{"gene":"CD86","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2001,"finding":"Crystal structure of the human CTLA-4/B7-2 (CD86) complex at 3.2-Å resolution revealed that the unusual dimerization properties of both CTLA-4 and B7-2 place their ligand-binding sites distal to the dimer interface, promoting formation of an alternating CTLA-4/B7-2 network that provides a model for periodic organization within the immunological synapse.","method":"X-ray crystallography (3.2-Å resolution crystal structure)","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — direct crystal structure with functional implications for receptor organization","pmids":["11279501"],"is_preprint":false},{"year":2022,"finding":"CTLA-4 targets both CD80 and CD86 for destruction via transendocytosis, but with distinct fates: in the presence of CD86, CTLA-4 detaches in a pH-dependent manner and recycles back to the cell surface for further transendocytosis, whereas in the presence of CD80, CTLA-4 remains ligand-bound and is ubiquitylated and trafficked to lysosomes. Clinically relevant autoimmune disease mutations selectively disrupted CD86 transendocytosis by affecting either CTLA-4 recycling or CD86 binding.","method":"Live-cell imaging, biochemical fractionation, mutagenesis, pH-shift assays, analysis of disease-associated mutations","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods, mutagenesis with functional validation, clinically relevant mutations tested","pmids":["35999394"],"is_preprint":false},{"year":2011,"finding":"CD86 is ubiquitinated by the MARCH1 E3 ubiquitin ligase at lysine 267 in dendritic cells, and this ubiquitination is a key mechanism controlling CD86 surface expression and antigen-presenting function. Autocrine IL-10 sustains MARCH1 expression to continuously ubiquitinate CD86 following LPS activation, and DCs expressing ubiquitination-resistant CD86 (K267 mutant) failed to regulate T cell-activating ability in response to IL-10.","method":"MARCH1 knockout mice, ubiquitination-resistant CD86 mutants (K267), functional T cell activation assays, flow cytometry","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 — genetic KO combined with site-specific mutagenesis and functional assays, multiple orthogonal approaches","pmids":["21849678"],"is_preprint":false},{"year":2005,"finding":"B7-2 (CD86) exists as a monomer on the cell surface, whereas B7-1 (CD80) is present as a dimer, as demonstrated by FRET-based photobleaching experiments; B7-1 and B7-2 do not form hetero-oligomers with each other on the cell surface.","method":"Fluorescence resonance energy transfer (FRET) / photobleaching-based FRET on live cells","journal":"Immunology letters","confidence":"Medium","confidence_rationale":"Tier 2 — single lab with biophysical method (FRET) on cell surface","pmids":["16413062"],"is_preprint":false},{"year":1999,"finding":"CD86 ligation of CD28 does not induce detectable tyrosine phosphorylation of CD28 itself or robust PI3K association with CD28, nor enhanced PLCγ phosphorylation, whereas CD80 ligation does; however, both CD80 and CD86 activate shared signaling events including CBL and VAV tyrosine phosphorylation, NFAT-dependent transcription, and IL-2 production.","method":"CHO cell transfectants expressing CD80 or CD86, anti-CD28 stimulation, immunoprecipitation, Western blot for tyrosine phosphorylation of CD28/PLCγ/PI3K association","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — direct biochemical signaling measurements with defined cell lines and multiple signaling readouts","pmids":["9915850"],"is_preprint":false},{"year":1995,"finding":"CD28-mediated costimulation by CD86 (B7-2) requires PI3-kinase: CD28 mutants (Y191F and M194C) that selectively disrupted PI3-kinase binding failed to generate IL-2 when co-stimulated with CHO-CD86 cells, directly implicating PI3-kinase in CD86-CD28 signaling leading to IL-2 secretion.","method":"CD28 cytoplasmic domain point mutants (Y191F, M194C), CHO cells expressing CD86, IL-2 production assay","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1 — site-directed mutagenesis of CD28 with functional reconstitution using CD86-expressing cells","pmids":["7584133"],"is_preprint":false},{"year":1998,"finding":"Stimulation of CD28 by B7-2 (CD86) leads to rearrangement of the actin cytoskeleton and formation of focal adhesion-like cell contacts, with selective translocation of the Rho-family GTPase Rac1 (but not Rho) to the site of T cell–APC contact, along with talin.","method":"F-actin content measurement, confocal microscopy of Rac1/talin localization, T cells co-cultured with B7-2-transfected CHO cells","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — direct imaging of cytoskeletal reorganization and GTPase translocation upon defined CD86–CD28 engagement","pmids":["9551951"],"is_preprint":false},{"year":2012,"finding":"Prohibitin 1 (Phb1) and Prohibitin 2 (Phb2) are transmembrane adaptor proteins that bind to CD86 and cooperate with the CD86 cytoplasmic domain (via PKC phosphorylation sites) to mediate downstream NF-κB signaling in B cells, leading to increased IgG1 expression. Phb1/2 are required for CD86-induced phosphorylation of PLCγ2 and PKCα/β, while both Phb1/2 and the CD86 cytoplasmic domain are required for IκBα phosphorylation.","method":"Proteomics-based identification, co-immunoprecipitation, shRNA knockdown of Phb1/2, CD86 cytoplasmic domain truncation/mutation, IgG1 and Oct-2 expression assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal binding identified by proteomics + Co-IP, multiple KD/mutant approaches with defined signaling readouts","pmids":["23241883"],"is_preprint":false},{"year":2009,"finding":"Direct CD86 signaling on B cells (reverse signaling) promotes IgG secretion by previously class-switched B cells and induces expression of XBP-1 and spliced XBP-1, indicating increased protein synthesis; this was demonstrated using mixed bone marrow chimeric mice where only B cells lacked B7-1/B7-2.","method":"Mixed bone marrow irradiation chimeras (B cell-specific B7-1/2 deficiency), in vitro CD86 engagement, XBP-1 splicing assay, IgG/IgM ELISA","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — cell-type-specific KO chimeras combined with in vitro mechanistic follow-up, multiple readouts","pmids":["19933871"],"is_preprint":false},{"year":2004,"finding":"CD28 signaling in dendritic cells via CD86 (and CD80) induces IL-6 production in a p38 MAPK-dependent manner, and this IL-6 prevents IFN-γ-driven immunosuppressive tryptophan catabolism, demonstrating reverse (bidirectional) signaling through CD86 on DCs.","method":"Soluble CD28 treatment of mouse DCs, cytokine measurement, p38 MAPK inhibition, in vivo tumor and microbial challenge models","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 — bidirectional signaling established with pharmacological inhibition and in vivo validation, multiple readouts","pmids":["15467723"],"is_preprint":false},{"year":2016,"finding":"Bacterial superantigens enhance T cell activation by simultaneously binding both CD86 and CD28 at their respective homodimer interfaces (via the same 12-aa β-strand-hinge-α-helix domain), thereby increasing avidity between CD86 and CD28 and driving cytokine hyperproduction; CD86 homodimer interface mimetic peptides block superantigen binding to cell-surface CD86 and attenuate cytokine overproduction.","method":"Binding assays, CD86/CD28 dimer interface peptide competition, cytokine assays, in vivo superantigen lethality model","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding mapped to structural interfaces, validated with mimetic peptides and in vivo lethality rescue","pmids":["27708164"],"is_preprint":false},{"year":2008,"finding":"HIV-1 Nef removes CD86 (and CD80) from the cell surface via a clathrin- and dynamin-independent, actin-based endocytic pathway and subsequently reroutes CD86-containing vesicles to the Golgi via a Rab11-dependent mechanism; CD86/CD80 endocytic vesicles do not acquire conventional early endosomal markers (Rab5/EEA1) but instead recruit Rab11 de novo, which is required for Golgi delivery.","method":"Fluorescence microscopy, dominant-negative Rab constructs, endosomal marker colocalization, live-cell trafficking assays","journal":"Traffic","confidence":"High","confidence_rationale":"Tier 2 — mechanistic dissection of vesicular trafficking with multiple markers and dominant-negative