{"gene":"CD80","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2001,"finding":"Crystal structure of the human CTLA-4/B7-1 complex resolved at 3.0 Å. CTLA-4 forms homodimers through a conserved interface, and B7-1 also forms homodimers; in the crystal lattice, bivalent CTLA-4 homodimers bridge bivalent B7-1 homodimers in a zipper-like oligomeric arrangement, providing structural basis for unusually stable inhibitory signaling complexes. The CTLA-4/B7-1 binding interface shows high shape complementarity.","method":"X-ray crystallography (3.0 Å resolution)","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure at 3.0 Å, single rigorous study with direct structural validation of dimerization and binding interface","pmids":["11279502"],"is_preprint":false},{"year":2000,"finding":"Crystal structure of the extracellular region of B7-1 (sB7-1) solved at 3 Å resolution reveals a novel combination of two Ig-like domains (one adhesion-type, one antigen-receptor-type). sB7-1 forms parallel, 2-fold rotationally symmetric homodimers in the crystal lattice and also dimerizes in solution (confirmed by analytical ultracentrifugation), suggesting avidity-enhanced binding to CTLA-4 homodimers favors formation of stable inhibitory signaling complexes.","method":"X-ray crystallography (3 Å) and analytical ultracentrifugation","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus orthogonal solution-phase biophysical confirmation of dimerization, single rigorous study","pmids":["10661405"],"is_preprint":false},{"year":1997,"finding":"Surface plasmon resonance at 37°C showed CD80 binds CTLA-4 with Kd ~0.42 µM and CD28 with Kd ~4 µM, both with very fast dissociation rate constants (koff ≥0.43 s⁻¹ for CTLA-4 and ≥1.6 s⁻¹ for CD28). These low affinities result from rapid kinetics, analogous to T cell adhesion molecules, potentially accommodating dynamic T cell–APC contacts.","method":"Surface plasmon resonance (Biacore) binding kinetics","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — quantitative in vitro binding kinetics with surface plasmon resonance, direct measurement of affinity and rate constants","pmids":["9053440"],"is_preprint":false},{"year":1994,"finding":"CD80 (B7-1) and CD86 (B7-2) bind CD28 and CTLA-4 with similar overall avidity (~2–3-fold difference), but CD80 binds the CTLA-4 mutant Y100A >200-fold better than CD86, CD80-CTLA4Ig complexes dissociate 5–8-fold more slowly, and inhibition of CD80-mediated responses requires ~100-fold lower CTLA4Ig concentrations, demonstrating distinct binding determinants and kinetics for CD80 vs. CD86.","method":"Cell binding assays, competitive inhibition assays, CTLA4Ig mutant Y100A binding, dissociation kinetics","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple in vitro binding methods with mutant proteins, directly comparing CD80 and CD86 binding to receptors","pmids":["7534620"],"is_preprint":false},{"year":2005,"finding":"Using photobleaching-based FRET (pbFRET) on live cells, B7-1 exists predominantly as dimers on the cell surface, whereas B7-2 exists as monomers. Mutations in B7-1 at the crystallographic dimer interface convert it to a predominantly monomeric species on the cell surface, validating the crystallographic dimer interface and suggesting B7-1 and B7-2 adopt different geometric organizations in the immunological synapse.","method":"Photobleaching-based FRET (pbFRET) on intact cells; site-directed mutagenesis of dimer interface","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct cell-surface FRET measurement validated by mutagenesis of the crystallographically-defined interface; two orthogonal approaches in one study","pmids":["16221763"],"is_preprint":false},{"year":2007,"finding":"B7-1 (CD80) and PD-L1 interact with affinity intermediate between B7-1:CD28 and B7-1:CTLA-4 interactions. The PD-L1:B7-1 interface overlaps with the B7-1:CTLA-4 and PD-L1:PD-1 interfaces. This interaction inhibits T cell activation and cytokine production. Genetic evidence using PD-1-deficient vs. PD-1,B7-1 double-deficient T cells and CD28,CTLA-4 double-deficient vs. triple-deficient T cells demonstrated that PD-L1 and B7-1 interact specifically to bidirectionally inhibit T cell activation.","method":"Binding affinity measurements, genetic double/triple-KO T cell functional assays, cytokine production assays","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple KO combinations plus direct binding characterization; replicated concept in multiple subsequent papers","pmids":["17629517"],"is_preprint":false},{"year":2018,"finding":"PD-L1 binds B7-1 only in cis (on the same cell surface), not in trans between two cells. Cell-to-cell binding assays showed PD-L1-transfected cells did not bind B7-1-transfected cells. By ELISA and flow cytometry, PD-L1 and B7-1 interact strongly only when PD-L1 is flexible. NanoBiT proximity assays directly demonstrated cis binding on the same cell surface. Soluble PD-1 and B7-1 competed for binding to PD-L1, and cis PD-L1:B7-1 interaction can block B7-1 binding to CD28.","method":"Cell-to-cell binding assay, ELISA with purified proteins, flow cytometry, NanoBiT proximity ligation assay","journal":"Cancer immunology research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (cell binding, ELISA, NanoBiT) in one study; replicated by Garrett-Thomson et al. 2020","pmids":["29871885"],"is_preprint":false},{"year":2020,"finding":"Mutagenesis mapping showed that the PD-L1 binding site on mB7-1 maps to the dimer interface surface of B7-1, distal from the CTLA-4/CD28 recognition surface. Although CTLA-4 and CD28 do not directly compete with PD-L1 for binding to B7-1, they can disrupt the cis PD-L1:B7-1 complex by reorganizing B7-1 on the cell surface. mPD-L1 and mB7-1 were confirmed to bind in cis using two independent approaches.","method":"Cell microarray and high-throughput FACS binding screen; site-directed mutagenesis of PD-L1 and B7-1; two independent cis-binding assays","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — interface mapping by mutagenesis plus two independent cis-binding assay methods in one study","pmids":["32497097"],"is_preprint":false},{"year":1996,"finding":"CTLA-4 substitutions in the MYPPPY domain differentially affect CD80 vs. CD86 binding: five single amino acid substitutions in the MYPPPY region had modest effects on CD80 binding but completely abrogated CD86 binding. CD80 and CD86 also showed different association/dissociation kinetics to CTLA-4 by surface plasmon resonance, demonstrating they bind similar but distinct sites on CTLA-4.","method":"Surface plasmon resonance; CTLA-4 point mutants tested by cell binding; competitive binding assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic mutagenesis combined with quantitative SPR, directly mapping the differential binding determinants","pmids":["8557978"],"is_preprint":false},{"year":1996,"finding":"A cell-type-specific enhancer approximately 3 kb upstream of the human B7.1 transcription start site was identified. This 183-bp region is both cell-type specific and inducible by LPS and dibutyryl cAMP. Site-directed mutagenesis revealed an NF-κB consensus sequence as a functionally critical cis-element; NF-κB family members in B7.1-positive B cells bind this element in vivo, linking NF-κB signaling to B7.1 transcriptional induction.","method":"DNase I hypersensitivity mapping, luciferase reporter assays, deletional and site-directed mutagenesis, EMSA/gel shift for NF-κB binding","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple mutagenesis and reporter assays identifying the functional NF-κB element; single lab but rigorous multi-method approach","pmids":["8642282"],"is_preprint":false},{"year":2003,"finding":"BCL6 directly represses CD80 (B7-1) expression in germinal center B cells. CD40 signaling induces CD80 transcription via NF-κB, and BCL6 prevents this by binding the CD80 promoter region in vivo and suppressing NF-κB-mediated transcriptional activation. BCL6-deficient mice show increased CD80 expression in B cells, and CD80 and BCL6 expression are mutually exclusive in B cells.","method":"ChIP (BCL6 binding to CD80 promoter in vivo), luciferase reporter assays, BCL6 knockout mice, flow cytometry","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP demonstrating direct promoter binding plus genetic KO mouse validation plus reporter assay, multiple orthogonal methods","pmids":["12860928"],"is_preprint":false},{"year":2004,"finding":"Ligation of B7-1/B7-2 on dendritic cells by CTLA-4/CD28 on T cells is obligately required to trigger functional IDO activity. IDO protein is constitutively expressed but remains inactive unless B7-1/B7-2 are engaged; disruption of this interaction keeps IDO inactive and prevents DC-mediated T cell suppression. Direct antibody-mediated cross-linking of B7-1/B7-2 fully restores IDO activation. Only CD4+ T cells (not CD8+) can trigger IDO induction.","method":"IDO enzymatic activity assay in DCs; T cell proliferation