with PD-L1 exclusively in cis on the same cell surface to block PD-1 inhibitory signaling; CD80 transcription is induced by CD40/NF-κB and repressed by BCL6; in podocytes CD80 signals through an Hsp90ab1-LRP5-β-catenin pathway to cause cytoskeletal injury; CD80 also directly signals in B cells to enhance IgG secretion and can trigger NK cell cytotoxicity through a CD28/CTLA-4-independent receptor.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CD80 (B7-1) is a homodimeric immunoglobulin-superfamily glycoprotein on antigen-presenting cells that serves as a central costimulatory and coinhibitory ligand governing T cell activation, tolerance, and immune regulation. CD80 binds CD28 (Kd ~4 µM) to deliver activating costimulation and CTLA-4 (Kd ~0.42 µM) to deliver inhibitory signals, with both interactions characterized by unusually fast dissociation kinetics; bivalent CD80 homodimers bridge CTLA-4 homodimers in a zipper-like oligomeric lattice that stabilizes inhibitory signaling, and CTLA-4 engagement of CD80 on dendritic cells activates indoleamine 2,3-dioxygenase (IDO) to suppress T cell proliferation [PMID:9053440, PMID:11279502, PMID:15034022]. CD80 also engages PD-L1 exclusively in cis on the same cell surface at a site on the B7-1 dimer interface distinct from the CTLA-4/CD28 binding face, competitively blocking both PD-L1/PD-1 and B7-1/CD28 trans interactions [PMID:29871885, PMID:32497097]. Transcription of CD80 is repressed by BCL6 in germinal center B cells and activated by NF-κB downstream of CD40 signaling and by STAT5a/b downstream of IL-2/Jak signaling; outside the immune system, CD80 is induced on podocytes under pathological stress where it signals through an Hsp90ab1–LRP5–β-catenin axis to drive cytoskeletal reorganization and proteinuria [PMID:12860928, PMID:24523507, PMID:15146236, PMID:35710882].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Establishing that CD80 and CD86, while sharing CD28/CTLA-4 as receptors, provide functionally non-redundant costimulatory signals and that constitutive B7-1 expression can paradoxically suppress T-dependent immunity resolved the question of whether the two B7 family members were interchangeable.\",\n      \"evidence\": \"Antibody blocking of B7-1/B7-2 in T cell proliferation assays and B7-1 transgenic mice with hapten-protein immunization\",\n      \"pmids\": [\"7519245\", \"7533646\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis for differential functional outcomes of B7-1 vs B7-2 not defined\", \"Whether the inhibitory effect of constitutive B7-1 is entirely CTLA-4-mediated was not resolved\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Demonstrating that B7-1 and B7-2 differentially bias Th1/Th2 polarization in vivo during autoimmune encephalomyelitis established that costimulatory ligand identity controls the quality, not just the magnitude, of adaptive immune responses.\",\n      \"evidence\": \"Anti-B7-1/B7-2 antibody blockade in EAE model with cytokine profiling and anti-IL-4 neutralization\",\n      \"pmids\": [\"7534215\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Th1/Th2 skewing reflects intrinsic signaling differences or kinetic/affinity differences between B7-1 and B7-2 was unresolved\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Discovery that CD80 triggers NK cell cytotoxicity independently of CD28 and CTLA-4 revealed an unsuspected receptor diversity for B7-1 on innate lymphocytes, and mapping of CD40 cytoplasmic residues controlling CD80 induction clarified upstream signaling requirements.\",\n      \"evidence\": \"NK cytotoxicity assays with anti-CD28/CTLA-4 blockade; CD40 cytoplasmic tail mutagenesis in B lymphoma cells\",\n      \"pmids\": [\"8885864\", \"8816387\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the CD28/CTLA-4-independent NK receptor for B7-1 was not determined\", \"Structural basis for CD40 domain-specific control of CD80 transcription unknown\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Quantitative kinetic characterization of CD80 interactions with CD28 and CTLA-4 by surface plasmon resonance established that both interactions have fast off-rates, with CTLA-4 binding ~10-fold stronger than CD28, providing a biophysical framework for understanding costimulatory competition at the immunological synapse.\",\n      \"evidence\": \"Surface plasmon resonance with recombinant CD80, CD28, and CTLA-4 ectodomains at 37°C\",\n      \"pmids\": [\"9053440\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinetics measured with soluble monomeric proteins may not fully capture avidity effects of homodimeric membrane-bound forms\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Showing that CTLA-4 engagement of B7-1 inhibits T cell activation even in the complete absence of CD28 proved that CTLA-4 delivers a cell-intrinsic inhibitory signal rather than merely competing with CD28 for ligand.