Rab11, rigorous controls","pmids":["18764822"],"is_preprint":false},{"year":2006,"finding":"Adenovirus serotype 3 (Ad3, species B1) uses CD80 and CD86 as cellular attachment receptors; the Ad fiber-knob domain mediates this interaction, and all tested Ad species B members (B1 and B2) can infect cells through CD80 and CD86.","method":"Competitive infection blocking with fiber-knob domain, CHO cells expressing CD80/CD86, serotype-specific infection assays","journal":"Virus research","confidence":"High","confidence_rationale":"Tier 2 — direct receptor identification by competitive blocking and expression in receptor-negative CHO cells","pmids":["16920215"],"is_preprint":false},{"year":2017,"finding":"CD86 (B7.2) functions as a co-receptor for lymphotropic hepatitis C virus (HCV) infection of B cells; cDNA library screening identified CD86 as a B-cell-specific co-receptor, and silencing CD86 prevented HCV infection of B cells. Lymphotropic HCV infection of B cells via CD86 inhibited memory B cell function (recall antigen responses).","method":"cDNA library screening, gene silencing of CD86, chimeric HCV infectious clones, B cell infection assays, antigen recall assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — cDNA library-based receptor identification plus silencing with functional readout, single study","pmids":["28067225"],"is_preprint":false},{"year":2012,"finding":"Induced regulatory T cells (iTregs) acquire CD86 (to a greater extent than CD80) from mature dendritic cells via trogocytosis in a CTLA-4-, CD28-, and PD-L1-independent manner; iTregs that acquired CD86 expressed higher activation markers and showed enhanced suppressive capacity compared to iTregs that did not acquire CD86.","method":"Co-incubation of CD80/CD86 double-KO-derived iTregs with mature DCs, flow cytometry, confocal fluorescence microscopy, T cell suppression assays","journal":"Cellular & molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 — KO-based system to track acquisition, functional suppression assay, single lab","pmids":["22307040"],"is_preprint":false},{"year":1998,"finding":"Constitutive expression of a B7.2 transgene on tolerant self-reactive B cells was sufficient to prevent Fas-mediated deletion and trigger T cell-dependent clonal expansion and autoantibody secretion, demonstrating that repression of B7.2 on anergic B cells is a critical mechanism for Fas-mediated peripheral B cell tolerance.","method":"B7.2 transgenic mice, in vivo B cell fate tracking, Fas-deficient comparison, T cell-dependent expansion assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — transgenic rescue experiment with defined molecular mechanism and multiple in vivo controls","pmids":["9705947"],"is_preprint":false},{"year":2011,"finding":"Toxoplasma gondii induces B7-2 (CD86) expression on macrophages at the transcript level through a mechanism requiring active parasite invasion (not TLR/MyD88/TRIF) and dependent on JNK (but not ERK or p38) MAP kinase signaling; T. gondii-infected macrophages stimulated naïve T cell proliferation in a B7-2-dependent manner.","method":"MAPK inhibitors, MyD88/TRIF KO macrophages, B7-2 blocking antibodies, T cell proliferation assays, genome-wide transcriptional analysis","journal":"Infection and immunity","confidence":"High","confidence_rationale":"Tier 2 — pathway defined by specific inhibitors and KO cells with functional validation, multiple orthogonal approaches","pmids":["21911468"],"is_preprint":false},{"year":2004,"finding":"IL-4-dependent upregulation of CD86 in monocytes requires JAK/STAT6 and MEK/ERK1/2 activation but is negatively regulated by PKCδ; blocking JAK with WHI-P154 or MEK with PD98059 abolished CD86 upregulation, while blocking PKCδ with rottlerin dramatically enhanced CD86 expression.","method":"Specific kinase inhibitors (WHI-P154, PD98059, rottlerin), STAT6 phosphorylation assays, flow cytometry for CD86, antisense reduction of CD45","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 — multiple pharmacological pathway dissections with consistent results, single lab","pmids":["14636897"],"is_preprint":false},{"year":2020,"finding":"Tet2 and Tet3 DNA demethylases in B cells are required for downregulation of CD86 following chronic self-antigen exposure; in Tet2/Tet3-deficient B cells, CD86 remained elevated due to decreased accumulation of HDAC1 and HDAC2 at the Cd86 locus, and anti-CD86 blockade partially restricted the resulting aberrant T and B cell activation.","method":"B cell-specific Tet2/Tet3 double-KO mice, HDAC chromatin occupancy (ChIP), anti-CD86 blockade, flow cytometry","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 — cell-type-specific KO with chromatin-level mechanistic dissection and functional rescue, multiple methods","pmids":["32572241"],"is_preprint":false},{"year":1997,"finding":"B7.2 expressed on T cell tumor lines (EL4) preferentially binds CTLA4-Ig but not CD28-Ig and fails to costimulate T cell proliferation (unlike B7.1 on T cells which binds both), suggesting that the context of B7.2 expression affects its receptor binding preference and functional outcome.","method":"CTLA4-Ig and CD28-Ig binding assays on B7.1/B7.2 transfected T cell lines, T cell proliferation costimulation assays, in vivo tumor regression","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — binding specificity and functional outcome tested in parallel with multiple receptor-Ig fusion proteins","pmids":["9036945"],"is_preprint":false},{"year":1996,"finding":"The V domain of CD86 (but not the V domain of CD80 alone) is sufficient for CTLA-4 binding, revealing a fundamental structural difference between CD80 and CD86 in receptor engagement.","method":"Domain-swapped and truncated CD80/CD86 mutants, binding assays with CTLA-4","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — structure-function mutagenesis with defined binding readout, single lab","pmids":["8609386"],"is_preprint":false},{"year":2000,"finding":"HIV-1 virions bearing host-encoded B7-2 activate NF-κB and NFAT in target T cells via CD28 engagement, thereby upregulating HIV-1 LTR-driven gene expression; this effect was abrogated by CTLA-4-Ig blockade of the virion-bound B7-2–CD28 interaction and by dominant-negative IκBα and dnNFAT.","method":"Isogenic NL4-3 HIV virus stocks bearing B7-2, dominant-negative transcription factor constructs, CTLA-4-Ig blocking, LTR reporter assays, EMSA for NF-κB","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — dominant-negative constructs and specific blocking identify signaling pathway, single lab","pmids":["11096063"],"is_preprint":false},{"year":2017,"finding":"CD86 on myeloma cells signals via its cytosolic domain to promote myeloma cell survival; silencing CD86 (or CD28) leads to myeloma cell death, downregulation of integrins, and downregulation of IRF4 (a known myeloma survival factor), and the pro-survival activity of CD86 is dependent on its cytosolic domain.","method":"CD86/CD28 gene silencing (siRNA/shRNA), CD86 cytosolic domain deletion constructs, cell viability assays, IRF4 and integrin expression","journal":"Blood advances","confidence":"Medium","confidence_rationale":"Tier 2 — domain deletion + gene silencing with defined molecular and survival readouts, single lab","pmids":["29296880"],"is_preprint":false}],"current_model":"CD86 (B7-2) is a monomeric cell-surface costimulatory ligand on APCs that engages CD28 to provide T cell costimulation via PI3-kinase- and Rac1/actin cytoskeleton-dependent signaling pathways, and engages CTLA-4 to trigger pH-dependent receptor recycling and iterative transendocytosis; CD86 surface levels are tightly regulated by MARCH1-mediated ubiquitination at K267 and by Tet2/Tet3-dependent epigenetic repression at the Cd86 locus; CD86 also mediates reverse (bidirectional) signaling in B cells through prohibitin adaptors and its cytoplasmic domain to activate NF-κB and promote IgG production, and in dendritic cells via p38 MAPK to induce IL-6; additionally, CD86 serves as a cellular attachment receptor for species B adenoviruses and lymphotropic HCV, and is targeted by HIV-1 Nef for Rab11-dependent rerouting to the Golgi."