inhibition assay; anti-B7 blocking antibodies; B7 cross-linking antibodies","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assay with multiple blocking and cross-linking conditions; single lab, human monocyte-derived DCs in vitro","pmids":["15034022"],"is_preprint":false},{"year":2004,"finding":"B7-1 (CD80) is induced in podocytes by LPS (via TLR4 signaling) and in multiple experimental and genetic kidney disease models. In vivo, LPS rapidly upregulates podocyte B7-1 causing nephrotic-range proteinuria in WT and SCID mice. B7-1-knockout mice are protected from LPS-induced nephrotic syndrome. In cultured podocytes, B7-1 activation reorganizes actin cytoskeleton and disrupts slit diaphragm proteins, revealing a non-immune cell-intrinsic function of B7-1 in modifying glomerular permselectivity.","method":"B7-1 knockout mice (in vivo LPS model); cultured podocyte B7-1 activation (in vitro actin/slit diaphragm assays); LPS challenge in SCID mice","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO in vivo plus in vitro mechanistic studies; single lab; some findings contested by later papers","pmids":["15146236"],"is_preprint":false},{"year":2006,"finding":"MCMV protein m138 (fcr-1) targets B7-1 in the secretory pathway and reroutes it to LAMP-1+ lysosomal compartments, causing rapid disappearance of B7-1 from the DC cell surface. m138-expressing DCs have impaired ability to activate CD8+ T cells, identifying m138 as the first viral protein that specifically targets B7-1 for degradation.","method":"Viral gene identification by mutant MCMV; biochemical fractionation; immunocytochemistry; CD8+ T cell activation assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — viral gene identified by genetic approach, biochemical and imaging evidence for lysosomal rerouting, functional CD8 T cell assay; single lab","pmids":["17142739"],"is_preprint":false},{"year":2001,"finding":"Naive CD4+ T cells acquire CD80 (B7-1) protein from syngeneic APCs after activation via a CD28-dependent mechanism (not endogenous synthesis, as confirmed by cycloheximide treatment and absence of CD80 mRNA in acquiring T cells). T cells that acquire CD80 can themselves act as APCs. Memory T cells that acquire CD80 undergo apoptosis when given increased TCR signal 1, revealing an immunoregulatory function.","method":"CD80/CD86 knockout APC donors; cycloheximide treatment; RT-PCR for CD80 mRNA; CD28-KO mice (negative control); confocal microscopy; functional APC assay; apoptosis assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple controls (KO APCs, cycloheximide, CD28-KO) to establish CD28-dependent protein transfer; single lab","pmids":["11160311"],"is_preprint":false},{"year":1998,"finding":"B7-1 engagement of CTLA-4 inhibits T cell activation in the absence of CD28, demonstrating that CTLA-4 can antagonize TCR-mediated signaling independently of competing with CD28. TCR-transgenic/RAG2-deficient/CD28-knockout T cells responded to B7-1-expressing stimulator cells with inhibition rather than costimulation; this inhibition was reversed by anti-B7-1 or anti-CTLA-4 mAb.","method":"TCR transgenic/RAG2-deficient/CD28-knockout mice; tumor stimulator cells with/without B7-1; anti-B7-1 and anti-CTLA-4 blocking antibodies; cytokine and proliferation assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic CD28-deficiency plus antibody rescue experiments directly demonstrate CTLA-4-mediated inhibition independent of CD28; rigorous epistatic design","pmids":["9653097"],"is_preprint":false},{"year":2011,"finding":"The PD-L1:B7-1 interaction inhibits diabetogenic effector T cell responses in vivo. Anti-PD-L1 mAb 10F.2H11, which selectively blocks only PD-L1:B7-1 (not PD-L1:PD-1), accelerated diabetes in older NOD mice and in adoptive transfer with effector (but not prediabetic) T cells. Dual-blocker anti-PD-L1 mAb was effective in all settings. PDL1 blockade failed to accelerate rejection in B7.1-deficient recipients, confirming that PDL1 inhibition depends on its interaction with B7-1 in vivo.","method":"NOD mouse diabetes model; selective blocking anti-PD-L1 mAbs; B7.1-deficient recipients; adoptive T cell transfer; diabetes incidence readout","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic and pharmacological epistasis across multiple complementary models; two independent anti-PD-L1 mAbs with different specificities tested in parallel","pmids":["21697456"],"is_preprint":false},{"year":2011,"finding":"In a heart transplant model, PDL1 blockade accelerated allograft rejection in B7.2-deficient but not B7.1-deficient recipients, demonstrating that PDL1:B7-1 interaction is required for PDL1-mediated inhibition of alloimmune responses in vivo. In vitro, blockade of PDL1 on dendritic cells (interacting with T cell B7-1) increased alloreactive CD4+ T cell IFN-γ production, while blocking DC B7-1 interaction with T cell PDL1 did not, indicating a directional dominance of PDL1(DC):B7-1(T cell) interaction.","method":"bm12→B6 heart transplant model; B7.1-KO and B7.2-KO recipients; anti-PD-L1 mAbs with distinct blocking specificities; in vitro blocking assay with DCs and T cells; IFN-γ ELISA","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic KO epistasis plus directional in vitro blocking experiments; two complementary papers published simultaneously","pmids":["21697455"],"is_preprint":false},{"year":2003,"finding":"B7-1 and B7-2 participate in negative selection (clonal deletion) of thymocytes. Following endogenous superantigen-driven deletion in B7-1- and/or B7-2-deficient mice, deletion was impaired. Either CD28 or an additional undefined co-receptor can mediate B7-dependent deletion signals. CTLA-4 delivers inhibitory signals opposing CD28 during thymic selection.","method":"B7-1/B7-2 single and double KO mice; CD28-KO and CD28/CTLA-4 double-KO mice; endogenous superantigen deletion model (thymocyte flow cytometry)","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic KO combinations tested in vivo; single lab; endogenous superantigen model","pmids":["12759417"],"is_preprint":false},{"year":2009,"finding":"Direct signaling through B7-1/B7-2 on B cells (reverse signaling) enhances IgG secretion. Mixed bone marrow chimeric mice lacking B7-1/2 only on B cells had reduced local IgG responses after influenza infection without affecting germinal center formation or CD4+ T cell activation. In vitro, B7-2 engagement on class-switched B cells dramatically enhanced IgG (but not IgM) secretion and induced XBP-1/spliced XBP-1 expression, indicating increased protein synthesis/secretory pathway activation.","method":"Mixed bone marrow irradiation chimeras (B7-1/2-deficient B cells); in vitro B7-2 engagement on class-switched B cells; IgG/IgM ELISA; XBP-1 mRNA splicing assay; influenza infection model","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo chimera plus in vitro mechanistic follow-up with signaling marker; single lab, two complementary experimental approaches","pmids":["19933871"],"is_preprint":false},{"year":1995,"finding":"B7-1 and B7-2 costimulatory molecules differentially activate Th1 and Th2 developmental pathways. Anti-B7-1 treatment in EAE reduced disease incidence and shifted T cells toward Th2 (anti-IL-4 reversed this protection), while anti-B7-2 increased disease severity. Neither antibody affected overall T cell induction but altered cytokine profiles.","method":"In vivo EAE model; anti-B7-1 and anti-B7-2 antibody blockade; Th1/Th2 cytokine profiling; adoptive transfer; anti-IL-4 co-treatment","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo blockade with functional cytokine readouts and adoptive transfer; single lab; later contested by other groups","pmids":["7534215"],"is_preprint":false},{"year":1994,"finding":"A cell-type-specific enhancer in the human B7.1 gene is regulated by NF-κB. The 183-bp enhancer ~3 kb upstream of the transcription start site is active in B7.1-positive B cells, responsive to LPS and dibutyryl cAMP, and contains a functional NF-κB consensus element whose mutation abrogates activity. NF-κB family members bind this element in B7.1-positive B cells.","method":"DNase I hypersensitive site mapping; deletion and site-directed mutagenesis of reporter constructs; gel shift/EMSA assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1 / Moderate — promoter mutagenesis plus protein-DNA binding assays; single lab but multiple orthogonal methods establishing NF-κB as transcriptional activator of CD80","pmids":["8642282"],"is_preprint":false},{"year":1994,"finding":"The extracellular region of B7-1 contains two IgSF domains: an N-terminal V-like domain (whose fold is distinct from classical IgSF V-sets) and a C-like domain compatible with IgSF C-set structures and best recognized by β2-microglobulin. Conserved residues in B7 molecules cluster on the surface of the C-domain, potentially involved in interactions with the V-like domain or other molecules.","method":"Inverse folding methodology (computational structure