\",\n      \"evidence\": \"TCR transgenic/CD28-KO/RAG2-KO mice with tumor immunization and anti-B7-1 blockade\",\n      \"pmids\": [\"9653097\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling pathway from CTLA-4 mediating CD28-independent inhibition not identified\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Crystal structure of the B7-1 extracellular region revealed homodimer architecture validated by analytical ultracentrifugation, providing the structural basis for bivalent engagement of CTLA-4 homodimers and explaining avidity-driven preferential assembly of inhibitory complexes.\",\n      \"evidence\": \"X-ray crystallography at 3 Å plus analytical ultracentrifugation of soluble B7-1\",\n      \"pmids\": [\"10661405\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of the B7-1/CD28 complex was available for comparison\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"The CTLA-4/B7-1 co-crystal structure revealed a zipper-like lattice of alternating homodimers, providing a molecular model for how stable signaling arrays form at the T cell–APC interface to sustain inhibitory signaling.\",\n      \"evidence\": \"X-ray crystallography of human CTLA-4/B7-1 complex at 3.0 Å\",\n      \"pmids\": [\"11279502\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether zipper-like arrays actually form on cell surfaces in vivo was not directly shown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identification of BCL6 as a direct transcriptional repressor of the CD80 promoter in germinal center B cells, opposing NF-κB-driven activation downstream of CD40, established how CD80 expression is dynamically restricted during B cell differentiation.\",\n      \"evidence\": \"ChIP of BCL6 at CD80 promoter, BCL6-KO mouse B cells, NF-κB reporter assays\",\n      \"pmids\": [\"12860928\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether additional transcription factors cooperate with BCL6 at the CD80 locus was not addressed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Two discoveries expanded CD80 function beyond T cell costimulation: reverse signaling through B7-1/B7-2 on dendritic cells activates IDO to suppress immunity, and pathological CD80 induction on podocytes drives cytoskeletal reorganization and nephrotic syndrome.\",\n      \"evidence\": \"DC/T cell co-culture with antibody cross-linking of B7 plus IDO activity assays; B7-1 KO mice protected from LPS-induced proteinuria plus in vitro podocyte assays\",\n      \"pmids\": [\"15034022\", \"15146236\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling cascade from B7-1 cross-linking to IDO activation in DCs not defined\", \"Receptor or adaptor mediating B7-1 signaling in podocytes was unknown at this time\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identification of STAT5a/b as direct transcriptional activators of CD80 in IL-2-dependent CTCL cells revealed how malignant T cells co-opt CD80 expression to engage CTLA-4 on normal T cells for immune evasion.\",\n      \"evidence\": \"siRNA knockdown of STAT5a/b, Jak inhibitors, IL-2 stimulation, CTLA-4/CD80 co-culture proliferation assays in CTCL lines\",\n      \"pmids\": [\"24523507\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether STAT5-driven CD80 expression occurs in other non-APC malignancies was not tested\", \"Direct STAT5 binding to CD80 promoter not shown by ChIP\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Discovery that PD-L1 binds B7-1 exclusively in cis on the same cell surface—not in trans—fundamentally reframed the PD-L1/B7-1 interaction as a cell-intrinsic regulatory mechanism that simultaneously blocks PD-1 and CD28 engagement.\",\n      \"evidence\": \"Cell-to-cell binding assays, ELISA, flow cytometry, NanoBiT split-luciferase proximity assays\",\n      \"pmids\": [\"29871885\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and affinity of the cis interaction on native membranes not quantified\", \"In vivo physiological consequences of cis PD-L1:B7-1 not directly tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Mutagenesis mapping placed the PD-L1 binding site on the B7-1 dimer interface, spatially separate from the CTLA-4/CD28 binding face, resolving how CTLA-4 disrupts the cis PD-L1:B7-1 complex through surface reorganization rather than direct steric competition.\",\n      \"evidence\": \"Cell microarray/FACS-based binding with systematic B7-1 and PD-L1 mutagenesis\",\n      \"pmids\": [\"32497097\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution structure of the PD-L1:B7-1 cis complex not determined\", \"Mechanism by which CTLA-4 reorganizes B7-1 on the membrane is unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of Hsp90ab1 as the intracellular effector linking podocyte B7-1 to LRP5/β-catenin signaling, with K69 of Hsp90ab1 as the critical contact residue, provided the first defined signaling pathway downstream of B7-1 outside the immune system.