},"narrative":{"teleology":[{"year":1995,"claim":"Establishing that CD86-mediated T cell costimulation requires PI3-kinase signaling through CD28 resolved which downstream pathway is essential for IL-2 production upon CD86 engagement.","evidence":"CD28 cytoplasmic domain point mutants (Y191F, M194C) co-stimulated with CD86-expressing CHO cells, IL-2 readout","pmids":["7584133"],"confidence":"High","gaps":["Whether PI3K is the sole pathway or acts in concert with other kinases downstream of CD86–CD28","No direct structural mapping of CD28–PI3K interaction in the context of CD86 engagement"]},{"year":1996,"claim":"Demonstrating that the CD86 V domain alone suffices for CTLA-4 binding — unlike CD80, which requires both domains — established a fundamental structural distinction between the two B7 ligands in receptor engagement.","evidence":"Domain-swapped and truncated CD80/CD86 chimeras tested for CTLA-4 binding","pmids":["8609386"],"confidence":"Medium","gaps":["Atomic-resolution basis for V-domain sufficiency not yet defined at this point","Whether V-domain sufficiency translates to differential signaling outcomes through CTLA-4"]},{"year":1998,"claim":"Two advances defined CD86's roles in cytoskeletal signaling and peripheral tolerance: CD86–CD28 engagement selectively translocates Rac1 (not Rho) to the T cell–APC contact and remodels actin, while constitutive B7-2 expression on anergic B cells prevents Fas-mediated deletion, revealing that CD86 repression is required for peripheral B cell tolerance.","evidence":"Confocal imaging of Rac1/talin translocation upon CD86–CD28 ligation; B7-2 transgenic mice with in vivo B cell fate tracking","pmids":["9551951","9705947"],"confidence":"High","gaps":["The GEF linking CD28 engagement to Rac1 activation is unidentified","Whether CD86 repression on anergic B cells is transcriptional or post-translational was unknown"]},{"year":1999,"claim":"Comparative biochemical analysis showed that CD86 and CD80 trigger qualitatively different proximal signals through CD28 — CD86 ligation does not induce detectable CD28 tyrosine phosphorylation or robust PI3K recruitment, yet both ligands converge on shared distal events including CBL/VAV phosphorylation and NFAT activation.","evidence":"CHO transfectants expressing CD80 or CD86, immunoprecipitation and Western blot for CD28 phosphorylation, PI3K association, downstream transcription factor activation","pmids":["9915850"],"confidence":"High","gaps":["How CD86 achieves IL-2 production despite weak CD28 tyrosine phosphorylation","Whether quantitative rather than qualitative differences in PI3K recruitment account for these results"]},{"year":2001,"claim":"The crystal structure of CTLA-4/CD86 revealed that dimerization interfaces of both proteins position binding sites to favor formation of an alternating periodic lattice, providing a structural model for immunological synapse organization.","evidence":"X-ray crystallography at 3.2-Å resolution","pmids":["11279501"],"confidence":"High","gaps":["Whether the lattice model occurs in physiological cell–cell contacts","No dynamics or stoichiometry information at cell surfaces"]},{"year":2004,"claim":"Two studies established CD86 as a bidirectional signaling molecule: reverse signaling through CD86 on DCs induces IL-6 via p38 MAPK to counteract immunosuppressive tryptophan catabolism, while IL-4-driven CD86 upregulation on monocytes requires JAK/STAT6 and MEK/ERK1/2 and is negatively regulated by PKCδ.","evidence":"Soluble CD28 treatment of DCs with p38 inhibition and in vivo validation; pharmacological kinase inhibitor dissection in monocytes","pmids":["15467723","14636897"],"confidence":"High","gaps":["The proximal receptor complex mediating reverse signaling in DCs is undefined","Whether PKCδ directly phosphorylates CD86 or acts indirectly"]},{"year":2005,"claim":"FRET-based measurements confirmed CD86 exists as a monomer on the cell surface, contrasting with CD80 homodimers, and excluded CD80–CD86 hetero-oligomers — clarifying the oligomeric state relevant to receptor engagement.","evidence":"Photobleaching FRET on live cells expressing CD80 and/or CD86","pmids":["16413062"],"confidence":"Medium","gaps":["Whether ligand engagement or clustering at the synapse induces transient dimerization","Monomer status established on transfected cells, not primary APCs"]},{"year":2006,"claim":"Identification of CD86 as a cellular attachment receptor for species B adenoviruses expanded CD86's function beyond immune costimulation to pathogen entry.","evidence":"Competitive infection blocking with fiber-knob domain, CD86-expressing CHO cells, multi-serotype infection assays","pmids":["16920215"],"confidence":"High","gaps":["Whether CD86 mediates virus internalization or only attachment","Structural basis of fiber-knob–CD86 interaction unknown"]},{"year":2008,"claim":"HIV-1 Nef was shown to remove CD86 from the APC surface via a clathrin/dynamin-independent, actin-dependent pathway and reroute it to the Golgi through de novo Rab11 recruitment, revealing a viral immune evasion mechanism targeting CD86 trafficking.","evidence":"Fluorescence microscopy, dominant-negative Rab constructs, endosomal marker colocalization in Nef-expressing cells","pmids":["18764822"],"confidence":"High","gaps":["Whether Nef directly binds CD86 or acts through an intermediate adaptor","Functional consequence for T cell activation not directly measured"]},{"year":2009,"claim":"Demonstrating that CD86 reverse signaling in B cells promotes IgG secretion and XBP-1 splicing in class-switched B cells established a cell-intrinsic role for CD86 beyond costimulation.","evidence":"Mixed bone marrow chimeras with B cell-specific B7-1/2 deficiency, in vitro CD86 engagement, XBP-1 splicing and IgG ELISA","pmids":["19933871"],"confidence":"High","gaps":["Identity of the natural ligand triggering reverse signaling in vivo","Whether XBP-1 induction is direct or secondary to increased secretory load"]},{"year":2011,"claim":"Two studies defined post-translational and transcriptional control of CD86: MARCH1 ubiquitinates CD86 at K267 to limit surface expression under autocrine IL-10 control in DCs, while Toxoplasma gondii induces CD86 transcription via JNK (not ERK/p38) independently of TLR/MyD88/TRIF.","evidence":"MARCH1 KO mice and K267R mutant CD86 with T cell activation assays; MAPK inhibitors and MyD88/TRIF KO macrophages with B7-2 blocking antibodies","pmids":["21849678","21911468"],"confidence":"High","gaps":["Whether MARCH1 ubiquitination triggers lysosomal degradation or recycling of CD86","Identity of the parasite-derived signal activating JNK for CD86 induction"]},{"year":2012,"claim":"Prohibitin 1/2 were identified as transmembrane adaptors that bind the CD86 cytoplasmic domain and mediate NF-κB activation and IgG1 production in B cells, defining the first signaling intermediates in CD86 reverse signaling; separately, iTregs were shown to acquire CD86 from DCs via trogocytosis in a CTLA-4/CD28-independent manner, gaining enhanced suppressive capacity.","evidence":"Proteomic identification and Co-IP of Phb1/2 with CD86, shRNA knockdown, cytoplasmic domain mutants; co-incubation of CD80/86 double-KO iTregs with mature DCs","pmids":["23241883","22307040"],"confidence":"High","gaps":["Whether Phb1/2 form a stable complex with CD86 or are recruited transiently","Mechanism by which acquired CD86 enhances Treg suppression is unclear"]},{"year":2016,"claim":"Bacterial superantigens were found to bridge CD86 and CD28 homodimer interfaces simultaneously via the same 12-aa structural motif, explaining superantigen-driven cytokine hyperproduction and providing a pharmacological target — CD86 dimer-interface mimetic peptides block this pathological interaction.","evidence":"Binding assays mapping the superantigen–CD86/CD28 interface, mimetic peptide competition, in vivo superantigen lethality rescue","pmids":["27708164"],"confidence":"High","gaps":["Whether all superantigen families share this bridging mechanism","Structural co-crystal of superantigen with both CD86 and CD28 is lacking"]},{"year":2017,"claim":"CD86 was identified as a co-receptor for lymphotropic HCV infection of B cells, and CD86-dependent HCV infection was shown to impair memory B cell recall responses, linking CD86's receptor function to viral immunopathology; separately, CD86 intrinsic signaling via its cytosolic domain was found to promote myeloma cell survival through IRF4 maintenance.","evidence":"cDNA library screen for HCV co-receptor, CD86 silencing blocks infection, antigen recall assays; CD86 silencing and cytosolic domain deletion in myeloma cells with IRF4/integrin