prediction validated against known structures); sequence conservation analysis mapped onto β2m crystal structure","journal":"Protein science","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational structural prediction only, no experimental structure determination; predates the actual crystal structure","pmids":["7535614"],"is_preprint":false},{"year":1996,"finding":"Insertion of two residues between the two Ig domains of CD80 decreased affinity for CTLA-4, while a similar insertion in CD86 had no effect, demonstrating that the inter-domain linker of CD80 contributes to CTLA-4 binding. Additionally, the V-domain of CD86 (but not CD80) is sufficient for CTLA-4 binding, revealing a fundamental structural difference between the two ligands in their receptor recognition mechanism.","method":"CD80/CD86 mutant domain-swap and insertion constructs; cell-binding assays with CTLA-4","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mutagenesis with direct binding readout; single lab; establishes mechanistic distinction between CD80 and CD86 receptor engagement","pmids":["8609386"],"is_preprint":false}],"current_model":"CD80 (B7-1) is a dimeric (confirmed by crystal structure and cell-surface FRET) IgSF glycoprotein on APCs that binds CD28 (Kd ~4 µM) and CTLA-4 (Kd ~0.42 µM) with rapid kinetics via overlapping but distinct interfaces, providing costimulatory signals through CD28 and inhibitory signals through CTLA-4 (which can suppress T cells even in the absence of CD28); it also engages PD-L1 exclusively in cis on the same cell surface at the B7-1 dimer interface—blocking both B7-1:CD28 and PD-L1:PD-1 axes—and its transcription is driven by NF-κB binding to a cell-type-specific upstream enhancer that is repressed in germinal center B cells by BCL6; in non-immune podocytes, B7-1 induction disrupts the actin cytoskeleton and slit diaphragm proteins, contributing to proteinuria."},"narrative":{"mechanistic_narrative":"CD80 (B7-1) is a cell-surface immunoglobulin-superfamily glycoprotein on antigen-presenting cells that controls T cell activation by engaging the costimulatory receptor CD28 and the inhibitory receptor CTLA-4 [PMID:9053440, PMID:9653097]. Its extracellular region comprises two Ig-like domains and assembles into 2-fold symmetric homodimers that persist both in crystals and in solution, and live-cell FRET confirms that B7-1 exists predominantly as dimers at the cell surface—distinct from the monomeric B7-2 [PMID:10661405, PMID:16221763]. CD80 binds CTLA-4 (Kd ~0.42 µM) more avidly than CD28 (Kd ~4 µM), with very fast dissociation kinetics, and bivalent CTLA-4 dimers bridge bivalent B7-1 dimers into a zipper-like oligomeric lattice that provides a structural basis for stable inhibitory signaling complexes [PMID:11279502, PMID:9053440]. CD80 and CD86 engage CTLA-4 through similar but distinct determinants, and the CD80 inter-domain linker specifically contributes to CTLA-4 binding [PMID:7534620, PMID:8557978, PMID:8609386]. CTLA-4 ligation of B7-1 inhibits T cell responses even in the complete absence of CD28, establishing an intrinsic inhibitory function independent of CD28 competition [PMID:9653097]. Beyond these receptors, CD80 binds PD-L1 with intermediate affinity exclusively in cis on the same cell surface, through an interface mapping to the B7-1 dimer surface that overlaps the CTLA-4/PD-1 contacts; this cis interaction bidirectionally inhibits T cell activation and is required in vivo for PD-L1-mediated suppression of effector and alloreactive T cells [PMID:17629517, PMID:29871885, PMID:32497097, PMID:21697456, PMID:21697455]. CD80 transcription is driven by NF-κB binding to a cell-type-specific enhancer ~3 kb upstream of the start site and is directly repressed in germinal-center B cells by BCL6 binding the promoter [PMID:8642282, PMID:12860928]. CD80 also functions outside the immune synapse: it is induced in kidney podocytes via TLR4 signaling, where its activation reorganizes the actin cytoskeleton and disrupts slit-diaphragm proteins to produce proteinuria [PMID:15146236].","teleology":[{"year":1994,"claim":"Establishing how CD80 transcription is controlled defined the cell-type-specific, signal-inducible logic of costimulator expression.","evidence":"DNase I hypersensitivity mapping, reporter assays, and EMSA identifying an upstream NF-κB-dependent enhancer in B7.1-positive B cells","pmids":["8642282"],"confidence":"High","gaps":["Does not identify which NF-κB subunits drive the response in vivo","Upstream receptor signals feeding the enhancer not fully resolved"]},{"year":1994,"claim":"Computational modeling first predicted CD80's two-Ig-domain architecture before any experimental structure existed.","evidence":"Inverse-folding prediction and conservation mapping onto β2-microglobulin","pmids":["7535614"],"confidence":"Low","gaps":["Prediction only; superseded by later crystal structures","No experimental validation of domain folds at the time"]},{"year":1994,"claim":"Comparing CD80 and CD86 binding to CD28/CTLA-4 showed the two ligands have distinct binding determinants and kinetics despite similar overall avidity, implying non-redundant roles.","evidence":"Cell-binding, competitive inhibition, and dissociation-kinetics assays with the CTLA-4 Y100A mutant","pmids":["7534620"],"confidence":"High","gaps":["Structural basis of the differential determinants not resolved here","Functional consequence of slower CD80 dissociation in vivo unclear"]},{"year":1995,"claim":"Antibody blockade tested whether CD80 and CD86 differentially shape effector T cell fate, linking costimulator choice to Th1/Th2 polarization.","evidence":"In vivo EAE model with anti-B7-1/anti-B7-2 blockade, cytokine profiling, and anti-IL-4 co-treatment","pmids":["7534215"],"confidence":"Medium","gaps":["Later contested by other groups","Mechanism by which B7-1 vs B7-2 biases cytokine output not defined"]},{"year":1996,"claim":"Mutagenesis dissected which CTLA-4 and CD80 residues control binding, mapping the differential recognition between the two B7 ligands.","evidence":"CTLA-4 MYPPPY point mutants and CD80/CD86 domain-swap/insertion constructs assayed by SPR and cell binding","pmids":["8557978","8609386"],"confidence":"Medium","gaps":["Interface positions inferred from binding loss without co-structure","Quantitative kinetic effects of individual residues incomplete"]},{"year":1997,"claim":"Quantifying CD80 affinity and kinetics for both receptors showed low-affinity, fast-off interactions suited to dynamic T cell–APC contacts.","evidence":"Surface plasmon resonance at 37°C measuring Kd and koff for CTLA-4 and CD28","pmids":["9053440"],"confidence":"High","gaps":["Does not address avidity effects of surface dimerization","Kinetics measured with soluble monomeric proteins"]},{"year":1998,"claim":"Genetic CD28 deletion plus antibody rescue established that CTLA-4 ligation by B7-1 inhibits T cells intrinsically, not merely by outcompeting CD28.","evidence":"TCR-transgenic/RAG2-deficient/CD28-knockout T cells stimulated with B7-1+ cells, reversed by anti-B7-1/anti-CTLA-4","pmids":["9653097"],"confidence":"High","gaps":["Downstream CTLA-4 signaling effectors not defined","Physiological setting where CD28-independent inhibition dominates unclear"]},{"year":2000,"claim":"Solving the B7-1 ectodomain structure revealed it forms symmetric homodimers in crystal and solution, providing a physical basis for avidity-enhanced CTLA-4 engagement.","evidence":"X-ray crystallography at 3 Å and analytical ultracentrifugation","pmids":["10661405"],"confidence":"High","gaps":["Dimer relevance on intact cell surface not yet shown","Stoichiometry of receptor complexes inferred, not directly observed"]},{"year":2001,"claim":"The CTLA-4/B7-1 co-crystal showed bivalent dimers bridging into a zipper-like lattice, explaining how stable inhibitory signaling complexes assemble.","evidence":"X-ray crystallography of the human CTLA-4/B7-1 complex at 3.0 Å","pmids":["11279502"],"confidence":"High","gaps":["Lattice oligomerization not confirmed at native synapse density","Does not address CD28 complex geometry"]},{"year":2001,"claim":"Tracking CD80 protein transfer revealed that T cells acquire CD80 from APCs via a CD28-dependent route, conferring an immunoregulatory APC-like and pro-apoptotic phenotype.","evidence":"KO APC donors, cycloheximide, RT-PCR, CD28-KO controls, confocal imaging, and apoptosis assays","pmids":["11160311"],"confidence":"Medium","gaps":["Molecular mechanism of trogocytosis not defined","In vivo prevalence and consequence of CD80 acquisition unclear"]},{"year":2003,"claim":"ChIP and KO mice identified BCL6 as a direct repressor of CD80 in germinal-center B cells, defining how NF-κB-driven CD80 induction is silenced during the GC reaction.","evidence":"ChIP of BCL6 at the CD80 promoter, reporter assays, and BCL6-deficient mice","pmids":["12860928"],"confidence":"High","gaps":["Co-repressor machinery recruited by BCL6 not specified","Reversal of repression