\",\n      \"evidence\": \"LC-MS/MS interactome, Hsp90ab1 K69 mutagenesis, Co-IP, B7-1 transgenic mice, adriamycin nephropathy model\",\n      \"pmids\": [\"35710882\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Hsp90ab1-mediated signaling operates in immune cells expressing B7-1 is unknown\", \"The positive feedback loop between β-catenin and B7-1 transcription needs independent validation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The identity of the CD28/CTLA-4-independent NK cell receptor for B7-1, the atomic structure of the cis PD-L1:B7-1 complex, and the signaling cascade from B7-1 reverse signaling to IDO activation in dendritic cells remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"NK receptor for B7-1 unidentified\", \"No atomic structure of cis PD-L1:B7-1 complex\", \"B7-1 reverse signaling cascade in DCs undefined\", \"In vivo validation of zipper-like CTLA-4:B7-1 arrays at cell surfaces lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 6, 7, 13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 5, 20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 4, 5, 16]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 6, 7, 9, 13, 23]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 10, 21]}\n    ],\n    \"complexes\": [\n      \"CTLA-4:B7-1 zipper-like lattice\",\n      \"cis PD-L1:B7-1 complex\"\n    ],\n    \"partners\": [\n      \"CTLA4\",\n      \"CD28\",\n      \"CD274\",\n      \"BCL6\",\n      \"HSP90AB1\",\n      \"LRP5\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"CD80 (B7-1) is a homodimeric type I transmembrane glycoprotein of the immunoglobulin superfamily expressed on activated antigen-presenting cells that functions as a central costimulatory and coinhibitory ligand governing T cell activation, tolerance, and immune checkpoint signaling. CD80 binds CD28 (Kd ~4 μM) to deliver T cell costimulatory signals promoting proliferation and IL-2 production, and binds CTLA-4 (Kd ~0.42 μM) with ~10-fold higher affinity and very fast kinetics to form zipper-like oligomeric lattices that favor stable inhibitory signaling; CTLA-4 additionally depletes CD80 from APCs by trans-endocytosis, reducing costimulatory capacity [PMID:9053440, PMID:11279502, PMID:21474713]. On the same cell surface, CD80 interacts with PD-L1 exclusively in cis, sequestering PD-L1 from engaging PD-1 on T cells and thereby restricting PD-1-mediated coinhibition while preserving CD28-dependent costimulation [PMID:29871885, PMID:31000591]. Beyond its canonical immune role, CD80 is induced on podocytes upon injury and signals through an Hsp90ab1–LRP5–β-catenin pathway to reorganize the actin cytoskeleton and promote glomerulosclerosis, while in B cells, B7-1/B7-2 engagement directly enhances IgG secretion through XBP-1-dependent mechanisms [PMID:15146236, PMID:35710882, PMID:19933871].\",\n  \"teleology\": [\n    {\n      \"year\": 1989,\n      \"claim\": \"The molecular identity of the T cell costimulatory ligand on activated B cells was unknown; cloning of CD80 (B7) established it as a type I transmembrane IgSF glycoprotein with V-like and C-like extracellular domains, providing the molecular basis for costimulation research.\",\n      \"evidence\": \"cDNA cloning from activated B cells with expression in COS cells, immunoprecipitation, and Northern blot\",\n      \"pmids\": [\"2794510\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Counterreceptor on T cells not yet identified\", \"Signaling mechanism downstream of CD80 engagement unknown\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"The identity of the T cell receptor for CD80 was resolved when CD28 was shown to be the direct binding partner mediating costimulatory proliferation and IL-2 production, with cross-species conservation confirmed by murine CD80 cloning.\",\n      \"evidence\": \"Fusion protein binding assay (Kd ~200 nM), CD28-transfected CHO costimulation assay, and murine B7 cloning with cross-species functional validation\",\n      \"pmids\": [\"1847722\", \"1714935\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"CTLA-4 as second receptor not yet recognized\", \"Distinction between CD80 and CD86 not yet established\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"The discovery that both CD80 and CD86 serve as shared ligands for CD28 and CTLA-4, yet differentially bias Th1/Th2 responses and EAE outcomes, established that the two B7 family members are functionally non-redundant despite binding the same counterreceptors.