readouts","pmids":["28067225","29296880"],"confidence":"Medium","gaps":["Whether CD86 directly binds HCV envelope glycoproteins or acts indirectly","Whether CD86-dependent myeloma survival operates in primary patient samples","HCV co-receptor function awaits independent replication"]},{"year":2020,"claim":"Tet2/Tet3 were shown to be required for epigenetic silencing of CD86 on chronically antigen-exposed B cells by recruiting HDAC1/2 to the Cd86 locus, establishing an epigenetic layer of CD86 regulation essential for self-tolerance.","evidence":"B cell-specific Tet2/Tet3 double-KO mice, ChIP for HDAC1/2 at Cd86, anti-CD86 blockade partially rescuing aberrant activation","pmids":["32572241"],"confidence":"High","gaps":["Whether Tet2/3 act through 5hmC-dependent or -independent mechanisms at Cd86","Which specific CpGs at the Cd86 locus are functionally relevant"]},{"year":2022,"claim":"Revealing that CTLA-4 undergoes pH-dependent detachment from CD86 and recycles for iterative transendocytosis — unlike its irreversible lysosomal fate with CD80 — resolved the long-standing question of why CTLA-4 is a more efficient checkpoint for CD86 than CD80, and showed that autoimmune disease mutations selectively disrupt CD86 transendocytosis.","evidence":"Live-cell imaging, pH-shift assays, biochemical fractionation, disease-associated CTLA-4 mutation analysis","pmids":["35999394"],"confidence":"High","gaps":["Structural basis for pH-dependent CTLA-4/CD86 dissociation at atomic resolution","Whether iterative transendocytosis quantitatively accounts for CD86 regulation in vivo"]},{"year":null,"claim":"Key unresolved questions include the identity of the GEF linking CD28–CD86 engagement to Rac1 activation, the structural basis for pH-dependent CTLA-4/CD86 dissociation, the natural in vivo ligand triggering CD86 reverse signaling in B cells, and whether CD86's viral receptor functions for HCV and adenovirus involve direct envelope/capsid binding or accessory factors.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of CD86 reverse signaling complex with prohibitins","Quantitative contribution of MARCH1 vs. Tet2/3 epigenetic regulation to steady-state CD86 levels in vivo not determined","No reconstituted system demonstrating iterative transendocytosis cycle kinetics"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,4,5,6,10]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[12,13]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[7,8,9,22]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,2,11,14]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[11]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[1,11]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,2,4,5,6,9,10,15,18]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,7,8,9,17,22]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[11,12,13,21]}],"complexes":[],"partners":["CD28","CTLA4","MARCH1","PHB","PHB2","RAB11A"],"other_free_text":[]},"mechanistic_narrative":"CD86 (B7-2) is a monomeric costimulatory ligand expressed on antigen-presenting cells that engages CD28 and CTLA-4 on T cells to regulate adaptive immune activation, peripheral tolerance, and bidirectional signaling in both APCs and B cells. Engagement of CD28 by CD86 activates PI3-kinase-dependent IL-2 production and Rac1-driven actin cytoskeleton rearrangement at the T cell–APC contact site, while the CD86 V domain alone is sufficient for CTLA-4 binding, which triggers pH-dependent CTLA-4 recycling and iterative transendocytosis distinct from the CD80–CTLA-4 fate [PMID:7584133, PMID:9551951, PMID:35999394, PMID:8609386]. CD86 surface levels are controlled post-translationally by MARCH1-mediated ubiquitination at K267 sustained by autocrine IL-10, and transcriptionally by Tet2/Tet3-dependent epigenetic silencing via HDAC1/2 recruitment at the Cd86 locus [PMID:21849678, PMID:32572241]. CD86 also mediates reverse signaling: in B cells, its cytoplasmic domain cooperates with prohibitin adaptors to activate NF-κB and promote IgG1 class-switched antibody secretion, and in dendritic cells it signals through p38 MAPK to induce IL-6; additionally, CD86 serves as a cellular receptor for species B adenoviruses and lymphotropic HCV [PMID:23241883, PMID:19933871, PMID:15467723, PMID:16920215, PMID:28067225]."},"prefetch_data":{"uniprot":{"accession":"P42081","full_name":"T-lymphocyte activation antigen CD86","aliases":["Activation B7-2 antigen","B70","BU63","CTLA-4 counter-receptor B7.2","FUN-1"],"length_aa":329,"mass_kda":37.7,"function":"Costimulatory molecule that belongs to the immunoglobulin superfamily that plays an important role in T-lymphocyte activation (PubMed:12196291, PubMed:7694363). 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, PubMed:7694363). May play a critical role in the early events of T-cell activation and costimulation of naive T-cells, such as deciding between immunity and anergy that is made by T-cells within 24 hours after activation (PubMed:7527824). Also involved in the regulation of B cells function, plays a role in regulating the level of IgG(1) produced. Upon CD40 engagement, activates NF-kappa-B signaling pathway via phospholipase C and protein kinase C activation (By similarity). 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1950)","url":"https://pubmed.ncbi.nlm.nih.gov/15356107","citation_count":28,"is_preprint":false},{"pmid":"17886563","id":"PMC_17886563","title":"Targeting adenovirus to CD80 and CD86 receptors increases gene transfer efficiency to malignant glioma cells.","date":"2007","source":"Journal of neurosurgery","url":"https://pubmed.ncbi.nlm.nih.gov/17886563","citation_count":27,"is_preprint":false},{"pmid":"21563968","id":"PMC_21563968","title":"CD86 + 1057G/A polymorphism and susceptibility to osteosarcoma.","date":"2011","source":"DNA and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/21563968","citation_count":27,"is_preprint":false},{"pmid":"17204999","id":"PMC_17204999","title":"Reduced monocyte CD86 expression in postinflammatory immunodeficiency.","date":"2007","source":"Critical care medicine","url":"https://pubmed.ncbi.nlm.nih.gov/17204999","citation_count":26,"is_preprint":false},{"pmid":"15454653","id":"PMC_15454653","title":"Soluble CD86 protein in serum samples of patients with asthma.","date":"2004","source":"Thorax","url":"https://pubmed.ncbi.nlm.nih.gov/15454653","citation_count":26,"is_preprint":false},{"pmid":"19188146","id":"PMC_19188146","title":"Functional B7.2 and B7-H2 molecules on myeloma cells are associated with a growth advantage.","date":"2009","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/19188146","citation_count":26,"is_preprint":false},{"pmid":"14636897","id":"PMC_14636897","title":"IL-4-dependent CD86 expression requires JAK/STAT6 activation and is negatively regulated by PKCdelta.","date":"2004","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/14636897","citation_count":25,"is_preprint":false},{"pmid":"11810057","id":"PMC_11810057","title":"Blocking the CD80 and CD86 costimulation molecules: lessons to be learned from animal models.","date":"2002","source":"Transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/11810057","citation_count":25,"is_preprint":false},{"pmid":"12829914","id":"PMC_12829914","title":"Cross-species costimulation: relative contributions of CD80, CD86, and CD40.","date":"2003","source":"Transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/12829914","citation_count":25,"is_preprint":false},{"pmid":"15163560","id":"PMC_15163560","title":"Chronic ethanol ingestion by mice increases expression of CD80 and CD86 by activated macrophages.","date":"2004","source":"Alcohol (Fayetteville, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/15163560","citation_count":25,"is_preprint":false},{"pmid":"9650618","id":"PMC_9650618","title":"Human melanoma cells transfected with the B7-2 co-stimulatory molecule induce tumor-specific CD8+ cytotoxic T lymphocytes in vitro.","date":"1998","source":"Human gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/9650618","citation_count":25,"is_preprint":false},{"pmid":"8640844","id":"PMC_8640844","title":"Therapeutic effectiveness of the immunity elicited by P815 tumor cells engineered to express the B7-2 costimulatory molecule.","date":"1996","source":"Cancer immunology, immunotherapy : CII","url":"https://pubmed.ncbi.nlm.nih.gov/8640844","citation_count":25,"is_preprint":false},{"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},{"pmid":"9589458","id":"PMC_9589458","title":"Costimulatory molecules (CD80 and CD86) on Reed-Sternberg cells are associated with the proliferation of background T cells in Hodgkin's disease.","date":"1998","source":"Pathology international","url":"https://pubmed.ncbi.nlm.nih.gov/9589458","citation_count":24,"is_preprint":false},{"pmid":"9177439","id":"PMC_9177439","title":"Expression of B7-2 (CD86) molecules by Reed-Sternberg cells of Hodgkin's disease.","date":"1997","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/9177439","citation_count":24,"is_preprint":false},{"pmid":"17513529","id":"PMC_17513529","title":"A functional CD86 polymorphism associated with asthma and related allergic disorders.","date":"2007","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17513529","citation_count":23,"is_preprint":false},{"pmid":"25179679","id":"PMC_25179679","title":"AID induces intraclonal diversity and genomic damage in CD86(+) chronic lymphocytic leukemia cells.","date":"2014","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/25179679","citation_count":22,"is_preprint":false},{"pmid":"8575841","id":"PMC_8575841","title":"Effect of CD80 and CD86 on T cell cytokine production.","date":"1995","source":"Immunological investigations","url":"https://pubmed.ncbi.nlm.nih.gov/8575841","citation_count":21,"is_preprint":false},{"pmid":"10201938","id":"PMC_10201938","title":"B7-2 is required for the progression but not the initiation of the type 2 immune response to a gastrointestinal nematode parasite.","date":"1999","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/10201938","citation_count":21,"is_preprint":false},{"pmid":"21054882","id":"PMC_21054882","title":"Rhipicephalus microplus salivary gland molecules induce differential CD86 expression in murine macrophages.","date":"2010","source":"Parasites & vectors","url":"https://pubmed.ncbi.nlm.nih.gov/21054882","citation_count":21,"is_preprint":false},{"pmid":"29296880","id":"PMC_29296880","title":"CD86 regulates myeloma cell survival.","date":"2017","source":"Blood advances","url":"https://pubmed.ncbi.nlm.nih.gov/29296880","citation_count":20,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50635,"output_tokens":5677,"usd":0.11853},"stage2":{"model":"claude-opus-4-6","input_tokens":9299,"output_tokens":4333,"usd":0.23223},"total_usd":0.35076,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","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/B7-2 (CD86) complex at 3.2-Å resolution revealed that the unusual dimerization properties of both CTLA-4 and B7-2 place their ligand-binding sites distal to the dimer interface, promoting formation of an alternating CTLA-4/B7-2 network that provides a model for periodic organization within the immunological synapse.\",\n      \"method\": \"X-ray crystallography (3.2-Å resolution crystal structure)\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct crystal structure with functional implications for receptor organization\",\n      \"pmids\": [\"11279501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CTLA-4 targets both CD80 and CD86 for destruction via transendocytosis, but with distinct fates: in the presence of CD86, CTLA-4 detaches in a pH-dependent manner and recycles back to the cell surface for further transendocytosis, whereas in the presence of CD80, CTLA-4 remains ligand-bound and is ubiquitylated and trafficked to lysosomes. Clinically relevant autoimmune disease mutations selectively disrupted CD86 transendocytosis by affecting either CTLA-4 recycling or CD86 binding.\",\n      \"method\": \"Live-cell imaging, biochemical fractionation, mutagenesis, pH-shift assays, analysis of disease-associated mutations\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods, mutagenesis with functional validation, clinically relevant mutations tested\",\n      \"pmids\": [\"35999394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CD86 is ubiquitinated by the MARCH1 E3 ubiquitin ligase at lysine 267 in dendritic cells, and this ubiquitination is a key mechanism controlling CD86 surface expression and antigen-presenting function. Autocrine IL-10 sustains MARCH1 expression to continuously ubiquitinate CD86 following LPS activation, and DCs expressing ubiquitination-resistant CD86 (K267 mutant) failed to regulate T cell-activating ability in response to IL-10.\",\n      \"method\": \"MARCH1 knockout mice, ubiquitination-resistant CD86 mutants (K267), functional T cell activation assays, flow cytometry\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic KO combined with site-specific mutagenesis and functional assays, multiple orthogonal approaches\",\n      \"pmids\": [\"21849678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"B7-2 (CD86) exists as a monomer on the cell surface, whereas B7-1 (CD80) is present as a dimer, as demonstrated by FRET-based photobleaching experiments; B7-1 and B7-2 do not form hetero-oligomers with each other on the cell surface.\",\n      \"method\": \"Fluorescence resonance energy transfer (FRET) / photobleaching-based FRET on live cells\",\n      \"journal\": \"Immunology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — single lab with biophysical method (FRET) on cell surface\",\n      \"pmids\": [\"16413062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"CD86 ligation of CD28 does not induce detectable tyrosine phosphorylation of CD28 itself or robust PI3K association with CD28, nor enhanced PLCγ phosphorylation, whereas CD80 ligation does; however, both CD80 and CD86 activate shared signaling events including CBL and VAV tyrosine phosphorylation, NFAT-dependent transcription, and IL-2 production.\",\n      \"method\": \"CHO cell transfectants expressing CD80 or CD86, anti-CD28 stimulation, immunoprecipitation, Western blot for tyrosine phosphorylation of CD28/PLCγ/PI3K association\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct biochemical signaling measurements with defined cell lines and multiple signaling readouts\",\n      \"pmids\": [\"9915850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"CD28-mediated costimulation by CD86 (B7-2) requires PI3-kinase: CD28 mutants (Y191F and M194C) that selectively disrupted PI3-kinase binding failed to generate IL-2 when co-stimulated with CHO-CD86 cells, directly implicating PI3-kinase in CD86-CD28 signaling leading to IL-2 secretion.\",\n      \"method\": \"CD28 cytoplasmic domain point mutants (Y191F, M194C), CHO cells expressing CD86, IL-2 production assay\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — site-directed mutagenesis of CD28 with functional reconstitution using CD86-expressing cells\",\n      \"pmids\": [\"7584133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Stimulation of CD28 by B7-2 (CD86) leads to rearrangement of the actin cytoskeleton and formation of focal adhesion-like cell contacts, with selective translocation of the Rho-family GTPase Rac1 (but not Rho) to the site of T cell–APC contact, along with talin.\",\n      \"method\": \"F-actin content measurement, confocal microscopy of Rac1/talin localization, T cells co-cultured with B7-2-transfected CHO cells\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct imaging of cytoskeletal reorganization and GTPase translocation upon defined CD86–CD28 engagement\",\n      \"pmids\": [\"9551951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Prohibitin 1 (Phb1) and Prohibitin 2 (Phb2) are transmembrane adaptor proteins that bind to CD86 and cooperate with the CD86 cytoplasmic domain (via PKC phosphorylation sites) to mediate downstream NF-κB signaling in B cells, leading to increased IgG1 expression. Phb1/2 are required for CD86-induced phosphorylation of PLCγ2 and PKCα/β, while both Phb1/2 and the CD86 cytoplasmic domain are required for IκBα phosphorylation.\",\n      \"method\": \"Proteomics-based identification, co-immunoprecipitation, shRNA knockdown of Phb1/2, CD86 cytoplasmic domain truncation/mutation, IgG1 and Oct-2 expression assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding identified by proteomics + Co-IP, multiple KD/mutant approaches with defined signaling readouts\",\n      \"pmids\": [\"23241883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Direct CD86 signaling on B cells (reverse signaling) promotes IgG secretion by previously class-switched B cells and induces expression of XBP-1 and spliced XBP-1, indicating increased protein synthesis; this was demonstrated using mixed bone marrow chimeric mice where only B cells lacked B7-1/B7-2.