upon GC exit not mapped"]},{"year":2003,"claim":"Genetic dissection placed B7-1/B7-2 in thymic negative selection, showing CD28 and an additional co-receptor mediate B7-dependent clonal deletion.","evidence":"B7-1/B7-2 and CD28/CTLA-4 KO mice in an endogenous superantigen deletion model","pmids":["12759417"],"confidence":"Medium","gaps":["Identity of the additional B7-binding co-receptor unknown","Quantitative contribution of B7-1 vs B7-2 not separated"]},{"year":2004,"claim":"Functional assays showed B7-1/B7-2 ligation by T cell CTLA-4/CD28 is obligatory to activate constitutively expressed IDO in DCs, revealing reverse signaling that drives tolerance.","evidence":"IDO enzymatic assays with anti-B7 blocking and cross-linking antibodies in human DCs","pmids":["15034022"],"confidence":"Medium","gaps":["Intracellular signaling pathway from B7 to IDO not defined","Single lab, in vitro human DC system"]},{"year":2004,"claim":"KO mice and podocyte cultures uncovered a non-immune, cell-intrinsic CD80 function in the kidney, where TLR4-driven induction disrupts the slit diaphragm and causes proteinuria.","evidence":"B7-1-knockout LPS nephrosis model, SCID mice, and cultured podocyte actin/slit-diaphragm assays","pmids":["15146236"],"confidence":"Medium","gaps":["Some findings contested by later studies","Downstream effector linking B7-1 to cytoskeletal reorganization unclear"]},{"year":2005,"claim":"Live-cell FRET validated the crystallographic dimer interface, confirming B7-1 is dimeric (and B7-2 monomeric) on intact cells, with implications for synapse geometry.","evidence":"Photobleaching-based FRET plus dimer-interface mutagenesis on intact cells","pmids":["16221763"],"confidence":"High","gaps":["Functional consequence of distinct B7-1/B7-2 geometry in synapse not directly tested","Dimer dynamics during receptor engagement not measured"]},{"year":2006,"claim":"Identifying MCMV m138 as a B7-1-degrading viral protein demonstrated that pathogens target CD80 to subvert CD8 T cell priming.","evidence":"Mutant MCMV gene identification, biochemical fractionation, imaging of lysosomal rerouting, and CD8 T cell activation assays","pmids":["17142739"],"confidence":"Medium","gaps":["Direct m138–B7-1 binding interface not mapped","Single lab; in vivo immune-evasion contribution not quantified"]},{"year":2007,"claim":"Discovery of the PD-L1:B7-1 interaction added a third receptor axis, with genetic epistasis showing this pair bidirectionally inhibits T cells.","evidence":"Binding affinity measurements and functional assays with PD-1/B7-1 and CD28/CTLA-4 multi-KO T cells","pmids":["17629517"],"confidence":"High","gaps":["Cis vs trans orientation not resolved at this stage","Structural interface not directly determined"]},{"year":2009,"claim":"B cell chimeras and in vitro engagement showed B7-1/B7-2 reverse signaling enhances IgG secretion via XBP-1 activation, a B-cell-intrinsic role independent of GC formation.","evidence":"Mixed bone marrow chimeras, in vitro B7-2 engagement, IgG/IgM ELISA, and XBP-1 splicing assay","pmids":["19933871"],"confidence":"Medium","gaps":["Signaling cascade from B7 cytoplasmic tail to XBP-1 not defined","Relative roles of B7-1 vs B7-2 not separated"]},{"year":2011,"claim":"In vivo blockade with selective anti-PD-L1 antibodies and B7-1-deficient recipients established that the PD-L1:B7-1 axis is required for PD-L1-mediated suppression of effector and alloreactive T cells.","evidence":"NOD diabetes and bm12→B6 heart transplant models with selective vs dual anti-PD-L1 mAbs and B7.1-/B7.2-KO recipients","pmids":["21697456","21697455"],"confidence":"High","gaps":["Directionality (DC vs T cell) mechanism not fully resolved","Did not yet establish whether the interaction was cis or trans"]},{"year":2018,"claim":"Multiple orthogonal binding assays established that PD-L1 binds B7-1 only in cis on the same cell, redefining the geometry of the interaction and explaining how cis PD-L1 sequesters B7-1 from CD28.","evidence":"Cell-to-cell binding, ELISA, flow cytometry, and NanoBiT proximity assays","pmids":["29871885"],"confidence":"High","gaps":["Precise interface residues not mapped in this study","Quantitative impact on synaptic CD28 engagement not measured"]},{"year":2020,"claim":"Interface mapping localized the PD-L1 binding site to the B7-1 dimer surface, distal from CTLA-4/CD28 sites, and showed CTLA-4/CD28 can disrupt cis PD-L1:B7-1 by reorganizing B7-1.","evidence":"Cell-microarray FACS binding screen and site-directed mutagenesis of PD-L1 and B7-1 with two independent cis-binding assays","pmids":["32497097"],"confidence":"High","gaps":["Co-structure of the cis complex not determined","Dynamics of B7-1 reorganization at the synapse not directly imaged"]},{"year":null,"claim":"How the multiple CD80 receptor axes (CD28, CTLA-4, cis PD-L1) are spatially partitioned and dynamically balanced within a single immunological synapse, and what intracellular reverse-signaling effectors couple CD80 ligation to outcomes in DCs and B cells, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated structural/imaging model of competing CD80 complexes at the native synapse","Cytoplasmic signaling machinery for B7-1 reverse signaling unidentified","Effector linking podocyte B7-1 to cytoskeletal disruption undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[2,5,15]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[11,19]},{"term_id":"GO:0005198","term_label":"structural molecule 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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 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glycosyl-phosphatidylinositol-B7-1 into tumor cell membranes: a novel approach to tumor immunotherapy.","date":"1999","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/10344754","citation_count":60,"is_preprint":false},{"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},{"pmid":"9743331","id":"PMC_9743331","title":"The role of B7-1 and B7-2 costimulation for the generation of CTL responses in vivo.","date":"1998","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/9743331","citation_count":58,"is_preprint":false},{"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 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Renal physiology","url":"https://pubmed.ncbi.nlm.nih.gov/26697986","citation_count":44,"is_preprint":false},{"pmid":"11439026","id":"PMC_11439026","title":"Building novel binding ligands to B7.1 and B7.2 based on human antibody single variable light chain domains.","date":"2001","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/11439026","citation_count":44,"is_preprint":false},{"pmid":"11342441","id":"PMC_11342441","title":"Targeting of a B7-1 (CD80) immunoglobulin G fusion protein to acute myeloid leukemia blasts increases their costimulatory activity for autologous remission T cells.","date":"2001","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/11342441","citation_count":44,"is_preprint":false},{"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},{"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},{"pmid":"9485191","id":"PMC_9485191","title":"Cryptococcus neoformans differently regulates B7-1 (CD80) and B7-2 (CD86) expression on human monocytes.","date":"1998","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/9485191","citation_count":40,"is_preprint":false},{"pmid":"9719501","id":"PMC_9719501","title":"Expression of costimulatory molecules, B7-1 and B7-2 on human gastric carcinoma.","date":"1998","source":"Journal of cancer research and clinical 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medicine","url":"https://pubmed.ncbi.nlm.nih.gov/11956287","citation_count":37,"is_preprint":false},{"pmid":"10975864","id":"PMC_10975864","title":"Autoantibody responses and pathology regulated by B7-1 and B7-2 costimulation in MRL/lpr lupus.","date":"2000","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/10975864","citation_count":36,"is_preprint":false},{"pmid":"11175312","id":"PMC_11175312","title":"Expression of B7.1 (CD80) in a renal cell carcinoma line allows expansion of tumor-associated cytotoxic T lymphocytes in the presence of an alloresponse.","date":"2000","source":"Gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/11175312","citation_count":36,"is_preprint":false},{"pmid":"10438973","id":"PMC_10438973","title":"B7.2 (CD86) but not B7.1 (CD80) costimulation is required for the induction of low dose oral tolerance.","date":"1999","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/10438973","citation_count":33,"is_preprint":false},{"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},{"pmid":"9652756","id":"PMC_9652756","title":"Immune stimulatory potential of B7.1 and B7.2 retrovirally transduced melanoma cells: suppression by interleukin 10.","date":"1998","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/9652756","citation_count":32,"is_preprint":false},{"pmid":"9148019","id":"PMC_9148019","title":"Anomalous expression