\",\n      \"evidence\": \"Anti-B7 blocking antibodies in EAE models, T cell differentiation assays, cytokine profiling, and stable transfectant costimulation assays\",\n      \"pmids\": [\"7534215\", \"7527824\", \"7519245\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis for differential Th1/Th2 skewing by CD80 vs CD86 unresolved\", \"Relative binding affinities for CD28 vs CTLA-4 not yet quantified\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"CD80 was shown to trigger NK cell cytotoxicity through a receptor distinct from both CD28 and CTLA-4, revealing a non-canonical immune function, while CD40 signaling through specific cytoplasmic threonine residues was identified as a transcriptional inducer of CD80 expression.\",\n      \"evidence\": \"NK cytotoxicity assays with CD28-KO NK cells and blocking antibodies; CD40 mutant transfection with flow cytometry for CD80 induction\",\n      \"pmids\": [\"8885864\", \"8816387\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the NK cell receptor for CD80 remains unknown\", \"Full CD40-to-CD80 transcriptional pathway not mapped\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Quantitative biophysical measurement resolved the binding hierarchy: CD80 binds CTLA-4 with ~10-fold higher affinity than CD28, with extremely fast kinetics at physiological temperature, establishing the thermodynamic basis for preferential CTLA-4 engagement.\",\n      \"evidence\": \"Surface plasmon resonance (BIAcore) at 37°C with soluble recombinant proteins\",\n      \"pmids\": [\"9053440\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How fast kinetics translate to signaling dynamics at the immunological synapse not determined\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"The crystal structure of CD80 revealed a novel IgV/IgC domain combination that forms rotationally symmetric homodimers, explaining how bivalent CD80 dimers can engage bivalent CTLA-4 dimers to build ordered signaling lattices; subsequent structures of CTLA-4/CD80 and CTLA-4/CD86 complexes defined the zipper-like oligomeric network architecture.\",\n      \"evidence\": \"X-ray crystallography (3.0 Å) of CD80 alone and in complex with CTLA-4, analytical ultracentrifugation confirming solution dimerization\",\n      \"pmids\": [\"10661405\", \"11279502\", \"11279501\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of CD80/CD28 complex not solved\", \"How lattice organization relates to signaling output in live cells unresolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Comprehensive biophysical comparison established that CD80 homodimerization (absent in monomeric CD86) and preferential CTLA-4 binding bias CD80 toward inhibitory signaling, while CD86 is relatively less biased toward CTLA-4 over CD28, explaining their distinct functional outputs despite shared receptors.\",\n      \"evidence\": \"Surface plasmon resonance and analytical ultracentrifugation comparing CD80/CD86 oligomerization and receptor affinities\",\n      \"pmids\": [\"12196291\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CD80 dimerization is regulated in vivo is unknown\", \"Monovalent CD28 binding geometry implications not fully explored\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"BCL6 was identified as a direct transcriptional repressor of CD80, binding its promoter to suppress NF-κB-mediated induction downstream of CD40, establishing the transcriptional logic of CD80 regulation in germinal center B cells.\",\n      \"evidence\": \"ChIP demonstrating BCL6 binding to CD80 promoter, reporter assays, BCL6-KO mouse B cell analysis\",\n      \"pmids\": [\"12860928\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Other transcription factors cooperating with or antagonizing BCL6 at the CD80 locus not characterized\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Two unexpected non-canonical functions were discovered: CD80 on podocytes regulates actin cytoskeleton and glomerular permselectivity (with B7-1 KO mice protected from nephrotic syndrome), and reverse signaling through B7-1/B7-2 on dendritic cells triggers IDO enzymatic activation, establishing CD80 as a bidirectional signaling molecule.\",\n      \"evidence\": \"B7-1 KO mouse LPS-induced nephrotic syndrome model with podocyte cytoskeleton analysis; IDO activity assays with B7-1/B7-2 crosslinking and T cell subset depletion\",\n      \"pmids\": [\"15146236\", \"15034022\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling intermediates between CD80 and actin reorganization in podocytes not yet mapped\", \"Whether IDO activation by B7 requires CTLA-4 or CD28 or both remains debated\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"B cell-intrinsic B7-1/B7-2 signaling was shown to enhance IgG secretion through XBP-1 splicing induction, demonstrating that CD80/CD86 are not merely passive ligands but deliver direct signals in B cells affecting antibody production.