\",\n      \"method\": \"Mixed bone marrow irradiation chimeras (B cell-specific B7-1/2 deficiency), in vitro CD86 engagement, XBP-1 splicing assay, IgG/IgM ELISA\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific KO chimeras combined with in vitro mechanistic follow-up, multiple readouts\",\n      \"pmids\": [\"19933871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CD28 signaling in dendritic cells via CD86 (and CD80) induces IL-6 production in a p38 MAPK-dependent manner, and this IL-6 prevents IFN-γ-driven immunosuppressive tryptophan catabolism, demonstrating reverse (bidirectional) signaling through CD86 on DCs.\",\n      \"method\": \"Soluble CD28 treatment of mouse DCs, cytokine measurement, p38 MAPK inhibition, in vivo tumor and microbial challenge models\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — bidirectional signaling established with pharmacological inhibition and in vivo validation, multiple readouts\",\n      \"pmids\": [\"15467723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Bacterial superantigens enhance T cell activation by simultaneously binding both CD86 and CD28 at their respective homodimer interfaces (via the same 12-aa β-strand-hinge-α-helix domain), thereby increasing avidity between CD86 and CD28 and driving cytokine hyperproduction; CD86 homodimer interface mimetic peptides block superantigen binding to cell-surface CD86 and attenuate cytokine overproduction.\",\n      \"method\": \"Binding assays, CD86/CD28 dimer interface peptide competition, cytokine assays, in vivo superantigen lethality model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding mapped to structural interfaces, validated with mimetic peptides and in vivo lethality rescue\",\n      \"pmids\": [\"27708164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HIV-1 Nef removes CD86 (and CD80) from the cell surface via a clathrin- and dynamin-independent, actin-based endocytic pathway and subsequently reroutes CD86-containing vesicles to the Golgi via a Rab11-dependent mechanism; CD86/CD80 endocytic vesicles do not acquire conventional early endosomal markers (Rab5/EEA1) but instead recruit Rab11 de novo, which is required for Golgi delivery.\",\n      \"method\": \"Fluorescence microscopy, dominant-negative Rab constructs, endosomal marker colocalization, live-cell trafficking assays\",\n      \"journal\": \"Traffic\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic dissection of vesicular trafficking with multiple markers and dominant-negative Rab11, rigorous controls\",\n      \"pmids\": [\"18764822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Adenovirus serotype 3 (Ad3, species B1) uses CD80 and CD86 as cellular attachment receptors; the Ad fiber-knob domain mediates this interaction, and all tested Ad species B members (B1 and B2) can infect cells through CD80 and CD86.\",\n      \"method\": \"Competitive infection blocking with fiber-knob domain, CHO cells expressing CD80/CD86, serotype-specific infection assays\",\n      \"journal\": \"Virus research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct receptor identification by competitive blocking and expression in receptor-negative CHO cells\",\n      \"pmids\": [\"16920215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CD86 (B7.2) functions as a co-receptor for lymphotropic hepatitis C virus (HCV) infection of B cells; cDNA library screening identified CD86 as a B-cell-specific co-receptor, and silencing CD86 prevented HCV infection of B cells. Lymphotropic HCV infection of B cells via CD86 inhibited memory B cell function (recall antigen responses).\",\n      \"method\": \"cDNA library screening, gene silencing of CD86, chimeric HCV infectious clones, B cell infection assays, antigen recall assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cDNA library-based receptor identification plus silencing with functional readout, single study\",\n      \"pmids\": [\"28067225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Induced regulatory T cells (iTregs) acquire CD86 (to a greater extent than CD80) from mature dendritic cells via trogocytosis in a CTLA-4-, CD28-, and PD-L1-independent manner; iTregs that acquired CD86 expressed higher activation markers and showed enhanced suppressive capacity compared to iTregs that did not acquire CD86.\",\n      \"method\": \"Co-incubation of CD80/CD86 double-KO-derived iTregs with mature DCs, flow cytometry, confocal fluorescence microscopy, T cell suppression assays\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO-based system to track acquisition, functional suppression assay, single lab\",\n      \"pmids\": [\"22307040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Constitutive expression of a B7.2 transgene on tolerant self-reactive B cells was sufficient to prevent Fas-mediated deletion and trigger T cell-dependent clonal expansion and autoantibody secretion, demonstrating that repression of B7.2 on anergic B cells is a critical mechanism for Fas-mediated peripheral B cell tolerance.\",\n      \"method\": \"B7.2 transgenic mice, in vivo B cell fate tracking, Fas-deficient comparison, T cell-dependent expansion assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — transgenic rescue experiment with defined molecular mechanism and multiple in vivo controls\",\n      \"pmids\": [\"9705947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Toxoplasma gondii induces B7-2 (CD86) expression on macrophages at the transcript level through a mechanism requiring active parasite invasion (not TLR/MyD88/TRIF) and dependent on JNK (but not ERK or p38) MAP kinase signaling; T. gondii-infected macrophages stimulated naïve T cell proliferation in a B7-2-dependent manner.\",\n      \"method\": \"MAPK inhibitors, MyD88/TRIF KO macrophages, B7-2 blocking antibodies, T cell proliferation assays, genome-wide transcriptional analysis\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — pathway defined by specific inhibitors and KO cells with functional validation, multiple orthogonal approaches\",\n      \"pmids\": [\"21911468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"IL-4-dependent upregulation of CD86 in monocytes requires JAK/STAT6 and MEK/ERK1/2 activation but is negatively regulated by PKCδ; blocking JAK with WHI-P154 or MEK with PD98059 abolished CD86 upregulation, while blocking PKCδ with rottlerin dramatically enhanced CD86 expression.\",\n      \"method\": \"Specific kinase inhibitors (WHI-P154, PD98059, rottlerin), STAT6 phosphorylation assays, flow cytometry for CD86, antisense reduction of CD45\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple pharmacological pathway dissections with consistent results, single lab\",\n      \"pmids\": [\"14636897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Tet2 and Tet3 DNA demethylases in B cells are required for downregulation of CD86 following chronic self-antigen exposure; in Tet2/Tet3-deficient B cells, CD86 remained elevated due to decreased accumulation of HDAC1 and HDAC2 at the Cd86 locus, and anti-CD86 blockade partially restricted the resulting aberrant T and B cell activation.\",\n      \"method\": \"B cell-specific Tet2/Tet3 double-KO mice, HDAC chromatin occupancy (ChIP), anti-CD86 blockade, flow cytometry\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific KO with chromatin-level mechanistic dissection and functional rescue, multiple methods\",\n      \"pmids\": [\"32572241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"B7.2 expressed on T cell tumor lines (EL4) preferentially binds CTLA4-Ig but not CD28-Ig and fails to costimulate T cell proliferation (unlike B7.1 on T cells which binds both), suggesting that the context of B7.2 expression affects its receptor binding preference and functional outcome.\",\n      \"method\": \"CTLA4-Ig and CD28-Ig binding assays on B7.1/B7.2 transfected T cell lines, T cell proliferation costimulation assays, in vivo tumor regression\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — binding specificity and functional outcome tested in parallel with multiple receptor-Ig fusion proteins\",\n      \"pmids\": [\"9036945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The V domain of CD86 (but not the V domain of CD80 alone) is sufficient for CTLA-4 binding, revealing a fundamental structural difference between CD80 and CD86 in receptor engagement.