of costimulatory molecules B7-1, B7-2 and CD28 in primary biliary cirrhosis.","date":"1997","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/9148019","citation_count":32,"is_preprint":false},{"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},{"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},{"pmid":"12372936","id":"PMC_12372936","title":"B7-1 (CD80) and B7-2 (CD 86) expression in human tubular epithelial cells in vivo and in vitro.","date":"2002","source":"Nephron","url":"https://pubmed.ncbi.nlm.nih.gov/12372936","citation_count":31,"is_preprint":false},{"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},{"pmid":"8923872","id":"PMC_8923872","title":"Lack of B7-1/BB1 and B7-2/B70 expression on thyrocytes of patients with Graves' disease. Delivery of costimulatory signals from bystander professional antigen-presenting cells.","date":"1996","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/8923872","citation_count":30,"is_preprint":false},{"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":29,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50556,"output_tokens":6909,"usd":0.127652,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15918,"output_tokens":5989,"usd":0.114657,"stage2_stop_reason":"end_turn"},"total_usd":0.242309,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"Crystal structure of the human CTLA-4/B7-1 complex resolved at 3.0 Å. CTLA-4 forms homodimers through a conserved interface, and B7-1 also forms homodimers; in the crystal lattice, bivalent CTLA-4 homodimers bridge bivalent B7-1 homodimers in a zipper-like oligomeric arrangement, providing structural basis for unusually stable inhibitory signaling complexes. The CTLA-4/B7-1 binding interface shows high shape complementarity.\",\n      \"method\": \"X-ray crystallography (3.0 Å resolution)\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure at 3.0 Å, single rigorous study with direct structural validation of dimerization and binding interface\",\n      \"pmids\": [\"11279502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Crystal structure of the extracellular region of B7-1 (sB7-1) solved at 3 Å resolution reveals a novel combination of two Ig-like domains (one adhesion-type, one antigen-receptor-type). sB7-1 forms parallel, 2-fold rotationally symmetric homodimers in the crystal lattice and also dimerizes in solution (confirmed by analytical ultracentrifugation), suggesting avidity-enhanced binding to CTLA-4 homodimers favors formation of stable inhibitory signaling complexes.\",\n      \"method\": \"X-ray crystallography (3 Å) and analytical ultracentrifugation\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus orthogonal solution-phase biophysical confirmation of dimerization, single rigorous study\",\n      \"pmids\": [\"10661405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Surface plasmon resonance at 37°C showed CD80 binds CTLA-4 with Kd ~0.42 µM and CD28 with Kd ~4 µM, both with very fast dissociation rate constants (koff ≥0.43 s⁻¹ for CTLA-4 and ≥1.6 s⁻¹ for CD28). These low affinities result from rapid kinetics, analogous to T cell adhesion molecules, potentially accommodating dynamic T cell–APC contacts.\",\n      \"method\": \"Surface plasmon resonance (Biacore) binding kinetics\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — quantitative in vitro binding kinetics with surface plasmon resonance, direct measurement of affinity and rate constants\",\n      \"pmids\": [\"9053440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"CD80 (B7-1) and CD86 (B7-2) bind CD28 and CTLA-4 with similar overall avidity (~2–3-fold difference), but CD80 binds the CTLA-4 mutant Y100A >200-fold better than CD86, CD80-CTLA4Ig complexes dissociate 5–8-fold more slowly, and inhibition of CD80-mediated responses requires ~100-fold lower CTLA4Ig concentrations, demonstrating distinct binding determinants and kinetics for CD80 vs. CD86.\",\n      \"method\": \"Cell binding assays, competitive inhibition assays, CTLA4Ig mutant Y100A binding, dissociation kinetics\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple in vitro binding methods with mutant proteins, directly comparing CD80 and CD86 binding to receptors\",\n      \"pmids\": [\"7534620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Using photobleaching-based FRET (pbFRET) on live cells, B7-1 exists predominantly as dimers on the cell surface, whereas B7-2 exists as monomers. Mutations in B7-1 at the crystallographic dimer interface convert it to a predominantly monomeric species on the cell surface, validating the crystallographic dimer interface and suggesting B7-1 and B7-2 adopt different geometric organizations in the immunological synapse.\",\n      \"method\": \"Photobleaching-based FRET (pbFRET) on intact cells; site-directed mutagenesis of dimer interface\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct cell-surface FRET measurement validated by mutagenesis of the crystallographically-defined interface; two orthogonal approaches in one study\",\n      \"pmids\": [\"16221763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"B7-1 (CD80) and PD-L1 interact with affinity intermediate between B7-1:CD28 and B7-1:CTLA-4 interactions. The PD-L1:B7-1 interface overlaps with the B7-1:CTLA-4 and PD-L1:PD-1 interfaces. This interaction inhibits T cell activation and cytokine production. Genetic evidence using PD-1-deficient vs. PD-1,B7-1 double-deficient T cells and CD28,CTLA-4 double-deficient vs. triple-deficient T cells demonstrated that PD-L1 and B7-1 interact specifically to bidirectionally inhibit T cell activation.\",\n      \"method\": \"Binding affinity measurements, genetic double/triple-KO T cell functional assays, cytokine production assays\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple KO combinations plus direct binding characterization; replicated concept in multiple subsequent papers\",\n      \"pmids\": [\"17629517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PD-L1 binds B7-1 only in cis (on the same cell surface), not in trans between two cells. Cell-to-cell binding assays showed PD-L1-transfected cells did not bind B7-1-transfected cells. By ELISA and flow cytometry, PD-L1 and B7-1 interact strongly only when PD-L1 is flexible. NanoBiT proximity assays directly demonstrated cis binding on the same cell surface. Soluble PD-1 and B7-1 competed for binding to PD-L1, and cis PD-L1:B7-1 interaction can block B7-1 binding to CD28.\",\n      \"method\": \"Cell-to-cell binding assay, ELISA with purified proteins, flow cytometry, NanoBiT proximity ligation assay\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (cell binding, ELISA, NanoBiT) in one study; replicated by Garrett-Thomson et al. 2020\",\n      \"pmids\": [\"29871885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Mutagenesis mapping showed that the PD-L1 binding site on mB7-1 maps to the dimer interface surface of B7-1, distal from the CTLA-4/CD28 recognition surface. Although CTLA-4 and CD28 do not directly compete with PD-L1 for binding to B7-1, they can disrupt the cis PD-L1:B7-1 complex by reorganizing B7-1 on the cell surface. mPD-L1 and mB7-1 were confirmed to bind in cis using two independent approaches.\",\n      \"method\": \"Cell microarray and high-throughput FACS binding screen; site-directed mutagenesis of PD-L1 and B7-1; two independent cis-binding assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — interface mapping by mutagenesis plus two independent cis-binding assay methods in one study\",\n      \"pmids\": [\"32497097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"CTLA-4 substitutions in the MYPPPY domain differentially affect CD80 vs. CD86 binding: five single amino acid substitutions in the MYPPPY region had modest effects on CD80 binding but completely abrogated CD86 binding. CD80 and CD86 also showed different association/dissociation kinetics to CTLA-4 by surface plasmon resonance, demonstrating they bind similar but distinct sites on CTLA-4.\",\n      \"method\": \"Surface plasmon resonance; CTLA-4 point mutants tested by cell binding; competitive binding assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic mutagenesis combined with quantitative SPR, directly mapping the differential binding determinants\",\n      \"pmids\": [\"8557978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"A cell-type-specific enhancer approximately 3 kb upstream of the human B7.1 transcription start site was identified. This 183-bp region is both cell-type specific and inducible by LPS and dibutyryl cAMP. Site-directed mutagenesis revealed an NF-κB consensus sequence as a functionally critical cis-element; NF-κB family members in B7.1-positive B cells bind this element in vivo, linking NF-κB signaling to B7.1 transcriptional induction.