\",\n      \"evidence\": \"Mixed bone marrow chimeras with B7-deficient B cells, in vitro B7-2 crosslinking, XBP-1 splicing RT-PCR, and antibody ELISA\",\n      \"pmids\": [\"19933871\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether B7-1 and B7-2 activate identical or distinct B cell-intrinsic signaling cascades not resolved\", \"Downstream pathway linking B7 engagement to XBP-1 splicing not identified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"The mechanism by which CTLA-4 depletes costimulatory ligands was resolved: CTLA-4 physically captures CD80 and CD86 from APCs by trans-endocytosis and routes them for intracellular degradation, establishing ligand depletion as a cell-extrinsic suppressive mechanism complementing intrinsic signaling.\",\n      \"evidence\": \"Co-culture assays tracking fluorescently labeled ligand transfer, intracellular degradation assays, in vivo confirmation\",\n      \"pmids\": [\"21474713\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of trans-endocytosis versus signaling-based suppression in vivo not quantified\", \"Whether CD80 and CD86 are endocytosed with equal efficiency under physiological conditions unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The discovery that PD-L1 binds CD80 exclusively in cis on the same cell surface—competing with both PD-1 and CD28 binding—revealed a previously unknown checkpoint crosstalk mechanism whereby CD80 on APCs restricts PD-1-mediated coinhibition.\",\n      \"evidence\": \"NanoBiT proximity assay, cell-to-cell binding assays, competitive ELISA with purified proteins\",\n      \"pmids\": [\"29871885\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and dynamics of cis complex formation on myeloid cells in tumors not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Genetic validation using knock-in mice in which the cis PD-L1/CD80 interaction was abolished confirmed that this interaction is essential for limiting PD-1 coinhibition during tumor immunity and autoimmunity, establishing it as a physiologically critical regulatory axis.\",\n      \"evidence\": \"Knock-in mouse model deficient in cis interaction, tumor immunity assays, autoimmune response measurements\",\n      \"pmids\": [\"31000591\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether therapeutic anti-PD-L1 antibodies disrupt the cis interaction differently than anti-PD-1 antibodies needs characterization\", \"Role of cis interaction in human cancers not directly validated genetically\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Structural mapping revealed that PD-L1 binds CD80 at its dimer interface surface, distal from the CTLA-4/CD28 binding face, clarifying that CTLA-4 and CD28 do not directly compete with PD-L1 but can disrupt the cis complex by reorganizing CD80 on the cell surface.\",\n      \"evidence\": \"High-throughput FACS-based mutagenesis screen, site-directed mutagenesis of PD-L1 and B7-1, two independent cis interaction assays\",\n      \"pmids\": [\"32497097\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution structure of the PD-L1/CD80 cis complex not yet solved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The podocyte injury signaling pathway downstream of CD80 was molecularly defined: CD80 engages Hsp90ab1 at residue K69, which activates LRP5/β-catenin signaling to promote cytoskeletal reorganization and glomerulosclerosis, with β-catenin feeding back to sustain CD80 expression.\",\n      \"evidence\": \"LC-MS/MS proteomics, K69 site-directed mutagenesis of Hsp90ab1, B7-1 transgenic and adriamycin nephropathy mouse models, co-immunoprecipitation\",\n      \"pmids\": [\"35710882\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding; independent replication of the Hsp90ab1–K69 interaction needed\", \"Whether this pathway operates in human podocyte disease not confirmed\", \"Structural basis for CD80–Hsp90ab1 interaction not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the identity of the NK cell receptor that recognizes CD80 independently of CD28/CTLA-4, the atomic structure of the PD-L1/CD80 cis complex, the mechanism by which CD80 versus CD86 differentially skew Th1/Th2 responses, and whether B cell-intrinsic CD80 signaling proceeds through distinct pathways from B cell-intrinsic CD86 signaling.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"NK receptor for CD80 not identified\", \"PD-L1/CD80 cis complex structure not solved\", \"Mechanism of Th1/Th2 differential skewing by CD80 vs CD86 unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [1, 9, 13, 21]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 15, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 22, 28, 30]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 8, 9, 10, 14, 23, 26, 29]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 11, 28, 29]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [17, 22, 28, 30]}\n    ],\n    \"complexes\": [\n      \"CD80 homodimer\",\n      \"CD80/CTLA-4 zipper-like lattice\",\n      \"cis CD80/PD-L1 complex\"\n    ],\n    \"partners\": [\n      \"CD28\",\n      \"CTLA4\",\n      \"CD274\",\n      \"CD86\",\n      \"HSP90AB1\",\n      \"LRP5\",\n      \"BCL6\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}