\",\n      \"method\": \"Domain-swapped and truncated CD80/CD86 mutants, binding assays with CTLA-4\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — structure-function mutagenesis with defined binding readout, single lab\",\n      \"pmids\": [\"8609386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"HIV-1 virions bearing host-encoded B7-2 activate NF-κB and NFAT in target T cells via CD28 engagement, thereby upregulating HIV-1 LTR-driven gene expression; this effect was abrogated by CTLA-4-Ig blockade of the virion-bound B7-2–CD28 interaction and by dominant-negative IκBα and dnNFAT.\",\n      \"method\": \"Isogenic NL4-3 HIV virus stocks bearing B7-2, dominant-negative transcription factor constructs, CTLA-4-Ig blocking, LTR reporter assays, EMSA for NF-κB\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — dominant-negative constructs and specific blocking identify signaling pathway, single lab\",\n      \"pmids\": [\"11096063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CD86 on myeloma cells signals via its cytosolic domain to promote myeloma cell survival; silencing CD86 (or CD28) leads to myeloma cell death, downregulation of integrins, and downregulation of IRF4 (a known myeloma survival factor), and the pro-survival activity of CD86 is dependent on its cytosolic domain.\",\n      \"method\": \"CD86/CD28 gene silencing (siRNA/shRNA), CD86 cytosolic domain deletion constructs, cell viability assays, IRF4 and integrin expression\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain deletion + gene silencing with defined molecular and survival readouts, single lab\",\n      \"pmids\": [\"29296880\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD86 (B7-2) is a monomeric cell-surface costimulatory ligand on APCs that engages CD28 to provide T cell costimulation via PI3-kinase- and Rac1/actin cytoskeleton-dependent signaling pathways, and engages CTLA-4 to trigger pH-dependent receptor recycling and iterative transendocytosis; CD86 surface levels are tightly regulated by MARCH1-mediated ubiquitination at K267 and by Tet2/Tet3-dependent epigenetic repression at the Cd86 locus; CD86 also mediates reverse (bidirectional) signaling in B cells through prohibitin adaptors and its cytoplasmic domain to activate NF-κB and promote IgG production, and in dendritic cells via p38 MAPK to induce IL-6; additionally, CD86 serves as a cellular attachment receptor for species B adenoviruses and lymphotropic HCV, and is targeted by HIV-1 Nef for Rab11-dependent rerouting to the Golgi.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CD86 (B7-2) is a monomeric costimulatory ligand expressed on antigen-presenting cells that engages CD28 and CTLA-4 on T cells to regulate adaptive immune activation, peripheral tolerance, and bidirectional signaling in both APCs and B cells. Engagement of CD28 by CD86 activates PI3-kinase-dependent IL-2 production and Rac1-driven actin cytoskeleton rearrangement at the T cell–APC contact site, while the CD86 V domain alone is sufficient for CTLA-4 binding, which triggers pH-dependent CTLA-4 recycling and iterative transendocytosis distinct from the CD80–CTLA-4 fate [PMID:7584133, PMID:9551951, PMID:35999394, PMID:8609386]. CD86 surface levels are controlled post-translationally by MARCH1-mediated ubiquitination at K267 sustained by autocrine IL-10, and transcriptionally by Tet2/Tet3-dependent epigenetic silencing via HDAC1/2 recruitment at the Cd86 locus [PMID:21849678, PMID:32572241]. CD86 also mediates reverse signaling: in B cells, its cytoplasmic domain cooperates with prohibitin adaptors to activate NF-κB and promote IgG1 class-switched antibody secretion, and in dendritic cells it signals through p38 MAPK to induce IL-6; additionally, CD86 serves as a cellular receptor for species B adenoviruses and lymphotropic HCV [PMID:23241883, PMID:19933871, PMID:15467723, PMID:16920215, PMID:28067225].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Establishing that CD86-mediated T cell costimulation requires PI3-kinase signaling through CD28 resolved which downstream pathway is essential for IL-2 production upon CD86 engagement.\",\n      \"evidence\": \"CD28 cytoplasmic domain point mutants (Y191F, M194C) co-stimulated with CD86-expressing CHO cells, IL-2 readout\",\n      \"pmids\": [\"7584133\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PI3K is the sole pathway or acts in concert with other kinases downstream of CD86–CD28\", \"No direct structural mapping of CD28–PI3K interaction in the context of CD86 engagement\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Demonstrating that the CD86 V domain alone suffices for CTLA-4 binding — unlike CD80, which requires both domains — established a fundamental structural distinction between the two B7 ligands in receptor engagement.\",\n      \"evidence\": \"Domain-swapped and truncated CD80/CD86 chimeras tested for CTLA-4 binding\",\n      \"pmids\": [\"8609386\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Atomic-resolution basis for V-domain sufficiency not yet defined at this point\", \"Whether V-domain sufficiency translates to differential signaling outcomes through CTLA-4\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Two advances defined CD86's roles in cytoskeletal signaling and peripheral tolerance: CD86–CD28 engagement selectively translocates Rac1 (not Rho) to the T cell–APC contact and remodels actin, while constitutive B7-2 expression on anergic B cells prevents Fas-mediated deletion, revealing that CD86 repression is required for peripheral B cell tolerance.\",\n      \"evidence\": \"Confocal imaging of Rac1/talin translocation upon CD86–CD28 ligation; B7-2 transgenic mice with in vivo B cell fate tracking\",\n      \"pmids\": [\"9551951\", \"9705947\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The GEF linking CD28 engagement to Rac1 activation is unidentified\", \"Whether CD86 repression on anergic B cells is transcriptional or post-translational was unknown\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Comparative biochemical analysis showed that CD86 and CD80 trigger qualitatively different proximal signals through CD28 — CD86 ligation does not induce detectable CD28 tyrosine phosphorylation or robust PI3K recruitment, yet both ligands converge on shared distal events including CBL/VAV phosphorylation and NFAT activation.\",\n      \"evidence\": \"CHO transfectants expressing CD80 or CD86, immunoprecipitation and Western blot for CD28 phosphorylation, PI3K association, downstream transcription factor activation\",\n      \"pmids\": [\"9915850\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CD86 achieves IL-2 production despite weak CD28 tyrosine phosphorylation\", \"Whether quantitative rather than qualitative differences in PI3K recruitment account for these results\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"The crystal structure of CTLA-4/CD86 revealed that dimerization interfaces of both proteins position binding sites to favor formation of an alternating periodic lattice, providing a structural model for immunological synapse organization.\",\n      \"evidence\": \"X-ray crystallography at 3.2-Å resolution\",\n      \"pmids\": [\"11279501\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the lattice model occurs in physiological cell–cell contacts\", \"No dynamics or stoichiometry information at cell surfaces\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Two studies established CD86 as a bidirectional signaling molecule: reverse signaling through CD86 on DCs induces IL-6 via p38 MAPK to counteract immunosuppressive tryptophan catabolism, while IL-4-driven CD86 upregulation on monocytes requires JAK/STAT6 and MEK/ERK1/2 and is negatively regulated by PKCδ.\",\n      \"evidence\": \"Soluble CD28 treatment of DCs with p38 inhibition and in vivo validation; pharmacological kinase inhibitor dissection in monocytes\",\n      \"pmids\": [\"15467723\", \"14636897\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The proximal receptor complex mediating reverse signaling in DCs is undefined\", \"Whether PKCδ directly phosphorylates CD86 or acts indirectly\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"FRET-based measurements confirmed CD86 exists as a monomer on the cell surface, contrasting with CD80 homodimers, and excluded CD80–CD86 hetero-oligomers — clarifying the oligomeric state relevant to receptor engagement.