\",\n      \"method\": \"DNase I hypersensitivity mapping, luciferase reporter assays, deletional and site-directed mutagenesis, EMSA/gel shift for NF-κB binding\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple mutagenesis and reporter assays identifying the functional NF-κB element; single lab but rigorous multi-method approach\",\n      \"pmids\": [\"8642282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"BCL6 directly represses CD80 (B7-1) expression in germinal center B cells. CD40 signaling induces CD80 transcription via NF-κB, and BCL6 prevents this by binding the CD80 promoter region in vivo and suppressing NF-κB-mediated transcriptional activation. BCL6-deficient mice show increased CD80 expression in B cells, and CD80 and BCL6 expression are mutually exclusive in B cells.\",\n      \"method\": \"ChIP (BCL6 binding to CD80 promoter in vivo), luciferase reporter assays, BCL6 knockout mice, flow cytometry\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP demonstrating direct promoter binding plus genetic KO mouse validation plus reporter assay, multiple orthogonal methods\",\n      \"pmids\": [\"12860928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Ligation of B7-1/B7-2 on dendritic cells by CTLA-4/CD28 on T cells is obligately required to trigger functional IDO activity. IDO protein is constitutively expressed but remains inactive unless B7-1/B7-2 are engaged; disruption of this interaction keeps IDO inactive and prevents DC-mediated T cell suppression. Direct antibody-mediated cross-linking of B7-1/B7-2 fully restores IDO activation. Only CD4+ T cells (not CD8+) can trigger IDO induction.\",\n      \"method\": \"IDO enzymatic activity assay in DCs; T cell proliferation inhibition assay; anti-B7 blocking antibodies; B7 cross-linking antibodies\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assay with multiple blocking and cross-linking conditions; single lab, human monocyte-derived DCs in vitro\",\n      \"pmids\": [\"15034022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"B7-1 (CD80) is induced in podocytes by LPS (via TLR4 signaling) and in multiple experimental and genetic kidney disease models. In vivo, LPS rapidly upregulates podocyte B7-1 causing nephrotic-range proteinuria in WT and SCID mice. B7-1-knockout mice are protected from LPS-induced nephrotic syndrome. In cultured podocytes, B7-1 activation reorganizes actin cytoskeleton and disrupts slit diaphragm proteins, revealing a non-immune cell-intrinsic function of B7-1 in modifying glomerular permselectivity.\",\n      \"method\": \"B7-1 knockout mice (in vivo LPS model); cultured podocyte B7-1 activation (in vitro actin/slit diaphragm assays); LPS challenge in SCID mice\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO in vivo plus in vitro mechanistic studies; single lab; some findings contested by later papers\",\n      \"pmids\": [\"15146236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"MCMV protein m138 (fcr-1) targets B7-1 in the secretory pathway and reroutes it to LAMP-1+ lysosomal compartments, causing rapid disappearance of B7-1 from the DC cell surface. m138-expressing DCs have impaired ability to activate CD8+ T cells, identifying m138 as the first viral protein that specifically targets B7-1 for degradation.\",\n      \"method\": \"Viral gene identification by mutant MCMV; biochemical fractionation; immunocytochemistry; CD8+ T cell activation assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — viral gene identified by genetic approach, biochemical and imaging evidence for lysosomal rerouting, functional CD8 T cell assay; single lab\",\n      \"pmids\": [\"17142739\"],\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 a CD28-dependent mechanism (not endogenous synthesis, as confirmed by cycloheximide treatment and absence of CD80 mRNA in acquiring T cells). T cells that acquire CD80 can themselves act as APCs. Memory T cells that acquire CD80 undergo apoptosis when given increased TCR signal 1, revealing an immunoregulatory function.\",\n      \"method\": \"CD80/CD86 knockout APC donors; cycloheximide treatment; RT-PCR for CD80 mRNA; CD28-KO mice (negative control); confocal microscopy; functional APC assay; apoptosis assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple controls (KO APCs, cycloheximide, CD28-KO) to establish CD28-dependent protein transfer; single lab\",\n      \"pmids\": [\"11160311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"B7-1 engagement of CTLA-4 inhibits T cell activation in the absence of CD28, demonstrating that CTLA-4 can antagonize TCR-mediated signaling independently of competing with CD28. TCR-transgenic/RAG2-deficient/CD28-knockout T cells responded to B7-1-expressing stimulator cells with inhibition rather than costimulation; this inhibition was reversed by anti-B7-1 or anti-CTLA-4 mAb.\",\n      \"method\": \"TCR transgenic/RAG2-deficient/CD28-knockout mice; tumor stimulator cells with/without B7-1; anti-B7-1 and anti-CTLA-4 blocking antibodies; cytokine and proliferation assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic CD28-deficiency plus antibody rescue experiments directly demonstrate CTLA-4-mediated inhibition independent of CD28; rigorous epistatic design\",\n      \"pmids\": [\"9653097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The PD-L1:B7-1 interaction inhibits diabetogenic effector T cell responses in vivo. Anti-PD-L1 mAb 10F.2H11, which selectively blocks only PD-L1:B7-1 (not PD-L1:PD-1), accelerated diabetes in older NOD mice and in adoptive transfer with effector (but not prediabetic) T cells. Dual-blocker anti-PD-L1 mAb was effective in all settings. PDL1 blockade failed to accelerate rejection in B7.1-deficient recipients, confirming that PDL1 inhibition depends on its interaction with B7-1 in vivo.\",\n      \"method\": \"NOD mouse diabetes model; selective blocking anti-PD-L1 mAbs; B7.1-deficient recipients; adoptive T cell transfer; diabetes incidence readout\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic and pharmacological epistasis across multiple complementary models; two independent anti-PD-L1 mAbs with different specificities tested in parallel\",\n      \"pmids\": [\"21697456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In a heart transplant model, PDL1 blockade accelerated allograft rejection in B7.2-deficient but not B7.1-deficient recipients, demonstrating that PDL1:B7-1 interaction is required for PDL1-mediated inhibition of alloimmune responses in vivo. In vitro, blockade of PDL1 on dendritic cells (interacting with T cell B7-1) increased alloreactive CD4+ T cell IFN-γ production, while blocking DC B7-1 interaction with T cell PDL1 did not, indicating a directional dominance of PDL1(DC):B7-1(T cell) interaction.\",\n      \"method\": \"bm12→B6 heart transplant model; B7.1-KO and B7.2-KO recipients; anti-PD-L1 mAbs with distinct blocking specificities; in vitro blocking assay with DCs and T cells; IFN-γ ELISA\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic KO epistasis plus directional in vitro blocking experiments; two complementary papers published simultaneously\",\n      \"pmids\": [\"21697455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"B7-1 and B7-2 participate in negative selection (clonal deletion) of thymocytes. Following endogenous superantigen-driven deletion in B7-1- and/or B7-2-deficient mice, deletion was impaired. Either CD28 or an additional undefined co-receptor can mediate B7-dependent deletion signals. CTLA-4 delivers inhibitory signals opposing CD28 during thymic selection.\",\n      \"method\": \"B7-1/B7-2 single and double KO mice; CD28-KO and CD28/CTLA-4 double-KO mice; endogenous superantigen deletion model (thymocyte flow cytometry)\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic KO combinations tested in vivo; single lab; endogenous superantigen model\",\n      \"pmids\": [\"12759417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Direct signaling through B7-1/B7-2 on B cells (reverse signaling) enhances IgG secretion. Mixed bone marrow chimeric mice lacking B7-1/2 only on B cells had reduced local IgG responses after influenza infection without affecting germinal center formation or CD4+ T cell activation. In vitro, B7-2 engagement on class-switched B cells dramatically enhanced IgG (but not IgM) secretion and induced XBP-1/spliced XBP-1 expression, indicating increased protein synthesis/secretory pathway activation.\",\n      \"method\": \"Mixed bone marrow irradiation chimeras (B7-1/2-deficient B cells); in vitro B7-2 engagement on class-switched B cells; IgG/IgM ELISA; XBP-1 mRNA splicing assay; influenza infection model\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo chimera plus in vitro mechanistic follow-up with signaling marker; single lab, two complementary experimental approaches\",\n      \"pmids\": [\"19933871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"B7-1 and B7-2 costimulatory molecules differentially activate Th1 and Th2 developmental pathways. Anti-B7-1 treatment in EAE reduced disease incidence and shifted T cells toward Th2 (anti-IL-4 reversed this protection), while anti-B7-2 increased disease severity. Neither antibody affected overall T cell induction but altered cytokine profiles.