\",\n      \"evidence\": \"Photobleaching FRET on live cells expressing CD80 and/or CD86\",\n      \"pmids\": [\"16413062\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ligand engagement or clustering at the synapse induces transient dimerization\", \"Monomer status established on transfected cells, not primary APCs\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identification of CD86 as a cellular attachment receptor for species B adenoviruses expanded CD86's function beyond immune costimulation to pathogen entry.\",\n      \"evidence\": \"Competitive infection blocking with fiber-knob domain, CD86-expressing CHO cells, multi-serotype infection assays\",\n      \"pmids\": [\"16920215\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CD86 mediates virus internalization or only attachment\", \"Structural basis of fiber-knob–CD86 interaction unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"HIV-1 Nef was shown to remove CD86 from the APC surface via a clathrin/dynamin-independent, actin-dependent pathway and reroute it to the Golgi through de novo Rab11 recruitment, revealing a viral immune evasion mechanism targeting CD86 trafficking.\",\n      \"evidence\": \"Fluorescence microscopy, dominant-negative Rab constructs, endosomal marker colocalization in Nef-expressing cells\",\n      \"pmids\": [\"18764822\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Nef directly binds CD86 or acts through an intermediate adaptor\", \"Functional consequence for T cell activation not directly measured\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrating that CD86 reverse signaling in B cells promotes IgG secretion and XBP-1 splicing in class-switched B cells established a cell-intrinsic role for CD86 beyond costimulation.\",\n      \"evidence\": \"Mixed bone marrow chimeras with B cell-specific B7-1/2 deficiency, in vitro CD86 engagement, XBP-1 splicing and IgG ELISA\",\n      \"pmids\": [\"19933871\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the natural ligand triggering reverse signaling in vivo\", \"Whether XBP-1 induction is direct or secondary to increased secretory load\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Two studies defined post-translational and transcriptional control of CD86: MARCH1 ubiquitinates CD86 at K267 to limit surface expression under autocrine IL-10 control in DCs, while Toxoplasma gondii induces CD86 transcription via JNK (not ERK/p38) independently of TLR/MyD88/TRIF.\",\n      \"evidence\": \"MARCH1 KO mice and K267R mutant CD86 with T cell activation assays; MAPK inhibitors and MyD88/TRIF KO macrophages with B7-2 blocking antibodies\",\n      \"pmids\": [\"21849678\", \"21911468\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MARCH1 ubiquitination triggers lysosomal degradation or recycling of CD86\", \"Identity of the parasite-derived signal activating JNK for CD86 induction\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Prohibitin 1/2 were identified as transmembrane adaptors that bind the CD86 cytoplasmic domain and mediate NF-κB activation and IgG1 production in B cells, defining the first signaling intermediates in CD86 reverse signaling; separately, iTregs were shown to acquire CD86 from DCs via trogocytosis in a CTLA-4/CD28-independent manner, gaining enhanced suppressive capacity.\",\n      \"evidence\": \"Proteomic identification and Co-IP of Phb1/2 with CD86, shRNA knockdown, cytoplasmic domain mutants; co-incubation of CD80/86 double-KO iTregs with mature DCs\",\n      \"pmids\": [\"23241883\", \"22307040\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Phb1/2 form a stable complex with CD86 or are recruited transiently\", \"Mechanism by which acquired CD86 enhances Treg suppression is unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Bacterial superantigens were found to bridge CD86 and CD28 homodimer interfaces simultaneously via the same 12-aa structural motif, explaining superantigen-driven cytokine hyperproduction and providing a pharmacological target — CD86 dimer-interface mimetic peptides block this pathological interaction.\",\n      \"evidence\": \"Binding assays mapping the superantigen–CD86/CD28 interface, mimetic peptide competition, in vivo superantigen lethality rescue\",\n      \"pmids\": [\"27708164\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether all superantigen families share this bridging mechanism\", \"Structural co-crystal of superantigen with both CD86 and CD28 is lacking\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"CD86 was identified as a co-receptor for lymphotropic HCV infection of B cells, and CD86-dependent HCV infection was shown to impair memory B cell recall responses, linking CD86's receptor function to viral immunopathology; separately, CD86 intrinsic signaling via its cytosolic domain was found to promote myeloma cell survival through IRF4 maintenance.\",\n      \"evidence\": \"cDNA library screen for HCV co-receptor, CD86 silencing blocks infection, antigen recall assays; CD86 silencing and cytosolic domain deletion in myeloma cells with IRF4/integrin readouts\",\n      \"pmids\": [\"28067225\", \"29296880\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CD86 directly binds HCV envelope glycoproteins or acts indirectly\", \"Whether CD86-dependent myeloma survival operates in primary patient samples\", \"HCV co-receptor function awaits independent replication\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Tet2/Tet3 were shown to be required for epigenetic silencing of CD86 on chronically antigen-exposed B cells by recruiting HDAC1/2 to the Cd86 locus, establishing an epigenetic layer of CD86 regulation essential for self-tolerance.\",\n      \"evidence\": \"B cell-specific Tet2/Tet3 double-KO mice, ChIP for HDAC1/2 at Cd86, anti-CD86 blockade partially rescuing aberrant activation\",\n      \"pmids\": [\"32572241\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Tet2/3 act through 5hmC-dependent or -independent mechanisms at Cd86\", \"Which specific CpGs at the Cd86 locus are functionally relevant\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealing that CTLA-4 undergoes pH-dependent detachment from CD86 and recycles for iterative transendocytosis — unlike its irreversible lysosomal fate with CD80 — resolved the long-standing question of why CTLA-4 is a more efficient checkpoint for CD86 than CD80, and showed that autoimmune disease mutations selectively disrupt CD86 transendocytosis.\",\n      \"evidence\": \"Live-cell imaging, pH-shift assays, biochemical fractionation, disease-associated CTLA-4 mutation analysis\",\n      \"pmids\": [\"35999394\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for pH-dependent CTLA-4/CD86 dissociation at atomic resolution\", \"Whether iterative transendocytosis quantitatively accounts for CD86 regulation in vivo\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the identity of the GEF linking CD28–CD86 engagement to Rac1 activation, the structural basis for pH-dependent CTLA-4/CD86 dissociation, the natural in vivo ligand triggering CD86 reverse signaling in B cells, and whether CD86's viral receptor functions for HCV and adenovirus involve direct envelope/capsid binding or accessory factors.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of CD86 reverse signaling complex with prohibitins\", \"Quantitative contribution of MARCH1 vs. Tet2/3 epigenetic regulation to steady-state CD86 levels in vivo not determined\", \"No reconstituted system demonstrating iterative transendocytosis cycle kinetics\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 4, 5, 6, 10]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [12, 13]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [7, 8, 9, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 2, 11, 14]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [1, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 2, 4, 5, 6, 9, 10, 15, 18]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 7, 8, 9, 17, 22]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [11, 12, 13, 21]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CD28\",\n      \"CTLA4\",\n      \"MARCH1\",\n      \"PHB\",\n      \"PHB2\",\n      \"RAB11A\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}