\",\n      \"method\": \"In vivo EAE model; anti-B7-1 and anti-B7-2 antibody blockade; Th1/Th2 cytokine profiling; adoptive transfer; anti-IL-4 co-treatment\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo blockade with functional cytokine readouts and adoptive transfer; single lab; later contested by other groups\",\n      \"pmids\": [\"7534215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"A cell-type-specific enhancer in the human B7.1 gene is regulated by NF-κB. The 183-bp enhancer ~3 kb upstream of the transcription start site is active in B7.1-positive B cells, responsive to LPS and dibutyryl cAMP, and contains a functional NF-κB consensus element whose mutation abrogates activity. NF-κB family members bind this element in B7.1-positive B cells.\",\n      \"method\": \"DNase I hypersensitive site mapping; deletion and site-directed mutagenesis of reporter constructs; gel shift/EMSA assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — promoter mutagenesis plus protein-DNA binding assays; single lab but multiple orthogonal methods establishing NF-κB as transcriptional activator of CD80\",\n      \"pmids\": [\"8642282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The extracellular region of B7-1 contains two IgSF domains: an N-terminal V-like domain (whose fold is distinct from classical IgSF V-sets) and a C-like domain compatible with IgSF C-set structures and best recognized by β2-microglobulin. Conserved residues in B7 molecules cluster on the surface of the C-domain, potentially involved in interactions with the V-like domain or other molecules.\",\n      \"method\": \"Inverse folding methodology (computational structure prediction validated against known structures); sequence conservation analysis mapped onto β2m crystal structure\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational structural prediction only, no experimental structure determination; predates the actual crystal structure\",\n      \"pmids\": [\"7535614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Insertion of two residues between the two Ig domains of CD80 decreased affinity for CTLA-4, while a similar insertion in CD86 had no effect, demonstrating that the inter-domain linker of CD80 contributes to CTLA-4 binding. Additionally, the V-domain of CD86 (but not CD80) is sufficient for CTLA-4 binding, revealing a fundamental structural difference between the two ligands in their receptor recognition mechanism.\",\n      \"method\": \"CD80/CD86 mutant domain-swap and insertion constructs; cell-binding assays with CTLA-4\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mutagenesis with direct binding readout; single lab; establishes mechanistic distinction between CD80 and CD86 receptor engagement\",\n      \"pmids\": [\"8609386\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD80 (B7-1) is a dimeric (confirmed by crystal structure and cell-surface FRET) IgSF glycoprotein on APCs that binds CD28 (Kd ~4 µM) and CTLA-4 (Kd ~0.42 µM) with rapid kinetics via overlapping but distinct interfaces, providing costimulatory signals through CD28 and inhibitory signals through CTLA-4 (which can suppress T cells even in the absence of CD28); it also engages PD-L1 exclusively in cis on the same cell surface at the B7-1 dimer interface—blocking both B7-1:CD28 and PD-L1:PD-1 axes—and its transcription is driven by NF-κB binding to a cell-type-specific upstream enhancer that is repressed in germinal center B cells by BCL6; in non-immune podocytes, B7-1 induction disrupts the actin cytoskeleton and slit diaphragm proteins, contributing to proteinuria.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CD80 (B7-1) is a cell-surface immunoglobulin-superfamily glycoprotein on antigen-presenting cells that controls T cell activation by engaging the costimulatory receptor CD28 and the inhibitory receptor CTLA-4 [#2, #15]. Its extracellular region comprises two Ig-like domains and assembles into 2-fold symmetric homodimers that persist both in crystals and in solution, and live-cell FRET confirms that B7-1 exists predominantly as dimers at the cell surface—distinct from the monomeric B7-2 [#1, #4]. CD80 binds CTLA-4 (Kd ~0.42 µM) more avidly than CD28 (Kd ~4 µM), with very fast dissociation kinetics, and bivalent CTLA-4 dimers bridge bivalent B7-1 dimers into a zipper-like oligomeric lattice that provides a structural basis for stable inhibitory signaling complexes [#0, #2]. CD80 and CD86 engage CTLA-4 through similar but distinct determinants, and the CD80 inter-domain linker specifically contributes to CTLA-4 binding [#3, #8, #23]. CTLA-4 ligation of B7-1 inhibits T cell responses even in the complete absence of CD28, establishing an intrinsic inhibitory function independent of CD28 competition [#15]. Beyond these receptors, CD80 binds PD-L1 with intermediate affinity exclusively in cis on the same cell surface, through an interface mapping to the B7-1 dimer surface that overlaps the CTLA-4/PD-1 contacts; this cis interaction bidirectionally inhibits T cell activation and is required in vivo for PD-L1-mediated suppression of effector and alloreactive T cells [#5, #6, #7, #16, #17]. CD80 transcription is driven by NF-κB binding to a cell-type-specific enhancer ~3 kb upstream of the start site and is directly repressed in germinal-center B cells by BCL6 binding the promoter [#9, #10, #21]. CD80 also functions outside the immune synapse: it is induced in kidney podocytes via TLR4 signaling, where its activation reorganizes the actin cytoskeleton and disrupts slit-diaphragm proteins to produce proteinuria [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Establishing how CD80 transcription is controlled defined the cell-type-specific, signal-inducible logic of costimulator expression.\",\n      \"evidence\": \"DNase I hypersensitivity mapping, reporter assays, and EMSA identifying an upstream NF-κB-dependent enhancer in B7.1-positive B cells\",\n      \"pmids\": [\"8642282\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not identify which NF-κB subunits drive the response in vivo\", \"Upstream receptor signals feeding the enhancer not fully resolved\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Computational modeling first predicted CD80's two-Ig-domain architecture before any experimental structure existed.\",\n      \"evidence\": \"Inverse-folding prediction and conservation mapping onto β2-microglobulin\",\n      \"pmids\": [\"7535614\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Prediction only; superseded by later crystal structures\", \"No experimental validation of domain folds at the time\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Comparing CD80 and CD86 binding to CD28/CTLA-4 showed the two ligands have distinct binding determinants and kinetics despite similar overall avidity, implying non-redundant roles.\",\n      \"evidence\": \"Cell-binding, competitive inhibition, and dissociation-kinetics assays with the CTLA-4 Y100A mutant\",\n      \"pmids\": [\"7534620\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the differential determinants not resolved here\", \"Functional consequence of slower CD80 dissociation in vivo unclear\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Antibody blockade tested whether CD80 and CD86 differentially shape effector T cell fate, linking costimulator choice to Th1/Th2 polarization.\",\n      \"evidence\": \"In vivo EAE model with anti-B7-1/anti-B7-2 blockade, cytokine profiling, and anti-IL-4 co-treatment\",\n      \"pmids\": [\"7534215\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Later contested by other groups\", \"Mechanism by which B7-1 vs B7-2 biases cytokine output not defined\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Mutagenesis dissected which CTLA-4 and CD80 residues control binding, mapping the differential recognition between the two B7 ligands.\",\n      \"evidence\": \"CTLA-4 MYPPPY point mutants and CD80/CD86 domain-swap/insertion constructs assayed by SPR and cell binding\",\n      \"pmids\": [\"8557978\", \"8609386\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interface positions inferred from binding loss without co-structure\", \"Quantitative kinetic effects of individual residues incomplete\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Quantifying CD80 affinity and kinetics for both receptors showed low-affinity, fast-off interactions suited to dynamic T cell–APC contacts.\",\n      \"evidence\": \"Surface plasmon resonance at 37°C measuring Kd and koff for CTLA-4 and CD28\",\n      \"pmids\": [\"9053440\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address avidity effects of surface dimerization\", \"Kinetics measured with soluble monomeric proteins\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Genetic CD28 deletion plus antibody rescue established that CTLA-4 ligation by B7-1 inhibits T cells intrinsically, not merely by outcompeting CD28.\",\n      \"evidence\": \"TCR-transgenic/RAG2-deficient/CD28-knockout T cells stimulated with B7-1+ cells, reversed by anti-B7-1/anti-CTLA-4\",\n      \"pmids\": [\"9653097\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream CTLA-4 signaling effectors not defined\", \"Physiological setting where CD28-independent inhibition dominates unclear\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Solving the B7-1 ectodomain structure revealed it forms symmetric homodimers in crystal and solution, providing a physical basis for avidity-enhanced CTLA-4 engagement.\",\n      \"evidence\": \"X-ray crystallography at 3 Å and analytical ultracentrifugation\",\n      \"pmids\": [\"10661405\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dimer relevance on intact cell surface not yet shown\", \"Stoichiometry of receptor complexes inferred, not directly observed\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"The CTLA-4/B7-1 co-crystal showed bivalent dimers bridging into a zipper-like lattice, explaining how stable inhibitory signaling complexes assemble.\",\n      \"evidence\": \"X-ray crystallography of the human CTLA-4/B7-1 complex at 3.0 Å\",\n      \"pmids\": [\"11279502\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Lattice oligomerization not confirmed at native synapse density\", \"Does not address CD28 complex geometry\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Tracking CD80 protein transfer revealed that T cells acquire CD80 from APCs via a CD28-dependent route, conferring an immunoregulatory APC-like and pro-apoptotic phenotype.\",\n      \"evidence\": \"KO APC donors, cycloheximide, RT-PCR, CD28-KO controls, confocal imaging, and apoptosis assays\",\n      \"pmids\": [\"11160311\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of trogocytosis not defined\", \"In vivo prevalence and consequence of CD80 acquisition unclear\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"ChIP and KO mice identified BCL6 as a direct repressor of CD80 in germinal-center B cells, defining how NF-κB-driven CD80 induction is silenced during the GC reaction.\",\n      \"evidence\": \"ChIP of BCL6 at the CD80 promoter, reporter assays, and BCL6-deficient mice\",\n      \"pmids\": [\"12860928\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Co-repressor machinery recruited by BCL6 not specified\", \"Reversal of repression upon GC exit not mapped\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Genetic dissection placed B7-1/B7-2 in thymic negative selection, showing CD28 and an additional co-receptor mediate B7-dependent clonal deletion.\",\n      \"evidence\": \"B7-1/B7-2 and CD28/CTLA-4 KO mice in an endogenous superantigen deletion model\",\n      \"pmids\": [\"12759417\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the additional B7-binding co-receptor unknown\", \"Quantitative contribution of B7-1 vs B7-2 not separated\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Functional assays showed B7-1/B7-2 ligation by T cell CTLA-4/CD28 is obligatory to activate constitutively expressed IDO in DCs, revealing reverse signaling that drives tolerance.\",\n      \"evidence\": \"IDO enzymatic assays with anti-B7 blocking and cross-linking antibodies in human DCs\",\n      \"pmids\": [\"15034022\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Intracellular signaling pathway from B7 to IDO not defined\", \"Single lab, in vitro human DC system\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"KO mice and podocyte cultures uncovered a non-immune, cell-intrinsic CD80 function in the kidney, where TLR4-driven induction disrupts the slit diaphragm and causes proteinuria.\",\n      \"evidence\": \"B7-1-knockout LPS nephrosis model, SCID mice, and cultured podocyte actin/slit-diaphragm assays\",\n      \"pmids\": [\"15146236\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Some findings contested by later studies\", \"Downstream effector linking B7-1 to cytoskeletal reorganization unclear\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Live-cell FRET validated the crystallographic dimer interface, confirming B7-1 is dimeric (and B7-2 monomeric) on intact cells, with implications for synapse geometry.\",\n      \"evidence\": \"Photobleaching-based FRET plus dimer-interface mutagenesis on intact cells\",\n      \"pmids\": [\"16221763\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of distinct B7-1/B7-2 geometry in synapse not directly tested\", \"Dimer dynamics during receptor engagement not measured\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identifying MCMV m138 as a B7-1-degrading viral protein demonstrated that pathogens target CD80 to subvert CD8 T cell priming.\",\n      \"evidence\": \"Mutant MCMV gene identification, biochemical fractionation, imaging of lysosomal rerouting, and CD8 T cell activation assays\",\n      \"pmids\": [\"17142739\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct m138–B7-1 binding interface not mapped\", \"Single lab; in vivo immune-evasion contribution not quantified\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Discovery of the PD-L1:B7-1 interaction added a third receptor axis, with genetic epistasis showing this pair bidirectionally inhibits T cells.\",\n      \"evidence\": \"Binding affinity measurements and functional assays with PD-1/B7-1 and CD28/CTLA-4 multi-KO T cells\",\n      \"pmids\": [\"17629517\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cis vs trans orientation not resolved at this stage\", \"Structural interface not directly determined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"B cell chimeras and in vitro engagement showed B7-1/B7-2 reverse signaling enhances IgG secretion via XBP-1 activation, a B-cell-intrinsic role independent of GC formation.\",\n      \"evidence\": \"Mixed bone marrow chimeras, in vitro B7-2 engagement, IgG/IgM ELISA, and XBP-1 splicing assay\",\n      \"pmids\": [\"19933871\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling cascade from B7 cytoplasmic tail to XBP-1 not defined\", \"Relative roles of B7-1 vs B7-2 not separated\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"In vivo blockade with selective anti-PD-L1 antibodies and B7-1-deficient recipients established that the PD-L1:B7-1 axis is required for PD-L1-mediated suppression of effector and alloreactive T cells.\",\n      \"evidence\": \"NOD diabetes and bm12→B6 heart transplant models with selective vs dual anti-PD-L1 mAbs and B7.1-/B7.2-KO recipients\",\n      \"pmids\": [\"21697456\", \"21697455\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Directionality (DC vs T cell) mechanism not fully resolved\", \"Did not yet establish whether the interaction was cis or trans\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Multiple orthogonal binding assays established that PD-L1 binds B7-1 only in cis on the same cell, redefining the geometry of the interaction and explaining how cis PD-L1 sequesters B7-1 from CD28.\",\n      \"evidence\": \"Cell-to-cell binding, ELISA, flow cytometry, and NanoBiT proximity assays\",\n      \"pmids\": [\"29871885\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise interface residues not mapped in this study\", \"Quantitative impact on synaptic CD28 engagement not measured\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Interface mapping localized the PD-L1 binding site to the B7-1 dimer surface, distal from CTLA-4/CD28 sites, and showed CTLA-4/CD28 can disrupt cis PD-L1:B7-1 by reorganizing B7-1.\",\n      \"evidence\": \"Cell-microarray FACS binding screen and site-directed mutagenesis of PD-L1 and B7-1 with two independent cis-binding assays\",\n      \"pmids\": [\"32497097\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Co-structure of the cis complex not determined\", \"Dynamics of B7-1 reorganization at the synapse not directly imaged\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple CD80 receptor axes (CD28, CTLA-4, cis PD-L1) are spatially partitioned and dynamically balanced within a single immunological synapse, and what intracellular reverse-signaling effectors couple CD80 ligation to outcomes in DCs and B cells, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated structural/imaging model of competing CD80 complexes at the native synapse\", \"Cytoplasmic signaling machinery for B7-1 reverse signaling unidentified\", \"Effector linking podocyte B7-1 to cytoskeletal disruption undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [2, 5, 15]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [11, 19]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 6, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 15, 18]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 15]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [9, 10, 21]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CTLA4\", \"CD28\", \"CD274\", \"BCL6\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}